MEETING OF THE ADVISORY 

COMMITTEE ON IMMUNIZATION 

PRACTICES (ACIP) 

FEBRUARY 22-24, 2023 

MEETING SUMMARY 

CONTENTS

WEDNESDAY: FEBRUARY 22, 2023 .......................................................................................................... 5 

WELCOME AND INTRODUCTIONS ...................................................................................... 5 

Call to Order/Roll Call ......................................................................................................... 5 

Announcements.................................................................................................................. 5 

MPOX VACCINE .................................................................................................................... 6 

Opening Remarks............................................................................................................... 6 

Session Introduction ........................................................................................................... 6 

Epidemiology of Mpox During the Current 2022 Outbreak in the United States................... 8 

JYNNEOS Vaccine Effectiveness ......................................................................................11 

JYNNEOS Vaccine Safety .................................................................................................13 

Mpox Vaccine Acceptability and Uptake from Cross-Sectional Surveys.............................17 

Interim Clinical Considerations...........................................................................................20 

EtR: Use of JYNNEOS During Mpox Outbreaks.................................................................22 

ACIP Discussion Points, Observations, Suggestions on Mpox Vaccine .............................27 

Vote: Mpox Vaccine ...........................................................................................................31 

RESPIRATORY DISEASE SURGE, FALL 2022, UNITED STATES ......................................31 

Discussion Points...............................................................................................................33 

INFLUENZA VACCINE ..........................................................................................................35 

Introduction........................................................................................................................35 

US Influenza Activity Update..............................................................................................35 

Preliminary 2022-2023 Influenza Vaccine Effectiveness: CDC Networks...........................36 

Preliminary 2022-2023 Influenza Vaccine Effectiveness: Wisconsin ..................................38 

Update on Published Estimates of LAIV4 Effectiveness: Background................................39 

ACIP Discussion Points, Observations, Suggestions on Influenza Vaccine........................40 
PNEUMOCOCCAL VACCINES .............................................................................................42 

Introduction........................................................................................................................42 

Epidemiology of Pneumococcal Disease among US Children............................................43 

Estimating the Impact of Higher-Valency PCVs on Pediatric Outpatient ARI Visits and 

Antibiotic Use.....................................................................................................................46 

PCV20 Phase 2/3 Study Results among Children..............................................................49 

Preliminary EtR/GRADE for PCV20 use in US Children.....................................................51 

Pneumococcal Vaccines WG Considerations and Next Steps ...........................................55 

Merck Comments...............................................................................................................56 

ACIP Discussion Points, Observations, Suggestions on Pneumococcal Vaccine...............57 

PUBLIC COMMENTS............................................................................................................59 

THURSDAY: FEBRUARY 23, 2023............................................................................................................62 

AGENCY UPDATES..............................................................................................................62 

Centers for Disease Control and Prevention ......................................................................62 

Centers for Medicare and Medicaid Services .....................................................................63 

Health Resources and Services Administration..................................................................64 

Indian Health Service.........................................................................................................64 

National Institutes of Health ...............................................................................................65 

Office of Infectious Disease and HIV/AIDS Policy ..............................................................65 

MENINGOCOCCAL VACCINES............................................................................................66 

Introduction........................................................................................................................66 

Epidemiology of Meningococcal Disease in the United States ...........................................66 

Pfizer Pentavalent Meningococcal Vaccine........................................................................68 

Workgroup Considerations.................................................................................................71 

ACIP Discussion Points, Observations, Suggestions on Meningococcal Vaccines.............73 

POLIO VACCINES ................................................................................................................75 

Introduction........................................................................................................................75 

Recommendations for Adult Polio Vaccination...................................................................75 

ACIP Discussion Points, Observations, Suggestions on Polio Vaccines ............................80 

RSV VACCINES: PEDIATRIC/MATERNAL ...........................................................................80 

Introduction........................................................................................................................80 

Cost-Effectiveness Analysis for Nirsevimab: CDC Model ...................................................81 

Cost-Effectiveness Analysis for Nirsevimab: Comparison to Manufacturer Model..............85 

EtR Framework for Nirsevimab ..........................................................................................89 

Clinical Considerations for Nirsevimab...............................................................................97 

Safety and Efficacy of RSV Bivalent Prefusion F (PreF) Maternal Vaccine ........................98 

Workgroup Considerations...............................................................................................103 

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........................................................................................................................................103 

ACIP Discussion Points, Observations, Suggestions on Pediatric/Maternal RSV Vaccines 

RSV VACCINES: ADULT ....................................................................................................107 

Introduction......................................................................................................................107 

Cost-Effectiveness of the GSK and Pfizer Vaccines: Main CDC Model............................108 

Comparison of Cost-Effectiveness Results of the Main CDC Model and Each Manufacturer 

Model (GSK & Pfizer).......................................................................................................111 

EtR/GRADE for 2 Vaccines (GSK & Pfizer)......................................................................115 

GSK Statement................................................................................................................123 

Pfizer Statement ..............................................................................................................124 

ACIP Discussion Points, Observations, Suggestions on Adult RSV Vaccines..................124 

CHIKUNGUNYA VACCINE..................................................................................................126 

Introduction......................................................................................................................126 

Global Epidemiology of Chikungunya...............................................................................127 

Chikungunya in US Travelers...........................................................................................129 

Persistent Arthralgia Following Chikungunya ...................................................................131 

Workgroup Considerations...............................................................................................134 

ACIP Discussion Points, Observations, Suggestions on Chikungunya Vaccines..............134 

DENGUE VACCINE.............................................................................................................135 

Introduction......................................................................................................................135 

Takeda Dengue Vaccine (TAK-003) Safety and Efficacy .................................................136 

Workgroup Considerations...............................................................................................139 

ACIP Discussion Points, Observations, Suggestions on Dengue Vaccines......................141 

VARICELLA.........................................................................................................................141 

Public Health Impact of 25 Years of Varicella Vaccination in the United States................141 

ACIP Discussion Points, Observations, Suggestions on Varicella Vaccines.....................144 

FRIDAY: FEBRUARY 24, 2023 ................................................................................................................144 

COVID-19 VACCINES.........................................................................................................144 

Introduction......................................................................................................................144 

Plan to End the COVID-19 Public Health Emergency (PHE) on May 11, 2023.................145 

COVID-19 Vaccine Safety Updates: CDC........................................................................146 

COVID-19 Vaccine Safety Updates: FDA.........................................................................151 

VaST Summary................................................................................................................154 

WG Interpretation and Summary......................................................................................155 

Updates on COVID-19 Hospitalizations: COVID-NET ......................................................157 

Updates to COVID-19 Vaccine Effectiveness in the United States...................................159 

Considerations for Transitioning to Bivalent Primary Series .............................................163 

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NCIRD Director Remarks.................................................................................................168 

Benefit-Risk for COVID-19 Vaccines................................................................................168 

COVID-19 Vaccines: Future Directions ............................................................................172 

ACIP Discussion Points, Observations, Suggestions on COVID-19 Vaccines..................177 

CERTIFICATION.......................................................................................................................................185 

ACIP MEMBERSHIP ROSTER ................................................................................................................186 

ACRONYMS USED IN THIS DOCUMENT...............................................................................................195 

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WEDNESDAY: FEBRUARY 22, 2023 

WELCOME AND INTRODUCTIONS 

Call to Order/Roll Call 

Dr. Grace Lee (ACIP Chair) called to order and presided over the February 22-24, 2023 

Advisory Committee on Immunization Practices (ACIP) meeting. Dr. Lee conducted a roll call 

each day, which established that a quorum was present. A list of Members, Ex Officios, and 

Liaison Representatives is included in the appendixes at the end of this summary document. 

The following conflicts of interest (COIs) were identified: 

 Dr. Camile Kotton is involved in a clinical trial for Takeda for an investigational antiviral for 

cytomegalovirus (CMV) but is not involved in any of their vaccine projects. 

Announcements 

Dr. Melinda Wharton (ACIP Executive Secretary, CDC) noted that copies of the slides for the 

meeting were available on the ACIP website and were made available through a ShareLinkTM 

file for ACIP Voting, Ex Officios, and Liaisons Members. The ACIP is, at its heart, a public body. 

Engagement with the public and transparency in all of its processes are vital to the committee’s 

work. She indicated that there would be 1 oral public comment session during this meeting, 

which was scheduled for 2:00 PM Eastern Time (ET) on February 22, 2023. To create a fair and 

more efficient process, individuals 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. If more 

people make requests than can be accommodated, a blind lottery is conducted to determine 

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

advance of the meeting. Members of the public also may submit written comments via 

https://www.regulations.gov using Docket Number ID CDC-2023-0007. Information on the 

written public comment process, including information on how to make a comment, can be 

found on the ACIP website. 

As noted in the ACIP Policies and Procedures manual, 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 may issue limited COI waivers. Members who conduct vaccine clinical trials or 

serve on data safety monitoring boards (DSMBs) may present to the committee on matters 

related to those vaccines, but those members are prohibited from participating in committee 

votes on issues related to those vaccines. Regarding other vaccines of the concerned company, 

a member may participate in discussions with the provision that he/she abstains on all votes 

related to that company. ACIP members state any COIs at the beginning of each meeting. 

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MPOX VACCINE 

Opening Remarks 

Dr. Melinda Wharton (ACIP Executive Secretary, CDC) provided opening remarks for the 

Mpox session. She reminded everyone that in November 2021, ACIP unanimously voted in 

favor of JYNNEOS as an alternative to the other available vaccine for prevention of Mpox in 

persons with certain occupational risk of exposure. During this session, ACIP would be asked to 

vote on an additional use of JYNNEOS vaccine for control of Mpox outbreaks. In 2022, a 

multinational outbreak of Mpox began with more than 30,000 cases in the United States. In 

response to this outbreak, JYNNEOS has been successfully used in accordance with 

recommendations in CDC’s interim clinical considerations, and there has been a dramatic 

reduction in case counts. Dr. Wharton emphasized that the vote for use in outbreaks would not 

change CDC’s recommendations for use of JYNNEOS in the current outbreak but represents an 

update to ACIP’s recommendations that were voted on in late 2021. It is expected that there will 

be additional decisions coming to ACIP for a vote in future meetings. The recent outbreak has 

highlighted the risks that infectious diseases can present to communities, the importance of a 

robust public health response at the state and local levels, the value of engaged partners and 

communities in responding to public health threats, and the impact that a vaccine can have in 

helping to bring an outbreak under control. 

Session Introduction 

Pablo Sanchez MD (The Ohio State University−Nationwide Children’s Hospital, ACIP

Mpox WG Chair) introduced the Mpox session. He pointed out that from a historical context, 

Mpox is a rare, sometimes life-threatening infection that is endemic in parts of West and Central 

Africa. It is caused by the monkeypox virus, which is an orthopoxvirus. There are 2 clades. 

Clade 1 was previously known as the Congo Basin Clade, while Clade 2 was previously known 

as the West African clade. Mpox can spread from infected animals to people and then personto-person from respiratory secretions, skin-to-skin contact with infected body fluids (e.g., fluid 

from lesions), and fomites (e.g., shared towels, clothing, and bedding). 

In terms of the timeline of notable human Mpox events, during 1970 to 2021, Mpox was known 

to be endemic in 9 African countries: Cameroon, Central African Republic, Côte d'Ivoire, 

Democratic Republic of Congo, Gabon, Liberia, Nigeria, Republic of Congo, and Sierra Leone. 

During recent years, there has been a re-emergence of human cases after decades of no 

reported cases. The first human case was identified in rural settings in 1970. In 2003, there was 

a US outbreak from pet prairie dogs with 47 cases identified. In 2017, there was an outbreak in 

Nigeria involving 17 states and 138 cases. In 2018, there were imported cases to the United 

Kingdom (UK) and Israel with 3 cases identified. In 2019, there were imported cases to the UK 

and Singapore with 2 cases identified. In 2021, there were imported human cases to the UK and 

the US with 3 cases identified. A multinational outbreak occurred in 2022. 

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Person-to-person spread has been seen. Historical outbreaks in Africa have been associated 

with close skin-to-skin contact and contact with fomites, with zoonotic exposure causing most 

cases and a few secondary cases among close contacts. In the US, a 2003 outbreak resulted in 

no secondary cases and no vaccination was offered. In 2021, there were no secondary cases 

and ACAM2000 was offered to some contacts.1 In the most recent outbreak in 2022, there were 

many secondary cases and over 1 million doses of the JYNNEOS vaccine were administered. 

In 2021, ACIP voted for the of orthopoxvirus vaccine, JYNNEOS that was licensed in 2019, for 

pre-exposure vaccination of people at occupational risk for orthopoxvirus exposures. The 

JYNNEOS vaccine is a 2-dose series that is administered subcutaneously. Recommendations 

were published in the Morbidity and Mortality Weekly Report (MMWR) on June 3, 2022.2 

Currently, there is no ACIP recommendation for the use of JYNNEOS during outbreaks. The 

current US national Mpox vaccine strategy is shown in this table: 

The US strategy for vaccination with JYNNEOS during the current outbreak has been that the 

intradermal route is preferred, but the subcutaneous route can be administered for persons ≥18 

years of age or older. The subcutaneous route is recommended for persons <18 years of age. 

This is a 2-dose series with a second dose administered 1 month after the first dose. 

Regarding the tentative timeline for ACIP discussions and votes, during the February 2023 

meeting, the ACIP would be voting on the use of 2-dose JYNNEOS for persons ≥18 years of 

age. In June 2023, ACIP will be discussing the use of 2-dose JYNNEOS for persons aged <18 

years of age and would hear updates about vaccine effectiveness (VE) and safety. In October 

2023, there will be consideration for a longer-term vaccination strategy for the 2-dose 

JYNNEOS vaccine. It is important to note that the current US Mpox vaccination strategy 

remains active, which is that populations at high risk should continue to be vaccinated. 

1 ACAM2000 was offered through a CDC Investigational New Drug Protocol that allows for vaccination after mpox exposure. Only 

contacts with highrisk exposures were offered vaccine; none accepted. 

2 https://www.cdc.gov/mmwr/volumes/71/wr/mm7122e1.htm 

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This session included updates from the ongoing outbreak in terms of epidemiology, VE, vaccine 

safety, community engagement, and equity and implementation; discussion about the use of the 

2-dose JYNNEOS subcutaneously during Mpox outbreaks with an Evidence-toRecommendations Framework presentation and an ACIP vote. Dr. Sanchez presented the 

following proposed wording for the vote: 

ACIP recommends the 2-dose* JYNNEOS vaccine series for persons aged 18 years and 

older at risk of Mpox during an Mpox outbreak.§ 

*Dose 2 administered one month after dose 1 

§ Public health authorities determine whether there is an mpox outbreak; a single case may be considered an mpox 

outbreak at the discretion of public health authorities. Other circumstances in which a public health response may be 

indicated include ongoing risk of introduction of mpox into a community due to disease activity in another geographic area. 

Epidemiology of Mpox During the Current 2022 Outbreak in the United States 

Sascha Ellington, PhD, MSPH (CDC/NCCDPHP) presented an update on the epidemiology of 

the current Mpox outbreak on behalf of the Epidemiology Task Force of CDC’s Mpox Response. 

The first US case associated with the current Mpox outbreak was identified in Massachusetts in 

May 2022. Cases initially were associated with travel. Since then, cases have been reported 

from all 50 states, DC, and Puerto Rico. More than 30,000 cases have been reported to date. 

States with the most cases including California, New York, Texas, Florida, Georgia, and Illinois 

all reporting more than 1,000 cases. Most cases have occurred in gay, bisexual, and other men 

who have sex with men(MSM). Cases have also been reported in men who have not reported 

sex with men, cisgender and transgender women, transgender men, gender diverse people, 

children, and teens. 

US cases peaked in August 2022 and have declined substantially since. Currently, the 7-day 

moving average is 2 cases per day in the US. As of February 8, 2023, 95% of all cases reported 

have been amongst cisgender men, 2.9% amongst cisgender women, and a combined 1.7% of 

cases have been among transgender men, transgender women, and gender diverse people. 

The age of people with Mpox ranges from 0, with a few cases reported in neonates, up to 89 

years of age. The median age is 34 years. Overall, cases have been reported primarily among 

Black, Hispanic, and White persons, with nearly a third in each of these groups. At the start of 

the outbreak, about 45% of cases were among White persons, which decreased over time. 

Cases in Black or African American persons increased and cases among Hispanic or Latino 

persons have remained fairly stable over the period of the outbreak. 

In terms of clinical characteristics and outcomes among cases reported to date, 53% of cases 

with available data have been among people living with HIV and 47% of cases have been 

among people who are human immunodeficiency virus (HIV)-negative, though only 30% of 

cases reported had data on HIV status. Among cases with available data, more than half had 

rash reported on the genitals or perianal area, trunk or limbs, head, face, or mouth. About a 

quarter had rash on the palms or soles of the feet. About 7.7% of people with Mpox have been 

hospitalized and 32 Mpox-associated deaths have been reported, representing 0.1% of cases. 

Deaths have occurred primarily in severely immunocompromised persons. 

During the current outbreak, Mpox has been spread primarily through sexual or close intimate 

contact. Other routes of transmission also have been reported, including household 

transmission through injury with a contaminated sharp instrument in a clinical setting, through 

piercing and tattooing, and perinatal transmission from an infected mother to an infant around 

the time of delivery. Current evidence suggests that some people can spread Mpox virus to 

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others 1 to 4 days before they become symptomatic. However, there is no evidence that people 

who never develop symptoms have spread the virus to others. This table summarizes the 

specimens in which Mpox has been detected by polymerase chain reaction (PCR), whether 

replication-competent viruses has been detected, and whether each exposure source has been 

associated with transmission: 

Replication-competent virus has been detected but isolated in skin lesions, oropharyngeal 

swabs, anorectal swabs, semen, urine, and ocular fluid. Mpox has been transmitted from skinto-skin contact, oral contact, and from a contaminated sharp. Transmission via exposure to 

some sources such as semen can be particularly challenging to assess since exposure typically 

occurs during close intimate contact that also includes skin-to-skin contact. For this reason, 

many exposure sources listed in the table have insufficient data to conclude definitively they are 

a source of infection. 

As previously mentioned, 95% of cases of Mpox have been reported amongst cisgender men, 

and cases have occurred primarily among gay, bisexual, and other MSM. Among the cases 

reported in men with data on recent sexual history, 75% reported sexual or close intimate 

contact with a man in the 3 weeks preceding symptom onset. However, in 25% of cases among 

men, no recent male-to-male sexual contact was reported. Over time, the percentage of cases 

in men that had recent male-to-male sexual contact has declined from over 80% initially to 

about 60%, increases have been observed in the missingness of sexual contact data, which 

may contribute at least partially to this decline. 

A few specific populations have been less affected overall, but the characteristics of these 

cases have contributed to the overall understanding of the epidemiology. Based on data from a 

publication that was published earlier this year reporting on cases in cisgender women,

3 about 

3% of the Mpox cases have been in cisgender women. The median age of cases in this group is 

32 years, ranging from 15─89 years. Of the cases among cisgender women, 44% were in 

Black, non-Hispanic women; 25% were in White, non-Hispanic women, and 23% were in 

Hispanic or Latino women. Of those with available data on HIV status, 8% of cases in cisgender 

3 http://dx.doi.org/10.15585/mmwr.mm7201a2 

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women were HIV-positive, and 92% were HIV negative. While the data were available for only 

22% of cases among cisgender women, this is markedly lower than the percent of total cases 

that were HIV-positive at 53% and 71% of cases among cisgender women reported a recent 

sexual or close intimate partner. 

The same publication also reported on cases in pregnant people. From May 11─November 7, 

2022, a total of 21 cases of Mpox were reported during pregnancy and 2 cases were reported in 

a recently pregnant person, which was defined as within 3 weeks of pregnancy. Among the 12 

with exposure data, 9 reported sexual contact and 3 reported household contact to a person 

with Mpox. Pregnant people had similar signs and symptoms of Mpox as those among nonpregnant people. Among pregnant people, 4 cases had general lesions during the pregnancy, 

but none had lesions at the time of delivery. Tecovirimat was provided to 48% of cases during 

pregnancy, with no adverse events (AEs) reported. None of the pregnant cases received postexposure prophylaxis (PEP) with JYNNEOS. Outcomes reported to date have included 4 

hospitalizations of pregnant people for Mpox indications. All were discharged while still 

pregnant. No pregnant cases required intensive care, intubation, or unplanned delivery. To date, 

pregnancy outcomes have been reported among 3 patients. Of these, 2 were uncomplicated 

live births with no transmission to the infant and 1 pregnancy resulted in a first trimester 

spontaneous abortion. Two recently pregnant persons experienced symptoms within 3 days of 

delivery and their newborns developed lesions within a week. The exact timing of transmission 

for these infant cases is unknown. 

In another recent report,4 the characteristics of Mpox cases were assessed among 466 

transgender and gender diverse persons. In this analysis, 43% were transgender women, 42% 

were gender diverse, and 15% were transgender men. Of the gender diverse persons, 96% 

were assigned male sex at birth. The median age of the transgender and gender diverse 

persons with Mpox was 32 years and ranged from 18─71 years. Among the transgender and 

gender diverse persons with Mpox, 28% were Black, 28% were White, and 37% were Hispanic 

or Latino. About half of the transgender and gender diverse persons with Mpox were HIVpositive, which is similar to the percentage observed among all persons with Mpox. Among 

transgender and gender diverse persons with Mpox, 84% reported recent sexual or close 

intimate partner contact. 

In another recent report of 83 cases in children from May 17–September 24, 2022,

5 there were 

16 cases in children aged 0─4 years, 12 cases in children aged 5─12 years, and 55 cases in 

children aged 13─17 years. Adolescents aged 13─17 years were overwhelmingly male and 

primarily had sexual exposures, mirroring the epidemiology of cases overall. In younger 

children, cases were more evenly divided by sex and were associated with household contact, 

frequently from an infected caregiver. While these findings are from a report analyzing data 

through September, investigation has continued in cases among children, particularly younger 

children, and findings have been similar. 

In terms of vaccine doses administered to date, as of February 7, 2023, a total of 1,185,907 

doses were administered. This includes 732,725 first doses. First doses and overall doses 

administered peaked in August at the same time when Mpox cases reported to CDC peaked. 

Doses administered have declined substantially since August. In the first week of February, 

1,314 first doses and 1,243 second doses were administered. While one-third of Mpox cases 

occurred among Black or African American persons, just 13% of first dose vaccine recipients 

4 https://www.cdc.gov/mmwr/volumes/71/wr/mm715152a1.htm?s_cid=mm715152a1_w 

5 http://dx.doi.org/10.15585/mmwr.mm7144a4 

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were Black or African American. While 31% of Mpox cases were among Hispanic or Latino 

persons, just 22% of first dose vaccine recipients were Hispanic or Latino. Additionally, 29% of 

Mpox cases were among White persons, while 52% of first dose vaccine recipients were among 

White persons. Hence, some substantial differences are observed by race and ethnicity when 

comparing those who have been infected versus those receiving vaccine. 

JYNNEOS Vaccine Effectiveness 

Anna Chard, PhD, MPH (CDC/NCIRD) presented on JYNNEOS VE on behalf of the Vaccine 

Task Force of CDC's Mpox Response. The efficacy of JYNNEOS vaccine against Mpox has 

been inferred from animal and immunogenicity studies, but it has never been demonstrated in 

clinical trials. Additionally, prior to the multinational outbreak, there were no real-world 

effectiveness estimates for JYNNEOS against Mpox disease. Therefore, the following key 

questions related to VE were developed: 

1. What is the effectiveness of JYNNEOS vaccine against Mpox disease for partial (1-dose) 

and full (2-dose) vaccination? 

2. Are there differences in VE by route of vaccination administration? On August 9, 2022, an 

Emergency Use Authorization (EUA) was issued for intradermal administration of a 2-dose 

series to increase vaccine supply, so it is important to examine the differences in VE by 

route of administration. 

3. Are there differences in VE among persons with immunocompromising conditions? The 

populations most at risk for Mpox disease are also at higher risk of immunocompromising 

conditions such as HIV. 

4. What is the duration of protection conferred from JYNNEOS vaccine? The duration of 

protection conferred by JYNNEOS vaccine is unknown. 

In this presentation, Dr. Chard presented evidence for the first 2 questions; however, evidence 

remains limited regarding VE among persons with immunocompromising conditions and the 

duration of protection from JYNNEOS vaccine. 

In terms of vaccine performance, Dr. Chard reviewed a study on the incidence of Mpox among 

unvaccinated persons versus persons receiving ≥1 JYNNEOS dose in the US.

6 For this 

analysis, investigators used surveillance data from confirmed and probable Mpox cases, 

vaccine administration data ascertained from interviews and immunization registries, and 

jurisdiction-specific estimates of the vaccine-eligible population to compare Mpox instance 

among persons who were unvaccinated and those who had received either one or two 

JYNNEOS doses. There were 9,544 reported Mpox cases among men 18─49 years of age from 

43 US jurisdictions during the analysis period of July 31─October 1, 2022. Investigators 

estimated weekly Mpox incidence for persons with partial (1 dose) and full (2 doses) vaccination 

and persons eligible but unvaccinated. The incidence rate ratio was calculated using negative 

binomial regression controlling for week. Mpox incidence among unvaccinated individuals was 

7.4 (95% CI = 6.0–9.1) times as high as persons receiving 1 dose of JYNNEOS vaccine. Mpox 

incidence among unvaccinated individuals was 9.6 (95% CI = 6.9–13.2) times as high as 

persons receiving 2 doses of JYNNEOS vaccine. No difference was observed in vaccine 

performance between subcutaneous and intradermal administration. 

6 Payne AB, et al. Reduced Risk for Mpox After Receipt of 1 or 2 Doses of JYNNEOS Vaccine Compared with Risk Among 

Unvaccinated Persons — 43 U.S. Jurisdictions, July 31–October 1, 2022. MMWR Morb Mortal Wkly Rep 2022;71:1560–1564. 

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The New York City Department of Health and Mental Hygiene (NYC Health) examined the VE of 

JYNNEOS administered as PEP using a cohort evaluation of individuals ≥18 years of age 

identified through contact investigations to a case patient with Mpox between March 22─August 

24, 2022.7 PEP was defined as receiving the first dose of JYNNEOS within 14 days of exposure 

and prior to symptom onset. Case patients were defined as exposed individuals who developed 

symptom onset within 21 days of exposure and had laboratory confirmation of Mpox. VE was 

77% among individuals who received PEP less than 14 days after their last exposure and 79% 

among individuals who received PEP less than 14 days after their first exposure. 

Investigators in Israel evaluated the real-world effectiveness of a single subcutaneous dose of 

Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), which uses the trade name JYNNEOS in 

the US.8 This was a retrospective, observational cohort study based on data obtained from 

electronic health records (EHRs) from a single integrated healthcare organization in Israel. The 

cohort included 2,054 men who were eligible for vaccination on July 31, 2022 when the 

vaccination campaign began who had completed at least 90 days of follow-up. Specific eligibility 

criteria were males aged 18─42 years of age who were dispensed HIV pre-exposure 

prophylaxis( PrEP) for at least 1 month since January 1, 2022, or males aged 18─42 years who 

were diagnosed with HIV and also were diagnosed with one or more sexually transmitted 

infections (STIs) since January 1, 2022. The time period for this analysis spans July 

31─December 25, 2022 such that all participants were followed for 90 to 120 days after cohort 

entry. VE was estimated using Cox proportional hazards regression with vaccination status as a 

time-varying covariate. The model adjusted for sociodemographic and clinical risk factors. 

During July 31─December 25, 2022 there were 5 cases among vaccinated individuals and 16 

cases among unvaccinated individuals. The adjusted single-dose VE was 86% (95% CI: 

59%-95%). 

In the EPIC-COSMOS case-control study,9 data were used from EPIC’s EHR platform, Cosmos, 

which includes records from over 169 million patients across the US. This was a case-control 

design in which cases were defined as patients with an Mpox diagnosis or a positive 

orthopoxvirus or positive Mpox virus laboratory result from the study period of August 

15─October 29, 2022. Controls were defined as patients with an instant HIV diagnosis or HIV 

PrEP prescription during the same study period and was determined based on the 

Administration for Strategic Preparedness and Response (ASPR) vaccine distribution guidance. 

VE was estimated using conditional logistic regression models, adjusting for a priori specified 

confounders. The analysis also was stratified to examine full and partial VE by route of 

administration and immunocompromised status. Adjusted VE was 66% for full vaccination and 

36% for partial vaccination. Among individuals with no immunocompromising conditions, VE 

was 76% for those fully vaccinated and 41% for those partially vaccinated. Although the 

analysis was controlled for immunocompromising conditions, VE could not be estimated among 

this population because vaccine coverage was low. Less than 1% of immunocompromised 

individuals were fully vaccinated. When examining VE by route of administration, very few 

patients were fully vaccinated with 2 subcutaneous doses or 2 intradermal doses. The 95% 

confidence intervals were wide, but the point estimates were similar to the overall estimate. For 

fully vaccinated persons with heterologous administration routes, VE was 75%, demonstrating 

that 2 doses confers protection regardless of the route of vaccine administration. 

7 Unpublished data 

8 Sagy, Y. W. et al. Real-world effectiveness of a single dose of mpox vaccine in males. Nature Medicine 

https://doi.org/10.1038/s41591-023-02229-3 (2023) 9 Unpublished data 

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A multi-jurisdictional case-control study is currently underway. This study examines VE among 

men 18─49 years of age who have sex with men and live in 12 US jurisdictions. Cases are 

identified through the jurisdictions’ probable and confirmed Mpox case lists. Controls are 

selected from healthcare settings providing HIV PrEP or from STI clinics. Cases are matched to 

controls based on time point within 4 weeks of clinic attendance and jurisdiction. Jurisdiction 

staff members collect data on participants’ demographics, exposure history, and vaccination 

history using electronic surveys. Vaccination status of enrolled participants is confirmed using 

state immunization registries. VE is estimated using multivariable logistic regression with 

random intercept for jurisdiction and adjusted for prior specified confounders. Notably, these are 

interim results as data collection is still underway. Results indicate that VE is 76% for full 

vaccination among those without immunocompromising conditions. VE is 90% for full 

vaccination. At this interim stage, there were few individuals with partial vaccination or with 

immunocompromising conditions. Therefore, data are not sufficiently powered to generate 

estimates for these strata. 

In a case-control study in New York State (NYS), investigators linked case surveillance data to 

the immunization registry. Cases were adult male Mpox cases diagnosed during July 

24─October 31, 2022. Controls were adult male STI cases with rectal gonorrhea or primary 

syphilis cases during the same time period. Cases and controls were matched on week of 

diagnosis and VE was estimated using conditional logistic regression. VE was 68% for partial 

vaccination and 89% for full vaccination. 

In summary, the existing body of evidence for VE of JYNNEOS against Mpox disease ranges 

from 66% to 83% for full vaccination and 36% to 86% for partial vaccination. This evidence 

indicates that the JYNNEOS vaccine is effective at reducing the risk of Mpox disease. 

Protection is provided by both 1 and 2 doses of JYNNEOS vaccine, but the highest protection is 

provided by 2 vaccine doses regardless of administration route. Further research is needed to 

assess whether immunocompromised status modulates VE. Due to small numbers in this 

population across studies, there was insufficient power to generate VE estimates among 

immunocompromised individuals. Additionally, because of a decline in Mpox cases and the 

limited follow-up period from studies to date, further research is needed to assess the duration 

of protection conferred by JYNNEOS vaccination. 

JYNNEOS Vaccine Safety 

Jonathan Duffy, MD, MPH (CDC/NCEZID) noted that while an MMWR report about JYNNEOS 

vaccine safety monitoring was published that included data collected through October 2022, this 

presentation would include data through January 2023 collected using 3 surveillance systems: 

1) the Vaccine Adverse Event Reporting System (VAERS), which is a national passive reporting 

system; 2) the Vaccine Safety Datalink (VSD), which performs medical visit-based active 

surveillance for pre-specified adverse events of special interest (AESI) in a population of more 

than 10 million people; and 3) v-safesm, which is a smartphone-based system that uses text 

messaging to initiate web-based survey monitoring for AEs. AEs also were collected as part of 

single-patient Emergency Investigational New Drug (EIND) procedures for persons <18 years of 

age who were vaccinated before the JYNNEOS EUA was issued that allowed administration in 

that age group. 

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To provide an overview of the VAERS findings, as a reminder VAERS is the national passive 

surveillance system for AE reporting after vaccination. VAERS accepts reports from healthcare 

providers (HCP), vaccine manufacturers, and the public. VAERS collects data on any AE 

following vaccination, be it coincidental or truly caused by a vaccine. The report of an AE to 

VAERS is not documentation that a vaccine caused the event. The FDA issued an EUA for 

JYNNEOS on August 9, 2022 that required mandatory reporting to VAERS of vaccine 

administration errors, regardless of whether they were associated with an AE; serious AEs 

(SAE), irrespective of attribution to vaccination; cases of cardiac events, including myocarditis 

and pericarditis; and cases of thromboembolic events and neurovascular events. 

The analysis presented during this session included VAERS reports received and processed by 

January 20, 2023. AE reporting rates were calculated by dividing the number of VAERS reports 

by the number of vaccine doses administered in the US. During the period May 22–January 13, 

2023, a total of 698,188 people received Dose 1 and a total of 426,980 received Dose 2 for a 

total of over more than 1.1 million doses administered. VAERS received 1,817 reports after 

JYNNEOS. Most of these reports were for male adults 18─64 years of age and for JYNNEOS 

given alone without other vaccines on the same day. Most reports were about Dose 1. The most 

common route of administration was intradermal, followed by subcutaneous. Intramuscular 

administrations also were reported, most of which were reported as an error in the route of 

administration. Vaccine administration errors were the subject of 50% of all JYNNEOS VAERS 

reports. Of these, 96% did not report an adverse health event. Vaccine administration errors 

have been reported for JYNNEOS about 3 times more often with intradermal compared to 

subcutaneous administration. The most common issue reported with intradermal administration 

has been absence of a wheal without vaccine leakage (42%). CDC's Interim Clinical 

Considerations for use of JYNNEOS state that absence of a wheal without vaccine leakage may 

be counted as valid administration. After excluding reports of vaccine administration errors 

alone, adverse health events were reported to VAERS at a similar rate for subcutaneous and 

intradermal administration. The most common types of events differed slightly by route of 

administration. Overall, the most common adverse health events reported to VAERS for adults 

were consistent with those reported in pre-licensure clinical trials. 

An SAE event is defined as a report of the occurrence of any of the following: death, a lifethreatening AE, hospitalization, a persistent or significant incapacity or substantial disruption of 

the ability to conduct normal life functions, a congenital anomaly or birth defect, or another 

important medical event that based on appropriate medical judgement may jeopardize the 

individual and may require medical or surgical intervention to prevent one of the outcomes listed 

above. About 1% of reports to VAERS after JYNNEOS were classified as SAEs. SAEs were 

reported at a rate of 22 reports per million doses administered. SAEs reported to VAERS after 

JYNNEOS are listed here: 

Myocarditis (n=5) 

Death (n=2)** 

Pericarditis (n=2) 

Urticaria (n=2) 

Appendicitis 

Aseptic meningitis 

Asthenia 

Atrial fibrillation 

Cellulitis 

Chest pain 

Dehydration 

Idiopathic thrombocytopenic 

purpura 

Injection site discoloration 

Injection site pain 

Injection site scar 

Methemoglobinemia 

Retrograde amnesia 

Rhabdomyolysis 

Sudden hearing loss 

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Not all AEs that occur after vaccination are caused by the vaccine. Two deaths were reported to 

VAERS after JYNNEOS administration. The local Medical Examiners (MEs) determined and 

reported the causes of death in these cases to be drowning and cocaine toxicity. Hospitalization 

for myocarditis or pericarditis were the most commonly reported SAEs. The single cases of the 

other conditions reported do not suggest safety signals for any of these conditions. 

To discuss the myocarditis and pericarditis findings in more detail, myocarditis and pericarditis 

have occurred following either primary vaccination or revaccination with live vaccinia virus 

smallpox vaccines in the past. The mechanism is poorly understood, and it was unknown 

whether persons who received JYNNEOS might experience myocarditis or pericarditis. In this 

epidemiologic analysis, the cases have been classified into 2 groups. The first is myocarditis 

with or without pericarditis and the second is acute pericarditis alone. The surveillance risk 

interval is defined as symptom onset within 30 days after vaccination. In VAERS, 2 cases of 

myocarditis were reported after Dose 1 for a rate of 2.75 cases per million persons vaccinated, 

while 3 cases were reported after Dose 2 for rate of 6.74 per million. In the VSD population, 

there were 37,646 people who received at least one dose of JYNNEOS. There was 1 case of 

myocarditis observed after each dose. The VSD incidence rate estimates have wide confidence 

intervals that range from about 1 to 250 cases per million. These confidence intervals overlap 

published historical population background rates, which range from 2.7 to 21.6 cases per million 

persons during a 30-day period. For context, the published historical rates after live replicating 

smallpox vaccines have ranged from 70 cases per million after Dryvax in a 2002 military cohort 

study, up to 5,000 per million cases after ACAM2000 in a 2018 military cohort study. In 

summary, the VAERS and VSD data do not suggest an increased risk for myocarditis following 

JYNNEOS compared to expected published background rates,10 but the possibility of a small 

risk cannot be excluded. 

In a similar analysis for pericarditis, there were a total of 6 cases reported to VAERS, only 2 of 

which were classified as serious due to hospitalization. There were 4 cases after Dose 1 and 2 

cases after Dose 2 for a rate up to 5.5 cases per million persons during a 30-day period. There 

were no cases identified in the VSD population. The VAERS reporting rate for pericarditis is 

similar to expected published historical background rates and less than that observed after live 

replicating smallpox vaccines in one military cohort study.11 

The v-safesm platform is a smartphone-based system that uses text messaging to initiate webbased survey monitoring for AEs following vaccination. The data from v-safesm are used to 

characterize the basic safety profile of a vaccine when given outside of a clinical trial setting and 

can facilitate reporting to VAERS for medically attended adverse events (MAAEs). This system 

is meant to supplement CDC’s other vaccine safety monitoring systems, VAERS and VSD. In 

terms of the characteristics of v-safesm participants, there were 181 active participants, defined 

as having completed at least one survey between November 16, 2022 – January 29, 2023, all of 

whom were adults and the majority of whom were male. Additional characteristics are shown on 

the following tables: 

10 References: Halsell, et all. DOI: 10.1001/jama.289.24.3283; Oster, et al. DOI:10.1001/jama.2021.24110; Mandra, et al. DOI: 

10.1017/dmp.2020.478 11 References: Imazio, et al. DOI: 10.1136/hrt.2006.104067; Kumar, et al. DOI: 10.1159/000445206; Engler, et al. 

DOI:10.1371/journal.pone.011828 

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In terms of the percentage of participants who reported reactions or health impact events at 

least once during Days 0 to 7 after vaccination by dose, about 80% reported any injection site 

reaction and 5% sought medical care. No participants reported SAEs. The most common type 

of injection site and systemic reaction reported overall was redness at the injection site, reported 

by 64% of participants. The most common systemic reaction was fatigue, reported by 40%. 

Regarding information about AEs in persons <18 years of age, CDC facilitated single-patient 

EIND authorization from the FDA to make JYNNEOS available for persons <than 18 years of 

when needed prior to the JYNNEOS EUA being issued on August 9, 2022 that allowed wider 

use in this age group. CDC solicited information from vaccine providers about AEs occurring in 

their patients during the 28 days after each dose. Persons vaccinated under the EIND ranged in 

age from 4 months to 17 years and 58% were male. AEs were reported for 10 (18%) of 57 

people after Dose 1 and 5 (21%) of 24 people after Dose 2. The types of events reported 

included injection site reactions of pain, erythema, swelling, and induration and systemic AEs of 

fever, fatigue, and headache. No SAEs were collected in this project. 

VAERS also was used to collect data on persons <18 years of age. JYNNEOS was 

administered to 1,245 persons <18 years of age in the US during the surveillance period. 

VAERS received 25 reports for this age group. Vaccinated persons’ ages ranged from 12 

through 17 years. Reports of vaccine administration errors accounted for 84% of these reports, 

with the most common being intradermal administration instead of subcutaneous, which is the 

authorized route for this age group. The only AE reported was 1 person with syncope and no 

SAEs were reported. 

The overall conclusions about vaccine safety monitoring are that JYNNEOS post-licensure and 

post-authorization vaccine safety surveillance findings to date are consistent with those 

observed in clinical trials. No new or unexpected safety concerns have been identified. SAEs 

were rare among adults and none have been identified among persons <18 years of age. 

VAERS and VSD data taken together do not suggest an increased risk for myocarditis or 

pericarditis following JYNNEOS, but the possibility of a small risk of myocarditis cannot be 

excluded. 

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Mpox Vaccine Acceptability and Uptake from Cross-Sectional Surveys 

Kevin P. Delaney, PhD, MPH (CDC/NCHHSTP) presented Mpox vaccine acceptability and 

uptake findings from cross-sectional surveys from among clinicians and vaccine interest, intent, 

and uptake among the general population and populations disproportionately affected by the 

current outbreak on behalf of the CDC Community Engagement Task Force. One source of 

information for this is surveys of clinicians. CDC has worked with Sermo to get some insights on 

this. Sermo is an online community of more than 1.3 million clinicians. At the beginning of 

August, the company conducted what they call a “Barometer” survey of physicians around the 

world with over 1,000 physicians total.12 During this session, Dr. Delaney presented data from 

the 415 US-based clinicians in that survey. He highlighted that in early August 2022, the 

majority of clinicians surveyed wanted more access to Mpox vaccine. At short follow-up was 

conducted on September 12, 2022 at CDC’s request that found both high vaccine demand and 

acceptability, with 76% of respondents saying they knew where to send patients for JYNNEOS 

vaccine. More importantly, 86% wanted to be able to offer vaccine in their practice. 

In terms of information from affected populations, this table provides an outline and overview of 

the 4 surveys conducted by CDC and partners during the current outbreak: 

The first survey is one that CDC conducted in partnership with Porter Novelli. Porter Novelli is a 

contractor who conducted 4 online general population surveys of US adults through the months 

of August, September, October, and December 2022 on knowledge, attitudes, and beliefs of 

Mpox-related topics. The data are weighted to match US Census proportions for age, gender, 

region, race, ethnicity, and education. They also ask a question about whether the respondent 

considered themselves to be a member of the lesbian, gay, bisexual, transgender, queer or 

questioning, or other (LGBTQ+) community. The December survey had the largest sample and 

asked several questions specifically designed to directly measure Mpox vaccine acceptability 

and value. In this general population survey, very few people overall disagreed with the 

statement that “The monkeypox vaccine is safe.” Although many of the general population, even 

those identifying as part of the LGBTQ+ community, said they did not know. For the current 

outbreak, which overwhelmingly has affected gay and bisexual men, 51% of those who 

identified as LGBTQ+ thought the vaccine was safe and 50% of that group also thought it was 

important to get the Mpox vaccine to protect themselves. For the second question, it is 

12 https://app.sermo.com/barometer/unitedstates 

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interesting that 31% of those who did not identify as LGBTQ+ or a member of the LGBTQ+ 

community also felt it would be important to get the Mpox vaccine to protect themselves. 

The American Transformative HIV Study (AMETHST)13 collected data from the community most 

affected by the current outbreak (e.g., gay, bisexual, and other MSM). AMETHYST is a National 

Institutes of Health (NIH)-funded online cohort that will eventually include 5,000 sexual minority 

men. This is a diverse group with higher risk of HIV acquisition than the general population, 

even of sexual minority men, by design. The study will be recruiting such that the cohort is no 

more than 50% non-Hispanic Whites, the majority-minority, by race and ethnicity. About 60% of 

the cohort will have reported recent methamphetamine use, which increases bio-behavioral 

vulnerability to HIV. To achieve the objective of enrolling 5,000 such men, the plan is to screen 

over 30,000 respondents with an online eligibility survey. Questions about Mpox knowledge, 

vaccine uptake, and behavior change have been added to the screening enrollment survey. The 

data presented during this session were from the first 8,500 participants screened from August 

6─November 15, 2022. 

Regarding the question, “How much have you worried about Mpox infection over the last 2 

weeks?” the number who said they worried some or more than half of the days decreased from 

66% in August to 35% in November and the number who said they never worry increased from 

34% in August to 66.4% in November. While Mpox concern decreased over time, about onethird of participants remain concerned about Mpox. Over 85% of respondents remain interested 

in vaccine. Vaccine coverage doubled between August and September but then flattened out, 

which is consistent with vaccine administration data. As of November, 30% of those recruited 

reported having received at least 1 dose. However, the proportion of people reporting the intent 

to take vaccine remained strong and there was minimal increase in the proportion of people who 

said they were unlikely to get vaccinated. Overall, 85% of those enrolled in the survey so far are 

either vaccinated or reported being likely to get vaccinated. In terms of vaccine uptake by race 

from August to November 2022 among AMETHYST participants surveyed at the peak of the 

outbreak, Black men had the highest proportion reporting receipt of at least 1 dose of vaccine. 

In August, Black participants had higher vaccine coverage than participants from other racial 

and ethnic groups but did not see the “doubling” in vaccine coverage that were reported overall. 

It also is important to think about other communities in terms of equity. AMETHYST may be the 

only or best source for this. There was much lower uptake of vaccine for gender diverse 

persons and for those who do not identify as gay. Moving forward with plans to improve equity 

and access, it is important to do a better job of specifically marketing and creating demand for 

those groups as well as Black men. 

The American Men’s Internet Survey (AMIS) is an Emory University annual online crosssectional survey of people who were born and currently identify as male that is typically 

conducted with recruitment from October to February of a given year. In August 2022, 

colleagues at Emory University conducted a special one-time survey that recontacted men who 

participated in the 2021 AMIS survey cycle interviewed between October 2021 and February 

2022 to explore knowledge, attitudes, and practices related to the US Mpox outbreak. The 

survey was conducted between August 5-15, 2022 during the peak of the current outbreak.14 

For those interested, Emory posted all of the questions that were asked in the August survey 

online. There are questions in this survey about vaccine knowledge, access, and desire to be 

vaccinated; barriers to vaccination; and sources of information on Mpox. As published in an 

MMWR that first appeared online on August 26th, 53% of AMIS participants reported concern 

13 https://grants.nih.gov/grants/guide/rfa-files/RFA-AI-21-018.html 14 https://www.cdc.gov/mmwr/volumes/71/wr/mm7135e1.htm 

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about getting Mpox at that time. At that time, 18.6% of MSM surveyed reported having received 

at least 1 dose of vaccine. This is consistent with the AMETHYST data. That MMWR also 

reported higher vaccine uptake for Black men compared to all other racial groups, lower vaccine 

uptake in more rural areas relative to urban areas, and lower vaccine uptake in the South and 

Midwest. At the time this was published, the MMWR called for more equitable vaccine delivery. 

These quotes are from the discussion section: 

“Equitable vaccine program implementation involve..., engaging diverse partners 

already working with special populations, delivering vaccines through mobile outreach 

and pop-up events, and diversifying times and locations for vaccine administration” 

“Expanding vaccine availability geographically, including diversifying vaccination 

locations to include nonurban areas, can help ensure that those who need vaccination 

have access to it.” 

Just 4 days after publication of the MMWR, the White House announced plans to support 

expansion of vaccine access through distribution to groups working to provide vaccine at large 

events and in spaces where they could reach populations who otherwise might not have 

access.15 The Mpox Vaccine Equity Pilot Program (VEPP) was created to: 1) support innovative 

ways to address vaccination disparities; 2) encourage vaccination coordination between health 

departments and community-based organizations (CBOs); and 3) promote innovation to 

strengthen existing vaccination infrastructure. The VEPP provided additional vaccine above the 

original allocation to 15 jurisdictions, 14 states, and Puerto Rico for 28 different vaccination 

programs and events. These were beyond the threshold supplies provided to states. This 

project delivered nearly 25,000 doses of vaccine at special vaccine equity events. 

The 2022-2023 AMIS is still recruiting. These data are from an abstract developed for 

submission to the International AIDS Society (IAS) meeting but are not yet published. 

Recruitment began in early October and by the end of December, over 3,000 men had been 

enrolled. At that point, 33% reported that they had received 1 dose of vaccine. Again, very 

consistent with the AMETHYST data for November and December. Vaccine uptake was 

associated with Mpox awareness and concern and also with factors that might be indicative of 

concern for or awareness of sexual health and access to sexual health services overall, 

including HIV care, STI testing, and HIV PrEP use. 

A study conducted by the CDC and the San Francisco Department of Public Health (SFDPH) 

specifically recruited another special population of people experiencing homelessness in San 

Francisco. This study was fielded from October 23─November 5 and sought to understand 

Mpox vaccine coverage and acceptability among people experiencing homelessness. This 

study also collected blood to assess seroprevalence in this community, though Dr. Delaney did 

not discuss that during this session. The take-home from this analysis is that 56% of those who 

reported any sexual risk and 74% of MSM, said that they would accept Mpox vaccination. 

Again, consistent with the AMETHYST data. 

15 https://www.whitehouse.gov/briefing-room/statements-releases/2022/08/30/fact-sheet-white-house-monkeypox-response-teamannounces-new-plans-to-support-large-lgbtqi-events-and-equity-interventions-to-reach-communities-at-highest-risk-ofcontracting-the-virus/ 

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Interim Clinical Considerations 

Rosalind Carter, PhD (CDC/NCIRD) provided a brief overview of CDC’s Mpox vaccine Interim 

Clinical Considerations (ICC) that were developed to guide vaccine implementation during the 

Mpox outbreak. It is important to remember that the ICC is a living document. As the 

epidemiology of the outbreak evolved and as feedback was received from the field in terms of 

new questions and concerns, the guidance was updated or clarified. The latest ICC updates 

continue to emphasize the importance of vaccination before exposure for those with the highest 

potential for exposure to Mpox, the importance of identifying and vaccinating persons living with 

HIV or who have other causes of immunosuppression who have had recent or anticipate 

potential Mpox exposure, and including explicit language stating that the definitions of risk 

groups also include adolescents. 

From the beginning of the 2022 Mpox outbreak, the US Government (USG) recognized that 

Mpox vaccine availability was the critical strategy to limit the rapid spread of Mpox. Two 

vaccines may be used for prevention of Mpox and were available from the Strategic National 

Stockpile (SNS). They included the JYNNEOS vaccine approved for prevention of smallpox and 

Mpox and licensed for use among persons 18 years of age and older. On August 9, 2022, FDA 

issued an Expanded Use Authorization (EUA) for intradermal administration among persons 18 

years of age and older. That is the primary vaccine being used during this outbreak in the US. 

ACAM2000 is an alternative to JYNNEOS and approved to protect against both smallpox and 

monkeypox. While it is available, it has not been used during this outbreak due to the higher risk 

of SAEs. 

On June 28, 2022, the federal government announced an enhanced nationwide strategy to 

vaccinate and protect people at risk for Mpox, prioritize vaccines for areas with the highest 

number of cases, and provide guidance to state, tribal, local, and territorial health officials to aid 

planning and response efforts. Multiple federal agencies, including the ASPR, SNS, Biomedical 

Advanced Research and Development Authority (BARDA), CDC, and FDA are working closely 

with partners to ensure there are enough vaccine doses available to vaccinate all people for 

whom vaccine is recommended. There are 2 primary strategies, which are 1) vaccination of 

individuals after known or presumed exposure to someone with Mpox; and 2) vaccination prior 

to exposure among persons at high risk for potential exposure. 

For PEP in the first strategy, CDC has defined people eligible for vaccine in the ICC as follows: 

 People who are known contacts to a person with Mpox, and identified by public health 

authorities as a “contact” from case investigation, contact tracing, or risk exposure 

assessment; or 

 People who are aware that a recent (within the past 14 days) sex partner was diagnosed 

with Mpox; or 

 Gay, bisexual, other MSM, and transgender or non-binary people (including adolescents) 

who have had sex with multiple partners, at a commercial sex venue, or sex in an 

association with an event, venue, or defined geographic area where Mpox transmission is 

occurring. 

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For PrEP in the second strategy, CDC has defined eligible groups in the ICC as those groups 

eligible for vaccination prior to Mpox exposure who either have highest potential risk for 

exposure or who anticipate potential exposure to Mpox: 

 Gay, bisexual, and other men who have sex with men, and transgender or nonbinary people 

(including adolescents) who, within the past 6 months, have had: 

− A new diagnosis of one or more sexually transmitted diseases (e.g., chlamydia, 

gonorrhea, syphilis); 

− More than one sex partner 

 People who have had any of the following in the past 6 months: 

− Sex at a commercial sex venue; or 

− Sex in association with a large public event in a geographic area where mpox 

transmission is occurring 

 Sexual partners of people with the above risks 

 People with HIV † infection or other causes of immunosuppression who have had recent or 

anticipate potential mpox exposure 

 People in certain occupational exposure risk groups (laboratory personnel working with 

orthopoxviruses) 

This is all in accordance with the ACIP 2022 recommendations. It is important to note that 

although the language describes the highest risk groups in an effort to improve equitable access 

to Mpox vaccines, persons who request vaccination can receive it without having to attest to 

meeting any of these specific criteria. 

Health equity principles outlined in the interim clinical guidance are incorporated into the 

National Vaccine Strategy as well as local implementation efforts. Some of these principles 

include engaging people from affected communities in the planning and design of vaccination 

efforts; using non-stigmatizing, plain language; reiterating privacy of information and how data 

will be used; engaging diverse partners already working with special populations; bringing 

vaccines to where affected populations are (e.g., pop-up events, mobile outreach); offering 

multiple appointment times and flexible walk-in opportunities, including evenings and weekends 

to improve vaccine accessibility; leveraging clinical venues such as the Federally Qualified 

Health Centers (FQHCs) that serve people who have historically had less access to primary 

care, sexual health clinics, transgender health clinics, and pharmacies to deliver vaccines; and 

minimizing systems that are first come, first-served. 

Looking quickly at the data, almost 1.2 million doses were administered and reported to CDC 

through February 7, 2023. This includes 734,000 first doses and 452 second doses. During the 

week of August 7-13, the EUA for intradermal administration was introduced. At that same time, 

additional vaccine vials were released from the SNS and provided to the states. Intradermal 

dosing greatly expanded the number of people vaccinated with first and second doses during 

the peak of the outbreak when demand was highest. Looking at data comparing Mpox cases to 

those vaccinated by race and ethnicity and whether vaccine equity improved over time, notably 

completeness for race and ethnicity data in vaccine administration database was very good 

quality. Over 91% of this information was completed. Summarizing the overall data from May 

through the end of January 2023 compared to the time periods of mid-June to mid-July and midJuly to mid-August, the proportion vaccinated who were Hispanic increased from 19% to 23% 

and the proportion of people vaccinated who were Black non-Hispanic increased from 7% to 

13%. While these proportions were maintained over time, improvements in vaccine equity in 

subsequent months have been modest. It is important to note that these data summarize the 

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national picture and individual jurisdictions, including many of the highest burden states that 

have made substantial progress in addressing equity gaps. Nonetheless, there is much work 

ahead in implementation to improve vaccine equity. 

To highlight a few elements of the current vaccine implementation as best practices for future 

outbreaks, vaccine strategies and implementation were adapted to local situations, local 

epidemiology, and population needs. This included adapting the eligibility criteria for local 

contexts. Some examples of this are that some states included sex workers in their definition of 

vaccine eligibility. Many others removed sexual orientation labels from eligibility criteria and 

reduced potential stigma by allowing people to self-attest to eligibility. The interim guidance for 

eligibility also evolved as the epidemiology, which was very dynamic, changed over time. CDC 

recognizes that vaccination offered in the context of broader prevention activities, as well as 

sexual health care, including HIV testing and PrEP initiation, increased access to vaccines as 

well as acceptance of vaccines. The importance of the key role that CBOs had cannot be 

emphasized enough in the success of vaccine implementation, both as trusted messengers and 

in logisticians in helping set up vaccine events in their neighborhoods and communities. It also 

is important to highlight the importance of planning resources for data collection, including 

collecting vaccine status and dates of vaccination on monkeypox reporting forms, which allowed 

CDC to measure vaccine performance early in the rollout. Including race and ethnicity data on 

vaccination reports, including on reports shared with CDC, is essential in driving program 

actions and course correction. 

In addition to the success stories, there were many challenges, most notably the limited supply 

of vaccine at the peak of the outbreak in mid-July when demand was high. The intradermal 

route of administration was an important public health intervention, increasing the vaccine 

supply 300% to 500% when it was most needed. CDC’s ASPR colleagues handled the complex 

logistics of moving JYNNEOS vaccine from the federal SNS to the jurisdictions. However, at the 

beginning, the SNS was limited to only 5 shipments per week during the outbreak peak, leaving 

the jurisdictions to manage redistribution to providers in critical areas. However, within about 6 

weeks, ASPR was able to increase their shipping capacity to provide directly to providers. The 

change from subcutaneous to intradermal administration required jurisdictions to provide skills 

training to vaccinators. However, on average, these jurisdictions were able to begin 

implementation of intradermal within 2 to 3 weeks of the EUA, which was a significant 

accomplishment and heavy lift. Initially, health departments and public clinics were the primary 

vaccine providers, providing more than 50% of all vaccinations. As the outbreak has subsided, 

the jurisdictions have increasingly engaged STI and HIV care providers, as well as pharmacies 

in some states to take on these roles. Despite these challenges, it is important to acknowledge 

the dedication and the hard work of the jurisdictional health departments that are truly 

responsible for the successful implementation of Mpox vaccines. 

EtR: Use of JYNNEOS During Mpox Outbreaks 

Agam Rao, MD (CDC/NCEZID) presented the EtR Framework for vaccination with JYNNEOS 

vaccine during any monkeypox outbreak that could be spread through travelers from countries 

where it is endemic, imported animals such as prairie dogs or other animals, et cetera. It is 

important to understand that even though a vote is being proposed for JYNNEOS for any 

outbreak, the current outbreak is not over and people are encouraged to continue to be 

vaccinated based on the ICC that Dr. Carter summarized for specific populations for whom 

JYNNEOS is recommended during the current outbreak. Dr. Rao cautioned that this 

presentation included photographs that might be difficult for some viewers and that she would 

provide advanced notice before showing them. 

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As a reminder, the EtR Framework is a structure to describe information considered in moving 

from evidence to ACIP vaccine recommendations. It provides transparency around the impact of 

additional factors on deliberations when considering a recommendation. There are 7 EtR 

domains: Public Health Problem, Benefits and Harms, Values, Acceptability, Equity, Feasibility, 

and Resource Use. Dr Rao presented the WG’s interpretation of the data for each of these 

domains and the response to the associated questions for each domain. The EtR question is: 

Does ACIP recommend the2-dose* JYNNEOS vaccine series for persons aged 18 years 

and older at risk of Mpox during an Mpox outbreak? § 

*Dose 2 administered 1 month after Dose 1 

§Public health authorities will determine whether there is an Mpox outbreak; a single case may be considered an Mpox 

outbreak at the discretion of public health authorities. Other circumstances in which a public health response may be 

indicated include ongoing risk of introduction of Mpox into a community due to disease activity in another geographic area. 

In terms of the Public Health Problem domain, there have been several notable public health 

events involving Mpox since it was first recognized in humans in 1970. Early cases were in rural 

settings in certain forested regions of Africa where the presumed animal reservoirs reside. The 

first outbreak outside of Africa occurred in the US in 2003 from pet prairie dogs that were cohoused with infected small mammals from Ghana. There were 47 cases associated with that 

outbreak. Going forward, cases continue to occur in Africa. The 9 African countries are the 

countries where we know that cases had occurred. Cameroon, Central African Republic, Côte 

d'Ivoire, Democratic Republic of Congo, Gabon, Liberia, Nigeria, Republic of Congo, and Sierra 

Leone. In 2017, there was a large outbreak in Nigeria involving 17 states. At that time, it was 

considered a very large outbreak involving 138 cases. During 2018─2021, there were imported 

cases in travelers from Nigeria to various countries, to the UK and Israel in 2018, and to the UK 

and Singapore in 2019. In 2021, there were 3 cases, 2 of which occurred in the US. In 2022, a 

multinational outbreak occurred. All of this to say that Mpox does seem to be of public health 

significance and importance. There have been a lot of cases, including a reemergence of 

human cases in recent years after decades of no reported cases in some countries. 

Even before the 2022 multinational Mpox outbreak, investigations for even a single case of 

Mpox have been intense. During the July 2021 investigation, in one of the investigations in the 

US 223 contacts had to be monitored. Fortunately, there were no high-risk exposures or 

secondary transmissions. There were a lot of contacts, including flight crew and fellow 

passengers on international and domestic flights and friends of the affected patient and a 

rideshare driver. All of these individuals were monitored by public health authorities. There were 

2 imported cases to the UK in 2019 and 2021 that resulted in secondary infections. In 2019, a 

HCW developed Mpox after presumed exposure while changing the bedding of an Mpox 

patient. In 2020, 2 household contacts of an Mpox patient developed Mpox. This outbreak is 

obviously involved in many cases that peaked in early August. Case counts are decreasing at 

this time, but this outbreak is not over. 

The typical presentation manifestation of Mpox during the current outbreak are small, firm, 

deep-seated, well-circumscribed lesions that can occur on the palms, soles, and other parts of 

the body. They often have been scattered or focused on one body part, most commonly the 

genitals. Prodromal symptoms, including fever and lymphadenopathy, have inconsistently 

occurred. When lesions have occurred in the perianal or genital region, the pain from lesions 

has been particularly pronounced. Rectal pain, abdominal pain, rectal bleeding, and tenesmus 

have all been reported. Typically, symptoms resolve with supportive care alone, including pain 

control. However, severe manifestations are occurring in some patients who have severe 

outcomes. Severe manifestations include ocular lesions, neurologic complications, 

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myopericarditis, and certain mucosal lesions that can affect patients regardless of immune 

status. Myopericarditis cases have been seen in people who developed Mpox. not just in 

individuals. Keratitis and conjunctival ulcer are associated with ocular Mpox. Ocular lesions can 

be very serious and can even cause blindness, as in other countries where classic Mpox has 

occurred in Africa. Myopericarditis and neurologic complications have been reported in a small 

number of patients who are uncertain of the reasons for this. It has occurred in individuals who 

have been immunocompetent. Encephalitis and transverse myelitis have occurred in patients 

with Mpox. When lesions occur on certain mucosal surfaces (e.g., urinary meatus, penis) they 

can cause complications, including obstruction. 

Lesions can be severe, necrotic, and require consultation from medical subspecialists such as 

urologists, gastroenterologists, and general surgeons depending upon the location of the 

lesions. While these are considered severe manifestations, the most severe and the lifethreatening lesions occur in patients with severe immunocompromise. Patients who are 

severely immunocompromised due to advanced HIV in particular have had the most severe 

manifestations of Mpox during the current outbreak. The etiology is believed to be uncontrolled 

viral spread in severely immunocompromised patients. Dr. Rao shared some images to illustrate 

the progression of illness and how different the lesions in these patients can be from the typical 

presentation. Medical therapeutics such as tecovirimat and brincidofovir may be helpful, but an 

optimized immune system through antiretroviral therapy, temporary halting of immunomodulator 

therapies, or some other mechanism is still the most critical aspect of care. Deaths have 

occurred because of these illnesses, often many weeks after hospitalization because of the 

progression and despite therapeutics. Therefore, the WG determined Mpox outbreaks to be of 

public health importance based on all of the data presented. 

Regarding the Benefits and Harms domain, there are early estimates and population-based 

estimates of VE. Vaccine performance has been evaluated through comparison of incidence of 

Mpox between vaccinated and unvaccinated persons in 43 US jurisdictions. Mpox incidence 

among unvaccinated was 7.4 times that among persons who received only 1 dose of JYNNEOS 

vaccine ≥14 days earlier, and 9.6 times that among persons who received Dose 2 ≥14 days

earlier. Population-based adjusted measures of VE using EMRs also have been performed. A 

retrospective population-based cohort study conducted in Israel showed that 5 Mpox infections 

occurred among subjects vaccinated with 1 subcutaneous dose and 16 infections occurred 

among unvaccinated subjects. The VE for Dose 1 was calculated as 86% with the confidence 

interval of 59% to 95%. A nationwide US case-control study with a 1:4 ratio of cases matched to 

controls had an adjusted VE of 35.8% with a 95% confidence interval of 22.1% to 47.1% for 1 

dose and 66% with a 95% confidence interval of 47.7% to 78.1% for 2 doses, regardless of the 

vaccination route. In terms of population-based adjusted measures of VE using case-control 

studies, a case-control study of adult MSM 18─49 years of age in 12 US jurisdictions had an 

adjusted VE of 76% with a confidence interval of 48% to 89% for the 2 doses. Those are interim 

results. This study is ongoing, so the WG hopes to have more information to present during the 

June 2023 ACIP meeting. Unpublished preliminary results from a NYS case-control study of 

adult male Mpox cases matched to STI controls had an adjusted VE of 68% with a confidence 

interval of 25% to 86% for 1 dose and 89% with a confidence interval of 44% to 98% for 2 

doses. These also are preliminary results and the analyses are ongoing. 

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In terms of PEP effectiveness and infections following a single JYNNEOS dose 

10% (11 out of 108 subjects) in France who were administered JYNNEOS after Mpox exposure 

became symptomatic with Mpox disease soon after vaccination. The interquartile range was 1 

to 6 days, with a median of 5 days. Notably, the clinical course was mild among those persons. 

Also in France, there was an observational study involving people who received a single 

subcutaneous dose. In this study, 4% were infected during the month after the vaccination and 

none had serious infection. In a NYC cohort study of individuals with high-risk exposure, VE was 

77% with PEP <14 days after last exposure and 79% with PEP <14 days after the first 

exposure. Based on all of this information that seemed to support the benefits of the vaccine, 

the WG’s interpretation was that the desirable anticipated effects of Mpox vaccine during an 

outbreak are large. 

Vaccine safety is focused on the subcutaneous route of administration during May 22, 2022 

through January 13, 2023. A total of 1,125,168 JYNNEOS vaccine doses were administered. 

CDC monitored JYNNEOS safety using VAERS and VSD for vaccine recipients of all ages. The 

most common AEs reported were non-serious and included injection site reactions consistent 

with pre-licensure studies. These were reported at similar rates for doses received by 

intradermal and subcutaneous administration and SAEs were rare among adults. The WG’s 

interpretation is that the undesirable anticipated effects of Mpox vaccine during an outbreak are 

small. The WG’s interpretation of the balance between the desirable and undesirable effects 

was that the desirable effects outweigh the undesirable effects and favored the intervention of 

vaccination with JYNNEOS. 

Regarding the Values domain, surveys have been used to assess the values of the individuals 

who are being vaccinated during the 2022 outbreak. Even though this vote is for Mpox 

outbreaks in general that may not be specific to male-to-male sexual contact, there are data 

from this outbreak to rely on to answer this question. In terms of populations at highest risk of 

Mpox, and August AMIS survey found that 53.1% of respondents had concerns about getting 

Mpox. During October─December, an AMIS survey showed that those with high Mpox concern 

had a 3.5 times odds of being vaccinated. Interest in the vaccine seemed to be high during 

August─November when greater than 85% of respondents in the AMETHYST study were 

interested in the vaccine. During August─December, 50% of Porter Novelli survey responders 

who identified as LGBTQ+ felt that the vaccination is important to protect from Mpox. That 

includes not only MSM, but also other LGBTQ. During October─November, greater than 70% of 

MSM in a San Francisco survey of persons experiencing homelessness reported that they 

would accept or have accepted vaccination. This is important because a disparity has been 

observed in that individuals experiencing homelessness have experienced a disproportionate 

number of cases just as those who are Black and Hispanic have. The WG’s interpretation was 

that the target population probably feels that the desirable effects are large relative to the 

undesirable effects. 

There is some uncertainty or variability in how many people might value the vaccination. During 

the 2022 Mpox outbreak, willingness to be vaccinated was dynamic and depended upon 

perceived vulnerabilities. Clear demand for JYNNEOS vaccination occurred, but many still 

remain unvaccinated for unclear reasons. The demographics of future outbreaks also would be 

unclear, which is why the WG believes there might be some uncertainty or variability. It is 

unknown what the demographics of future outbreaks might be, who the affected populations 

might be, and whether the values expressed by the population most affected by the 2022 Mpox 

outbreak can be extrapolated to all other populations. For this reason, the WG’s interpretation 

was that there is possibly important uncertainty or variability. 

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Moving to the Acceptability domain, stakeholder perceptions are very important to this question. 

Sermo is an online community of greater than 1.3 million clinicians. During July 31─August 1, 

2022, survey results of US clinicians (n=415) showed that 69% felt that the US was without 

enough Mpox vaccine to handle the outbreak, indicating that they wanted vaccine to be 

available. A September 12, 2022 survey among 62 US clinicians showed that 66% had treated 

at least 1 Mpox patient, 76% knew where a patient could get JYNNEOS vaccination, and 86% 

wanted to be able to provide vaccination to their office. Taken together, the WG interpreted this 

as the clinician stakeholders being supportive of vaccination. 

In terms of health departments and CBOs, health departments have been requesting JYNNEOS 

and organizing vaccination campaigns. Approximately 70% of the allotted JYNNEOS vaccine 

doses already have been requested and shipped to states in response to requests from 

stakeholders. In addition, the VEPP has enabled jurisdictions to request more than their allotted 

amount of JYNNEOS vaccine. It was established to support innovative ways to address 

vaccination disparities, encourage vaccination coordination between health departments and 

CBOs, and promote innovation to strengthen existing vaccination infrastructure. A total of 28 

programs involving 15 jurisdictions and approximately 25,000 doses have been associated with 

the VEPP. This is above and beyond the initially allotted amounts, all of which illustrates that 

there seems to be support among stakeholders, health departments, and CBOs. The WG’s 

interpretation is that the intervention is acceptable to key stakeholders. 

Regarding the Resource Use domain, JYNNEOS vaccine is provided from the HHS SNS free of 

charge. Vaccines are a good use of resources during an outbreak and this EtR and ACIP vote 

are intended for any outbreaks. However, there are costs and challenges associated with 

mobile pop-up vaccination sites. A cost-effectiveness analysis of vaccine implementation during 

the current outbreak is not currently available. As comments during previous sessions have 

indicated, use of the SNS is sometimes not as efficient as would be preferred. The WG was split 

on their interpretation of whether the intervention is a reasonable and efficient allocation of 

resources. Some WG members felt that it was reasonable, but that the efficient element was 

uncertain. Therefore, the interpretation was that it varies. 

With respect to the Equity domain, no groups or settings are disadvantaged by a 

recommendation for JYNNEOS use during Mpox outbreaks. Effectiveness is the same for all 

immunocompetent persons. Implementation to assure equitable access will be important, 

particularly among persons who are at high risk for severe outcomes. This recommendation by 

ACIP might facilitate broad acceptance of the vaccine (e.g., by insurance companies and health 

departments) because it is an endorsement by ACIP after rigorous review of the evidence. The 

WG’s interpretation was that interpreting equity as independent of implementation challenges, 

the impact on health equity is that equity probably would be increased. 

In terms of the Feasibility domain, the feasibility of conducting vaccine campaigns in 

communities, at events, and within the public health facilities was demonstrated in 2022. 

Vaccinations can be integrated into provider’ practices. Standing orders are available, the IIS 

requirements for reporting vaccinations are the same as for COVID-19 vaccines, and JYNNEOS 

can be stored refrigerated for 8 weeks. A wide range of vaccinators can administer JYNNEOS 

unlike the other orthopoxvirus vaccine, which some clinicians are hesitant to administer. All of 

these elements support the feasibility of vaccines and the vaccine recommendation. 

which some clinicians are hesitant to administer. The WG thought carefully about this and felt 

that the JYNNEOS vaccination probably is sustainable during outbreaks. Vaccine access is an 

important concern. There needs to be increased, convenient, and low stigma access for all 

persons who might be at risk. Considerations to ensure vaccine equity include strong ties with 

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CBOs, support for vaccination events, engagement of trusted messengers, and ensuring that 

there is access, including in rural areas. The WG’s interpretation was that the intervention is 

feasible to implement. 

To summarize the responses to all of the EtR questions, the WG felt that there was possibly 

important uncertainty or variability, mostly because they did not have data about stakeholders 

who might be affected during other types of Mpox outbreaks. The WG felt that it is reasonable to 

have vaccines during an outbreak if it would prevent infections, which the Mpox vaccine does. 

There was some concern about whether use of this intervention is an efficient allocation of 

resources, so the WG’s interpretation of whether the intervention is reasonable and efficient 

allocation of resources is that this varies. In terms of the balance of consequences, the WG felt 

that the desirable consequences clearly outweigh the undesirable consequences in most 

settings and drafted the following proposed recommendation language for ACIP’s consideration: 

ACIP recommends the 2-dose* JYNNEOS vaccine series for persons aged 18 years and 

older at risk of Mpox during an Mpox outbreak? § 

*Dose 2 administered 1 month after Dose 1 

§Public health authorities will determine whether there is an Mpox outbreak; a single case may be considered an Mpox 

outbreak at the discretion of public health authorities. Other circumstances in which a public health response may be 

indicated include ongoing risk of introduction of Mpox into a community due to disease activity in another geographic area. 

The WG also proposed the following Clinical Considerations: 

 In an outbreak setting, vaccine is ideally given pre-exposure but may also be given as postexposure prophylaxis (PEP), although evidence has not been reviewed by ACIP for PEP at 

this time. 

 The complete 2-dose vaccine series should be given regardless of the timing of the 

exposure. 

 Although ACIP has not reviewed the evidence, if there are vaccine supply shortages, the 

intradermal route of administration can be used. 

The WG will be talking more about data for the intradermal route of administration during the 

June ACIP meeting. The entire outbreak language from this meeting and the June meeting will 

be consolidated into one MMWR after that. During the June ACIP meeting, the WG will provide 

updates about VE and safety and will propose a separate vote for administration of the 

JYNNEOS vaccine in people less than the age of 18 years. The focus during this meeting was 

on persons ≥18 years partly because that is simply an expansion of the 2022 ACIP 

recommendations for persons at occupational risk. It is the same age range, but for a different 

group of people. Depending upon the epidemiology of this outbreak, if cases are continuing to 

occur in large numbers, there will be more discussion and consideration for a longer-term 

vaccination strategy with the 2-dose JYNNEOS series during the October 2023 ACIP meeting. 

ACIP Discussion Points, Observations, Suggestions on Mpox Vaccine 

Following Dr. Ellington’s Presentation 

• It would be beneficial to have additional details on the individual who had a spontaneous 

abortion. 

Following Dr. Chard’s Presentation 

• Concern was expressed about the large difference in the estimates of single dose 

coverage. 

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• It would be beneficial to have information about whether delivering vaccine too deeply 

affects VE. 

• Concern was expressed about very few people being able to administer intradermal 

vaccine anymore. Dr. Rao emphasized that early on the intradermal route was 

recommended due to the shortage of vaccine. There is more vaccine available now and 

route of administration should not be a reason someone is not vaccinated. 

• In the future, it would be helpful to share VE estimates of people with different organ 

transplants taking different pharmaceutical medications and HIV diagnosis codes. 

• As more information is collected on intradermal versus subcutaneous administration, it 

would be useful, if possible, to look at that combined with full versus partial vaccination 

to understand if there is any differential impact in the setting of an outbreak if there is a 

preference for one or the other. 

Following Dr. Duffy’s Presentation 

• While it is reassuring that the rate of myocarditis/pericarditis is lower than following 

Dryvax, the numbers of people vaccinated are still very small. 

• In response to a request for the benefit of the public to explain what it means to have an 

absence of wheal without vaccine leakage, Dr. Buffy indicated that with intradermal 

administration, the idea is that there will be a wheal or small area where the skin is 

raised after an injection. Some people have reported to VAERS that when they have 

attempted intradermal administration but have not seen a wheal forming. That is why 

CDC issued some guidance to indicate that just because the wheal is not seen does not 

mean that the intradermal vaccination was not successful. 

• This is another example that reveals that the US has a multifaceted safety surveillance 

system in which each platform complements the other in terms of strengths and 

limitations. 

• Though v-safesm had low uptake for Mpox, with the understanding that this likely was a 

timing issue, it is laudable that CDC plans to use this system in the future for other types 

of vaccines and that in non-emergency response and routine vaccination programs, it is 

expected to be available early in the launch of new vaccines. 

• It would be beneficial to have information on JYNNEOS vaccine in pregnancy. Dr. Buffy 

indicated that v-safesm has a question about pregnancy. 

• Monitoring vaccine safety in general in pregnancy and among immunocompromised 

persons is crucial. The lessons learned from COVID-19 in terms of these populations 

have been very positive and reassuring, which is extremely helpful in terms of 

communication efforts. 

Following Dr. Delaney’s Presentation 

• Regarding a question about what types of practices were involved in the Sermo crosssectional surveys, Dr. Delaney indicated that most clinicians surveyed were from primary 

care or infectious disease practices. In terms of geography and racial distribution, they 

were primarily in the Northeast. The survey was quick and was open for only about 48 

hours. The follow-up survey included a more diverse pool of respondents from the US. 

The data are available online. 

• Looking at safety data, efficacy data, and outreach is a good approach in general in 

terms of how ACIP views a theoretical upcoming vote on this vaccine. 

• It would be beneficial to hear more about the reason African Americans had the highest 

rate of vaccine uptake at the beginning but the lowest rate as time progressed in terms 

of whether it was related more to access or lessening interest in the vaccine. Dr. 

28 
 

 

 

 

 

 

 

 

 

Delaney noted that the AMETHYST questions could unpack that more, though intention 

to get vaccine has not yet been assessed by race and ethnicity. 

• It seems that more education is needed to make at risk populations aware of the 

problem, given that the target populations do not know much about the vaccine and/or 

Mpox disease. Dr. Delaney acknowledged that the AMETHYST and AMIS cohorts 

showed that there were gaps in knowledge, so CDC adapted its messaging based on 

those early survey results to be more sex-positive and to ensure that the vaccine was 

being talked about as a sexual health intervention, because most of the places where 

the vaccine was available outside of the health equity events were STI and PrEP clinics 

and HIV care sites. The Community Engagement Task Force developed the materials 

and the social media marketing and worked with CDC’s community partners to get the 

message out to the most affected communities. He agreed that more needs to be done. 

• The difference between the number of people who are interested in the vaccine and the 

number who actually have taken the vaccine is striking. That disconnect suggests that 

there is creative work to be done. 

• One approach to address the equity issue is positive deviance; that is, highlight 

successes and figure out how to learn from them. 

• From a local public health standpoint, the aspect of achieving equity is often a matter of 

having adequate resources for local public health and their partners to conduct effective 

outreach to those who are at higher risk. ACIP’s guidance and identification of potential 

equity issues can help to direct resources accordingly. 

• Equity always has been increased in terms of pediatric vaccines because of the 

Vaccines for Children Program (VFC). Because there is not a comparable program for 

adult vaccines, barriers can increase equity among adult populations. 

Following Dr. Carter’s Presentation 

• The launch of this response was very difficult because the vaccine distribution system 

was totally different from what all of the public health immunization programs had been 

utilizing beforehand. In terms of the issue of equity, states were only allowed to have 5 

sites receive vaccine. That is one of the reasons why there was such limited distribution 

of the vaccine. If the SNS is going to be used via ASPR, consideration must be given to 

the efficiency of that distribution system. 

• This presentation highlighted the complexity of the response and how many people were 

involved, both on the frontline and behind the scenes. The data with doses by month 

addressed the equity issue and demonstrated clearly that the concerted efforts were 

effective. All jurisdictions should be encouraged to look at their data in a similar way. 

• Immunization registry reporting is critical to determine what doses have been given and 

to avoid errors. 

• The lessons learned from Mpox should be applied to other outbreaks to inform quick 

mobilization versus spending months gearing up for an unexpected outbreak. 

• It would be nice to have an overall statement saying that ACIP does not recommend 

routine HCP vaccination for frontline workers, along with more guidance about when 

PEP should be offered to frontline HCP who perhaps were not using personal protective 

equipment (PPE) and later finds out a patient has Mpox. Dr. Carter indicated that CDC 

worked closely with its Healthcare Worker Task Force and NIOSH colleagues to review 

this carefully and the conclusion was that PPE recommendations provided adequate 

protection against the risk of Mpox transmission and therefore, JYNNEOS vaccine was 

not recommended for HCP. Certainly, someone who is exposed to Mpox who was not 

adequately protected could be offered PEP. 

29 
 

 

 

 

 

• It would be beneficial to continue to have the flexibility to offer either the intradermal or 

subcutaneous route of administration, especially since intradermal can be stigmatizing. 

Following Dr. Rao’s Presentation 

• Looking at the entire picture, this is a common disease. Even now at its lowest, there are 

still 2 cases per week. That is higher than the number of cases per week in the past few 

years, and there is a fairly high death rate. There is a very effective vaccine with good 

data. 

• It was observed that case counts also have decreased in many countries where no 

vaccine is available. While vaccine is certainly playing a role, behavioral changes also 

may be having an impact. 

• Significant information is still lacking for immunocompromised patients. In general, it 

seems that immunocompromised patients need additional doses. Perhaps during the 

October ACIP meeting, consideration can be given to additional doses of JYNNEOS for 

immunocompromised patients. Dr. Rao indicated that CDC is collaborating with other 

partners to try to conduct some immunogenicity studies to better understand the role of 

JYNNEOS for immunocompromised patients and plans to discuss this with the WG. 

Clinicians on the WG have raised this concern for HIV, immunocompromised, transplant, 

and other patients who have higher risk. 

• Concern was expressed that having a risk-based recommendation could limit access, be 

stigmatizing to some extent, and present inherent challenges for future Mpox outbreaks 

or other infectious diseases with similar characteristics. While education will help, it will 

not solve the problem to the extent that someone who is not aware they are at risk 

needs to be seen in a clinical setting and that their risk needs to be assessed. CDC and 

the WG emphasized that the ICC explains that individuals should not have to explain 

their rationale for wanting to be vaccinated and that there is a need for continual 

community engagement and education to keep Mpox in the public eye. 

• It will be important for longer-term recommendations and the ICC to address booster 

dosing, which will be part of the WG’s discussion after June 2023. 

• The question often arises about whether someone who recovered from Mpox should be 

vaccinated, which the WG is not currently recommending because it is believed that 

these individuals will have protection from their natural illness. There are booster studies 

underway that will inform booster dosing recommendations in the coming years. 

• There can be complicated political considerations in declaring an outbreak. The 

proposed recommendation language is broad and as such offers the flexibility to 

implement more aggressive vaccination measures if state and local health departments 

feel that is needed. 

• It is impressive that over 90% accurate data were captured on race and ethnicity. It 

would be great to capture that information and information on disabilities in all clinical 

trials and other studies in order to inform and enhance access. 

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Vote: Mpox Vaccine 

Agam Rao, MD (CDC/NCEZID) displayed and read the proposed vote language following the 

public comment period. The vote was combined with the Mpox session for ease of reading: 

ACIP recommends the2-dose* JYNNEOS vaccine series for persons aged 18 years and 

older at risk of Mpox during an Mpox outbreak? § 

*Dose 2 administered 1 month after Dose 1 

§Public health authorities will determine whether there is an Mpox outbreak; a single case may be considered an Mpox 

outbreak at the discretion of public health authorities. Other circumstances in which a public health response may be 

indicated include ongoing risk of introduction of Mpox into a community due to disease activity in another geographic area. 

Motion/Vote: Mpox Vaccine 

Dr. Loehr made a motion to approve the recommendation as stated, which Dr. Poehling 

seconded. No COIs were declared. The motion carried with 14 affirmative votes, 0 negative 

votes, and 0 abstentions. The disposition of the vote was as follows: 

14 Favored: Bahta, Bell, Brooks, Chen, Cineas, Daley, Kotton, Lee, Loehr, Long, McNally, 

Poehling, Sanchez, Talbot 

0 Opposed: N/A 

0 Abstained: N/A 

RESPIRATORY DISEASE SURGE, FALL 2022, UNITED STATES 

José R. Romero, MD (CDC, Director NCIRD) emphasized that it was a pleasure to speak to 

ACIP in his role as Director of NCIRD. Having previously served as a member and the Chair of 

the CDC’s ACIP, he truly understands and greatly appreciates the time and effort required by its 

members to convene a meeting of the ACIP. He observed that over the course of the meeting, 

the committee would hear presentations on influenza and COVID-19 vaccines, as well as novel 

RSV vaccines. To set the scene for the next few sessions, he wanted to give a brief overview of 

the co-circulating respiratory viruses that are observed over the Winter and Fall and highlight 

how they are of critical importance in terms of vaccination. This past Fall and Winter, the US 

saw high co-circulation of respiratory syncytial virus (RSV), influenza virus, and SARS-CoV-2. 

These put significant stress on healthcare systems and the drug supply chain. After a brief and 

anticipated uptick of hospitalizations and cases around the holidays, there is now a continued 

decrease in COVID, influenza, and RSV cases and hospitalizations nationally. 

For those who are not pediatricians, he explained that RSV is a well-recognized respiratory 

pathogen of infants and a common cause of respiratory disease in older adults. In adults, RSV 

can be difficult to differentiate from COVID-19 and influenza based on symptoms alone and is 

frequently overlooked as a diagnosis for viral respiratory disease in adults. In the elderly or in 

those with certain comorbid conditions, RSV infections can be significant and life-threatening. 

Typically, adults experience mild cold-like symptoms, although some can develop a lower 

respiratory tract infection (LRTI) such as pneumonia. Older adults, adults with chronic heart and 

lung conditions or diseases, and those with weakened immune systems are at higher risk for 

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severe RSV infections. RSV is also known to lead to worsening of chronic conditions common in 

adults, such as asthma, congestive heart failure, and chronic obstructive pulmonary disease 

(COPD). Each year in the US, it is estimated that between 60,000 and 160,000 hospitalizations 

occur and 6 to 10,000 deaths result in older adults due to RSV infections. This past fall, the 

CDC surveillance team saw an increase in RSV detections, RSV-associated emergency room 

department visits, and hospitalizations, including among older adults. Current national trends for 

RSV activity indicate that it has returned to baseline levels. For seasonal influenza, the activity 

continues to decline across the country. While influenza activity is declining, it remains possible 

that a second wave may occur later in the season as it has in the past. 

CDC has responded to the increase in co-circulating respiratory viruses in multiple ways, but Dr. 

Romero thought the most important way to bring before the ACIP was that in January 2023, 

CDC released 2 new respiratory diseases surveillance dashboards that are accessible to public 

health medical professionals and the public in general. The first is the Respiratory Virus 

Hospitalization Surveillance Network (RESP-NET), which is an interactive dashboard that 

displays respiratory virus-associated hospitalizations from 3 existing surveillance platforms: 

Coronavirus Disease 2019 (COVID-19) Hospitalization Surveillance Network (COVID-NET), 

Influenza Hospitalization Surveillance Network (FluSurv-NET), and Respiratory Syncytial Virus 

Hospitalization Surveillance Network (RSV-NET). The second dashboard is the National 

Emergency Department Visits for COVID-19, Influenza, and Respiratory Syncytial Virus, which 

displays data on emergency room visits for multiple respiratory conditions as tracked by the 

National Syndromic Surveillance Program (NSSP). This dashboard presents data captured from 

approximately 75% of all emergency departments (EDs) in the US, so it is a very robust 

database. These dashboards allow users to easily see hospitalizations and ED data for these 3 

viruses by age and track and compare the trends for SARS-CoV-2, influenza, and RSV disease. 

Recent outbreaks highlight the importance of remaining vigilant about prevention. CDC 

continues to conduct outreach to clinicians, public health, and school partners and the public to 

raise awareness about the importance of vaccination for COVID-19 and influenza for everyone 

6 months of age and older. Dr. Romero noted that during the first day of this meeting, there 

would be presentations and discussion on pediatric and maternal RSV vaccines that may 

become available for the prevention of RSV-related disease in the near future. Since the 

detection of the first case of SARS-CoV-2 virus over 3 years ago, more than 1 million 

Americans, including 2,000 children, have tragically died as a result of COVID-19 infection. 

Nearly 6 million individuals have been hospitalized and many more continue to suffer from longCOVID conditions. Fortunately, due to the rapid development of safe and effective vaccines, the 

position is very different from 3 years ago. COVID-19 vaccinations have prevented millions of 

severe illnesses, hospitalizations, and deaths since their introduction in December 2020. Many 

current members of the ACIP were on the committee at that time. Now 80% of Americans have 

received at least 1 dose of the primary COVID-19 vaccine series and over 667 million doses of 

vaccine have been administered. However, despite the introduction of a bivalent booster in 

September 2022, uptake has been low with only 15% of the US population having received an 

updated booster. The numbers are even lower for pediatric patients. Vaccinations and antivirals 

continue to be the best protection against serious illness for COVID-19. 

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Unfortunately, during the COVID-19 pandemic, there was a concerning decrease in routine 

immunizations for both adults and children. Routine vaccinations are rebounding, although 

unevenly, and have yet to fully recover in all groups. A significant and extremely concerning 

example is that the percentage of uninsured children not vaccinated by their second birthday 

was recently found to be 8 times that of privately insured children. That is even in the context of 

VFC, a program that is designed to address these inequities in healthcare insurance. While 

continuing to investigate the impact of the pandemic on routine immunizations, it is imperative to 

take steps to help get everyone back on track with their routine immunizations. Everyone must 

continue to work together to improve vaccination coverage by reducing barriers, increasing 

access, and strengthening vaccine confidence. For influenza and COVID-19, safe, effective, 

licensed or authorized vaccines are currently available for the prevention of serious disease. It is 

very possible that in the not-too-distant future, Americans also may have options for the 

prevention of a third respiratory virus, RSV. With that, Dr. Romero thanked ACIP and wished 

them good luck with their deliberations and discussions. 

Discussion Points 

Before opening the floor for discussion, Dr. Lee emphasized Dr. Romero’s key points. First, 

context is everything. Many families with children and/or older adult members have had multiple 

respiratory viral illnesses this Winter. On top of that, pediatric providers had such a significant 

respiratory surge during a certain period of time, all due to multiple respiratory illnesses, they 

had to divert and redirect many of the children who were very ill and needed care. There also 

were other children who needed to come in for other reasons. This has had a major impact on 

the healthcare delivery system and families. One reason the ACIP was so grateful to Dr. 

Romero for being willing to speak about this context was that for the first time in a long time, 

ACIP had the opportunity during this meeting to review data on influenza vaccines, RSV, 

COVID-19, and pneumococcal vaccines. All of those are important preventive measures for 

ACIP to consider as part of a potential respiratory disease prevention platform. While they would 

take each of these vaccines into consideration on an individual basis, it also is important to think 

through the broader implementation context for young children and older adults to ensure that 

as the committee is making these recommendations, they also are thinking ahead about how 

these programs would be deployed in the various populations. 

In response to Dr. Loehr’s request to speak further to Dr. Romero’s revelation that the 

percentage of uninsured children not vaccinated by their second birthday was recently found to 

be 8 times that of privately insured children, Dr. Romero said that given that the VFC was in 

place and functioning well pre-pandemic, this suggests a major problem. The VFC was 

established to address barriers in access, yet this problem of lower vaccine rates has been 

particularly severe among racial and ethnic populations, rural areas, and areas experiencing 

poverty. 

Dr. Talbot expressed excitement about viral vaccines coming online for older adults, but 

lamented how complicated vaccines are for adults over 65 years of age because of Medicare. 

She asked whether any processes are in the works to streamline vaccines under Medicare Part 

B so that physicians can vaccines while patients are in the clinic. 

Dr. Wharton indicated that there have been some changes in policy with recent legislation. She 

called upon Mary Beth Hance to make some brief comments about the changes to Medicare 

vaccine reimbursement issues under Medicare Part B and D from the Inflation Reduction Act 

(IRA). 

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Mary Beth Hance (HRSA) indicated that the IRA made changes to coverage of vaccines for 

adults in Medicare. COVID-19 was added as a Part B covered vaccine. For Part D, there is no 

cost sharing for patients. Covered Part B vaccines now include influenza, pneumococcal, 

hepatitis B for individuals at high and intermediate risk, COVID-19 vaccines, and vaccines that 

are reasonable and necessary to treat an injury or exposure to a disease. There is coverage of 

ACIP-recommended vaccines with no cost-sharing under Part D. 

Dr. Romero added that while this benefits those with insurance, there is still a large population 

of adults in the US who do not have insurance. Serious consideration of a program that would 

offer vaccine to those individuals, a Vaccines for Adults (VFA) modelled in some way after the 

VFC, is something the American public needs to consider moving forward in order to catch all 

Americans up on vaccinations and make these vaccinations available to all. 

Dr. Daley asked what is known about vaccination rates for adults without insurance and if there 

is a comparable figure for influenza or COVID vaccination, and what would be required to 

establish a VFA program. 

Dr. Romero indicated that he could share specific data during the Agency Update session, but 

that rates are substantially lower for those who are uninsured. Even a co-pay can be a deterrent 

to accessing vaccines. Establishment of a VFA would need to be appropriated for within the 

President’s Budget and legislated by Congress. 

Dr. Goldman (ACP) asked whether it would be within CDC’s purview to handle certain state 

jurisdictions deliberately spreading disinformation regarding the safety and efficacy of the 

vaccines. 

Dr. Romero responded that CDC, as always, is engaged with educating the public and providing 

information that is scientifically correct and sound. It is not within the realm of CDC to actively 

involve itself within jurisdictions. Simply put, these are decisions made by the jurisdiction or 

jurisdictions involved. 

Dr. Hogue (APhA) said he was struck by the inequities that still exist in US society and 

emphasized that they should all do what they could to address them. He reported that America's 

pharmacies are having significant issues with the Part D plans and the inconsistency with which 

the Part D plans cover the administration of vaccines. They treat vaccines as drugs because 

they have a National Drug Code (NDC) number, but many of the Part D plans either try to 

bundle the administration fee with the vaccine for administration simplification or they pay very 

little or no administration fee at all. His concern is that during the pandemic, people have 

become quite dependent upon community-based pharmacies to improve access points, 

especially in rural areas of the country. If the Part D plans are not held to account by CMS to 

consistently pay a meaningful administration fee and stop clawbacks, which are very common in 

the pharmacy world for drugs, it could result in a situation of pharmacies being unable to offer 

vaccines for Medicare beneficiaries under the Part D plan in the future. Therefore, he wanted to 

raise this awareness and an alarm bell so that colleagues at CMS would work with them to try to 

correct this situation in the coming Part D Call Letter. 

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INFLUENZA VACCINE 

Introduction 

H. Keipp Talbot, MD, MPH (ACIP, WG Chair) indicated that this session would include 

presentations focused on influenza activity, interim influenza VE against inpatient, ED, and 

outpatient illness in the 2022-2023 season, interim estimates of 2022-2023 influenza VE from 2 

studies in Wisconsin, and published estimates of live attenuated influenza vaccine (LAIV). 

US Influenza Activity Update 

Lisa Grohskopf MD, MPH (CDC/NCIRD) presented a brief update of the 2022-2023 US 

influenza activity. In terms of virological surveillance data, results of influenza-positive tests are 

reported weekly to CDC from a very large network of clinical and public health laboratories. The 

percent of positive influenza tests is one of the indices of influenza activity. For 2022-2023, the 

percent of positive tests peaked in late November/early December at about 26%. The percent 

positive has been decreasing for about the 9th consecutive week to 1.7%. The peak of 26% is 

roughly comparable to other recent seasons. However, the peak shifted earlier than is typical. 

The peak also was higher than the 2 seasons immediately preceding 2022-2023. The other 

component of this system, Public Health Laboratories (PHLs), provides a sense of the influenza 

viral types and subtypes in circulation. H3N2 viruses have predominated, although there also 

has been appreciable co-circulation of H1N1pdm09-like viruses. About 99.4% of the viruses 

characterized thus far have been influenza A. Very little influenza B has been seen at this point 

in the season. 

Laboratory-confirmed influenza-associated hospitalizations come from FluSurv-NET. 

Cumulative hospitalizations have leveled off at about 59.5 per 100,000 and have stayed flat in 

recent weeks. As with the peak shift, influenza-associated hospitalization activity shifted earlier 

in the season as well. Deaths of children associated with laboratory-confirmed influenza has 

been reportable in the US since 2004. Thus far, as of the weekend ending February 11, 2023, a 

total of 111 pediatric deaths have been reported through the Fluview mechanism. This is 

unfortunately more than in 2020-2021, for which 1 pediatric death was reported and 2021-2022, 

for which 45 pediatric deaths were reported. 

To summarize influenza activity as of the week ending February 11, 2023, US influenza activity 

rose early, peaking nationally during late November/early December. The percent that tested 

positive peaked at about 26% and is currently down to about 1.7%. Influenza A(H3N2) virus has 

predominated so far with co-circulation of A(H1NI)pdm09. The cumulative influenza-associated 

hospitalization rate has leveled in recent weeks to about 59 per 100,000. A total of 111 

influenza-associated pediatric deaths have been reported thus far this season. Overall influenza 

activity is increased compared with the previous 2 seasons. US influenza activity is currently 

low. 

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Preliminary 2022-2023 Influenza Vaccine Effectiveness: CDC Networks

Samantha Olson, MPH; Nathaniel Lewis, PhD; and Mark Tenforde, MD, PhD (CDC/NCIRD) 

presented preliminary 2022-2023 influenza VE results from 3 CDC networks: New Vaccine 

Surveillance Network (NVSN), Investigating Respiratory Viruses in the Acutely Ill (IVY), and the 

VISION Vaccine Effectiveness Network. Ms. Olson explained that CDC uses these 3 networks 

to evaluate VE against laboratory-confirmed influenza-associated outpatient visits, emergency 

department visits, and hospitalization. Across all 3 networks, the methods are similar. For this 

analysis, patients were enrolled with acute respiratory illness (ARI) from Fall 2022 through early 

2023. Each study has a test-negative design comparing vaccination odds among case patients 

with influenza A confirmed by molecular assay versus control patients testing negative for 

influenza and SARS-CoV-2. Vaccination status was defined as the receipt of any 2022 through 

2023 influenza vaccine according to medical records, immunization registries, claims data, 

and/or a self-report. For each analysis, VE was calculated as (1 ─ the adjusted odds ratio) x 

100. 

The NVSN analysis calculated VE against influenza-associated hospitalizations and ED visits 

among children 6 months through 17 years of age. NVSN conducts active surveillance at 7 sites 

across the country: Seattle Children’s, Children’s Mercy Hospital Kansas City, Texas Children’s 

Hospital Houston, Vanderbilt University Nashville, Cincinnati Children’s, University of Rochester, 

and Children’s Hospital of Pittsburgh. NVSN enrolled inpatient and ED patients 6 months 

through 17 years of age with acute respiratory illness within 10 days of illness onset from 

September 13─January 25 for this analysis. A test-negative design was used in which patients 

were considered vaccinated if they received at least 1 dose regardless of their age and relied on 

verified vaccination or self-report. Logistic regression was used for this analysis, adjusting for 

site, age, and calendar time of admission. 

In terms of preliminary VE estimates against pediatric hospitalizations and emergency 

department visits among children 6 months through 17 years of age. There were 640 influenzapositive cases and 2,256 controls included in this analysis. Nineteen percent of cases versus 

33% of controls received a seasonal influenza vaccine. Overall VE was 49% among inpatients, 

with a higher-point estimate of 68% observed. Among ED visits, 42% VE was calculated. When 

stratified by subtype, effectiveness against H3N2 was 45% and against H1N1 was 56%. To 

summarize, based on preliminary estimates for the 2022─2023 influenza season, influenza 

vaccinations significantly reduced laboratory-confirmed medically-attended influenza in children. 

Effectiveness against pediatric hospitalizations was 68%. Effectiveness against pediatric ED 

visits was 42%, and important protection was observed against both H3N2- and H1N1-

associated illness. 

Dr. Lewis explained that the IVY analysis assessed VE against influenza-associated 

hospitalization among adults ≥18 years of age receiving inpatient medically-attended treatment 

for influenza. This analysis was drawn specifically from patients at 24 medical centers in 19 

states in the IVY network shown in the map below: 

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The methods used in IVY are very similar to the NVSN methods. The data rage for the analysis 

was October 1─January 31, 2023. This analysis used a test-negative case-control method that 

assessed the odds of vaccination among cases versus controls. This analysis was adjusted for 

Census region, age, sex, race/ethnicity, and month of illness onset. Fairly encouraging results 

were seen in this analysis of 219 cases who tested positive for influenza and 921 controls who 

tested negative for both influenza and SARS-CoV-2. Vaccination coverage was 31% among 

cases and 43% among controls. Overall, VE was 43% for persons ≥18 years of age. As 

expected, there was some variation by age group, with lower protection among those ≥65 years 

and older of 35% versus 51% among those 18─64 years of age. Importantly, significant 

protection was observed in the immunocompromised subgroup that was very similar to that of 

overall VE in the network, albeit with a wider and overlapping confidence interval. About twothirds of the 77 specimens analyzed through the end of 2022 were H3N2 and the remaining 

third were H1N1. The important takeaway is that influenza vaccination significantly reduced 

medically-attended hospitalized influenza at a VE of 43%. Significant protection was observed in 

the older adult population and among immunocompromised adults. 

Dr. Tenforde presented preliminary results from the VISION network on influenza VE results 

against influenza-associated hospitalizations and ED or urgent care (UC) visits. VISION is an 

electronic VE network that consists of health systems with integrated laboratory, clinical, and 

vaccination records. The 3 partners contributed data for this analysis, including Kaiser 

Permanente Northern California (KPNC), Intermountain Healthcare, and HealthPartners in 4 

states. For this analysis, encounters included ED or UC visits or hospitalizations between 

October 15─January 24, 2023 among adults ≥18 years of age who received clinical testing for 

influenza and had 1 or more ARI-associated discharge codes. Using a test-negative design, VE 

was estimated by comparing influenza vaccination odds among patients who tested positive for 

influenza A versus controls who tested negative for influenza and SARS-CoV-2. VE models 

applied inverse-propensity-to-be-vaccinated weights and adjusted for potential confounders 

including patient age, study site, and calendar time. 

Preliminary VE estimates against adult ED or UC visits were calculated for 14,011 influenzapositive cases and 43,196 influenza-negative controls included in this analysis. Twenty-three 

percent of cases versus 36% of controls had received a 2022-2023 seasonal influenza vaccine. 

Overall VE was 44% in all adults ≥18 years of age, including 46% in adults 18─64 years and 

39% in adults ≥65 years of age. A lower point estimate of 30% was seen among adults with 

immunocompromising conditions. In terms of VE estimates against adult hospitalizations, the 

analysis included 1,760 influenza-positive cases and 9,377 influenza-negative controls. Thirty37 
 

 

 

 

 

 

 

 

 

 

 

 

eight percent of cases versus 49% of controls had received a seasonal influenza vaccine. 

Overall VE was 39%, including 29% in adults 18─64 years of age and 42% in adults ≥65 years 

of age. VE was 31% among adults with immunocompromising conditions. 

In summary, through almost the end of January 2023, influenza vaccinations significantly 

reduced laboratory-confirmed medically-attended influenza with an estimated VE of 39% 

against adult hospitalizations and 44% against adult ED or UC visits. Effectiveness was 

observed across all age groups and in those with immunocompromising conditions. These 

estimates were higher than VISION Network VE estimates against hospitalization and ED or UC 

visits from the same sites during the prior 2021-2022 season when mostly vaccine mismatched 

H3N2 viruses were circulating. A limitation of this analysis was a lack of data to estimate VE by 

influenza A subtype including H1 and H3 viruses. 

In conclusion, across 3 influenza VE platforms, very consistent influenza VE was observed 

during the early 2022-2023 influenza season. Vaccination provided substantial protection 

against inpatient ED and outpatient illness across all ages. Influenza vaccination also provided 

substantial protection among important high-risk groups, including older adults and those with 

immunocompromising conditions. 

Preliminary 2022-2023 Influenza Vaccine Effectiveness: Wisconsin 

Huong McLean PhD, MPH (Marshfield Clinic Research Institute) presenting interim 

estimates of influenza VE from 2 studies in Wisconsin: A test-negative case-control study 

funded by CSL Seqirus and a community cohort study funded by CDC. The methods of the testnegative case-control study are similar to what was presented for the 3 CDC networks, except 

that the enrollees are outpatients who presented for COVID-19 testing aged 6 months through 

64 years with ARI with a cough of ≤7 days duration. Data presented are from enrollments from 

December 2, 2022 through February 10, 2023. Influenza vaccination was defined as 

documentation in the patient’s health record of current season influenza vaccine receipt ≥14 

days before illness onset according to the ACIP recommendations. VE estimates were adjusted 

for age, month of illness onset, and presence of high-risk conditions. 

Influenza positive RT-PCR results were highest at the beginning of the enrollment period in 

December and have declined since. Of the viruses, 73% were A(H3N2) and 26% 

A(H1N1pdm09). All of the 43 characterized viruses were genetically similar to the vaccine 

components. A total of 545 patients with medically-attended ARI were included in this analysis. 

Among participants, 34% were vaccinated, of whom the majority (84%) received cell-culture 

based vaccine (ccIIV4). The percentage vaccinated differed by sex, high-risk conditions, and 

COVID-19 vaccination status. Among the 116 participants positive for influenza, 22% were 

vaccinated compared to 37% of 429 participants who tested negative for influenza and SARSCoV-2. The adjusted VE against outpatient medically-attended influenza A was 54%, with a 

95% confidence interval of 23% to 73%. VE against influenza A(H3N2) viruses was 60%, with a 

95% confidence interval of 25% to 79%. 

The prospective community cohort study is an ongoing study in Central Wisconsin of 241 

children who have been followed weekly since September 5, 2022. Each week, children or their 

guardians report the absence or presence of the following symptoms over the past 7 days: 

fever, cough, loss of smell or taste, sore throat, muscle or body aches, shortness of breath, 

diarrhea, nasal congestion or runny nose, or nausea or vomiting. New symptom onset prompts 

self- or guardian-collection of anterior nasal swab for influenza and SARS-CoV-2 research 

testing. Other relevant information collected from surveys and extracted from EHRs include 

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vaccination history and clinic influenza test results. To estimate VE against symptomatic 

influenza infection in the cohort, a Cox proportional hazards model was used with time-varying 

vaccination status. The at-risk window began October 23, 2022 (7 days before the first case 

was identified) and ended February 10, 2023 (positive influenza infection date)—whichever 

occurred first. Vaccinated person time began ≥14 days after receipt of the influenza vaccine. 

Unvaccinated person-time was the time before receipt of influenza vaccine. Person-time was 

censored for the 13 days after receipt of influenza vaccine. An influenza case was defined as a 

positive influenza result from a research or clinical test during the at-risk period. VE 

effectiveness was calculated as 1 minus the adjusted hazards ratio x 100% where the hazards 

ratios represented the ratio of influenza infections in the vaccinated to unvaccinated persontime. The model adjusted for age, higher at-risk condition, and COVID-19 vacation. Among the 

241 children in the cohort, 39% were vaccinated, of whom 84% received ccIIV4 and 65% 

received 2 or more doses of COVID-19 vaccine. A total of 34 (14%) of children were positive for 

influenza. 

In terms of influenza and SARS-CoV-2 infections by week of onset, influenza incidence was 

highest late November and early December and has declined since. Of the influenza infections, 

85% were caused by A(H3N2), 3% were caused by A(H1N1pdm09), and the remaining 12% 

were influenza A with unknown subtype. The characterized A(H3N2) viruses in this population 

were genetically similar to the vaccine component. Regarding VE against symptomatic influenza 

among children, there were 6 influenza A infections during the 7,292 vaccinated person days of 

follow-up, resulting in an incidence of 0.82 infections per 1,000 person-days. A total of 28 cases 

occurred during the 15,678 unvaccinated person-days, resulting in an incidence of 1.79 

infections per 1,000 person days. VE against symptomatic influenza A virus infection was 71% 

with a 95% confidence interval in 31% to 90% among children in this cohort. 

There are several limitations to consider for these studies. First, both studies were conducted in 

a single geographic area, Central Wisconsin. However, the viruses that predominated in the 

study population was similar to those that predominated across the US. Second, adults ≥65 

years of age who generally have lower VE estimates against A(H3N2) were excluded. Third, the 

sample sizes were small. This resulted in wide confidence intervals, so it was not possible to 

estimate VE against A(H1N1pdm09) or by age groups. Finally, confounding and bias are 

concerns with observational studies. However, estimates were comparable across the 2 study 

designs. 

To summarize, interim results indicate substantial vaccine-induced protection against influenza 

A during the current season. VE effectiveness was 54% against medically-attended influenza A 

in children and working-age adults and 71% against symptomatic influenza A infection in 

children. These estimates are consistent with reported estimates from the 4 CDC networks and 

in Canada and are consistent with a good vaccine match. All characterized viruses from the 

study population belong to the same genetic subclade as the viruses included in the 2022-2023 

Northern Hemisphere influenza vaccine. 

Update on Published Estimates of LAIV4 Effectiveness: Background 

Lisa Grohskopf MD, MPH (CDC/NCIRD) presented a brief update of published estimates of 

live attenuated influenza vaccine (LAIV) effectiveness, noting that these are not CDC data. 

LAIV4, the quadrivalent LAIV, was initially approved in the US in 2012 and came into use during 

the 2013-2014 season after having had a trivalent formation available since 2003 in the US. 

LAIV4 was not recommended in the US for use during the 2016-2017 and 2017-2018 seasons 

following observation of low effectiveness specifically against H1N1pdm09-like viruses among 

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children 2─17 years of age that was noticed during the 2013-2014 season and during the 2015-

2016 season, both of which had some H1N1 predominance. It was not clear what was going on 

when this first was noticed. The 2013-2014 season was the first H1N1-predominant season that 

had occurred since the 2009 influenza pandemic. It also was the first season the quadrivalent 

product was available. However, subsequent studies suggested decreased replicative fitness of 

the LAIV4 H1N1pdm09-like vaccine virus. Live virus vaccine such as this requires replication of 

the virus in the nasopharyngeal mucosa in order to be effective. Following those studies, the 

vaccine virus was updated and replaced in the vaccine. LAIV4 was again a recommended 

option in the US starting in 2018-2019 after a discussion of 3 streams of data during the 

February 2018 ACIP meeting. These included a combined US individual patient level VE 

analysis that consisted of data from several US sources, a systematic review of post-2009 US 

and non-US LAIV VE estimates, and MedImmune data on the new H1N1pdm09-like vaccine 

virus that indicated a better immunogenicity and fitness of that new virus. 

Unfortunately, subsequently LAIV4 use within the CDC US VE networks has been low since the 

2018-2019 season, which has precluded assessment of vaccine-specific VE in the US from 

these networks. However, LAIV VE estimates have been published from non-US observational 

studies.16 For comparison, an effort was made to pool from the same papers where available, 

either IIV inactivated vaccine quadrivalent VE estimates, or if such were not available, estimates 

for all vaccines. These estimates are all for children for whom the age groups vary somewhat, 

given that they represent the age groups for whom vaccine was licensed. Starting with Finland 

for 2018-2019, LAIV4 VE estimate for children 2─6 years of age was 36% and VE for IIV4 for

children 6 months─6 years of age was 54%. For UK, 2018-2019 VE for LAIV VE was 49% for 

children 2─17 years of age and 53% for all vaccines in this same age group. For 2019-2020, 

estimated LAIV4 VE of 45% was reported in the UK for children 2─17 years of age. For 2021-

2022, estimated LAIV4 VE of 72% was reported in the UK for children 2─17 years of age. For 

2021-2022 in Denmark, VE for all vaccines among non-hospitalized children 2─6 years of age 

was 64% and was 63% for hospitalized children of the same age. This paper notes that these 

children were offered LAIV4, which 92% received. Others received inactivated vaccine, so these 

are predominantly LAIV4 estimates. 

ACIP Discussion Points, Observations, Suggestions on Influenza Vaccine 

Following Dr. Grohskopf’s First Presentation 

• Regarding questions about whether the pattern of the 111 pediatric death cases was 

similar to prior years with 50% having no co-morbidities, Dr. Grohskopf indicated this 

was not yet known for this season. It takes a while for this information to come in, but the 

50% that was published in a 2018 paper from her group is fairly typical. 

• In terms of questions about why influenza began and peaked so early this season, Dr. 

Grohskopf noted that influenza seasons are unpredictable, and this is not the first time 

an early influenza season has occurred. She referred to a chart on the CDC webpage 

that covers about 39 influenza seasons to date that shows a couple of seasons that 

peaked as early as October. 

• The hospitalization rate seems somewhat low despite the brisk influenza season, which 

raised questions about whether this was due to better diagnostics and therapeutics 

and/or better recognition of viral disease. Dr. Grohskopf indicated that this cannot be 

discerned form the type of data that come from that system, but it is certainly plausible to 

16 A) Stuurman et al Vaccine 2020;38:6455-64632; B) Pebody, Vaccine 38 (2020) 489–4; C) Stuurman et al Vaccine 2021;39:3964-

3973; D) https://webarchive.nationalarchives.gov.uk/ukgwa/20220401215804/https://www.gov.uk/government/statistics/annual-flureports; E) https://www.gov.uk/government/statistics/annual-flu-reports/surveillance-of-influenza-and-other-seasonal-respiratoryviruses-in-winter-2021-to-2022; and F) Emborg, Euro Surveill2022;27:pii=2200278 

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think that people have a lower index of wanting to get checked by a medical provider 

given all that everyone has been through over the last couple of years. Certainly, 

influenza seasons vary in severity. H3N2 seasons are generally more severe than 

H1N1, and there appears to be a reasonably good vaccine match. 

Following Presentations by Ms. Olson, Dr. Lewis, and Dr. Tenforde 

• Regarding an inquiry about what percentage of persons ≥65 years of age in the IVY and

VISIONS studies received the preferentially recommend high-dose vaccine, Dr. 

Tenforde indicated that most persons 18─64 years of age received standard-dose 

inactivated quadrivalent vaccines and the majority (90%) of individuals ≥65 years of age

received either a high-dose vaccine or adjuvanted vaccine product. Dr. Lewis added that 

while they are awaiting more complete product data for IVY, the breakdown in the past 

has been similar with the majority of persons 18─64 years of age receiving standarddose inactivated quadrivalent vaccines and the majority (90%) of individuals ≥65 years

of age receiving some type of enhanced vaccine product. 

• With regard to an inquiry about how many children received LAIV, Ms. Olson indicated 

that LAIV uptake has been low within the NVSN Network facilities. 

• In terms of why SARS-CoV-2 was excluded from the analyses and if that changed the 

comparisons to past years, Dr. Tenforde indicated that patients had to be negative for 

influenza and SARS-CoV-2 to be part of this analysis. Most patients who received 

influenza testing also received testing for SARS-CoV-2. The reason they were excluded 

as controls was because there is a potential for a confounding relationship where receipt 

of influenza vaccination is correlated with receipt of COVID-19 vaccination. Essentially, 

controls can be enriched with patients who had COVID-19 and potentially bias VE 

estimates. 

• It is important to highlight that among the pediatric deaths, only about 22% were fully 

vaccinated with 2 doses. 

• With respect to whether the WG is aware of any new influenza vaccines on the horizon 

with less disappointing efficacy, Dr. Talbot pointed out that everyone would like to find 

the Holy Grail. A unique aspect of influenza infection in adults is that adults have been 

exposed to RSV and influenza many times in their lives. Yet, the vaccine is still being 

expected to do something that the human immune system has not figured out. There are 

multiple components to this, including the aging immune system, the changing virus, and 

the vaccines primarily induce a B-cell response. There is some T-cell response, but 

there is very little internal protein in current vaccines that would stimulate the T-cells. 

While many scientists including herself are looking for a universal influenza vaccine, they 

still have the vaccine that was developed originally for military recruits. It is somewhat 

cleaner and less reactogenic than it was when it was first discovered, and it still prevents 

a fair number of hospitalizations and deaths each year. Therefore, it will continue to be 

used until the Holy Grail appears. 

Following Dr. McClean’s Presentation 

• The prospective cohort study is intriguing. The incidence per 1,000 person-days of 0.82 

for the vaccinated and 1.79 for unvaccinated persons results in approximately 1 per 

1,000 person days. Based on a 3-month influenza season, the number needed to 

vaccinate (NNV) would be 10 people to prevent 1 illness. 

• Notably, the test-negative case-control study began in December and likely missed 

some cases due to the early start of the influenza season. 

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Following Dr. Grohskopf’s Second Presentation 

• Notably, the measures, definitions, and criteria vary in the non-US studies. Dr. 

Grohskopf emphasized that some variations are expected because there are variations 

in matches from season-to-season and in methods, especially among observational 

studies. 

• There appears to be a theme that this vaccine is unlike Coronavirus vaccine in that it 

does not seem to protect better against worse outcomes. It may be somewhat different 

for ARI and hospitalization, but not as dramatically. It was not clear whether this was real 

or the way that people are being investigated. Dr. Grohskopf said that to be completely 

honest, she was not sure. Much of the data she is familiar with on prevention of severe 

outcomes focuses more on influenza vaccines broadly, while she was less familiar with 

the specifics on LAIV. She will look this up and provide a response at a later time. 

• One of the major challenges that will need to be addressed is that because people are 

able to test themselves at home, they may be less likely to go to their doctor. Those who 

do present to medical settings are getting multiplex testing. As more point-of-care 

diagnostics move into the home setting, consideration will have to be given to how 

meaningful surveillance can continue to be conducted in that context. These data are 

needed in order to continue to ensure the benefit-risk balance of prevention programs. 

• It would be beneficial to include LAIV information in any publications regarding VE, given 

that many parents have questions and would like to see these data. 

PNEUMOCOCCAL VACCINES 

Introduction 

Katherine A. Poehling, MD, MPH (ACIP WG Chair) reminded everyone that pneumococcal 

vaccines currently recommended for use in the US include PCV13 and PCV20 for adults. 

PCV13 and PCV15 are recommended for children. PPSV3 has a risk-based recommendation 

for children. PPSV3 is recommended for adults who previously received PCV13 or PCV15, but 

not for those receiving PCV2020. The goal is to move forward with fewer differences. As a 

reminder, all children under 2 years of age have the same pneumococcal vaccine 

recommendation for 3 primary series and a booster, often known as the 3 + 1 schedule. The 

primary series doses are administered at 2, 4, and 6 months and the booster is given at 12 to 15 

months later. Currently, either PCV13 or PCV15 can be given to US children. Children with 

certain underlying conditions are recommended to receive PPSV23. Children with chronic 

medical conditions (CMC), cerebrospinal fluid (CSF) leak, and cochlear implants are 

recommended to receive PPSV23 ≥8 weeks after the conjugate vaccine. Children with 

immunocompromising conditions are recommended to receive PPSV23 ≥8 weeks after the 

conjugate vaccine. Then ≥5 years later, a second dose of PPSV23 is recommended. Children 

6─8 years of age with CMC can receive PPSV23 if they did not receive pneumococcal 

conjugate vaccine. Of note, CMC includes chronic heart disease (CHD), chronic lung disease 

(CLD),and diabetes mellitus (DM). 

Approval of PVC20 use among children is anticipated later this year. It is anticipated that later in 

Quarter 2 of 2023, pediatric PCV20 will be approved. Pediatric PCV15 use was approved in 

June 2022. With that in mind, the WG is considering the following policy questions: 

 Should PCV20 be recommended as an option for pneumococcal conjugate vaccination 

according to currently recommended dosing and schedules for US children aged <2 years? 

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 Should PCV20 without PPSV23 be recommended as an option for pneumococcal

vaccination for US children aged 2─18 years of age with underlying medical conditions that

increase the risk of pneumococcal disease?

Presentations during this session focused on the epidemiology of pneumococcal disease 

among US children, pediatric outpatient ARI visits and antibiotic use attributable to serotypes in 

higher valency pneumococcal conjugate vaccines, PCV20 Phase 2/3 study results among 

children, preliminary EtR for PCV20 use in children, and WG considerations and next steps. 

Epidemiology of Pneumococcal Disease among US Children 

Ryan Gierke, MPH (CDC/NCIRD) presented an update on the current epidemiology of pediatric 

pneumococcal disease in the US, beginning with a background on the spectrum of 

pneumococcal disease. Pneumococcus is transmitted through airborne droplets from person-toperson. It can colonize in the nasopharynx and can be spread locally to the ears to cause otitis 

media. It also can be aspirated and cause pneumonia. Pneumococcus also can infect the blood 

and cause septicemia. These different infections can be characterized as either noninvasive 

disease or invasive disease. Invasive pneumococcal disease (IPD) is a less frequent but severe 

form of the illness. Noninvasive disease is more frequent. In children, otitis media is one of the 

most common forms of pneumococcal disease. Note that pneumococcal pneumonia can be 

either invasive or noninvasive, depending on whether a sterile body site like blood becomes 

infected in addition to the lungs. 

This presentation focused on: 1) IPD data in terms of the impact of pneumococcal conjugate 

vaccines (PCVs) and IPD incidence and serotype distribution; IPD incidence caused by 

serotypes covered in the new conjugate vaccines, PCV15 and PCV20; and changes in IPD 

incidence and serotype distribution resulting from the COVID-19 pandemic; 2) the impact of 

PCV13 on acute otitis media (AOM) and incidence estimates; and 3) the impact of PCV13 on 

all-cause and pneumococcal pneumonia in children and recent estimates of pneumonia 

incidence. 

In terms of the impact of pneumococcal conjugate vaccines on pediatric IPD incidence and 

serotype distribution among children in the US, data on IPD are obtained from the Active 

Bacterial Core (ABCs) surveillance system, which provides population-based surveillance at 10 

sites across the US. Those are defined as pneumococcus-isolated from a normally sterile site in 

residents of the 10 surveillance areas shown in the map below: 

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Isolates are serotyped at reference laboratories using whole-genome sequencing (WGS), 

Quellung, or PCR at reference laboratories. For analysis purposes, serotypes are grouped by 

vaccine types. US Census Bureau estimates were used as denominators to calculate incidence 

rates for overall and serotype-specific IPD and are presented as cases per 100,000 persons. 

From 1998─2019, before introduction of conjugate vaccines in the US, incidence rates of IPD 

among children <5 years of age were approximately cases per 100,000 persons. PCV13-type 

IPD caused the majority of disease. Note that 6C included with the PCV13 serotypes due to 

cross-protection provided from the 6A antigen included in the vaccine. After the introduction of 

PCV7 in 2000, rates of IPD declined significantly. There were additional declines in disease 

following PCV13 introduction in 2010. Around 2013, declines in PCV13-type IPD rates 

plateaued at <2 cases per 100,000. This trend continued onward through 2019. Rates of overall 

IPD are now <10 cases per 100,000 persons, with much of the remaining disease caused by 

non-PCV13 serotypes. 

Focusing on more recent years from 2007─2021, the COVID-19 pandemic resulted in a 50% 

reduction in rates of overall IPD in 2020 compared with 2018─2019. However, rates began to 

rebound in 2021 with a 30% increase compared to 2020 rates. Data for 2022 are not yet 

finalized, but looking at 2021 data by month, the monthly rates of IPD were back to the prepandemic levels after around August 2021. IPD rates were examined for individual serotypes in 

PCV13 among children <5 years of age from 2011─2021. After PCV13 introduction in children, 

rates of IPD declined for many PCV13 serotypes. However, reductions were not seen in 

serotypes 3 or 19F. Together, these serotypes accounted for almost 80% of remaining PCV13-

type disease in 2018 and 2019. The impact of the COVID-19 pandemic led to a change in the 

serotype distribution of PCV13-type disease. In 2020 and 2021, serotype 19F rebounded 

quickly and now accounts for the majority of remaining disease, while the proportion caused by 

serotype 3 has declined. This will continue to be monitored to determine whether these changes 

continue. 

Now to review the current pediatric IPD burden among PCV15 and PCV20 serotypes, this table 

shows the serotypes contained in the 3 conjugate vaccines and PPSV23. Serotypes covered by 

PCV13 are shown in yellow; additional serotypes covered by the new conjugate vaccines, 

PCV15 and PCV20, are shown in green; and PCV15 contains the 13 serotypes included in 

PCV13 plus serotypes 22F and 33F: 

For analysis purposes: 

 PCV13+6C: includes serotype 6C with PCV13 types due to cross protection from 6A antigen

 PCV15 non-PCV13: includes serotypes 22F and 33F

 PCV20 non-PCV15: includes serotypes 8, 10A, 11A, 12F, and 15B

 PPSV23 non-PCV20: includes serotypes 2, 9N, 17F, and 20

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Rates of IPD incidence among children <5 grouped by vaccine type from 2011─2021 remained 

relatively stable for PCV15/non-PCV13 and PCV20/non-PCV15 serotypes in recent years 

before the COVID-19 pandemic. Although rates of IPD were lower in 2020 and 2021, PCV15/ 

non-PCV13 and PCV20/non-PCV15 serotypes still account for a similar proportion of IPD at 

around 15% each. There has been great variability over the years among children 5─18 years

of age, which is likely due to having much fewer number of cases. Unlike what was observed for 

younger children, IPD did not start to rebound in 2021 among children 5─18 years of age. 

Children with immunocompromising conditions are at increased risk of IPD. In terms of IPD 

among children with select immunocompromising conditions, children <5 years of age with a 

hematologic malignancy had rates of IPD around 230 times higher than children without a 

hematologic malignancy. African-American children with sickle cell disease had rates of IPD at 

around 30 to 70 times higher than African-American children without sickle cell disease, 

depending upon their age. Among children with immunocompromising conditions, a higher 

proportion of IPD is caused by non-vaccine serotypes compared to children without 

immunocompromising conditions. 

To review the impact of PCV13 on AOM and available data on incidence estimates for AOM,17 

AOM is a major cause of childhood morbidity and pneumococcus is a common cause of AOM, 

accounting for around a quarter of bacterial AOM. Studies have shown that AOM incidence has 

decreased after PCV13 introduction, with declines ranging from 11% to 14% depending on the 

age groups and years examined. AOM estimates vary among studies, but incidence is 

consistently highest among children <5 years of age. 

Regarding the data on the impact of PCV13 on all-cause and pneumococcal pneumonia and 

estimated incidence of pneumonia in children, multiple studies have shown reductions in allcause and pneumococcal pneumonia among children following introduction of PCV13. 

Reductions in all-cause pneumonia range from 17% to 35% among children, depending on the 

age group, with reductions largest among children <2 years of age. There was an estimated 

40% reduction in pneumococcal pneumonia among children <1 year of age and a 51% 

reduction in pneumonia among children 5─17 years of age. To summarize all-cause pneumonia 

and all-cause inpatient pneumonia incidence estimates in cases per 100,000 person years 

among children, pneumonia incidence is lower than AOM incidence but higher than IPD 

incidence. Again, the highest incidence is observed among children <5 years of age. 

In conclusion, the use of PCVs has significantly decreased the incidence of pneumococcal 

disease in US children. However, risk of disease remains higher among children with 

immunocompromising conditions compared to those without. In 2018 and 2019, the proportion 

of IPD caused by vaccine serotypes was about 15% of IPD for PCV15/non-PCV13 serotypes 

and about 30% of IPD for PCV20/non-PCV13 serotypes. 

17 Tong et al. BMC 2018; King et al. ASHE 2021; Casey et al Clin Pediatr 2014; Kaur et al. EJCMID 2022 

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Estimating the Impact of Higher-Valency PCVs on Pediatric Outpatient ARI Visits and 

Antibiotic Use 

Laura King, MPH (UC Berkeley) presented results from a University of California Berkeley 

study estimating pediatric outpatient ARI visits and antibiotic use attributable to serotypes in 

higher valency PCVs. This presentation focused on pediatric outpatient visit and antibiotic 

prescription incidence, AOM vaccine serotype attributable proportion and incidence, and 

sinusitis and pneumonia vaccine serotype attributable proportion and incidence. In terms of 

background, ARIs account for a large proportion of all outpatient visits and antibiotic 

prescriptions among children. Previous work looking at a commercially-insured population 

established that there were over 1,200 ARI visits per 1,000 children in 2018.18 A separate study 

established that there were about 250 ARI-associated antibiotic prescriptions per 1,000 children 

issued from US doctors’ offices and EDs per year in 2014 and 2015.19 Streptococcus 

pneumoniae (S. pneumoniae) is a known etiology of several ARIs, including AOM, sinusitis, and 

pneumonia. However, the contribution of pneumococcus to the total burden of these conditions 

and the visits and antibiotic prescriptions associated with them is still unknown. 

Time series data demonstrate decreases in outpatient visits and antibiotic use associated with 

PCVs. A previously published study examining the number of all antibiotic prescriptions per 

1,000 persons stratified by age group20 showed that the rate of antibiotic prescriptions 

decreased from 2011 to 2014, coinciding with uptake of PCV13 after its introduction in 2010. 

This decrease was especially pronounced in children <2 years of age, the age group eligible for 

vaccination. In considering PCV20 and PCV15 for pediatric use, it is important to better 

understand the potential impacts of these higher valency vaccines on outpatient visits and 

antibiotic use. This was the impetus for the current study with an overall objective to estimate 

the incidence of pediatric outpatient visits and antibiotic prescriptions for AOM, sinusitis, and 

pneumonia caused by S. pneumoniae serotypes found in the new higher valency PCVs, PCV15 

and PCV20. This study focuses on the additional serotypes in PCV15 and PCV20 that are not in 

PCV13 to quantify the additive potential of these vaccines. These are referred to as PCV20-13 

and PCV15-13 serotypes. 

The study focuses specifically on AOM, abbreviated AOM, sinusitis, and pneumonia as these 

are ARIs with established pneumococcal involvement. The overall study objective is composed 

of two parts, which are to: 1) estimate the incidence of all-cause visits and antibiotic 

prescriptions for these conditions; and 2) estimate the proportion of outpatient disease caused 

by PCV15-13 and PCV20-13 serotypes. Multiplying the results from these 2 components will 

provide the incidence of visits and antibiotic prescriptions for these conditions attributable to 

PCV15-13 and PCV20-13 serotypes. 

Beginning with the first project component to estimate all-cause visit and antibiotic prescription 

incidence for AOM, pneumonia, and sinusitis, 2 data sources were used to capture visits and 

antibiotic prescriptions across all outpatient settings in the US. Visits to and antibiotic 

prescriptions from physician offices and EDs were estimated using the National Ambulatory 

Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey 

(NHAMCS). These are nationally representative surveys administered by CDC’s National 

Center for Healthcare Statistics (NCHS). Data were used from 2016 and 2018, as later years 

and in 2017 were not available in NAMCS at the time of the analysis. Because NAMCS and 

18 King LM, et al. Antimicrob Steward Healthc Epidemiol. 2021;1(1):1-8. doi: 10.1017/ash.2021.230 19 Hersh AL, et al. Clin Infect Dis. 2021;72(1):133-137. doi: 10.1093/cid/ciaa667 20 King et al., Clin Infect Dis. 2020; 70(3):370-377). doi: 10.1093/cid/ciz225 

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NHAMCS only cover physician offices and EDs, the MarketScan Commercial and Medicaid 

Databases were used to estimate visits and prescribing in alternative outpatient settings such as 

urgent care and retail health clinics. In both datasets, a single diagnosis was assigned to each 

visit using an established tiered methodology that prioritizes diagnoses most likely to result in an 

antibiotic prescription. All incidence estimates were standardized per 1,000 person-years at risk 

and total incidence was estimated by combining the sum of the estimates from NAMCS, 

NHAMCS, and MarketScan. Using those methods, total incidence of outpatient visits for all 3 

conditions was estimated to be 208 visits per 1,000 person-years. Total incidence of outpatient 

antibiotic prescriptions was estimated to be 181 prescriptions per 1,000 person-years. Notably, 

overall incidence was driven primarily by AOM. 

In terms of the second project component and estimating vaccine serotype attributable 

proportions and incidence, it is important to note that there are several major challenges in 

evaluating pneumococcal and serotype-specific contributions to outpatient disease. First, 

children are frequently colonized with pneumococcus. Published estimates of nasopharyngeal 

pneumococcal carriage range from 11% to 60% in healthy children from high-income countries. 

Second, samples from infection sites are not regularly obtained for outpatient pneumococcal 

disease. There are some studies using samples of middle ear fluid in children with AOM. 

However, the children sampled in these studies often have severe or recurrent disease. Third, 

few studies have been conducted for non-AOM ARIs in pediatric outpatients. 

Given these challenges, 3 methods were used to estimate the proportion of outpatient AOM 

attributable to PCV15-13 and PCV20-13 serotypes. All of these methods have their own 

limitations, and no one method is likely definitive. However, using multiple methods allowed for 

estimation of ranges of likely values, taking into account the uncertainties inherent in estimating 

etiology in outpatient disease. For all methods, previously published data were used to generate 

estimates. The first method used was a vaccine probe approach. In vaccine probe studies, VE 

against vaccine type in all-cause disease is used to estimate the proportion of disease 

attributable to a specific pathogen, in this case, the vaccine serotypes. The second approach 

used considered pneumococcal prevalence and serotype distribution for middle ear fluid 

sampled from children with AOM to estimate attributable proportions. The third approach used 

differential nasopharyngeal carriage prevalence in children with AOM and healthy children to 

estimate the pneumococcal attributable proportion and combined this with the distribution of 

serotypes and carriage in children with AOM. 

Using these 3 methods, pneumococcus was estimated to account for 14% to 22% of outpatient 

AOM cases, PCV15-13 serotypes accounted for 0.7% to 1% of outpatient AOM, and PCV20-13 

serotypes accounted for 3.7% to 5.1% of outpatient AOM. The highest attributable percents 

were observed from the approach using pneumococcal prevalence and serotype distribution in 

middle ear fluid. Regardless of method, the distribution of vaccine serotype groups remained 

fairly constant, with PCV20-13 serotypes accounting for about 5 times the proportion of 

outpatient disease covered by PCV15-13 serotypes. Using these attributable percents and the 

all-cause AOM visit and prescription incidence data presented earlier, incidence was estimated 

for outpatient visits per 1,000 person-years and the annual number of outpatient AOM visits in 

children. It was estimated that 76,000 to 109,000 visits per year were attributable to PCV15-13 

serotypes and 397,000 to 543,000 visits were attributable to PCV20-13 serotypes. Looking at 

the same data for AOM-associated antibiotic prescriptions, PCV15-13 serotypes were 

associated with 65,000 to 93,000 outpatient antibiotic prescriptions annually and PCV20-13 

serotypes were associated with 340,000 to 464,000 outpatient antibiotic prescriptions annually. 

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Regarding the attributable proportion and incidence estimates for pneumonia and sinusitis, less 

data were available for these conditions. The ability to estimate attributable proportions in 

pneumonia and sinusitis was limited to the vaccine probe and differential carriage approaches. 

Using these methods, 12% to 18% of pediatric outpatient pneumonia were estimated to be 

attributable to pneumococcus. PCV15-13 serotypes accounted for less than 1% of outpatient 

pediatric pneumonia cases and PCV20-13 serotypes accounted for 2.8% to 4.4% of outpatient 

pediatric pneumonia cases. The attributable proportions were multiplied by the all-cause visit 

and antibiotic prescription estimates presented earlier, which estimated that PCV15-13 

serotypes accounted for 9,000 to 14,000 visits and 7,000 to 11,000 antibiotic prescriptions for 

outpatient pediatric pneumonia per year. PCV20-13 serotypes account for 43,000 to 68,000 

visits and 34,000 to 53,000 antibiotic prescriptions for outpatient pediatric pneumonia per year. 

For sinusitis, it was estimated that 12% to 30% of all outpatient pediatric cases were attributable 

to pneumococcus. PCV15-13 serotypes accounted for 0.6% to 1.5% of sinusitis cases and 

PCV20-13 serotypes accounted for 2.8% to 7.3% of sinusitis cases. The differential carriage 

estimates were the same for pneumonia and sinusitis because the same estimates were used 

for all non-AOM ARIs in that approach given the scarcity of data. For sinusitis, it was estimated 

that PCV15-13 serotypes accounted for 17,000 to 44,000 visits and 16,000 to 43,000 antibiotic 

prescriptions per year. PCV20-13 serotypes accounted for 82,000 to 216,000 visits and 79,000 

to 209,000 antibiotic prescriptions per year. 

To summarize the ranges of point estimates for each condition by vaccine serotype group 

estimated using the multiple methods described earlier, for all 3 conditions, PCV15-13 

serotypes accounted for 1.9% to 3.4% of outpatient disease in children, translating to 103,000 to 

168,000 pediatric outpatient visits and 90,000 to 148,000 outpatient antibiotic prescriptions 

annually in the US. PCV20-13 serotypes account for 9.4% to 16.8% of outpatient AOM, 

pneumonia, and sinusitis, translating to 527,000 to 831,000 pediatric outpatient visits and 

458,000 to 731,000 outpatient antibiotic prescriptions annually in the US. 

This study had several limitations. First, it relied upon previously published data to estimate 

attributable proportions. Consequently, although data on pneumococcus in all outpatient 

conditions was limited, this was especially true for sinusitis and pneumonia. Therefore, it was 

necessary to rely on AOM as a proxy for these conditions in some cases. Additionally, due to 

data limitations at the time of the analysis, the incidence estimates were based on all-cause 

incidence data from 2016─2018. Finally, it was assumed that healthcare utilization was constant 

across serotypes for outpatient disease. 

In conclusion, this study estimated that the additional serotypes included in PCV15 and PCV20 

accounted for approximately 100,000 to 830,000 outpatient visits and 90,000 to 730,000 

outpatient antibiotic prescriptions for AOM, pneumonia, and sinusitis in US children annually. 

Specifically, PCV15-13 serotypes accounted for 103,000 to 168,000 visits and 90,000 to 

148,000 antibiotic prescriptions. PCV20-13 serotypes account for 527,000 to 831,000 visits and 

458,000 to 731,000 antibiotic prescriptions. The percent of outpatient disease attributable to 

PCV20-13 serotypes was greater than the percent attributable to PCV15-13 serotypes. As a 

result, the estimated incidence of outpatient pediatric visits and antibiotic prescriptions 

attributable to PCV20-13 serotypes was 4 to 5 times that attributable to PCV15-13 serotypes. 

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PCV20 Phase 2/3 Study Results among Children 

Wendy Watson, MD (Pfizer) presented key results from Pfizer’s PCV20 Pediatric Clinical 

Development Program from the Phase 2/3 trial. PCV20 is built on the 20-plus year legacy of 

PCV7 and PCV13. PCV20 contains all of the components of PCV13, with 7 additional 

conjugates. Pfizer is seeking to expand PCV20 currently licensed in adults to include the same 

pediatric indications as PCV13. PCV20 builds upon the clinical experience of previous 

generations of PCV7 and PCV13. PCV7 was licensed based on a randomized controlled clinical 

(RCT) efficacy trial of IPD in California. In this study of 38,000 infants, high efficacy was 

demonstrated. Subsequently, high VE was shown following PCV7 introduction. When PCV13 

was developed to expand protection against 6 additional serotypes, it was not considered 

feasible to perform an efficacy trial. Therefore, a licensing pathway similar to other vaccines, like 

a conjugate vaccine, was pursued. Immunogenicity bridging comparing PCV13 to PCV7 was 

used to support licensure globally. Similarly, PCV20 licensure for pediatrics will be based on 

immunogenicity bridging with non-inferiority comparisons to PCV13—a vaccine that now has 

more than 10 years of demonstrated effectiveness against disease due to vaccine serotypes. 

This table shows the studies Pfizer submitted to the FDA to support the PCV20 pediatric 

indication: 

These pediatric studies were generally modeled on the PCV13 pediatric studies and consisting 

of Phase 2 and Phase 3 studies. The studies listed in the table were conducted in children in the 

US, including Puerto Rico, except for the safety study on the bottom row that also included 

infants from other countries. For this presentation, Dr. Watson focused on the pivotal 

immunogenicity study in infants in the second row and the single dose study in children in the 

third row. 

The Phase 3 pivotal infant trial was a multi-center, randomized, double-blind study enrolling 

infants in the US, including Puerto Rico. The study enrolled approximately 2,000 participants 

who were randomized equally to receive 4 doses of PCV20 or PCV13. PEDIARIX and HIBERIX 

were given concomitantly with the first 3 doses and MMR and varicella vaccines were given with 

the fourth dose. Influenza and rotavirus vaccines were permitted to be given with study vaccine 

in age-eligible participants. Blood was collected for immunogenicity assessments 1 month after 

the third dose, before the fourth dose, and 1 month after the fourth dose. The primary study 

objectives were to: 1) describe safety; 2) evaluate the immunogenicity of PCV20, including noninferiority comparisons of PCV20 to PCV13; and 3) assess responses of specific concomitantly 

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administered vaccines. In terms of the disposition and demographics of the study population, 

the groups were well-balanced with respect to sex, race, and ethnicity. 

PCV generate complex and diverse cellular and humoral immune responses that play a role in 

imparting protection. The primary and key secondary objectives that were agreed to 

prospectively with the FDA include 2 co-primary objectives to assess noninferiority of 

immunoglobulin G (IgG) geometric mean concentrations (GMCs) after the toddler dose and 

assess noninferiority of the percentage of participants with IgG above predefined levels after the 

infant series. The key secondary objective was to assess noninferiority of IgG GMC after the 

infant series. Other aspects of the responses also were assessed, including other IgG 

responses, functional antibodies measured as opsonophagocytic activity (OPA) titers, and 

boosting of IgG and OPA antibody levels that are indicative of immune memory. The 

assessment of the totality of data for serotypes that missed non-inferiority was agreed to 

prospectively by the FDA. An example of how important this assessment is comes from the 

previous experience with PCV13 and serotypes 6b and 9b. These 2 serotypes missed a coprimary objective for non-inferiority compared to PCV7, but the totality of immunogenicity data 

supported licensure and subsequent real-world effectiveness has shown that PCV13 protects 

against IPD caused by these two serotypes. 

For the co-primary objective percentage of participants with the predefined IgG concentration 

after dose 3, non-inferiority was declared if the 95% confidence interval of the difference was 

greater than -10%. The additional 7 serotypes were compared to the lowest result in the PCV13 

group, excluding serotype 3. In this case, the comparison was to serotype 23F result in the 

PCV13 group. For this objective, non-inferiority was met for 14 serotypes and 6 serotypes 

missed non-inferiority, although serotypes 1, 4, 9V, and 23F missed statistical non-inferiority by 

only a small margin. Serotypes 3 and 12F missed by a greater margin, but the totality of data 

was supportive. Additionally, public reference standard that was used to calculate 12F IgG 

concentrations may be underestimating 12f IgG results. Pfizer has shared these findings with 

the FDA. 

Continuing to look at the response after Dose 3, the IgG GMC ratios in the PCV20 group 

compared to the PCV13 group for each vaccine serotype was the key secondary objective in 

the study. Non-inferiority was to be declared for this objective if the lower bound of the 95% 

confidence interval of the ratio was greater than 0.5. All 20 serotypes met non-inferiority for this 

comparison, including serotypes 3 and 12F. There also was comparison of the 7 additional 

serotypes to the result of a vaccine serotype in the PCV13 group. The IgG GMCs to those 7 

additional serotypes in the PCV13 group after Dose 3 were low. The IgG GMCs for the 7 

additional serotypes were substantially higher in the PCV20 group compared to the PCV13 

control group. This was also the case after Dose 4. Functional antibodies elicited by the vaccine 

after Dose 3 also were assessed. The OPA GMC responses for the 13 matched serotypes were 

similar between groups, even for serotypes that missed the co-primary IgG objective for this 

dose. PCV20 also elicited very robust functional activity to the 7 additional serotypes, including 

12F. 

Moving on to the response after the toddler dose, Dose 4 in the study, non-inferiority was 

declared if the lower confidence interval was above 0.5. Similar to the result for the IgG GMC 

ratios after Dose 3, all 20 vaccine serotypes met non-inferiority after Dose 4. An important 

property of conjugate vaccines is their ability to elicit memory responses. Looking at the 

antibody levels in the PCV20 group after Dose 3 and after Dose 4, it is clear that there were 

numerically higher antibody levels after the toddler dose than after the infant series. This was 

observed for both IgG GMCs and OPA GMTs for the vaccine serotypes. This indicates that 

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immune response after the toddler dose is a significant marker indicating that a memory 

response has been induced after the infant series by PCV20. 

In addition to evaluating the pneumococcal responses, Pfizer evaluated responses to 

concomitant vaccines. Regarding the difference in percent of participants with pre-specified 

antibody levels to the different antigens in PEDIARIX and HIBERIX given with the 3 infant doses 

of PCV20 or PCV13, all met the non-inferiority criteria. In terms of the responses to MMR and 

varicella vaccines given with Dose 4 of PCV20 or PCV13, all met the non-inferiority criteria. 

These data support PCV20 use in routine pediatric schedules. 

Regarding safety, injection site pain, drowsiness, and irritability were the most common events. 

Most reactions were mild or moderate, rates were similar across both groups, and were 

consistent with the historical experience with PCV13. As mentioned previously, another 

important Phase 3 study assessed the safety and immunogenicity of a single dose of PCV20 in 

children 15 months to less than 18 years of age. This study was conducted in the US to support 

the use of PCV20 in children through 17 years of age. This multi-center, single arm trial enrolled 

approximately 800 healthy participants of approximately 200 per age group. Participants 15 

months─5 years of age were required to have documentation of at least 3 doses of PCV13 prior 

to enrollment. In terms of IgG GMCs for the 2 age groups less than 5 years of age, 1 dose of 

PCV20 elicited a robust IgG response to all 20 serotypes in children 15 to <24 months and 2 to 

<5 Years previously vaccinated with PCV13. Data from the youngest group also supports the 

potential for replacement of PCV13 with PCV20 in the schedule. There was a similar pattern in 

the functional antibody responses in these age groups, as well as IgG and OPA responses in 

older children. The safety data were consistent with historical experience with PCV13. There 

were no clinically significant differences in the AEs in the PCV20 and PCV13 control group. 

SAEs were reported in 4.5% of PCV20 recipients and 3.7% of PCV13 recipients in the infant 

studies supporting US licensure. No SAEs in this dataset were considered to be related to 

vaccine and no deaths were reported. 

In summary, PCV20 is well-tolerated when administered as a 4-dose series to infants and as a 

single dose to toddlers through older children, with a safety profile similar to PCV13. The totality 

of data shows that PCV20 elicits IgA, IgG, and OPA responses in infants for all vaccine 

serotypes consistent with PCV13. A single dose of PCV20 elicited IgG and functional immune 

responses to all 20 serotypes in children 15 months to less than 18 years of age, including 

those with prior PCV13. PCV20 is compatible with routine pediatric vaccines. PCV20 is currently 

under review by the FDA for use in pediatric populations 6 weeks to less than 18 years of age, 

with a target action date in April 2023. PCV20 has the potential to address the substantial 

burden of pneumococcal disease in children. 

Preliminary EtR/GRADE for PCV20 use in US Children 

Miwako Kobayashi, MD, MPH (CDC/NCIRD) provided the EtR Framework for PCV20 use in 

US children, pointing out that while the EtR includes 7 domains, the focus of this session would 

cover 3 of the domains: Public Health Problem, Benefits and Harms, and Equity. Currently, all 

children under 2 years of age have the same pneumococcal vaccine recommendations to 

receive either PCV13 and PCV15 using a 3-dose series at 2, 4, and 6 months of age and a 

booster dose at 12 to 15 months of age. Children ≥2 years of age with certain underlying 

conditions are recommended to receive PPSV23 in addition. 

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For this EtR analysis, there were 2 policy questions: 

 Should PCV20 be recommended as an option for pneumococcal conjugate vaccination 

according to currently recommended dosing and schedules for US children aged <2 years? 

 Should PCV20 without PPSV23 be recommended as an option for pneumococcal 

vaccination for US children aged 2–18 years with underlying medical conditions that 

increase the risk of pneumococcal disease? 

Combined into the PICO question regarding whether PCV20 should be recommended as an 

option for pneumococcal vaccination for US children, the population is all US children aged <2 

years and US children aged 2–18 years with underlying medical conditions. The comparison is 

the current recommendations for the respective groups. The critical outcomes include: VaccineType IPD (VT-IPD), VT-Pneumonia, VT- AOM, VT-Pneumococcal Deaths, and SAEs Following 

Vaccination. 

Beginning with the Public Health domain, use of pneumococcal conjugate vaccines significantly 

decreased the incidence of pneumococcal disease in US children. Outpatient acute respiratory 

illness caused by pneumococcus such as AOM, sinusitis, and pneumonia are common causes 

of outpatient visits and antibiotic prescribing. The risk of disease remains high in children with 

underlying conditions that increase the risk of pneumococcal disease. In 2018─2019, the 

proportion of IPD caused by vaccine serotypes was approximately 30% for additional serotypes 

contained in PCV20 but not in PCV13 and 15% for additional serotypes contained in PCV15 

and not in PCV13.21 The WG determined that pneumococcal disease is of public health 

importance for both groups of children. There was variability in the WG’s interpretation for 

children <2 years of age due to the significant reductions in pneumococcal disease among 

these children. However, most WG members agreed that pneumococcal disease continues to 

be of public health importance due to the remaining disease burden. 

For the Benefits and Harms domain, the WG interpretation of this domain was informed 

primarily by the great evidence profile for the PICO question. The outcomes deemed critical 

were VT-IPD, VT-pneumonia, VT-AOM, and VT-pneumococcal deaths. Given that there are 

currently no studies assessing PCV20 effectiveness against these clinical outcomes, PCV20 

immunogenicity studies were used as evidence for these outcomes. To supplement this, the 

WG also reviewed post-licensure PCV13 and PPSV23 effectiveness data against these 

outcomes as a background. 

Regarding outcomes related to harms, WG members deemed SAEs as being of critical 

importance. Evidence of SAEs was available and reviewed for PCV20. First, a summary of the 

post-licensure PCV13 VE data. Several post-licensure studies assessed PCV13 effectiveness 

against IPD. In general, these studies showed that PCV13 is highly effective against VT-IPD. 

Data on PCV13 effectiveness against VT-pneumonia in children are limited. Based on the 2 

studies done in China and Israel, PCV13 is likely to be protective against VT-pneumococcal 

pneumonia, but with a wide confidence interval. Data on PCV13 effectiveness against VTpneumococcal AOA also are limited. Estimates from these studies also tend to have wide 

confidence intervals, though the data suggest that PCV13 is likely protective against VEpneumococcal AOM. 

21 Gierke. February 2023 ACIP meeting presentation; King. February 2023 ACIP meeting presentation 

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Data on PPSV23 effectiveness against pneumococcal disease in children with underlying 

conditions are limited.22 A study conducted before the introduction of PCV in the US showed 

that PPSV23 is protective against VT-IPD among children with underlying medical conditions.23 

Data on PPSV23 effectiveness against non-invasive pneumococcal disease in children are even 

more limited. In a recent systematic review, no studies were identified that assessed PPSV23 

VE against AOM. Two RCTs that evaluated the efficacy of administrating both PCV7 and 

PPSV23 against AOM did not show any efficacy in the intervention groups.24 

To summarize the data on PCV20 use in children, the WG conducted a systematic review of 

literature on PCV20 use among children.25 Overall, 4 studies were included for GRADE 

(Grading of Recommendation Assessment, Development and Evaluation). Of these, 3 were 

considered for evidence of routine PCV20 use and 1 was considered for evidence of PCV20 

use in children with underlying medical conditions. Evidence of benefits of PCV20 use among 

children <2 years of age was informed by 2 RCTs (Phase II and III) that randomized healthy 

children to receive either PCV13 or PCV20.26 In the pivotal trial, PCVs were given using the 3-

dose primary series followed by a booster dose. The study showed that PCV20 had numerically 

lower immune responses compared with PCV13 for most of the 13 shared serotypes. Post-dose 

3, PCV20 did not meet the non-inferiority criteria compared with PCV13 for some serotypes for 

the primary immunogenicity outcome. Post-dose 4, PCV20 met the non-inferiority criteria 

compared with PCV13 for all 13 shared serotypes and for all 7 additional serotypes. Evidence of 

harms was informed by findings from 3 RCTs.

27 Across the 3 studies, SAEs were reported in 

4.5% of the PCV20 recipients compared with 3.7% of the PCV13 recipients, but none were 

considered to be vaccine-related. 

The overall certainty of evidence was moderate. Certainty of evidence for benefits was 

downgraded since these are immunogenicity studies and there are no correlates of protection 

established for most outcomes of interest. For harms, certainty of evidence was downgraded for 

imprecision due to lack of vaccine-related SAEs being reported. The WG determined that the 

desirable anticipated effects of PCV20 were moderate. PCV20 provides the broadest serotype 

coverage among available PCVs, so it is expected to prevent more disease. However, it is 

unknown how substantial the protection conferred from PCV20 will be based on available data. 

The undesirable anticipated effects were considered to be minimal. The WG’s interpretation of 

whether the desirable effects outweigh the undesirable effects was split between “favors 

intervention” of PCV20 use and “favors both” the intervention and the comparator of either 

PCV13 or PCV15 use. Those who favored the intervention believe that PCV20 is expected to 

prevent more disease compared with current PCVs. Those who favored both considered the 

uncertainties of the clinical implications of the lower immunogenicity of PCV20 and improved 

immunogenicity of PCV15 against serotype 3 compared with PCV13. 

22 Marra et al. Value Health 2022 23 Fiore et al. EID 1999 24 Veenhoven et al. Lancet 2003; and Van Kempen et al. Int J Pediatr Otorhinolaryngol 2006 25 The search strategy and search terms used are available in the supplementary slides from this presentation 26 Senders et al. PIDJ 2021; and Pfizer unpublished data from B7471011 27 Senders et al. PIDJ 2021; Pfizer B7471011, unpublished data; Pfizer B7471013, unpublished data, limited to US and Puerto Rico 

sites 

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Findings from the pediatric PCV15 immunogenicity studies were presented during the February 

2022 ACIP meeting.28 No studies were conducted among children 2─18 years of age with 

underlying medical conditions. Evidence on benefits was informed by 1 Phase 3 nonrandomized clinical trial with no comparator that evaluated the safety and immunogenicity of 

PCV20 use in healthy children 15 months─17 years of age. This included children <5 years of 

age who received at least 3 doses of PCV13. All participants received a dose of PCV20. The 

study showed that PCV20 was immunogenic for all 20 vaccine serotypes when assessed 1 

month after vaccination compared with pre-vaccination baseline. SAEs after vaccination was 

reported in 0.6% of the participants and none were considered to be vaccine-related. 

The overall certainty of evidence was very low. Certainty of evidence was downgraded further 

for this study since this was an open-label non-randomized controlled trial with no comparator 

group and did not include children with underlying conditions. The WG determined that the 

desirable anticipated effects of PCV20 use were moderate, the reasons for which were similar 

to those for routine use for children <2 years of age. In addition, there are no data on PCV20 

use among children with underlying medical conditions. The undesirable anticipated effects 

were considered to be minimal. The WG’s interpretation of whether the desirable effects 

outweigh the undesirable effects was split between “favors intervention” of PCV20 use and 

“favors both” the intervention and the comparator of PPSV23 use after currently recommended 

PCV doses. Those who favored the intervention believed that PCV20 is expected to prevent 

more disease compared with current recommendations. Those who favored both considered the 

fact that there are no data on PCV20 use in this population and that the clinical implications of 

improved immunogenicity of PCV15 against serotype 3 compared with PCV13 are unknown. 

For the Equity domain, data were reviewed of estimated pneumococcal conjugate vaccine 

coverage by 24 months of age among children born during 2018─2019 by health insurance 

status using data from the National Immunization Survey-Child (NIS-Child). Compared with 

coverage among children with private insurance only, children who were uninsured and those 

insured by Medicaid and other insurance was lower. Nationally representative PPSV23 vaccine 

coverage data among children with indications are limited. In a study among children enrolled in 

the Michigan Medicaid program,29 64% of children with sickle cell anemia received 4 doses of 

PCV followed by a dose of PPSV23 as recommended by 5 years of age and 53% received 4 

doses of PCV followed by 2 doses of PPSV23 as recommended by 10 years of age. Other 

studies that assessed PPSV23 coverage among children with underlying medical conditions 

were much lower, ranging from 20% to 40%.30 

An unpublished analysis using CDC’s ABCs data assessed the incidence rate difference of IPD 

among children ≤17 years of age in the highest and the lowest Census tract poverty categories 

by year for all serotypes, PCV13 serotypes, PCV15/non-PCV13 serotypes, PCV20/non-PCV13 

serotypes, PCV20/non-PCV15 serotypes, and non-vaccine serotypes from 2010─2019. For all 

serotypes in PCV13 serotypes, incidence rate difference decreased after 2010 after PCV13 was 

recommended for use in children. There was essentially no incidence rate difference for 

PCV15/non-PCV13 serotypes in 2018─2019. The IPD incidence rate difference for the 

additional serotypes contained in PCV20 remained, and there was a slightly larger incidence 

rate difference for non-vaccine serotypes. 

28 Banniettis. February 24, 2022 ACIP meeting presentation 29 Reeves et al. Pediatric Blood & Cancer, 2018 30 Tran et al. Frontiers in Pediatrics, 2021; Mirza et al. The Ochsner Journal, 2022; Harris et al. Pediatrics, 2022 

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The WG believed that PCV20 use among children in both groups will “probably increase” health 

equity. However, there were some differences in the interpretation among WG members. For 

routine PCV20 use among children <2 years of age, some believed that new interventions like 

PCV20 are likely to be accessible to the wealthy communities first and, therefore, could reduce 

health equity. However, others believed that programs such as VFC and school requirements 

allow for high vaccine coverage across the population and post-PCV13 data showed that 

vaccine can reduce disparities due to VT-pneumococcal disease. Some WG members believed 

that there probably is no impact since remaining disparities in VT-pneumococcal disease seem 

to be minimal. Some believed that equity will be increased based on the experience postPCV13. For PCV20 use in children with underlying conditions, some WG members believed a 

risk-based recommendation is less likely to be equitable compared with routine vaccine 

recommendations. Others believed that PCV20 use could simplify the current risk-based 

pneumococcal vaccine recommendations and improve vaccine coverage. 

In terms of the preliminary summary of the WG’s interpretation of the 3 EtR domains for the 2 

policy questions, the WG believed that pneumococcal disease is of public health importance. 

Compared with the current recommendations, the benefits of PCV20 use were considered to be 

moderate and have minimal undesirable effects. The WG’s interpretation was split between 

“favors intervention” of PCV20 use and “favors both” the intervention and current 

recommendations. The certainty of evidence was moderate for benefits and harms for routine 

PCV20 use in children <2 years of age, while the certainty of evidence was very low for children 

2─18 years of age with risk-based recommendations. PCV20 use was considered to probably 

increase health equity, although some WG members expressed different opinions. 

Pneumococcal Vaccines WG Considerations and Next Steps 

Miwako Kobayashi, MD, MPH (CDC/NCIRD) reminded everyone that the policy question 

under consideration are: 

 Should PCV20 be recommended as an option for pneumococcal conjugate vaccination 

according to currently recommended dosing and schedules for US children aged <2 years? 

 Should PCV20 without PPSV23 be recommended as an option for pneumococcal 

vaccination for US children aged 2–18 years with underlying medical conditions that 

increase the risk of pneumococcal disease? 

In addition, a cost-effectiveness analysis will be conducted to assess the incremental benefit of 

PPSV23 use in addition to PCV20 in children 2─18 years with underlying medical conditions, 

and the incremental benefit of PCV20 use in children who completed the recommended PCV 

series with either PCV13 or PCV15. The WG also is reviewing evidence to revisit some of the 

conditions for risk-based pneumococcal vaccine recommendations. Here are the specific 

questions that are being considered by the WG: 

 Are children with asthma at increased risk of pneumococcal disease regardless of high-dose 

oral corticosteroid use? 

 Are children with CLD at increased risk of pneumococcal disease? 

 Are children with CKD of any stage at increased risk of pneumococcal disease? 

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Currently, there are differences between the pediatric and adult recommendations regarding the 

indications for pneumococcal vaccine use for people with asthma. The current pediatric 

recommendation31 states, “Including asthma if treated with high-dose oral corticosteroid 

therapy.” The current adult recommendation states, “Includes chronic obstructive pulmonary 

disease, emphysema, and asthma.

32 

There are certain conditions or risk factors that currently are part of adult risk-based 

recommendations, but not for the pediatric recommendations. These include alcoholism, CLD, 

and cigarette smoking. The WG is considering whether to add CLD as part of pediatric riskbased recommendations. Chronic renal failure historically has been interpreted as those on 

dialysis or about to be on dialysis. The WG is discussing whether the risk-based 

recommendation should be expanded to children with all CKD stages. 

The next steps for the WG are to: 

 Review of evidence and WG interpretation of the remaining EtR domains (e.g., Values, 

Acceptability, Resource Use, Feasibility). 

 Review findings from cost-effectiveness analyses by CDC and other groups. 

 Review draft policy options for PCV20 use in US children for consideration by the 

committee. 

Questions for the ACIP include the following: 

 Does the Committee agree with the policy questions being considered by the WG? 

 Are there additional data the Committee would like to see before deciding on policy options 

for a vote? 

Merck Comments 

Richard Haupt (Head, Global Medical & Scientific Affairs, Merck) commented on the 

pneumococcal disease burden in children in the US, emphasizing that the day’s discussion 

highlighted the importance of maintaining important epidemiological vigilance as the 

pneumococcal vaccine landscape evolves. This was the first time post-COVID disease burden 

trends have been seen. It is notable that serotypes 3, 19A, and 19F remain important in causing 

disease in children and underscores the need to maintain protection against these PCV15 and 

PCV13 vaccine serotypes. The trends also were notable for the disease burden of the youngest 

age group. The CDC presentation included estimates for pneumonia in children less than a year 

of age, and similar trends have been observed for other outcomes such as IPD in children less 

than one year of age, highlighting the importance of early vaccine protection. Pneumococcal 

vaccination coverage rates revealed persistent disparities. This was particularly true for the 

fourth dose where roughly 20% of Medicaid children missed that booster dose, therefore relying 

on early protection from the 3-dose primary series. The vaccine community clearly needs to 

address this vaccine series completion rate disparity for all pneumococcal vaccines that are 

developed or used. 

31 Nuorti et al. MMWR RR 2010; Kobayashi et al. MMWR 2022. 71(37); 1174–1181 32 Matanock et al. MMWR 2019; Kobayashi et al. MMWR 2022. 71(4); 109–117 

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ACIP Discussion Points, Observations, Suggestions on Pneumococcal Vaccine 

Following Mr. Gierke’s Presentation 

• There appears to be a differential even after vaccine introduction for children 2─4 years

of age in terms of why it seems protective for the younger and older children and not as 

much for children 2─4 years of age. It may just be that there is a lot of variability in these

studies in terms of the age groups, so the numbers might have been too small. While 

there seems to be a downward trend, it was not found to be significant. It would be helpful 

to see the references and review the data. 

• It will be helpful to see a further breakdown of the children <5 years of age for whom a 

decrease was seen that was followed by a rebound in terms of immunization information 

when it is updated for 2021. 

• In terms of whether more data are anticipated from 2022 that could help to better 

understand more complicated pneumonias that were see this winter than any other 

winter, Mr. Gierke indicated that this was assessed, but the data were not complete, 

especially for the latter part of the year. They could assess just pneumonia and just IPD. 

They are working to update the 2022 data on IPD. Dr. Kobayashi added that they also 

tried to look at this through the NDSS for which an uptick was observed in children <5 

years of age, so there definitely is a trend. A limitation of the NDSS data is that they are 

self-reported. 

Following Ms. King’s Presentation 

• It would be beneficial to have the NNV. 

• Regarding the “big picture” in terms of trying to understand how the various vaccines 

together could reduce the overall impact of respiratory disease in young children, Dr. King 

emphasized that because it is a nasty respiratory season with horrific pneumonia and 

influenza, increasing vaccinations for both should significantly improve the health of 

children and keep them out of the hospital. 

• Perhaps it could be an aspirational goal for the respiratory disease prevention platform to 

increase vaccination for influenza and pneumonia. 

Following Dr. Watson’s Presentation 

• Regarding a request to provide more detail about the types of SAEs, Dr. Watson 

indicated that the SAEs were comprised of a multitude of other infections that had a 

diagnosed etiology, accidents, traumatic injuries, dehydration, failure to thrive, and 

malnutrition in both groups. There were more SAEs in the 20-valent group. 

• In terms of an inquiry about why for the GMR on Slide 7 a lower confidence interval of 0.5 

was used for most of the comparisons versus 0.67, Dr. Watson indicated that this is a 

longstanding endpoint and criteria that they have used for pneumococcal conjugate 

vaccines. That means that the actual point estimate has to be within 2-fold or closer to 

the actual control. When measuring multiple valencies and making 40 to 60 comparisons, 

having too rigid of a lower bound criterion like 0.67 probably would run into feasibility and, 

by chance, prevent a good vaccine from being licensed. 

• With regard to a request to describe the Grade 3 fevers that occurred post-vaccination 

with PCV-20, Dr. Watson reported that there were 7 cases in the 20-valent group and 2 

cases in the 13-valent group of fevers greater than 104o

F. None of these had febrile 

seizures. There were 9 febrile seizures total over the course of the 4 pediatric studies, 

which comprised 0.2% in the PCV20 group and 0.1% in the PCV13 group. There were 2 

cases of febrile seizure within 2 weeks of vaccination. In one case, the child also had a 

concurrent COVID illness. In the other case, fever occurred 14 days after Dose 4. The 

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investigator considered this possibly related to MMR and varicella but did not consider it 

related to vaccination. The remaining febrile seizures occurred much further out from 

vaccination. 

• Given that the ACIP will be making a decision based on immunogenicity data, concern 

was expressed that there potentially could be a tradeoff between functional antibody 

response and quality of the response, as well as opportunity costs, even though there 

would be a gain of 7 additional serotypes. Dr. Watson said she thought the quality of the 

response is most important rather than the absolute IgG level. Both have to be taken into 

consideration in terms of responses. Functional antibody and memory responses both 

play a big role. Functional antibody was assessed in subsets of participants because 

there would not have been sufficient volume from infants for the OPA sample size as 

needed. It is important not to base things solely on one end point, which is known from 

Prevnar 13 for which non-inferiority was missed for 2 serotypes but protection of those 2 

serotypes was good. The reverse cumulative distribution curves for IgG are reassuring in 

that protection was added for additional serotypes and IgG concentrations were kept 

fairly similar. Even though one data point showed missed non-inferiority for serotype 3 

compared to the lowest Prevnar 13 serotypes, it was well above the Prevnar 13 group. 

• Recalling a theoretical concern with respect to PCV7 and PCV13 that there is biological 

plausibility to the argument that response to 1 serotype could compete against response 

to another serotype, Dr. Watson responded that this was a concern in moving from PCV7 

to PCV13, but there have not been any problems observed with containing or controlling 

the shared serotypes between PCV7 and PCV13. They are seeing a small increment in 

the immune response—not a large magnitude. 

• Regarding an inquiry about whether there are any concerns about immunogenicity and/or 

efficacy and effectiveness among individuals who are immunocompromised or by 

race/ethnicity, Dr. Watson indicated that Pfizer did not conduct specific studies with 

immunocompromised children or those with sickle cell disease. They have a lot of 

experience with Prevnar 7 and Prevnar 13 showing that safety is acceptable in those 

populations comparable to the general population. They have some safety data for late 

preterm infants of 34─37 weeks gestation for which the safety looks very similar to term

infants. Immunocompromised infants were not included in the trials for PCV20. They also 

looked at subgroups of African Americans, which is the largest single population in 

addition to the White population, and no significant differences were seen. If anything, 

immunogenicity was slightly higher for some serotypes, but it is important to keep in mind 

that those were smaller datasets. 

Following Dr. Kobayashi’s Presentations 

• It appears that PCV20 could help to eliminate about a quarter of what is left of the 

remaining disease, most of which was addressed with the prior 2 vaccines. It would be 

beneficial for ACIP to see data regarding how cost-effective this would be. Dr. Kobayashi 

indicated that the plan was to present cost-effective analyses during the next ACIP 

meeting. 

• Given the concern regarding a possible tradeoff being less serotype 3 or 19F disease, 

Kobayashi reiterated that the WG’s interpretations of whether the benefits outweigh the 

harms was split between “favors intervention” with PCV20 and “favors both.” Among 

those who favored both, one concern was that the clinical implication of the 

immunogenicity studies are not yet known. There also were concerns regarding last 

year’s presentation from Merck representatives about the PCV15 data and how that 

would translate in terms of clinical protection. The remaining unknowns were reflected in 

the WG’s interpretation. 

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• Reflecting on the EtR framework itself, the indirect impact of vaccinating children on older 

adults is potentially substantial. It feels like at least acknowledging the potential indirect 

impact on herd immunity would be an important aspect of the benefits of pneumococcal 

conjugate vaccines. 

• The pneumococcal vaccine experts on the WG did not think PPSV23 vaccine has the 

immunogenicity or “legs” to be considered as an addition to or replacement of a PCV. 

Given that PCV20 induces immunologic memory and gets T-cells to participate, the 

experts all believe that it is so superior to PPSV23 that this would be desirable even at 

the expense of potentially losing PPSV23. 

• The incidence among children with immunocompromising conditions of 270 times greater 

risk, even with vaccination, is striking. 

• It is important to remember that even after the MMWR is published following an ACIP 

vaccine recommendation, insurance companies have a year before they have to start 

covering the vaccines. Some insurance companies are still not covering PCV15 for 

children. This is frustrating, delays care, and has resulted in some practices and hospitals 

continuing to give PCV13. In addition, there were delays in getting VFC PCV15. Difficulty 

getting coverage and delays in VFC vaccine may occur with PCV20 as well. 

• Regarding whether PCV13 would be removed from the market if there is a PCV20 

indication, Alejandro Cané from Pfizer confirmed that once PCV20 is approved for the 

pediatric indication, PCV13 will be phased out in the US. 

PUBLIC COMMENTS 

The floor was opened for public comment on February 22, 2023 at 2:00 PM ET. Given that 

many more individuals registered to make oral public comments than could be accommodated 

during this meeting, selection was made randomly via a lottery. Dr. Lee provided a gentle 

reminder that the ACIP appreciates diverse viewpoints that are respectful in nature and issuefocused rather than comments directed at individuals. The comments made during the meeting 

are included in this document. Members of the public also were invited to submit written public 

comments to ACIP through the Federal eRulemaking Portal under Docket Number ID CDC2023-0007. Visit http://www.regulations.gov for access to the docket or to submit comments or 

read background documents and comments received. 

Mr. Jack Baker 

National Foundation for Infectious Diseases 

Good afternoon. I am Jack Baker with the National Foundation for Infectious Diseases, or NFID. 

As NFID commemorates its 50th anniversary during 2023, we celebrate the remarkable impact 

that vaccines have had in protecting public health and saving lives. As a long-standing partner 

of CDC, NFID appreciates the valuable work of ACIP in guiding US immunization policy to 

protect public health through the ongoing review and analysis of vaccine safety and advocacy 

data. Our comments today focus on 2 respiratory viruses of concern, influenza and RSV. Now 

influenza, or flu, is not just a cold but can cause potentially life-threatening complications—even 

in healthy children and adults. During the current flu season, estimates show that at least 25 

million people in the US have become sick with flu; 280,000 have been hospitalized; and 17,000 

have died from flu and related complications, including more than 100 children. Those affected 

are far more than just numbers, as clearly illustrated by the dozens of personal stories that NFID 

has collected of people whose lives have been impacted by vaccine-preventable diseases. Data 

also show that flu has a disproportionate impact on communities of color. Black adults are more 

likely to be hospitalized with flu-related complications and are less likely to get vaccinated 

59 
 

 

 

 

 

 

 

 

 

 

 

 

against flu than White and Asian adults. In fact, during most flu seasons in the past decade, 

hospitalization rates among Black adults have been about 2 times higher than among White 

adults. To help address these disparities, NFID is working with partner organizations to increase 

awareness of the importance of annual flu vaccination through the #ShowUp and #FightFlu 

campaign. Another respiratory virus of concern in the US, RSV, also has a substantial impact on 

individuals of all ages. Each year in the US, RSV causes an estimated 58,000 hospitalizations 

and 100 to 500 deaths among children younger than age 5 years, as well as 177,000 

hospitalizations and 14,000 deaths in adults aged 65 years and older. In 2022, NFID issued a 

Call to Action on reducing the burden of RSV across the lifespan, which outlined key strategic 

priorities to drive progress in RSV surveillance, diagnosis, prevention, and treatment. Like flu, 

RSV also has a disproportionate impact on communities of color. As the ACIP evaluates new 

interventions to protect both infants and older adults against RSV, swift action will be essential 

to ensure equitable access through private and public payors, including the Vaccines for 

Children program. Additionally, developing clear, consistent communications will be critical in 

building public confidence and ensuring that these potentially life-saving new tools are available 

to all who need them. NFID values its long-standing partnership with CDC, and we look forward 

to continued collaboration to raise awareness about the importance of disease prevention 

through vaccination. On behalf of NFID, thank you for your dedicated service. 

Mrs. Angie Bluford 

Vaccine-Injured Individual 

Thank you. Good afternoon. I am Angie Bluford, a 49-year-old mom of 2. At the beginning of 

2021, I was in the best shape of my life due to a recent found love of kickboxing. On April 15th of 

2021, I gladly took my second Moderna vaccine to protect my family, friends, and return to the 

gym. Since that day, I feel like I’m wearing a lead suit. The migraines, excruciating head 

pressure, and bone pain keep me from smiling as much as I used to. The shortness of breath, 

fatigue, cognitive, and speech issues have forced my second leave of absence since the 

vaccine. I’ve been denied short-term disability and most likely will be again, considering that no 

one wants to acknowledge our injuries. The mRNA vaccine has put me and my family in 

financial, emotional, and physical strain. It robs the injured of our families, friends, employment, 

and hobbies. Why would we, the injured, choose to make this up? Per the CDC’s website, 

verified again today, the mRNA from the vaccines is broken down within a few days after 

vaccination and discarded from the body. I have a test result showing that the spike protein was 

still present and wreaking havoc in my body 603 days after my last Moderna vaccine, and I’ve 

never had COVID. Per Dr. David Wiseman, Moderna disclosed at September’s ACIP that their 

bivalents produced non-natural spiked heterotrimers, something acknowledged to React19 by 

FDA’s Dr. Marks. EMA papers reveal Pfizer’s bivalents likely do the same. Since this is new 

chemistry and new immunology, how can you recommend tetravalent vaccines with new, 

untested toxicology? Dr. Wiseman also shared that the CDC and FDA’s statement at January’s 

VRBPAC that an ischemic stroke signal was only found in one database, FSD, is incorrect. 

Highly significant values for the PRR safety signals in VAERS emerge from CDC’s recent FOIA 

disclosure and an NIH-sponsored calculator. How can CDC withhold this information from 

unsuspecting seniors it is studying without informed consent? Last year, the German Ministry of 

Health publicly acknowledged post-vac syndrome, a disease like long COVID that occurs after 

COVID vaccination. Post-COVID vaccine syndrome is most certainly happening to Americans, 

too. Why is the CDC silent with these important side effects? I implore you to remove the 

COVID vaccines from the schedule of recommended vaccinations for children until further study 

of adverse effects. Please hear, acknowledge, and help us. Thank you. 

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Ms. Sarah Regenspan

Vaccine-Injured Individual 

Hello. Thank you very much to the committee for the opportunity to speak, and I acknowledge 

that I didn’t have the time to be as prepared as our previous speaker. I was also injured by the 

COVID vaccine. I took my third Pfizer vaccine on January 7, 2022 and within hours, I developed 

burning chest pain and called my primary care doctor. I’ve never been hospitalized, but I was 

diagnosed by a cardiologist with vaccine-induced pericarditis. Over 13 months later, I am still 

suffering from symptoms that are preventing me from exercising normally and having a normal 

quality of life. My cardiologist has told me that they don’t know why I’m still experiencing 

symptoms and that they have no more help to offer me. My primary care doctor says the same, 

although I’m very lucky that I have providers who do believe that this is a vaccine-induced injury. 

I made a VAERS report. I’ve applied to the Counter Measures Injury Compensation Program. I 

would be happy to submit my medical records and proof of those filings to any members of the 

committee here who would like to see them. And I just want to point out that even vaccine 

injuries that do not result in hospitalization are extremely traumatic and lead to a great loss of 

quality of life. And there are no answers being provided for people like me. And I would really 

love to see the CDC and this committee offer some support to those in the community like me 

who rolled up our sleeves and took not 1, not 2, but 3 of these vaccines because we were told it 

was for the greater good and we wanted to be of service to the community. I’ve now spent close 

to $25,000 of my own money and gone into credit card debt doing experimental treatments to 

try to recover, as traditional cardiology medications have not solved the problem for me. So, this 

has been an extremely painful and traumatic time in my life. It’s been a very, very lonely 

journey. And it’s disappointing to not see more support from government entities like the CDC. 

And my worry is that it is going to continue to produce resistance to public health measures in 

the future, as friends and family of those who are injured see that we are getting no support and 

no options for medical treatment and no acknowledgement from the CDC. So, I really would 

urge you to look into these injuries and take them seriously so that the public will trust and be 

part of public health measures in the future. Thank you. 

Christina LaBette 

Vaccine Injured Individual 

Good afternoon. My name is Christina LaBette. On April 21, 2021, I freely received my second 

dose of the Pfizer COVID vaccine. Within 36 hours, my nightmare began being rushed to the 

hospital experiencing stroke symptoms. Today marks the 22-month anniversary of my injury and 

I wish for you to please listen to my story. Prior to my injury, I traveled, did many outdoor 

activities, was the mom who volunteered at school whenever needed, a cheer mom, a devoted 

wife, an active person who was free to do what I needed without assistance. Now, 22 months 

later, my life has forever changed struggling to live with debilitating cardiac and neurological 

symptoms, having to take multiple medications, and needing assistance with daily basic needs. 

Not only has my health deteriorated, I’m no longer able to be the mother or the wife that I was 

prior to the Pfizer injection. I have accrued over $35,000 in traditional medical bills and I have no 

improvement. I am begging for help to heal from these injuries. I now suffer from over 30 new 

diagnoses with conditions such as blood-clotting issues, tachycardia, dysautonomia, hemiplegic 

migraine disorder, diastolic dysfunction, small fiber neuropathy—these are just to name a few. I 

have been suffering unimaginable symptoms. These conditions are without question from my 

COVID vaccine. My life is consumed by appointments, testing, treatments. I’m just trying to 

survive this nightmare. It is a full-time job managing all of my health issues from the Pfizer 

vaccine. During our infertility journey in 2020, I had extensive clotting workups prior to starting 

treatments. All indicated I had no clotting genetics or factors. And now, my labs are riddled with 

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clotting issues and worse yet, my husband and I can no longer pursue our dream of having 

another child due to the Pfizer vaccine. I am mostly bedridden and housebound now. I can’t 

garden or provide for my family as I did previous to my injection. I just can’t up and go, as my 

body now dictates if I am capable of doing anything, including driving. I live in fear if I’m going to 

live or die, as well as my child fears losing her mother—so terrified she is in counseling now. I 

did my job getting the vaccine, so I ask you, why aren’t you doing your job to help us get better? 

Why aren’t you giving us a chance to recover from these injuries? We know you know this is 

happening. Why aren’t you helping us? Here is a question for you all. What if this was your 

child? Your parent? Your loved one? What would you be doing to help them if they were injured 

by these vaccines? Why aren’t you doing that to help me? To help us? We are real, we matter, 

and we need your help. The German government has even acknowledged these reactions as 

post-vax COVID syndrome, like a long COVID-like disease after COVID vaccination. So, I ask 

you again, why aren’t you helping us? 

THURSDAY: FEBRUARY 23, 2023

AGENCY UPDATES 

Centers for Disease Control and Prevention 

José R. Romero, MD noted that during the upcoming ACIP sessions, the audience would hear 

the most current information on many of CDC’s efforts. Because of this, he kept his CDC update 

brief and limited to comments on updates on polio, measles, and childhood vaccination 

coverage. As a reminder, a case of paralytic poliomyelitis was confirmed in an unvaccinated 

person in Rockland County, New York on July 21, 2022. Shortly thereafter, CDC deployed staff 

to New York’s Rockland and Orange Counties to assist with the investigation and vaccination 

efforts. CDC continues to support these efforts. CDC also is partnering with select jurisdictions 

on plans to expand wastewater testing where communities are at risk for poliovirus 

transmission. It is encouraging to note that for more than 7 months, no new paralytic 

poliomyelitis cases have been identified in the US. The last poliovirus detection was in 

December 2022. 

Moving to measles, provisional data indicate that there were 121 cases of measles in the US in 

2022. As of January 27, 2023, there have been 2 cases in two US jurisdictions. Early in 

February 2023, Columbus Public Health Department in Ohio declared the measles outbreak 

over after 85 cases were identified. As a reminder, a measles outbreak is declared over when 2 

incubations periods, 42 days, have passed without another case. Jurisdictions at highest risk for 

measles continue to be those communities with persistently low vaccination coverage and at 

risk for importations from locations outside the US where measles is endemic or experiencing 

outbreaks. 

Turning to current efforts for maintaining childhood vaccination coverage, in January 2023, CDC 

published new data providing an updated assessment of the impact of the COVID-19 pandemic 

on routine childhood immunization. To highlight some of the key findings of these reports, 

vaccination coverage has dropped a total of 2 percentage points since the start of the 

pandemic, decreasing from 95% reported in the 2019-2020 school year to 93% in the 2021-

2022 school year. This steady decline means that nearly 250,000 kindergarteners are 

potentially not protected against measles. MMR vaccination coverage for kindergarten children 

is now the lowest it has been in over a decade. It is additionally concerning that the percentage 

of uninsured children not vaccinated by their second birthday is 8 times that of privately insured 

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children—even with the VFC Program in place. There were differences in vaccination coverage 

among children living below poverty and in rural areas, with a 4% to 5% decrease in coverage 

among children in those groups during the pandemic. These data add to previous research that 

highlights the impact of the COVID-19 pandemic on routine childhood vaccinations and ongoing 

disparities in coverage and reinforces the importance of vaccination to protect children from 

serious illness and death. While overall routine vaccination remains high, the recent outbreaks 

of measles and polio underscore that under- and un-vaccinated children are at risk for serious 

illness. To help address pandemic-related declines in routine immunizations, CDC has recently 

launched Let’s RISE (Routine Immunizations on Schedule for Everyone), an effort to equip 

partners and HCP with actionable strategies, resources, and data to support getting all 

Americans back on schedule with routine immunizations. It is important to continue to work 

together and remain vigilant in efforts to ensure that children receive the vaccines they need in 

order to protect them against serious and sometimes deadly disease. 

In terms of vaccination rates among adults with insufficient insurance coverage, individuals with 

incomes less than $20,000 a year compared to those with incomes of $40,000 or more were 

less likely to receive influenza vaccination. Adults with an out-of-pocket payment of $30 for an 

influenza vaccine are 58% less likely to get vaccinated than adults who have no out-of-pocket 

payment. Current estimates suggest that approximately 35%, one-third, of adults ages 18─64 

years of age were uninsured (14%) or underinsured (21%) for the first half of 2001. There are 

ethnic and minority disparities and these groups are less likely to be vaccinated, even if they are 

covered by insurance. Uninsured adults have the lowest rates of those reporting having 

received a vaccine for influenza in the previous 2 months. This supports the need for a VFA 

Program similar to the VFC Program. 

Centers for Medicare and Medicaid Services 

Mary Beth Hance reported that a major change to Medicare under the Inflation Reduction Act 

provisions was to eliminate cost-sharing for the Part D vaccines that started in January 2023. 

Part D plans may not apply a deductible to co-insurance or other enrolling cost-sharing 

requirements for Part D-covered adult vaccines recommend by the ACIP. CMS issued an MLN 

Fact Sheet in December 2022 highlighting this called “Medicare Part D Vaccines.”33 There is a 

larger change coming for adult coverage in Medicaid as a result of the Inflation Reduction Act. 

Beginning in October 2023, the Inflation Reduction Act expands coverage of ACIPrecommended adult vaccines without cost-sharing for adults in Medicaid and the Children’s 

Health Insurance Program (CHIP). In the expansion population for Medicaid, there already is 

coverage without cost-sharing for ACIP-recommended vaccines. For pre-adults who are eligible 

under the pre-expansion, referred to as traditional Medicaid, coverage of vaccines for adults is a 

state option. While most states cover some vaccines, they may not have covered all of the 

recommended vaccines or may do so but not necessarily without cost-sharing. This will be a 

significant change for the Medicaid Program. CMS is in the process of working on guidance that 

will be released prior to the October 2023 start date. In terms of childhood immunization rates, 

CMS continues to work closely with CDC to address the immunization gaps and to work hard to 

ensure that children in Medicaid and CHIP and others who are eligible for the VFC program 

have access to and obtain their childhood immunizations. 

33 https://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network MLN/MLNProducts/Downloads/Vaccines-Part-DFactsheet-ICN908764.pdf 

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Health Resources and Services Administration

CDR Reed Grimes, MD, MPH reported that the National Vaccine Injury Compensation 

Program (VIPC) continues to process an increased number of claims. In fiscal year 2022, 

petitioners filed 1,029 claims with the VICP. Nearly $196 million was awarded to petitioners 

and $34.2 million was awarded to pay attorney’s fees and costs. As of February 1, 2023 in 

fiscal year 2023, petitioners have filed 380 claims with the VICP and $61 million has been 

awarded, including petitioners’ attorney’s fees and costs. As of February 15, 2023, the VICP 

has a backlog of 1,453 claims alleging vaccine injury that are awaiting review. More data 

about the VICP can be obtained at www.hrsa.gov/vaccinetackcompensation/data/index.html. 

As of February 21, 2023, a total of 11,196 claims alleging injuries or death from COVID-19 

countermeasures have been filed with the Countermeasures Injury Compensation Program 

(CICP), including 8,447 claims alleging injuries from COVID-19 vaccines. CICP has rendered 

decisions on 543 COVID-19 countermeasure claims, all of which are COVID-19 vaccine 

claims, have been determined to be eligible for compensation and are pending a review of 

eligible expenses. Among the COVID-19 countermeasure claims, 524 have been denied 

compensation because requested medical records were not submitted. Of those, 144 missed 

the filing deadline, and 141 did not specify CICP-covered products. For 251, the standard of 

proof for causation was not met and/or a covered injury was not sustained. More information 

about the CICP can be found at www.hrsa.gov/CICP. 

Indian Health Service

Matthew Clark, MD, FAAP, FACP reported that the IHS continues to prioritize access, 

quality, and equity in vaccine distribution and administration for American Indian/Alaskan 

Native (AI/AN) tribal communities served by the IHS system of care. During the COVID 

pandemic, IHS has worked closely with its federal and tribal partners to ensure vaccine 

access and support vaccine acceptance. IHS is currently engaged in efforts to promote 

primary series and bivalent booster vaccination in all age groups in every region. Throughout 

the Mpox public health emergency, IHS took a proactive approach to the distribution and 

administration of JYNNEOS vaccine among high-risk persons in tribal communities. 

Recognizing the potential impacts on its service population, IHS was among the first of the 

jurisdictions to expand access to JYNNEOS vaccine as PrEP as part of its Mpox PrEP 

initiative, which was implemented broadly across the IHS system of care. Multiple IHS areas 

and facilities also implemented equity pilot projects to enhance vaccine access for the most 

vulnerable patients. In November, IHS announced a new national vaccine strategy, the E3 

Vaccine Strategy, which is designed to promote access for every patient at every encounter to 

every recommended vaccine when appropriate. This includes all ACIP-recommended 

vaccines in all age groups, which are provided at no cost to IHS’s AI/AN service population. 

Working in collaboration with key stakeholders, especially tribal communities, IHS seeks to 

leverage the lessons learned from the COVID vaccine campaign to improve general 

vaccination rates in tribal communities. The E3 Operational Plan includes a bottom-up 

approach to encourage innovation, incentivize efforts, and recognize success, drawing on the 

adaptability of the comprehensive healthcare system to cross-pollenate federal, tribal, and 

urban Indian programs using best practices developed in Indian Country for Indian Country. 

The IHS looks forward to continued collaboration with its tribal, urban, and federal partners to 

ensure safe access to effective vaccines across the age spectrum for AI/AN populations 

served by the IHS. 

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National Institutes of Health

John Beigel, MD reported that the NIH continues to support basic and clinical research to 

improve human health. A large part of that involves preventing infectious diseases by 

developing new and better vaccines. He highlighted a few studies that may be of interest to the 

ACIP. For COVID-19, in a pre-print for early serologic responses from a randomized trial 

comparing a COVID wild-type BA1 versus wild-type BA4/BA5 bivalent, there is a lot of 

discussion about whether the BA1 or the BA4/BA5 bivalent is a better. While this is not an 

efficacy study, a detailed immunologic response helps inform that discussion. For Ebola, a 

group at the NIH has developed a vaccine against Sudan Ebola virus disease (SEVD) that was 

causing outbreaks in Uganda that completely protected against SEVD challenge. It has not yet 

entered into human studies. While fortunately the outbreak seems to be under control, having 

an effective vaccine is important and this represents the first step. A group at the NIH developed 

an experimental Marburg virus vaccine that was put into Phase I trials. Human trials showed it 

was safe and achieved a robust immune response. Marburg virus has periodic outbreaks, so 

having an effective vaccine is quite important for prevention of this disease. This also is a 

tremendous first step. HIV continues to be elusive for vaccines. Many people were interested in 

a large study on the Mosaic HIV vaccine, which was an investigational HIV vaccine that was 

used in MSM and transgender. While it was found to be safe, it was not protective. Therefore, 

the DSMB recommended that study be stopped. The study is still in follow-up, but reporting of 

the reasons it was stopped has been made public. Regarding malaria, a monoclonal antibody 

has been shown to be safe and protective. It was 82% effective in preventing infection in nonpregnant adults in Mali. This is the first time that monoclonal antibody prevented malaria 

infection in an endemic region. This is a tremendous first step and hopefully a target toward a 

more effective malaria vaccine strategy. 

Office of Infectious Disease and HIV/AIDS Policy

Dr. David Kim, MD, MA 

CDR Valeria Marshall, MPH, PMP reported that in January 2023, the Vaccines Federal 

Implementation Plan (VFIP) was approved by the HHS Secretary, Xavier Becerra, and Assistant 

Secretary for Health, Admiral Rachel Levine. The VFIP is a companion document to the 

Vaccines National Strategic Plan (VNSP or Vaccine Plan) published in January 2021, which 

describes specific actions that federal agencies will take to eliminate vaccine-preventable 

diseases. The actions described in the VFIP align with the VNSP across the 5 stated major 

goals. The VFIP was developed in collaboration with the Federal Interagency Vaccine 

Workgroup (IVWG), which consists of senior leadership from 11 US Departments, 11 US HHS 

agencies and 3 additional federal departments. The VFIP highlights vaccine development, 

administration, and policy based on the federal agencies’ missions, priorities, regulatory and 

legislative directives, resources, and capacities. The Office of the Assistant Secretary for Health 

(OASH) will host a webinar entitled “The Importance of Preventive Services and Lessons 

Learned from the Pandemic” on March 21. 2023. The program will discuss the following Healthy 

People 2030 objectives: 1) Immunization and Infectious Diseases (IIS) Objective 9, which is to 

increase the proportion of persons who are vaccinated annually against seasonal influenza; 2) 

Maternal, Infant, and Child Health (MICH) Objective 8, which is to increase the proportion of 

pregnant women who receive early and adequate prenatal care; and 3) STI Objective 4, which 

is to reduce congenital syphilis. As a reminder, the vaccination rate against seasonal influenza 

has been identified in Healthy People 2030 as a leading health indicator for the IIS subcomponent of Healthy People 2030. The National Vaccine Advisory Committee (NVAC) met on 

February 2-3, 2023. During this virtual 2-day meeting, the NVAC heard from experts and 

scientists who presented information on immunization equity, vaccine safety, vaccine 

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innovation, and other topics. This meeting supported in the subcommittees that are working to 

address the charges Admiral Rachel Lavigne, the Assistant Secretary for Health, gave the 

committee on vaccine safety and innovation and immunization. There are 2 other in-person 

meetings scheduled for 2023, one in June and one in September. Additional information about 

these meetings will be posted on the website. 

MENINGOCOCCAL VACCINES 

Introduction 

Katherine Poehling, MD, MPH (WG Chair) provided an introduction on behalf of the 

Meningococcal Vaccines WG. She reminded everyone that during the October 2022 meeting, 

the WG reported on the Menveo 1-vial presentation and the 2 new MenABCWY vaccines, one 

that will be produced by GSK and the other by Pfizer. The MenABCWY vaccines presentations 

described the WG policy questions, PICOs, and the WG’s plans for the near future. Results 

from GSK’s clinical trials were not available in time to review for that meeting, so both would be 

reviewed during this session but would be decoupled moving forward. The WG will continue to 

aim to be ready for an ACIP vote on the Pfizer vaccine during the October 2023 meeting, 

presuming licensure occurs before then. There is now some additional time to prepare for the 

GSK vaccine vote. The revised proposed timeline for the next few ACIP meetings include 

presentations during this meeting on the epidemiology of meningococcal disease in the US and 

Pfizer clinical trial. The June 2023 meeting will include GRADE, EtR, and cost presentations for 

the Pfizer vaccine and GSK clinical trial data. In October 2023, the WG will prepare for an ACIP 

voted on the Pfizer vaccine if it is licensed by then and GRADE, EtR, and cost-effectiveness 

presentations for the GSK vaccine. GSK has not confirmed when its vaccine will be ready for a 

vote, but the WG will be prepared. 

Since the October 2022 ACIP meeting, GSK and Pfizer presented to the WG on their 

pentavalent vaccines in the WG asked clarifying questions. The WG also considered whether to 

revisit the current adolescent immunization schedule based on the discussions during the 

October ACIP meeting. These topics are somewhat intertwined, so the WG needed to 

determine how to proceed. During the January 2023 WG meeting, the WG decided to postpone 

the assessment of the schedule until after both pentavalent vaccines have been reviewed. 

Because of the complexity of these reviews and an unclear picture of how meningococcal 

disease epidemiology might be evolving after 2 years of COVID-19, the WG will plan to revisit 

this topic in Spring 2024 when another year of epidemiologic data is available to better inform 

this discussion. 

Epidemiology of Meningococcal Disease in the United States 

Amy Rubis, MPH (CDC/NCIRD) described the current epidemiology of meningococcal disease 

and reviewed recent notable cases and outbreaks during this session. Meningococcal disease 

cases are reported to CDC through the National Notifiable Diseases Surveillance System 

(NNDSS). Additional serogroup, outcome information, and clinical characteristics are collected 

nationally from all jurisdictions through Enhanced Meningococcal Disease Surveillance (EMDS). 

All available isolates are also submitted to CDC for WGS as part of the EMDS. 

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Meningococcal disease surveillance data are typically finalized in the fall of the following year. 

Because of the COVID-19 pandemic, there have been delays in obtaining and finalizing NNDSS 

and EMDS data. 2020 data are finalized, but 2021 and 2022 are not yet final. Cases are known 

to have been low in 2020 and 2021 because of COVID-19 mitigation measures, but there is not 

yet a complete sense of what happened in 2022. For 2022, preliminary case counts have been 

collected with age and serogroup information. However, these data are less complete than the 

final data are expected to be. Additionally, CDC has not yet received and tested all available 

isolates for 2021 and 2022 to confirm serogroup and antimicrobial susceptibility. 

Since the last 1990’s, a sustained decline has been observed in the US in the incidence of 

meningococcal disease with a decrease from 1.2 to 0.11 cases per 100,000 population from 

1996─2019. This decline in incidence began prior to the introduction of a quadrivalent 

meningococcal conjugate, MenACWY, vaccine in adolescents or the availability of serogroup B 

or MenB vaccines. During the COVID-19 pandemic, cases declined to a preliminary incidence of 

0.06 cases per 100,000 population in 2021. In 2022, cases increased almost 50% to a 

preliminary incidence of 0.09 cases per 100,000 population. Incidence is still below prepandemic levels, but it is unknown whether cases will stabilize at this level or will continue to 

rebound. Incidence decreased over time in all 3 primary disease-causing serogroups B, C, and 

Y, while the incidence of serogroup W and other serogroups remained stably low. During 2020 

and 2021, the largest declines in incidence were observed for serogroup B. In 2022, there was 

an increase in serogroup C to above pre-pandemic levels, driven largely by 1 outbreak. 

Looking at incidence age group and serogroup from 2010─2019, incidence in serogroup 

distribution varied by age group, with the highest incidence observed in children <2 years of age 

and adults 85+ years. A peak in incidence also was observed among adolescents and young 

adults 16─25 years of age. Serogroup B was the predominant group in children <5 years of age. 

In children in adolescence 5─20 years of age, serogroup B accounted for approximately half of 

cases. Among adults >20 years of age, serogroups C, W, and Y caused the majority of disease. 

In 2020─2022, a slightly different incidence distribution was seen across age groups. While 

overall incidence during this time period was lower, declines in adults 26─64 years of age were 

not as pronounced as in other age groups. 

Now to highlight some recent unusual developments in meningococcal disease epidemiology in 

the US. Historically, resistance to any of the antibiotics used for treatment or prophylaxis of 

meningococcal disease was rare. In 2020, ciprofloxacin- and penicillin-resistant serogroup Y 

cases were identified. To date, 27 ciprofloxacin- and penicillin-resistant serogroup Y cases have 

been reported for 2019─2022 and have occurred primarily (78%) among Hispanic or Latino 

persons. The age ranges for these cases was <1 year of age through 97 years of age. Only 1 

case occurred in individuals 11─20 years of age. This is consistent with the expectation not to 

see cases in this age group since they are routinely recommended to receive ACWY vaccine 

and should be protected from serogroup Y. None of the ciprofloxacin- and penicillin-resistant 

serogroup Y cases were in vaccinated individuals. Taking a more detailed look at the 

ciprofloxacin- and penicillin-resistant serogroup Y cases and dual-resistant cases, large declines 

were reported in meningococcal disease incidence in 2020 and 2021. While preliminary 

incidence for 2021 is approximately half, the incidence of 2019 had the same number of dualresistant cases reported for 2021 compared to 2019. As previously mentioned, CDC has not 

received and tested all available isolates for 2021 and especially for 2022, so the number of 

resistant cases may increase. 

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Some unusual outbreaks have occurred over the past year. During 2022 in Florida, the largest 

outbreak that has been reported to CDC to date occurred of cases predominantly among MSM. 

There have been 43 serogroup C cases, including 9 deaths for a case fatality rate (CFR) of 21% 

in this ongoing outbreak since January 2022. All 43 cases are genetically closely related. Of the 

43 cases, 12 were either in men not known to be MSM or were female. The isolates from these 

cases are genetically closely related to those from the MSM cases. Of the 43 cases, 14 

occurred in people living with HIV. The age of cases ranges from 20─77 years, with a mean of 

35 and median of 31. The second unusual recent outbreak is a community outbreak caused by 

what appears to be an unusually lethal strain of serogroup Y. Since mid-June 2022, a total of 11 

cases have been reported with 3 deaths, for a CFR rate of 27%. The average CFR for 

serogroup Y cases for the past 5 years was 12%. Of the 11 cases, 10 were in Black or African 

American persons. The age range is 30─78 years. No connections have been identified among 

any of the cases to date. In the past few months, cases of this strain have been observed in 

other states that have affected a similar population to this outbreak, with a similarly elevated 

CFR, but with no known epidemiologic connections to the outbreak. Outbreaks also have 

continued to be seen among people experiencing homelessness, with 1 small serogroup C 

outbreak each year in 2021 and 2022. 

In summary, incidence of meningococcal disease declined in 2020 and 2021, but increased in 

2022. In recent years, new strains have been emerging in the US. Both new serogroup Y strains 

are predominantly affecting racial and ethnic minority groups. Given these unusual new strains, 

it is unclear how meningococcal disease epidemiology may change in the coming years. More 

complete 2022 data will be available in Fall 2023 and these data, combined with additional 

years of data post-pandemic, will provide a clearer picture of current meningococcal disease 

epidemiology. An increase in cases has been observed following the COVID-19 pandemic, but 

more years of data are needed to understand whether the number of cases will level off and if 

so, when. 

Pfizer Pentavalent Meningococcal Vaccine 

Jason D. Maguire, MD, MPH (Pfizer) presented an update on Pfizer’s meningococcal 

pentavalent vaccine safety and immunogenicity data. Pfizer is seeking licensure for its 

pentavalent meningococcal MenABCWY vaccine as 2 doses administered at least 6 months 

apart in individuals 10─25 years of age prevent invasive meningococcal disease (IMD) caused 

by all 5 serogroups. MenABCWY vaccine is composed of 2 vaccines:1) Trumenba® (MenBfHbp), which is licensed in the US for the prevention of invasive disease caused by Neisseria 

meningitidis group B in individuals 10─25 years of age; and 2) Nimenrix® (MenACWY-TT), 

which is licensed outside the US for the prevention of invasive disease caused by Neisseria 

meningitidis serogroups A, C, W, and Y in individuals 6 weeks of age and older. 

In terms of the adolescent meningococcal vaccination platform options for MenABCWY vaccine, 

the current US recommendation is for ACWY administered at 11─12 years of age and ACWY 

and B at 16─23 years of age. The pentavalent development program was designed to generate 

data that would inform how MenABCWY might generally be incorporated across the platform 

and provide the maximum protection against all 5 serogroups. One option of how MenABCWY 

could be incorporated would be as a single dose in early adolescence at 11─12 years of age to 

protect against IMD caused by serogroups ABCWY or 2 doses administered 6 months apart in 

later adolescents among individuals 16─23 years of age to boost ACWY and protect against 

MenB. The pentavalent development program includes studies supporting the proposed 

pathology for 2 doses administered 6 to 12 months apart to protect against all 5 serogroups and 

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a single dose to protect against ACWY, as well as a study including a booster dose 

administered 4 years after completing the primary series. 

The MenABCWY vaccine clinical program consists of 3 main studies involving more than 4,000 

participants 10─25 years of age who are naïve to prior MenB vaccination. In the Phase 3 study 

(C35110001), 80% of the participants were Caucasian, 10% were Black or African American, 

and 25% were Hispanic or Latino. The Phase 3 study evaluated MenABCWY vaccine 

administered on a 0,6 month schedule in approximately 2,400 ACW naïve and ACWY primed 

adolescents and young adults compared to Trumenba® administered on a 0,6 month schedule 

and co-administered with Menveo® at Dose 1. This study is now complete, so ACWY responses 

after 1 or 2 doses of MenABCWY in naïve and primed individuals and B responses after 2 

doses in all participants are available. A Phase 2 study (C3511004) of safety and 

immunogenicity in approximately 300 ACWY naïve children 11─14 years of age were dosed 

with MenABCWY on a 0, 12 month schedule. This group is in the persistence follow-up phase. 

A 0,36 month schedule group will be receiving their second dose later in 2023, For this session, 

results were available for ABCWY responses after 2 doses (0,12 months). The third study 

(B1971057) is a Phase 2 MenABCWY 0,6 month 2-dose study in approximately 1,600 

participants 10─25 years of age that includes a 4-year immune persistence phase and booster 

dose safety and immunogenicity evaluation, which is now complete and for which the 

persistence and booster data were available to present during this session. 

Beginning with reactogenicity for the Phase 3 study (C35110001) primary vaccination series by 

vaccine and group, there were no clinically significant differences between ACWY-naïve and 

primed individuals or between the primary vaccination schedule and the booster dose. E-diaries 

were used to collect reactogenicity data for 7 days following each vaccination. Local 

reactogenicity was measured in the arm where either pentavalent or Trumenba® were 

administered. Local reactogenicity to Menveo® administered in the contralateral arm was not 

evaluated. Pain, swelling, and redness at the injection sites event were mild to moderate in 

severity, with slightly higher proportions experiencing events in the pentavalent group compared 

to Trumenba®. There was a reduction in both groups between vaccination 1 and 2. Pain at the 

injection site was the most frequently experienced local event and proportions are consistent 

with what already is known for Trumenba®. Minor differences in point estimates were considered 

not clinically significant and there were no withdrawals from the Phase 3 study due to either 

local or systemic reactogenicity events. 

For systemic reactogenicity events, the pattern was consistent with what is already known for 

Trumenba®. Fatigue and headache were the most frequently experienced systemic events and 

were mostly mild to moderate in severity, with no clinically significant differences between either 

group or vaccination 1 and 2. Frequencies of other systemic events are even lower and no 

fevers >40o C occurred in any participants in this study. For unsolicited AEs, rates were similar 

between the pentavalent and Trumenba® + Menveo® groups for AEs at around 20% for MAAEs 

at around 15%. There also were very few related or severe events in this study. Although there 

were 7 SAEs in the pentavalent group during the vaccination phase and none in the Trumenba® 

+ Menveo® group, none of these were considered to be vaccine-related. There were slightly 

more newly diagnosed chronic medical conditions occurring in the pentavalent group compared 

to the Trumenba® + Menveo® groups, of which the majority were psychiatric disorders and in 

particular attention deficit hyperactivity disorder (ADHD), for which further investigation 

confirmed that for most of these cases, symptoms of ADHD were present prior to study entry 

and formal diagnosis. 

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In terms of the immunogenicity objectives, Dr. Maguire focused on the hypothesis testing 

endpoints agreed upon with the FDA: 

 ACWY evaluation (non-inferiority after 1 and 2 doses of MenABCWY vaccine versus 

MenACWY-CRM) defined as a proportion of participants achieving a ≥4-fold rise in hSBA 

titers above baseline. 

 B evaluation (non-inferiority after 2 doses of MenABCWY vaccine versus MenB-fHbp) 

defined as the proportion achieving protective titers ≥1:8 or ≥1:16 depending on the strain 

for all 4 group B test strains combined. 

Non-inferiority was achieved for serogroups ACWY and the 4 MenB test strains when the lower 

bound confidence interval for the difference between the proportion of participants achieving 

seroresponses was greater than -10%. The approach taken for assessment of MenB 

bactericidal responses for pentavalent was the same as that which supported the licensure of 

Trumenba® in the US and non-inferiority was defined the same as for ACWY. Looking 

specifically at data supporting that a single dose of MenABCWY vaccine can be used as an 

alternative to ACWY vaccines in ACWY-naïve adolescents in the Phase 3 study, 1 dose of 

MenABCWY vaccine was noninferior to 1 dose of MenACWY-CRM in ACWY-naïve participants. 

Approximately 82% to 99% of participants had serogroups ACWY hSBA titers ≥1:8 after 1 dose 

of MenABCWY vaccine. 

Given that Pfizer also is seeking licensure of MenABCWY vaccine as a 2-dose series to provide 

protection against all 5 serogroups, it also was important to evaluate the ACWY responses 

following 2 doses administered relatively close together. As expected, 2 doses of MenABCWY 

vaccine elicited higher responses versus a single dose of MenACWY-CRM in ACWY-naïve 

participants. Approximately 83% to 99% of participants had serogroups ACWY hSBA titers ≥1:8 

after 2 doses of MenABCWY vaccine. In addition, 2 doses of MenABCWY vaccine elicited 

higher responses versus 2 doses of MenB-fHbp in B-naïve participants. The 2 doses of 

MenABCWY vaccine were noninferior to 2 doses of MenB-fHbp. Approximately 83% to 98% of 

participants had serogroup B hSBA titers ≥1:8 after 2 doses of MenABCWY vaccine across the 

board against all 4 test strains as well as the composite response. Responses were statistically 

higher for 2 of the test strains, B24 and B44, and the composite response. 

For the second study (C3511004) among adolescents 11─14 years of age naïve to all 5 

serogroups MenABCWY vaccine protected against all 5 serogroups with 2 doses given 6 

to 12 months apart. Approximately 98% to 100% of participants had serogroups ABCWY hSBA 

titers ≥1:8 following 2 doses of MenABCWY vaccine given 12 months apart. Serogroup B 

responses were generally higher for the 12-month schedule compared with the 6-month 

schedule, albeit under different study conditions. The key take-away from the data presented 

thus far is that in ACWY-naïve individuals 11─12 years of age when they would be receiving 

their first dose of an ACWY conjugate vaccine in the US, a single dose of MenABCWY can be 

used as an alternative and 2 doses at either 6 or 12 months apart provide protection against all 

5 serogroups. 

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Given that the current platform of preventing IMD caused by serogroups ACW and Y is based 

on the consensus that the first dose in early adolescents provides protection until a second dose 

is administered later in adolescents to maintain protection through early adulthood, the Phase 2 

proof-of-concept study (B1971057) included a 4-year immune persistence follow-up phase in a 

booster stage. During the 4 years following a 2-dose series of MenABCWY or 4.5 years 

following a single dose of Menveo®, proportions of participants with protective titers for ACWY 

declined to a lesser degree in the MenABCWY compared to Menveo® recipients. Overall, they 

remained high, with a substantial proportion still protected 4 years out. After a MenABCWY 

booster dose, the GMT rose above those following the primary series, with 100% seroprotection 

across all 4 serogroups. Proportions with protected titers for the 4 MenB test strains over the 4 

years following the 2-dose primary series were similar between the MenABCWY and 

Trumenba® groups and, similar to what has been observed in prior Trumenba® studies, declined 

over the first year and remained stable thereafter. Again, a very robust response was seen of 

95% to 100% seroprotection following the booster dose. 

Considering older adolescents who have received a single dose of an ACWY conjugate vaccine 

in early adolescents, a single dose of MenABCWY vaccine potentially could be used as an 

alternative to ACWY vaccines in ACWY-primed adolescents. A single dose of MenABCWY 

vaccine was noninferior to 1 dose of MenACWY-CRM in ACWY-primed participants. 

Approximately 99% to 100% of participants had serogroups ACWY hSBA titers ≥1:8 after 1 

dose of MenABCWY vaccine. These data are from Study C3511001 among adolescents 11─14 

years of age. Data from the same study show that 2 doses of MenABCWY vaccine can be used 

as an alternative to 1 dose of MenACWY-CRM and 2 doses of MenB-fHbp in ACWY-primed 

adolescents. Data showed that 2 doses of MenABCWY vaccine were noninferior to 1 dose of 

MenACWY-CRM in ACWY-primed participants. Approximately 99% to 100% had serogroups 

ACWY hSBA titers ≥1:8 after 2 doses of MenABCWY vaccine. As a reminder, 100% of ACWYprimed participants had protective titers 4 years after 2 doses of MenABCWY vaccine (Study 

B1971057). 

In conclusion, MenABCWY vaccine was well-tolerated and safe. A single dose of MenABCWY 

vaccine could be used as an ACWY conjugate alternative in naïve and primed individuals. Two 

doses administered on a 0,6 or 0,12 schedule provide a high degree of protection against all 5 

serogroups. After 2 doses of MenABCWY vaccine administered at 11─12 years of age, a single 

dose produced all 5 serogroups at age 16. A single dose of MenABCWY vaccine could be used 

as a booster for ACWY at around age 16. Immunopersistance after 2 doses of MenABCWY 

vaccine is similar to a single dose of ACWY conjugate and 2 doses of Trumenba®. 

Workgroup Considerations 

Sam Crowe, PhD, MPH (Pfizer) presented the WG’s interpretation of Pfizer’s MenABCWY 

vaccine clinical trials data. As a reminder, the policy questions for each pentavalent vaccine are 

as follows: 

 Should a pentavalent vaccine be included as an option for MenACWY/MenB vaccination in 

people currently recommended to receive both vaccines? For example, 16-year-olds are 

recommended to get MenACWY and can receive MenB based on shared clinical decisionmaking. 

 Should the pentavalent vaccine be included as an option for people currently recommended 

to receive MenACWY only. For example, this would include adolescents 11─12 years of

age. 

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 Should the pentavalent vaccine be included as an option for people currently recommended 

to receive MenB only? An example would be during a serogroup B outbreak. 

The WG decided to add the second and third policy questions because of concern that some 

providers might not carry MenACWY and MenB vaccines once the pentavalent vaccine 

becomes available. 

To provide an overview of the Pfizer MenABCWY vaccine and trials, Pfizer’s pentavalent 

vaccine is comprised of Nimenrix® (serogroups ACWY) and Trumenba® (serogroup B). 

Trumenba® is currently licensed and available in the US and Nimenrix®. Nimenrix® is used 

extensively in Europe and elsewhere. Two related clinical trials have been completed 

(NCT03135834, NCT04440163) that assess the safety immunogenicity of the pentavalent 

vaccine by comparing it to Trumenba® (serogroup B) and Menveo® (MenACWY). The trials 

included participants 10─25 years of age and studied single and 2-dose (0,6 month) schedules. 

Four-year persistence and a booster dose also were evaluated. An extended interval study 

(NCT04440176) is currently underway with 2 arms: Study arm 1 — 0, 12 months (data 

available) and Study arm 2 — 0, 36 months. 

Vaccine safety was assessed by monitoring for and comparing local reactions, systemic events, 

MAAEs, SAEs, and newly diagnosed chronic medical conditions (NDCMC). Local reactions 

include pain, redness, and swelling and were compared using the pentavalent vaccine and the 

MenB vaccine because the latter is usually more reactogenic than the MenACWY vaccine. A 

slightly higher percentage of participants had a local reaction to the pentavalent vaccine for both 

first and second doses than the MenB vaccine. The percentage of systemic events were similar 

between the pentavalent vaccine and the MenACWY/MenB comparison. The percentage varies 

slightly between groups by systemic event and by dose, with the comparison group having 

slightly more systemic events after Dose 1 and the pentavalent group had slightly more after 

Dose 2. There were similar percentages of MAAEs between the study groups of than 15%. 

More SAEs were reported for the pentavalent group at 0.4% versus 0%, but none were 

assessed to be related to the pentavalent vaccine (e.g., hospitalization due to other medical 

conditions). NDCMC were reported for the pentavalent vaccine of 1.1% versus 0.3%. Pfizer staff 

explained that a higher number of participants with ADHD were in the pentavalent group, most 

of whom had related symptoms before entering the study. Of note, higher risk patients were not 

included in the trials (e.g., competent deficiency). 

The immunogenicity standard for serogroups A,C,W, and Y was the percentage of participants 

achieving MenACWY seroresponse in hSBA titer 1 month after 1 dose and 1 month after 2 

doses. Seroresponse was defined as a 4-fold increase in titer over baseline. The 

immunogenicity standards for serogroup B was the percentage of participants achieving MenB 

seroresponse in hSBA 1 month after 2 doses, with a composite response provided. 

Seroresponse was defined as a 4-fold increase in titer over baseline. 

For serogroups A,C,W,Y, 1 dose of the pentavalent vaccine was noninferior to 1 dose of 

MenACWY and both ACWY-naïve and ACWY-primed participants 1 month after administration. 

In addition, 2 doses of pentavalent given 6 months apart were noninferior to 1 dose of 

MenACWY in both naïve and primed participants 2 month after administration. For persistence 

of immunity after 2 doses, data are available out to 4 years. Seroprotection persists for that time 

period in vaccine-naïve participants. Seroprotection also persists for up to 4 years in primed 

participants. This also is true after a 2-dose series of pentavalent vaccine compared to 1 dose of 

MenACWY vaccine. For serogroup B, 2 doses of pentavalent vaccine given 6 months apart are 

non-inferior to 2 doses of MenB in naïve participants. Primed individuals were not assessed. 

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Waning of immunity for the pentavalent vaccine is very similar to that observed with MenB, 

dropping substantially by 12 months post-Dose 2. The WG noted that data were not presented 

on a 3-dose schedule pentavalent vaccine. However, a 3-dose schedule of Trumenba® is 

currently recommended for certain high-risk groups (e.g., people affected by a serogroup B 

outbreak). Data also were not available in people older than 25 years of age. This is the same 

as Men B vaccines, which are licensed for individuals 10─25 years of age. MenACWY vaccines 

are licensed up to 55 years of age and older depending upon the vaccine. 

Based on the clinical trials data presented, Pfizer’s MenABCWY vaccine appears to be 

noninferior to the MenACWY+MenB comparison based on the clinical trial data presented. 

There are some data gaps at this point in terms of the 3-dose schedule for high-risk populations 

and adults older than 25 years of age. In terms of next steps, the WG will be reviewing 

additional immunologic persistence data for a single dose of pentavalent vaccine. After that, the 

WG will turn to GRADE and the EtR Framework, with a focus on pentavalent vaccine studies. A 

cost-effectiveness study also will be conducted. 

ACIP Discussion Points, Observations, Suggestions on Meningococcal Vaccines 

Following Ms. Rubis’s Presentation 

• Regarding an inquiry about whether any of the cases in the Florida outbreak were known 

to be vaccinated with a conjugate vaccine, Ms. Rubis reported that 3 of the cases in the 

MSM outbreak in Florida were known to be vaccinated. However, the most recent dose 

of vaccine was received 7 to 10 years previously among the 3 cases. None of the cases 

in the serogroup Y group were known to have received vaccines. 

• With respect to a question about whether the specific cases of resistance were in some 

way geographically clustered, Ms. Rubis indicated that the resistance cases were not 

geographically clustered in one area. While several cases have been reported in 1 

metropolitan area, the 27 cases are spread across the country. 

Following Dr. Maguire’s Presentation 

• Regarding a request for more specifics about the SAEs and MAAEs, Dr. Maguire 

responded that there were 9 events among 7 participants following pentavalent 

vaccination. These included salmonella, depression with anxiety and suicide attempts, 

postural orthostatic tachycardia syndrome (POTS), dyspnea, head injury, traumatic 

spinal cord injury, and depression with suicidal ideations. There were no events in the 

MenB-fHbp + MenACWY-CRM group. In the vaccination follow-up phase, there were 5 

events in 4 participants in the pentavalent group. These included post-tonsillectomy 

hemorrhage and oral intolerance, open tibia fracture, depression, and disruptive mood 

dysregulation disorder. In the MenB-fHbp + MenACWY-CRM group, events include 

appendicitis, E-coli UTI, drug overdose, and migraine headache. POTS is not an AESI 

given that this individual had a history of fainting episodes. 

• In terms of a request for details about age, gender, ethnicity, and immunocompromised 

status among participants, Dr. Maguire indicated that participants were fairly equal 

across genders, approximately 78% were White, 10% were Black/African American, 

2.5% were Asian, 1.6% were multi-racial, and 25% were Hispanic or Latino. Based on 

the design of the study, about two-thirds of the participants were children and one-third 

were adults. The mean age at first vaccination was about 16 years and 75% of the 

participants were from the US and the remaining were from the European Union (EU). 

Immunocompromised individuals were excluded from the study. This included 

individuals who had immune diseases that potentially would put them at increased risk 

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by participation in the study or who were not likely to mount a specific immune response 

to the vaccine. 

• It is important to remember that the ACIP currently does not have an indication for MenB 

at age 11, so this is information outside of the normal schedule. The case incidence rate 

is 1 in a million, which is highly relevant. 

• Regarding whether any studies are planned to assess vaccine response among the 

population of people who are getting complement inhibitors like eculizumab, Dr. Maguire 

indicated that Pfizer is not planning to conduct such studies at this time. 

• In terms of a question about what Pfizer attributes what look to be statistically significant 

increases in hSBA titers ≥1:8, Paul Balmer from Pfizer indicated that they do not yet

have an explanation for some of the higher titers observed with the pentavalent 

vaccine—particularly for the group B response. They speculate that the combination is 

increasing immunogenicity. 

• With respect to whether the recommendation would be for all individuals 10─25 years of 

age to receive pentavalent vaccine, even though the immunocompromised were 

excluded from the study, Dr. Maguire indicated he could not give a recommendation but 

the indication Pfizer is seeking in that age group is for 2 doses to protect against all 5 

serogroups or 1 dose to protect against ACWY only. 

• Regarding whether persistence was going to be assessed beyond 4 years, Dr. Maguire 

indicated that there have been some discussions internally about how modeling might be 

used out to longer time frames based on the data they have. 

• ACIP is interested in information about cost per dose, given that this should factor into 

the committee’s considerations. Alejandro Cané from Pfizer reminded everyone that the 

pentavalent vaccine has not yet been approved by FDA and the list price has not yet 

been finalized. As part of the regulatory process, Pfizer is taking a value-based pricing 

approach and will inform the ACIP of the price as soon as this is known. 

• Consistency across clinical trials presentations from all manufacturers would be 

extremely beneficial for the ACIP in terms of demographics and immunocompromised 

individuals. 

Following Dr. Crowe’s Presentation 

• The potential for needing to stock numerous meningococcal vaccines may be 

overwhelming to providers, particularly those in adult clinics. More data are needed as 

soon as possible on adults, especially immunocompromised hosts and those who 

receive eculizumab. 

• Additional data would be appreciated on the immunogenicity experience with the vaccine 

that is not licensed in the US but has been used extensively in Europe to better 

understand what is being inferred with regard to that vaccine. 

• Close attention should be paid to data on vulnerable populations with high-risk factors 

(e.g., sickle cell disease, splenectomy for whatever reason, age ≥85 years, et cetera). 

Recognizing that it is difficult to do, it is surprising that studies are not planned in 

vulnerable populations. 

• Vaccines should be tested among those for whom they actually will be used. 

• Cost information will be imperative to have, especially for the cost-effectiveness 

evaluation so that true economic models will be available. 

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POLIO VACCINES 

Introduction 

Oliver Brooks, MD, FAAP (WG Chair) pointed out that the Polio Vaccination WG was formed 

because of 1 case identified in New York City that was determined to be an outbreak and that 

this would be the first presentation to the ACIP. The WG’s Terms of Reference (TOR) policy 

topics under consideration are to determine: 1) whether more specific guidance on adult 

vaccination, including use of adult booster doses, can be provided in the context of circulating 

poliovirus; 2) whether adults who are immunocompromised should be recommended an 

additional adult booster of a polio-containing vaccine; 3) whether fractional doses of inactivated 

polio vaccine (IPV), as prequalified by WHO, should meet polio vaccination requirements, 

including for people immigrating to the US; and 4) which criteria under which novel oral polio 

vaccine type 2 (nOPV2) might be used in areas with outbreaks or persistent circulation of 

poliovirus. During this session, the WG presented on the first TOR. 

Recommendations for Adult Polio Vaccination 

Sarah Kidd, MD, MPH (CDC/NCIRD) presented on behalf of the Polio Vaccination WG. As Dr. 

Brooks mentioned, the WG was established in October 2022. Dr. Kathleen Dooling presented 

some background on the WG’s TOR during the last ACIP meeting in October 2022. During this 

session, Dr. Kidd briefly summarized the WG’s deliberations on adult polio vaccination to date, 

presented some proposed language for adult polio vaccination recommendations in anticipation 

of an ACIP vote during the June 2023 meeting, and solicited ACIP’s feedback and 

identifications of areas where more data are needed prior to an ACIP vote. As background, the 

most recent ACIP statement on adult polio vaccination was published in 2000 and contains 

some ambiguous and outdated language. The 2000 statement states the following: 

 Vaccination is recommended for certain adults who are at greater risk for exposure to polio 

viruses than the general population. 

 Unvaccinated adults who are at increased risk should receive a primary vaccination series 

with IPV. 

 Adults who have had a primary series of OPV or IPV and who are at increased risk can 

receive another dose of IPV. 

Multiple problems and questions with the recommendations came to light last year when the 

New York poliomyelitis case was identified. First, the 2000 statement focused almost exclusively 

on adults who were at increased risk of exposure to polio virus. Second, it was unclear how 

increased risk should be defined in the setting of circulating vaccine-derived poliovirus in the 

US. Third, the recommendations for unvaccinated adults who were not considered to be at 

increased risk of exposure were unclear. Fourth, the recommendation for vaccinated adults and 

when or if a booster was advised also was unclear. The first policy question the WG addressed 

follows: 

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Policy Question #1 

 Should completion of a primary polio vaccination series with IPV be recommended for

unvaccinated and incompletely vaccinated adults in the US?

− Population: Unvaccinated and incompletely vaccinated (with OPV or IPV) US adults

>18 years.

− Intervention: Completion of a primary vaccination series with IPV.

− Comparison: No vaccination or partial series completion.

− Outcomes:

• Prevention of paralytic poliomyelitis

• Serologic immunity to polio viruses types 1, 2, and 3

• SAEs following a vaccination

• Indirect effects (e.g., community transmission, impact on health systems)

In terms of the current definition of “fully vaccinated,” an adult is considered fully vaccinated if 

they received: 

A primary series of ≥3 doses of trivalent OPV (tOPV) or IPV in any combination 

administered ≥4 weeks apart 

AND 

The last dose in the series was given on or after the 4th birthday 

AND 

The last dose in the series was given ≥6 months after the previous dose 

In terms of the public health problem, poliovirus infection can cause poliomyelitis and lifelong 

paralysis. Paralytic disease occurs in fewer than 1% of infections, with the exact frequency 

varying by serotype. Most poliovirus infections are asymptomatic. The incidence of paralytic 

polio decreased rapidly in the US after introduction of the Salk IPV quickly followed by the Sabin 

polio vaccine. Sabin vaccine was used for routine childhood immunization in the US for 

decades. In 1997, an enhanced potency IPV was introduced as part of a sequential schedule 

with OPV. In 2000, the US moved to an IPV only schedule. IPV has been the only polio vaccine 

recommended in the US since that time. Wild poliovirus type 1 (WPV1) and vaccine-derived 

poliovirus (VDPV) types 1, 2, and 3 still circulate in certain parts of the world. This graphic 

shows the distribution of paralytic polio cases in the last 12 months: 

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Approximately 650 paralytic cases have been identified globally in the last 12 months. A case of 

paralytic polio caused by vaccine-derived poliovirus type 2 (VDPV2) was confirmed in an 

unvaccinated young adult from Rockland County, New York on July 21, 2022. Genetic 

sequencing has indicated a linkage of the virus from this case to polioviruses collected in 

wastewater in Israel, the United Kingdom (UK), and Canada. Of note, Rockland County has 

reported overall low vaccine coverage for over 20 years. In the Summer of 2022, 60% of 

children under 2 years of age had received the recommended 3 doses of IPV. However, zip 

code-level coverage was as low as 37% in some areas. Poliovirus related to the case was 

detected in wastewater in Rockland and several other New York counties and in New York City. 

Retrospective testing detected poliovirus in the area as early as April 2022. The most recent 

positive sample was collected on December 15, 2022. Samples collected in the last 7 to 8 

weeks have all been negative and no additional paralytic polio cases have been identified. 

There are no reliable data on vaccination coverage for people who are currently adults in 2023. 

The best estimate of adults who are protected against paralytic polio comes from serosurveys. 

Serosurveys indicate that a large majority of Americans have protected antibodies to poliovirus. 

In a National Health and Nutrition Examination Survey (NHANES) survey that was conducted in 

2009 to 2010, seroprevalence varied by poliovirus serotype, but was high in all the age groups 

studied. Seroprevalence for Type 3 was consistently the lowest but remained high even in the 

oldest age group studied. 

The effectiveness of enhanced potency IPV has been established. The presence of detectable 

neutralizing antibody is an accepted correlate of protection against paralytic disease. However, 

immunity against paralytic disease may be present even in the absence of detectable 

antibodies. Studies of the serologic immunogenicity among infants and children show that 70% 

to 100% are seropositive after 2 doses and 88% to 100% are seropositive after 3 doses.34 

There are limited data on the VE of the current IPV formulation, but estimates range from 36% 

to 89% for 1 dose and 89% to 98% for 2 doses.35 Not surprisingly, because this is a routine 

childhood vaccine, there is a paucity of data for adults who receive a primary series. 

In addition to serologic immunity, which protects against severe disease and paralysis, it is also 

important to consider mucosal immunity and the potential effect of IPV on transmission. IPV 

does not decrease the proportion of people who will shed poliovirus when exposed. In terms of 

intestinal immunity, multiple studies36 have shown that there is no significant difference between 

IPV and unvaccinated individuals in terms of the odds of shedding from the intestines. IPV 

vaccination does appear to reduce the quantity and perhaps the duration of shedding, although 

a recent modeling study indicated no impact of IPV on the duration of shedding. There are fewer 

data on nasopharyngeal (NP) immunity following IPV vaccination. But data from 2 studies37 

suggest that rates of NP shedding are similar and low among both OPV and IPV vaccinees. 

The safety of IPV is also well-established and IPV is well-tolerated. Local reactions at the 

injection site were reported during trials, with up to a third reporting erythema, induration, and 

tenderness at the injection site. Combining IPV with other vaccines has not been associated 

with increased frequency or severity of reported adverse reactions compared to when the other 

vaccines are administered alone. No AEs have been causally associated with the use of the 

current formulation of IPV. In a paper that looked at 2000-2012 data38 from VAERS during a 

34 Vidor et al review, PIDJ 1997 35 Stoeckel et al, Rev Infect Dis 1984. CDC, MMWR 1988. John, Rev Med Virol 1993 36 Hird and Grassly meta-analysis, PLoS Pathogens 2012 37 Kok et al, Bulletin of WHO 1992. Onorato et al, JID 1991; and Brouwer et al, J R Soc Interface 2022 

38 Iqbal et al, Lancet ID 2015 

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period when more than 250 million IPV containing vaccine doses were distributed, a total of 

41,792 AE reports were submitted for IPV-containing vaccines. The majority of these were for 

non-serious events. Not surprisingly, 95% were among persons under 7 years of age. Most 

events were associated with IPV co-administered with other vaccines. Standalone IPV 

accounted for just 0.5% of reports. It is important to remember that VAERS is a passive 

reporting system and cannot assess causal associations between vaccination and AEs. 

Reported AEs were similar and proportional to those reported for other vaccines. 

Most of the WG deliberations focused on whether the recommendation for unvaccinated adults 

should be a risk-based recommendation or a uniform recommendation for all unvaccinated 

adults. Currently, situations that are considered to put adults at increased risk of poliovirus 

exposure include international travelers, laboratory and healthcare workers, and healthcare 

workers or other caregivers. In addition, unvaccinated or incompletely vaccinated adults whose 

children will be receiving an OPV or unvaccinated or incompletely vaccinated adults who are 

living or working in a community where poliovirus is circulating are considered to be at 

increased risk of exposure. During the WG’s deliberations, it became clear that there is a 

difference and that most of these situations pose risk at the individual-level and that there would 

be an opportunity to anticipate the risk and vaccinate prior to potential exposure. The situation is 

somewhat different for unvaccinated and incompletely vaccinated adults in a community where 

poliovirus is circulating, given that this would affect an entire population and the community 

already would be at increased risk at the time the risk is recognized. This means there 

potentially would be missed opportunities for vaccination prior to exposure if the 

recommendation remained risk-based. 

When considering the pros and cons of a uniform versus a risk-based recommendation, the 

pros of a uniform recommendation are that it allows unvaccinated adults and their healthcare 

providers to take advantage of opportunities to get vaccinated before they are at increased risk 

of exposure. It also brings adult polio vaccination policy closer in line with other routine 

childhood vaccines (e.g., MMR and varicella vaccines). In addition, it is a less complicated 

policy to communicate and understand in that a recommendation regarding who is at increased 

risk does not change based on the latest wastewater data. The cons of a uniform 

recommendation are that most adults in the US have a low risk of poliovirus exposure and 

paralytic polio, and most adults already received a primary polio vaccination series as children. 

In addition, demand for IPV potentially could exceed supply, particularly if a large number of 

adults without documentation of polio vaccination status were to assume they were not 

vaccinated. However, this issue could be mitigated by providing guidance for this group in the 

Clinical Considerations. In terms of proposed language for unvaccinated and incompletely 

vaccinated adults, the majority of the WG members believe the pros of uniform recommendation 

outweigh the cons and support a uniform recommendation. However, approximately one-third of 

the WG favor maintaining a risk-based recommendation. For the majority, the proposed 

recommendation language and Clinical Consideration would be as follows: 

Majority Recommendation:

Adults who are known or suspected to be unvaccinated or incompletely vaccinated against polio 

should complete a primary vaccination series with IPV. 

Clinical Considerations: 

In general, unless there are specific reasons to believe they were not vaccinated, most adults 

who were born and raised in the US can assume they were vaccinated against polio as children. 

78 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

Policy Question #2 

 Should a booster IPV dose be recommended for adults in the US who have previously 

completed a primary polio vaccination series? 

− Population: US adults aged >18 years who have completed a primary polio vaccination 

series (with trivalent OPV, IPV, or a combination of both) 

− Intervention: Booster dose of IPV 

− Comparison: Adults who completed a primary series but did not receive a booster dose 

− Outcomes: 

• Prevention of paralytic poliomyelitis 

• Serologic immunity to poliovirus types 1, 2, and 3 

• SAEs following vaccination 

• Indirect effects (e.g., community transmission, impact on health systems) 

The current recommendation regarding adult boosters is as follows: 

 2000 Statement: “Adults who have had a primary series of OPV or IPV and who are at 

increased risk can receive another dose of IPV. Available data do not indicate the need for 

more than a single lifetime booster dose with IPV for adults.” 

In terms of the rationale, this has been a longstanding recommendation since trivalent OPV 

(tOPV) was used in routine immunization. While the actual need for a supplementary dose has 

not been established, it was thought that “there is value in assuring protection against infection 

with wild polioviruses when exposure can reasonably be expected” (1977 ACIP Statement). Of 

note, there have been at least 2 reported cases of paralytic polio in adult travelers who have 

completed a primary series with either Salk IPV or tOPV. However, further details on these 

cases are not available and it is not clear whether a booster dose would have prevented these 

cases. It is unclear whether previously vaccinated adults need an IPV booster for protection. 

Looking again at the results of the NHANES serosurvey, the seroprevalence of neutralizing 

antibodies is high for all 3 serotypes and all the age groups studied.

39 While there are no data 

on the comparative VE of a primary series plus booster compared to a primary series only, 

serologic studies40 in adults with heterogenous pre-booster vaccination histories and 

heterogenous seropositivity have shown that 98% to 100% were seropositive 1 month after 

receiving an IPV-containing booster. One study also followed up trial participants 10 years later 

and 98% to 100% were still positive at that time for those who followed up. 

The majority of the WG agree with the current recommendation for adult IPV boosters. This 

recommendation is risk-based and is based on shared clinical decision-making. The proposed 

language includes some slight edits to modernize the language, namely substituting the word 

“may” for “can” from the 2000 statement. The proposed recommendation language would be as 

follows: 

Proposed Recommendation:

Adults who have received a primary series of tOPV or IPV in any combination and who are at 

increased risk of poliovirus exposure may receive another dose of IPV. Available data do not 

indicate the need for more than a single lifetime booster dose with IPV for adults. 

39 Wallace et al, BMC Public Health 2016 40 Broderick et al, Vaccine 2015; Domenicus et al, Vaccine 2014; Fukushima et al, Vaccines 2022; Grimprel et al, Vaccine 2005; 

Kovac et al, Vaccine 2015; Larnaudie et al, Human Vaccines 2010; Zimmermann et al, Vaccine 2013. 

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ACIP Discussion Points, Observations, Suggestions on Polio Vaccines 

Following Dr. Kidd’s Presentation 

• Many immunocompromised persons in their 60s and 70s are traveling, which calls into 

question the recommendation for a single lifetime booster. For instance, persons who 

received a booster 20 or 30 years ago who are immunocompromised might be more 

vulnerable. Dr. Kidd indicated that the WG is planning to address immunocompromised 

persons in the next few months, so they will consider this. 

• Regarding an inquiry about someone born in 1940 who now would be 83 years old, Dr. 

Kidd indicated that they have data for estimated coverage for people born in 1950 and 

later for whom seroprevalence data indicate that a high percent are protected. That 

could be from primary immunization or secondary immunization from exposure to 

somebody who received OPV. The seroprevalence data indicate high levels of 

protection in terms of neutralizing antibodies. They also have some Salk vaccination 

coverage data for people who were children and adults during that campaign that 

indicate coverage of 50% to 60% in young adults. 

• Concern remains that many adults have no idea whether they were vaccinated, so the 

Clinical Considerations will need to clearly state who will be considered protected. For 

instance, there are people born in the US who do not have vaccine records, refugees, 

and others for whom guidance will be needed about whether a primary series or onetime booster is needed. 

• Some international travelers may be required to have another booster dose to comply 

with a particular country’s international standard. Travel clinics and others will need 

some guidance about this niche question. 

• Clarification will be beneficial on proof of polio vaccination for those who immigrate to the 

US, those who have visitor visas, those who enter through refugee programs, et cetera. 

• It seems like there is a lot of opportunity for the Clinical Considerations to provide 

specific guidance for particular circumstances. 

• Equity and access are likely going to be issues, so understanding the numbers of people 

who are unvaccinated or under-vaccinated seems crucial. It is important to be able to 

offer reasonable access to individuals who may want vaccines who are unvaccinated or 

under-vaccinated, particularly if these individuals do not have medical homes and/or 

insurance coverage. It seems that the ACIP has a responsibility to those individuals in 

terms of making sure that they have the ability to get covered. 

RSV VACCINES: PEDIATRIC/MATERNAL 

Introduction 

Sarah S. Long, MD (Chair, Maternal/Pediatric RSV WG) emphasized that the WG process 

and decisions are remarkable and complex. While other WGs and the ACIP realize the 

complexity of the decisions, RSV is even more complicated. The Maternal/Pediatric RSV WG 

has presented the epidemiology and burden of RSV disease in infants in terms of RSV 

seasonality in the US and outpatient, ED visits, hospitalization and deaths. The WG also has 

presented to the ACIP on the virology and immunology of the organism. In addition, the WG has 

begun to present safety and efficacy data on nirsevimab, the first passive immunization. 

Nirsevimab is a prefusion RSV antibody with neutralizing capacity that is potent and of long 

duration. The WG has previously presented the Phase 3 study in infants born near-term at ≥35 

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weeks gestation,41 the 2b study of infants born prematurely 29–34 weeks gestation, and the 

Phase 2/3 safety and pharmacokinetic study in infants at high risk for RSV disease who were 

eligible for palivizumab. 

The agenda for this session was broad and deep, with presentations on the following topic 

areas: 

 Cost-effective analysis: CDC Model 

 Cost-effective analysis: Comparison of the CDC and manufacturer models 

 EtR Framework for nirsevimab 

 Clinical considerations for the monoclonal antibody 

 Safety and efficacy of RSV Bivalent A and B Prefusion (PreF) maternal vaccine 

 WG consideration 

Dr. Long clarified that neither of the products has been approved by the FDA. The FDA has not 

completed the evaluation of either the monoclonal antibody or the maternal vaccine. Any 

recommendation that ACIP would make would follow licensure of the products. 

Cost-Effectiveness Analysis for Nirsevimab: CDC Model 

David W. Hutton, PhD, MS (University of Michigan) shared the results of economic analysis 

of nirsevimab in pediatric populations referred to as the CDC Model, which included 

collaborators from the University of Michigan and CDC, many of whom have extensive RSV 

expertise. The overall goal was to evaluate the cost-effectiveness of nirsevimab by: 1) 

evaluating the population burden of disease in the pediatric US population by examining the 

outcomes of annual resource utilization, total cases, total costs, deaths, and quality-adjusted life 

years (QALYs) lost from RSV; 2) comparing the incremental cost-effectiveness ratio (ICER) of 

nirsevimab to no prevention; and 3) exploring scenario analyses to examine key areas of 

uncertainty related to these questions. 

In order to conduct this analysis, a decision-tree model was used. The target population was a 

US pediatric population <7 months of age entering their first RSV season. In a secondary 

analysis, high-risk infants were examined in their second season at 7─18 months of age. The 

intervention compared were no nirsevimab (natural history) to nirsevimab against RSV illness. 

The time horizon was one RSV season. A lifetime analytic horizon was used to look at 

outcomes that might last beyond that year, like years lost due to deaths. In order to conduct the 

analysis, the decision tree incorporated several components. With no prophylaxis, individuals 

can become infected. The infection can lead to hospitalization, ED visits, outpatient visits, or 

none of these. Children who are hospitalized potentially could die. Receiving the nirsevimab 

intervention may involve any of several or no AEs and individuals could experience the same 

RSV outcomes as with no prophylaxis. However, the likelihood of those RSV outcomes is lower 

with nirsevimab. Using a decision tree, it is possible to calculate numbers of events and costs, 

QALYs, numbers needed to prophylax for different outcomes, and cost per QALY life year 

gained. Because this is a decision-tree model, it does not take into account reductions in RSV 

transmission. As such, the named results were not dependent on uptake of nirsevimab. The 

model also does not take into account infections that were not medically attended. 

41 Initial results from start of trial until pause for COVID-19 pandemic and updated results that included entire sample 

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The estimation of RSV hospitalization incidence came from CDC’s NVSN from the season 

starting in 2016 and ending in 2020. The rates were higher for younger age groups and dropped 

off for older children. In the base case, it was assumed nirsevimab only reduces lower 

respiratory tract infections (LRTI). Therefore, an assumption had to be made about how many of 

visits were due to LRTI. It was assumed that 100% of these hospitalizations are from LRTI 

based on a study by Rainisch, et al. In terms of incidence of ED and outpatient visits per 

100,000 children, rates were higher for the youngest age groups and dropped as children get 

older. These rates come from studies by Lively, Hall, and Jackson. Assumptions also were 

made about the proportion of these ED and outpatient visits that were due to LRTIs. These 

estimates also came from the study by Rainisch. In this model, RSV mortality was linked to 

hospitalization. The model incorporated information in monthly time periods to track incidence of 

RSV along with the timing of nirsevimab administration, and waning protection was tracked over 

time. Regarding the seasonality of RSV each month throughout the year, most of the infections 

occur from November through April. The seasonality data came from the National Respiratory 

and Enteric Virus Surveillance System (NREVSS) for 2015─2019. 

With regard to modeling efficacy, the average efficacy in the first 5 months was equivalent to the 

efficacy observed in the trial. The efficacy in months 6─10 was lower and then assumed to drop 

to 0 after month 10. A majority of the high efficacy was in the first few months. For the precise 

numbers for the efficacy assumptions, the initial efficacy in months 1─5 was 80% based on the 

MELODY trial and the phase 2b recommended dose. For months 6─10, the base efficacy 

assumption was 25%, but was varied from 0.0% to 50% in the sensitivity analysis. Efficacy was 

assumed to be 0.0% in month 10 and after. The model assumed that nirsevimab was given at 

birth for those born during the RSV season from October─March. For all children born outside 

the RSV season, nirsevimab would be given at the regularly schedule at approximately their 2-, 

4-, or 6-month visits, which would occur in October or November depending upon when the 

child is born. 

In terms of RSV costs used in the model, disease-specific hospitalization costs were just under 

$11,500, ED costs a little over $550, and outpatient visits were a little over $80. These 

estimates came from a systematic review by Bowser published in 2022. Because the analysis 

was conducted from a societal perspective, productivity costs also were included. Days of 

productivity lost for caregivers if their child gets sick with a medically-attended case of RSV and 

productivity lost if the infant child dies were included. This is in addition to QALY years lost. The 

cost of the intervention also was included. In the base case, $300 per dose was assumed for 

nirsevimab. That was varied in the sensitivity analysis from $50 to $600. The model also 

included quality of life lost due to RSV for the child and the caregiver. Different levels of QALY 

were included for outpatient visits, ED visits, and hospitalizations. QALY of life lost was shown 

in terms of quality-adjusted life days lost so that it would be more intuitive since RSV typically 

affects children in time scales of days. As an example, an outpatient visit would lead a child to 

lose 3.1 quality-adjusted life days and also would cause a caregiver to lose 1.5 quality-adjusted 

life days. In the end, quality-adjusted life days were converted to QALYs by dividing the values 

by 365. There is a lot of uncertainty surrounding quality of life losses from RSV. The lower 

ranges were based on study by Grosse in 2019 and the upper bound was based on an 

unpublished survey conducted during the pandemic that asked for quality of life lost from 

outpatient and inpatient RSV events for children and their caregivers. Inputs also related 

nirsevimab AEs also were included for systemic reactions, injection site reactions, SAEs, 

medical costs, productivity costs, and QALYs lost associated with those AEs. 

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In addition to the base case results, many uncertainty analyses were conducted. A one-way 

sensitivity analysis was conducted varying each parameter one at a time. Some scenario 

analyses also were run, one of which examined whether nirsevimab also reduced upper 

respiratory tract infections (URTIs) to the same extent that they reduced LTRIs. Another 

scenario analysis examined the impact of changing the timing of nirsevimab administration. An 

additional scenario examined high-risk children entering their second RSV season. 

The results start with a base-case that looked at a hypothetical cohort of 1,000 births with the 

assumption of 100% uptake of nirsevimab. This analysis looked at the first RSV season and 

assumed a cost of $300 per dose and that nirsevimab only reduces LRTIs. In terms of some of 

the resulting health outcomes with natural history and nirsevimab, LTRIs were reduced with 

nirsevimab and the URTIs were not shrinking. Events averted with nirsevimab per 1,000 births 

included 59 outpatient visits, 20.9 ED visits, 7.8 inpatient visits, 1.7 ICU stays, 42.3 inpatient 

days, and 5.2 ICU days. Looking at the results in terms of the number needed to prophylax to 

avoid one of these events also can be assessed. For example, 128 people would need to be 

prophylaxed to avoid 1 inpatient stay. 

Regarding costs, nirsevimab has a little over $300,000 in intervention costs in AEs. The 

intervention costs are higher for nirsevimab than for natural history. However, in the other cost 

categories related to RSV disease are lower (e.g., outpatient, ED, inpatient, and deaths). 

Nirsevimab saves costs associated with RSV disease. However, the healthcare and productivity 

cost savings from reduced RSV do not quite offset the cost of providing nirsevimab. In the end, 

nirsevimab is more expensive than natural history. The cost per event averted with nirsevimab 

is about $2,476 per outpatient visit averted or $18,515 for inpatient visit averted. In terms of the 

QALYs lost from a population of 1,000 births, with nirsevimab 0.03 QALYs were lost due to AEs. 

Far fewer QALYs were lost overall with nirsevimab as compared to natural history because of 

averted RSV outcomes and impacts to the children and their caregivers. Overall, natural history 

would lose 4.73 QALYs whereas the nirsevimab strategy only lost 3.32 QALYs. Overall, the 

nirsevimab strategy is $144,926 more expensive than no prophylaxis. But 1.42 QALYs would be 

saved with nirsevimab. The overall ICER ratio was $102,805 per QALY gained. 

Now to look at the sensitivity analysis. Because this is a new product, there were many 

uncertainties. This graph shows how the top 10 most influential parameter assumptions affect 

the cost-effectiveness of nirsevimab: 

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Recall that the base-case ICER was about $100,000 per QALY gained. If the nirsevimab costs 

were lower at $50 per dose, providing nirsevimab would be cost-saving. However, if nirsevimab 

costs were higher at $600 per dose, the ICER would increase to $315,613 per QALY year 

gained. The next section below in nirsevimab cost in the light-gray subsection is parameters 

related to nirsevimab efficacy. If the nirsevimab efficacy is higher, then the incremental costeffectiveness ratio drops. The other parameters in that light gray section are related to the 

fraction of RSV infections that nirsevimab might impact. The section below that in the lightest 

gray includes parameters related to the QALYs lost from RSV. The dark blue portion of the bars 

suggest that children and their caregivers would be losing a lot of quality of life from RSV. If that 

is the case, nirsevimab looks more cost effective. 

The first important parameter is cost. The ICER varies as the cost of nirsevimab changes. The 

initial assumption was $300 per dose, but if it were more expensive, the ICER would rise. If 

nirsevimab were cheaper, the ICER would drop. If nirsevimab is assumed to affect only LRTIs, 

only 57 outpatient visits would be averted in the base-case. If nirsevimab is assumed to reduce 

URTI with the same effectiveness as has been shown to reduced LRTI, infections averted would 

be 108 outpatient visits and 33.5 ED visits. If nirsevimab also reduces URTIs, it would 

substantially lower the cost-effectiveness ratio. In this scenario, the ICER would drop to $45,092 

per QALY gained if nirsevimab cost $300 per dose. 

In terms of how changing the timing of administration of nirsevimab might affect its costeffectiveness, recall that in the base-case it was assumed that nirsevimab would be given to 

newborns in October─March. This analysis assessed administration to newborns in 

October─February or October─April. Those born out of the season would still be given 

nirsevimab at the beginning of the season in October or November. It also would vary the 

efficacy in months 6─10 from 0.0% to 50%. In months 6─10, the timing of administration does 

not have a huge impact on the overall ICER. Whether children born in March or April receive 

nirsevimab at birth or in the Fall does not make a huge difference in the ICER. There are 

tradeoffs between providing nirsevimab at birth when the children are most vulnerable and 

providing nirsevimab in the Fall when protection would be most likely to match the peak of the 

RSV season. These effects roughly cancel each other out, so the timing does not make a major 

difference in terms of cost-effectiveness. 

Another scenario of interest is whether giving nirsevimab would lead to reduction in palivizumab 

use being given to high-risk children. In the base-case, palivizumab usage was not changed. 

This analysis shows what the potential cost impact might be if clinicians chose to give 

nirsevimab instead of palivizumab to infants who are currently getting palivizumab. A few 

additional assumptions included about the current use of palivizumab were that 1.6% of infants 

were high-risk and palivizumab-eligible, uptake was 75% in high-risk infants, 4.1 palivizumab 

doses per person were administered on average, and palivizumab cost was $1,228 per dose. If 

nirsevimab replaces palivizumab, the incremental cost of nirsevimab would decrease. It would 

not be quite as increasingly expensive. With essentially the same health outcomes, the ICER 

was $59,250 per QALY gained. 

In a scenario with higher-risk children entering their second RSV season, it was assumed that 

immunization was administered in October for those under 19 months of age. To define highrisk, a range of increased incidence of RSV-associated hospitalization and mortality was 

explored. This analysis looked at 1x, 2x, 4x, 6x, and 10x higher incidence for RSV-associated 

hospitalization and increases in mortality given hospitalization. It also assessed a $600 cost, 

which is equivalent to 2 doses at $300 and $1,000 total cost which is two $500 doses. Looking 

at the cost-effectiveness results for nirsevimab in a second season, with no increased risk not 

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many events would be averted, but those are older children who have lower risks to start with. 

However, in a high-risk population at 6 to 10 times the risk of hospitalization or death, the events 

averted would be much higher. This shows the cost-effectiveness results for nirsevimab in the 

second season for the $600 and $1,000 total cost of nirsevimab: 

Nirsevimab given in the second season is very expensive if the population is not at much higher 

risk. However, a population with a much higher risk than the general population, perhaps at 6 to 

10 times the base risk of hospitalization and death, giving nirsevimab potentially could be a lot 

more cost-effective. 

There are some limitations to these analyses. The model structure does not contain varying risk 

groups besides age. The analysis of the first season was done for all children regardless of risk. 

The model does not include dynamic transmission, so nirsevimab was not reducing population 

transmission of RSV. Additionally, models like this are a function of the underlying parameter 

assumptions, and there were many uncertain inputs. There was uncertainty about what the 

actual nirsevimab costs would be for payers, and there was not great information on quality of 

life with RSV and data were lacking on long-term efficacy. 

In summary, the cost-effectiveness of nirsevimab depends on many factors, particularly the cost 

per dose that could cause the ICER to vary between being cost-saving to over $300,000 per 

QALY gained. Nirsevimab efficacy, particularly against URTIs could cause the ICER to vary 

between roughly $75 and $150,000 per QALY gained. Variations in the QALY with RSV for both 

children and caregivers could cause the ICER to vary between $40,000 and $125,000 per 

QALY gained. Under certain conditions, nirsevimab may be cost-effective. Under other 

conditions, it might be less favorable. 

Cost-Effectiveness Analysis for Nirsevimab: Comparison to Manufacturer Model 

Ismael R. Ortega-Sanchez, PhD (CDC/NCIRD) compared and summarized key elements and 

findings of 2 economic models on the use of nirsevimab for the prevention of LRTI caused by 

RSV among infants in the US. These models have been presented and discussed with the 

Maternal/Pediatric WG. The first study was conducted by Sanofi and its collaborators. Sanofi 

manufactures nirsevimab. The second study was the CDC-University of Michigan study 

presented by Dr. Hutton. For full disclosure, Dr. Ortega-Sanchez indicated that he was part of 

the team that conducted the CDC model. None of the authors had any COIs for any part of the 

CDC model. 

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In terms of the policy questions and considerations, most comparisons in this presentation 

focused on how the 2 models addressed the first question in the following policy questions, and 

touch on the second part of the question in a few areas: 

Policy Questions: 

1) Should one dose of nirsevimab be recommended 

a) at birth for all infants born during October to March and

b) for all infants born during April through September and <8 months of age when 

entering their first RSV season? 

2) Should nirsevimab be recommended for children <20 months of age entering their second 

RSV season who remain at increased risk of severe disease? 

To consider the economics of the policy question is to consider simultaneously the health 

benefits and costs of nirsevimab utilization; namely, “Is the use of nirsevimab against RSV LRTI 

in all infants <8 months entering their first RSV season and in high-risk children <20 months 

entering the second season cost-effective?” To answer this question, the 2 models used the 

same standard of care in infants in first season and high-risk children entering the second 

season. Standard of care assumes palivizumab only for infants eligible as per the American 

Association of Pediatrics (AAP) recommendation and no immunization for all other pre-term and 

term infants. The base-case scenario focused on analyzing the cost-effectiveness of giving 

nirsevimab to infants in the first season and high-risk children in the second season. 

Depending on the policy question, key elements of this economic model were defined on: 1) the 

modelling approach, including targeted population(s), perspective (healthcare vs. societal), and 

intervention strategies and comparators; 2) the inputs for RSV disease burden, nirsevimab 

efficacy, and costs, including incidence of RSV disease and rates of outcomes, direct and 

indirect costs of RSV disease, and the intervention in terms of efficacy, duration of protection, 

safety, and program costs; and 3) influential assumptions that were compared across the 2 

models. 

In general, the 2 models followed similar designs. Both used a static analytical decision-making 

approach, relying on probabilistic simulation sensitivity analyses to manage data uncertainties. 

Both modeled hypothetical populations of infants <8 months of age and high-risk children 8─19 

months of age and used reasonable time frames, analytical horizons, and discount rates. They 

also accounted for loss of income associated with temporary productivity loss in caregivers or 

premature death in patients. Once the models were set, they were fed by different types of input 

data, including clinical, epidemiological, economic, and QALY data including nirsevimab clinical 

characteristics. Across models, the sources, specific values, and assumptions of these 

parameters had some overlaps, but there were marked differences as well. Dr. Ortega-Sanchez 

noted that the full report with these input data and assumptions from these models could be 

made available to ACIP members. 

This table delineates the standard outcomes estimated and reported by the 2 models, ratios of 

incremental cost per QALY saved, and the number needed to immunize (NNI) to prevent a 

health outcome: 

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In the Sanofi model, the base-case estimate for all infants <7 months in Season 1 with a 

nirsevimab cost assumed of $500 dose was determined to be about $70,000 per QALY saved. 

The QALY findings was supported with simulations and sensitivity analysis, most of which were 

somewhat costly, but there also were some gains in QALYs. For the UM-CDC base-case 

estimates for all infants <8 months for Season 1 with a nirsevimab cost assumed of $300 per 

dose was approximately $102,000 per QALY saved. Both models agree that nirsevimab will be 

costly, but it also will prevent LRTIs, hospitalizations, and saved QALYs among infants and 

caregivers. This table shows the Sanofi and UM-CDC model comparisons for selected outcome 

ratios for nirsevimab: 

It is important to note that even though the CDC model used a lower nirsevimab cost per dose, 

the costs per QALY saved were higher than those of Sanofi. The same observation could be 

made for the cost per hospitalization averted. 

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To understand the discrepancies in these estimates, Dr. Ortega-Sanchez discussed the main 

sources driving these differences. In the UM-CDC model, nirsevimab cost was the most 

influential variable, followed by nirsevimab efficacy in hospitalized infants, QALY with RSV LRTI 

diagnosis, and epidemiological barriers. Sanofi similarly reported one-way sensitivity analysis 

for key variables. Ranked most influential were epidemiological variables like the risk of RSV, 

followed treatment cost and efficacy. The price of nirsevimab did not appear in the Sanofi 

analysis. Aside from the cost per dose, the common most influential barrier identified in the 

review of this analysis, the following 4 categories of variables were identified that could be 

influential in the difference of these estimates: 

 RSV-hospitalization rate 

− Sanofi: Age and term-specific hospitalization rates reported in McLaurin (2016)42 

− UM-CDC: From RSV-associated hospitalization rates43 among children aged ≤2 years

 Unitary medical cost of RSV hospitalization 

− Sanofi: Cost varies by term at birth and by whether Intensive Care Unit or Mechanical 

Ventilator were needed as reported in McLaurin (2016)43 

− UM-CDC: Unit cost was a weighted average by term at birth and age as reported in 

Bowser (2022)44 

 RSV season & intervention period 

− Sanofi: MA RSV season based on Rainisch (2020)45 but intervention ends in February 

− UM-CDC: RSV-season and intervention period based on CDC surveillance data (2016-

2019)43 

 Initial efficacy & waning 

− Sanofi: Constant first 5 months as in trials, linear decay from month 6 to month 

− 10 UM-CDC: Sigmoid decay up to 10 months; average residual protection in first 5 

months equals constant efficacy from trials 

There were marked differences in the rates of hospitalization, medical costs per RSV 

hospitalization, and medical costs per RSV outpatient visit. The inputs in the Sanofi model were 

on the high end, while those used in the CDC model were on the lower end. For example, 

medical costs per RSV hospitalization was $11,487 in the CDC model and $18,790 to $28,812 

in the Sanofi model. Particularly influential was the rate of hospitalization, which also was the 

input data with sizeable uncertainty. Sanofi used the age- and term-specific hospitalization rates 

in McLaurin published in 2016, while the CDC model used the RSV-associated hospitalization 

rates among children <3 years of age from the laboratory-confirmed rates in the NVSN. 

Likewise, data sources of RSV season for the percent of RSV cases by month and how 

interventions were modelled have some marked difference. Although both intervention seasons 

began in October, the Sanofi intervention finished in February and the CDC model ran until the 

end of March. There are a number of other elements regarding the RSV season and 

intervention that could have impacted the differences between the models. 

42 McLaurin et al. J Perinatol. 2016;36(11):990-996 43 CDC unpublished data from the New Vaccine Surveillance Network (NVSN) (December 2016 to September 2020) 44 Bowser et al., J Infect Dis. 2022 Aug 15; 226(Suppl 2): S225–S235 

45 Rainisch et al. Vaccine. 2020;38(2):251-257 

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Both models used similar initial nirsevimab efficacy and uptake, which was 80.0 (68.5 – 86.1) in 

the UM-CDC model and 79.0 (68.5 – 86.1) in the Sanofi model. It is important to understand 

that within the context of duration of protection. The 2 models relied on the available duration of 

protection data from similar trials that covered approximately 5 to 6 months. However, the 

residual protection was based on assumptions after this initial period. The Sanofi and CDC 

models assumed no residual protection after 10 months, although the Sanofi model followed 

linear decay of efficacy from Month 6 to Month 10 and CDC used a Sigmoid decay up to Month 

10 and then 0% afterwards. 

An effort was made to use the assumptions made by Sanofi in the CDC model to try to calculate 

a summary of the estimates. For instance, when the base case and the scenarios used the 

Sanofi assumption of a nirsevimab cost of $500 per dose in one-year timeframe, the cost per 

QALY was about 150% higher when using the input data from the CDC model approach. If the 

intervention period was October─February, the cost per QALY would be approximately 6% 

higher. If the lower bound medical costs for hospitalization were used, the cost per QALY would 

be around 10% higher. Conversely, if all medically-attended RSV visits included LRTI and URTI, 

the cost per QALY would be reduced up to approximately 50%. Similarly, if the nirsevimab price 

per dose was $200 per dose, the cost per QALY would drop to less than one-third relative to the 

base-case cost per QALY. 

In terms of limitations, there are factors not considered that may result in overestimating the 

ICER, which means that cost-effectiveness may be underestimated. For instance, in the basecase both models assume no protection against URTI and no protection against 

asymptomatic/unattended LRTI. In addition, neither model included RSV-related costs incurred 

after discharge from an RSV-associated hospitalization or ED visit (e.g., productivity losses 

incurred by caregivers after discharge are not taken into account). Both models assumed no 

indirect effects of nirsevimab immunization (e.g., no indirect protection against RSV 

transmission is included). 

In conclusion, the differences in key inputs among the Sanofi and CDC models explains the 

differences in the results. The most significant of these variables include nirsevimab cost per 

dose, seasonality and intervention period, duration of nirsevimab efficacy, hospitalization rates, 

and medical costs. In terms of the base case in both models, it can generally be said that 

nirsevimab would significantly reduce RSV disease burden in infants. Data from clinical trials 

support impact estimates on disease reduction. However, the economic value of using 

nirsevimab in infants could be costly or cost-effective. Reasonable nirsevimab price and 

duration of protection, combined with careful design of seasonal interventions, would determine 

the cost-effectiveness value of routine prophylaxis among infants ≤7 months of age entering 

their first RSV season and those born during the RSV season. 

EtR Framework for Nirsevimab 

Jefferson Jones MD, MPH, FAAP, CDR USPHS (CDC/NCIRD) presented the EtR Framework 

for nirsevimab, which he noted he would refer to as “immunization” at times because it is a form 

of passive immunization. Active immunity results from infection or vaccination, which triggers an 

immune response. Passive immunity is when a person receives antibodies from an external 

source. One example is antibodies transferred from a mother to baby through the placenta or 

breast milk. Another example is direct administration of antibodies through intravenous immune 

globulin (IVIG) or monoclonal antibodies such as nirsevimab.46 

46 https://www.cdc.gov/vaccines/vac-gen/immunity -types.htm 

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During this session, Dr. Jones reviewed the EtR Framework for the following 2 policy questions: 

 Should one dose of nirsevimab be recommended a) at birth for all infants born during 

October to March and b) when entering the first RSV season and <8 months of age for all 

infants born during April through September. (PICO Question 1) 

 Should one dose of nirsevimab be recommended for children <20 months of age with 

increased risk of severe disease entering their second RSV season? (PICO Question 2) 

For PICO Question 1, the population was all infants born during April to September who are <8 

months of age when entering the first RSV season and infants born during October to March. 

The intervention was nirsevimab and the comparison was no nirsevimab. The outcomes 

included medically-attended RSV-associated lower respiratory tract infection (MA-LRTI), RSVassociated LRTI with hospitalization, RSV-associated LRTI with ICU admission, RSVassociated death, all-cause MA-LRTI, all-cause LRTI-associated hospitalization, and SAEs. 

The question for the Public Health Problem domain was, “Is RSV-associated disease among 

infants <8 months of age entering their first RSV season and infants born during the RSV 

season of public health importance?” Prior to the COVID-19 pandemic, RSV transmission had 

followed a consistent seasonal pattern. The 2016─2020 seasons consistently peaked during 

December to February. However, the COVID-19 pandemic interrupted seasonal circulation of 

RSV and many other respiratory viruses. Following over a year of limited RSV circulation, the 

US experienced an inter-seasonal RSV wave that peaked in early August 2021. That peak 

continued throughout the Fall into late December. In summer 2022, limited regional interseasonal transmission occurred, largely in the South and South Central US. RSV peaked in 

October to November 2022 and is decreasing, suggesting that RSV circulation might be 

transitioning to typical winter seasonality. 

It is estimated that each year among US children <5 years of age, RSV is associated with 100 

to 300 deaths;

47 approximately 58,000 to 80,000 hospitalizations;48 520,000 ED visits;49 and 1.5 

million outpatient visits.50 Pre-pandemic RSV seasonality is well-defined with limited geographic 

variability in most of the US. RSV is the most common cause of hospitalization in US infants. 

The highest hospitalization rates are in the first months of life, and risk declines with increasing 

age in infancy and during early childhood. Prematurity and other chronic diseases increase the 

risk of RSV-associated hospitalization, but most hospitalizations are in healthy term infants. The 

workgroup felt that RSV-associated disease among infants is of public health importance. 

For the Benefits and Harms domain question regarding whether the desirable effects outweigh 

the undesirable affects, the WG used both published data and additional data requested by the 

WG. The critical outcomes identified by the WG included MA RSV LRTI, RSV LRTI with 

hospitalization, RSV LRTI with ICU admission, and death due to RSV. Important outcomes were 

all-cause MA LRTI, all-cause LRTI-associated hospitalization, and SAEs. All outcomes were 

evaluated using pooled estimates from the Phase 3 and Phase 2b RCTs that were presented 

during the October 2022 ACIP meeting using the recommended dose. Aggregate data for 

additional outcomes were provided by the manufacturer to the WG. This differs from the full 

data submission to the FDA as part of the Biologics License Application (BLA) used for 

regulatory purposes. Given that no deaths were identified in these trials, this outcome could not 

47 Thompson et al, JAMA, 2003 48 Hall et al, NEJM, 2009; Rha et al., Peds, 2020; McLaughlin et al, J Infect Dis, 2022 49 Hall et al, NEJM, 2009 50 3Hall et al, NEJM, 2009 

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be evaluated. Pooled estimates combined the Phase 2b and Phase 3 trials using the 

recommended dose. The estimated efficacy was 79% for MA RSV LRTI, 80.6% for 

hospitalization, 90% for ICU admission. The Phase 3 trial was conducted partially during the 

COVID-19 pandemic, which temporarily led to lower than expected incidence of RSV. This 

concern applied to all outcomes for indirectness but was deemed not serious. For protection 

against ICU admission, few ICU admissions were reported, which led to wide confidence 

intervals. This was rated a serious concern because of fragility or imprecision of the estimates of 

efficacy for ICU admissions. Because no deaths were recorded, this outcome could not be 

evaluated. The estimated efficacy against all-cause MA LRTI was 34.8% and against all-cause 

LRTI hospitalization was 44.9%. The risk ratio comparing SAEs in infants receiving nirsevimab 

versus receiving placebo was 0.73. Because too few participants were included in the trials to 

detect rare events like anaphylaxis, which is typical for trials, the WG rated this as a serious 

concern for imprecision. 

In summary, there was high certainty that nirsevimab is effective in preventing MA RSV and 

RSV hospitalization in addition to preventing all-cause MA LRTI and LRTI hospitalization. There 

was moderate certainty that nirsevimab was effective in protecting against RSV LRTI with ICU 

admission and that SAEs were not more common in infants receiving nirsevimab than placebo. 

It was not possible to evaluate death. Overall, the WG rated the evidence as moderate certainty 

because of concerns in the precision of protection against ICU admission and ability to detect 

rare SAEs. The WG felt that the anticipated effect for the main desirable outcomes was large, 

but some members felt the effects were moderate. The WG felt that the anticipated effect for 

undesirable outcomes was minimal to small. The WG felt that the balance between the 

desirable effects relative to the undesirable effects favored nirsevimab more than no 

intervention. 

In terms of the Values domain question regarding whether the target population feel that the 

desirable effects are large relative to the undesirable effects and if there is important uncertainty 

in these values, in a survey conducted by the University of Iowa of 523 people who were 

actively pregnant or pregnant within the last 12 months, about one-third of respondents thought 

their baby definitely or probably would get an RSV infection within one year after being born. A 

total of 70% of respondents said they definitely or probably would get an RSV antibody injection 

for their baby if safe and effective, licensed by FDA, and recommended by CDC. A total of 63% 

of respondents said they were more worried or equally worried about their baby experiencing 

side effects from an RSV antibody injection versus symptoms if sick with RSV. A total of 38% of 

respondents believed that their baby would have no symptoms or mild symptoms if they got sick 

with RSV, and 24% expressed uncertainty about the disease severity or treatability if their baby 

got sick with RSV. Despite being unsure if receiving risk to be low, respondents were worried 

their baby would need to be hospitalized if they got sick with RSV, with a mean response of 4 

out of 5, with 5 being most worried. The WG felt that the target population probably feels that 

the desirable effects are large relative to the undesirable effects. However, the WG varied in 

whether they felt there was important uncertainty about or variability in how much people valued 

the main outcomes. 

For the Acceptability domain question regarding whether immunization with nirsevimab is 

acceptable to key stakeholders, in a survey by the Alliance for Patient Access and National 

Coalition for Infant Health of 175 providers using YouGov to poll US physicians, over 99% of 

respondents agreed that parents need more information about RSV, 86% reported that they 

already include RSV education as part of routine care, 97% said immunization could help 

prevent RSV, and 92% agreed that immunization policy should ensure that all children get 

access. The AAP has stated that the development of a safe and effective RSV immunization is 

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a priority. In 2021, the National Foundation for Infectious Disease held a roundtable that agreed 

on the importance of rapid adoption and deployment of evidence-based RSV prevention. This 

roundtable included the National Association of County and City Health Officials. The WG felt 

that immunization with nirsevimab is acceptable to key stakeholders. 

In terms of the Feasibility domain question regarding whether nirsevimab is feasible to 

implement among all infants <8 months of age entering their first RSV season and infants born 

during the RSV season, nirsevimab is administered as an intramuscular injection using prefilled, 

single-use syringes available in two different doses for infants born during or entering the first 

RSV season. The dosages are 50mg (0.5mL) for infants weighing <5 kilograms or 100mg 

(1.0mL) for infants weighing ≥5 kilograms or more. For high-risk infants and children entering 

the second RSV season, the dosing is 200mg (or 2 doses of 100mg administered at the same 

time). Only one dose of nirsevimab is recommended per RSV season. It is stored at refrigerator 

temperatures (2°C - 8°C) and may be kept at room temperature (20°C - 25°C) when protected 

from light for a maximum of 8 hours. Nirsevimab would be the first passive immunization 

product to be independently included in the CDC immunization schedule. Certain 

immunoglobulin products are already included but are in conjunction with vaccines (e.g., 

hepatitis B immunoglobulin and the hepatitis B vaccination). One reason for this is that the 

proposed indication is for all infants. Widespread use of nirsevimab would result in populationlevel impact. It is unknown at this time if nirsevimab will be included in the VFC program. 

FDA has indicated they likely will classify nirsevimab as a drug. Some related WG 

considerations included that certain types of healthcare workers, particularly medical assistants, 

can administer vaccines but might not be able to administer a monoclonal antibody under 

current rules, which may require modification to enable administration of nirsevimab. AE would 

be reported to the FDA Adverse Event Reporting System (FAERS) rather than VAERS. Many 

providers are more familiar with VAERS and the methodology is to analyze how these systems 

differ. Billing and administration codes for nirsevimab have not been finalized and differ for 

vaccines versus drugs. Some state immunization information systems might not be able to 

include products that are considered drugs and not vaccines. 

The WG felt that nirsevimab is probably feasible to implement. However, some members said 

this was dependent upon inclusion of VFC and others said they did not know or had concerns 

until more information on VFC was available. 

Pertaining to the Resource Use domain regarding the question about whether nirsevimab 

immunization among all infants <8 months of age entering their first RSV season and infants 

born during the RSV season is a reasonable and efficient allocation of resources, the primary 

source of data was from the cost-effectiveness analyses that were previously presented. There 

was a brief summary in the base case with nirsevimab for the CDC model at a cost of $300 per 

infant. The ICER was just over $100,000 per QALY at a cost of $300 per infant and a little under 

$245,000 per QALY at a cost of $500 per infant. The WG was concerned about the potential 

cost of nirsevimab, so 2 polls were taken. At a cost of $300 per infant, the majority of the WG 

said “probably yes” and the minority said “yes” that use of nirsevimab would be a reasonable 

and efficient allocation of resources. At a cost of $500 per infant, approximately half of the 

workgroup members said “probably yes” and the remainder said “no,” “probably no,” or “don't 

know” if use of nirsevimab would be a reasonable and efficient allocation of resources. 

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For the Equity domain question regarding what the impact of nirsevimab would be on equity, the 

inclusion of nirsevimab in the VFC program is undetermined. If not included in VFC, state 

Medicaid, Medicaid expansion, or CHIP and private insurance likely would cover nirsevimab, 

underinsured, uninsured, and those without Medicaid or Medicaid expansion likely would have 

reduced access without a VFC option. Multiple studies have shown increased rates of RSV 

hospitalization among children who are AI/AN compared with the general population. One 

recent study from RSV Surveillance among Native American Persons (SuNA) highlighted 

seasonal incidence per 1,000 children among 4 AI/AN communities. Rates in infant were 19 to 

112 hospitalizations per 1,000 infants. These rates were frequently 4 to 10 times the rate in the 

general population. This is thought to be due to social determinants of health (SDOH), such as 

increased rates of poverty and crowding.51 

The literature comparing rates of severe disease among non-Hispanic White, non-Hispanic 

Black, and Hispanic children have shown mixed results. National studies of death certificates 

have found higher rates among non-Hispanic Black compared with non-Hispanic White 

children.52 Hospitalization rates using NVSN surveillance data have shown mixed results.53 

Several NVSN studies have shown no significant differences by race or ethnicity.54 Other 

studies have shown differences, but even when they have, the relative risk of hospitalization for 

non-Hispanic Black and Hispanic children compared with non-Hispanic White children has been 

mildly increased (e.g., relative risk of 1.2 to 2.2) and has differed by age group.55 

The WG varied in their opinion of nirsevimab’s impact on equity. A large concern was 

uncertainty about inclusion in VFC. To summarize the overall WG interpretations of all infants 

receiving nirsevimab in their first RSV season, the WG felt that the desirable consequences 

probably or clearly outweigh the undesirable consequences in most settings and the WG 

recommended the intervention. 

For PICO Question 2 regarding whether one dose of nirsevimab should be recommended for 

children <20 months of age with increased risk of severe disease entering their second RSV 

season, the population was children <20 months of age at increased risk of severe disease with 

RSV and who are entering their second RSV season. The intervention was nirsevimab of 

200mg and the comparison was no nirsevimab. The outcomes were the same as those used for 

PICO Question 1, including MA-LRTI, RSV-associated LRTI with hospitalization, RSVassociated LRTI with ICU admission, RSV-associated death, all-cause MA-LRTI, all-cause 

LRTI-associated hospitalization, and SAEs. 

For the Public Health Problem domain question regarding whether RSV disease among children 

who are at high risk of severe disease in their second RSV season is of public health 

importance, NVSN incidence of RSV-associated hospitalization for the years 2016─2020 were 

used. The incidence is lower in children 12─23 months of age compared with children 0─5 

months and 6─11 months of age. Incidence rate ratios from the NVSN further illustrate these 

differences. The hospitalization incidence rate ratio for infants 0─2 months of age versus 12─23 

months of age was 6.1. For infants 3─5 months versus 12─23 months of age was 3.4. For 

infants 6─11 months of age versus 12─23 months of age, the rate ratio was 1.9. 

51 Hartman et al, RSV2022 12th International Symposium, Belfast 9/29/2022-10/2/2022; Atwell et al. (manuscript submitted, under 

peer-review) 52 Hansen J Infect Dis 2022 Aug 15;226(Suppl 2):S255 -S266 53 NVSN analyses compared incidence rates of non-Hispanic Black, non-Hispanic White, and Hispanic children 54 Hall Pediatrics 2013 Aug;132(2):e341; Hall NEJM 2009;360(6):588–598; and IwanePediatrics 2004 Jun;113(6):1758-64, findings 

differed by age group 55 IwanePediatrics 2004 Jun;113(6):1758-64, findings differed by age group; and Rha Pediatrics 2020 Jul;146(1):e20193611, 

findings differed by age group 

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The manufacturers proposed that some children up to 24 months of age who remain vulnerable 

to severe RSV disease through their second RSV season might warrant nirsevimab when 

entering their second RSV. This includes, but is not limited to, children with the following 

conditions and perhaps others: 

 Chronic lung disease of prematurity (CLD) 

 Hemodynamically significant congenital heart disease (CHD) 

 Immunocompromised states 

 Down syndrome 

 Cystic fibrosis 

 Neuromuscular disease 

 Congenital airway anomalies 

The MEDLEY study, a pharmacokinetics and safety study, included palivizumab-eligible 

children with hemodynamically significant CHD and CLD for the second season, but no other 

conditions. Palivizumab is the only product currently licensed for prevention of RSV-associated 

disease in the US. The AAP has identified groups of children at risk of severe disease from RSV 

during their second RSV season for the purposes of recommending palivizumab.56 Palivizumab 

is recommended for children with CLD if they require medical support within 6 months of the 

start of the second RSV season, and palivizumab can be considered for children who are 

profoundly immunocompromised or have cystic fibrosis if there are manifestations of severe 

lung disease. 

After reviewing available evidence, the WG felt that the same children currently eligible for 

palivizumab when entering their second RSV season per the AAP recommendations could be 

considered high risk for nirsevimab administration when entering their second RSV season. 

These group are described more specifically as follows, and other conditions are under review: 

 Children with chronic lung disease of prematurity if require medical support (chronic 

corticosteroid therapy, diuretic therapy, or supplemental oxygen) during the 6-month period 

before the start of the second RSV season 

 Children who are profoundly immunocompromised 

 Children with cystic fibrosis with manifestations of severe lung disease (previous 

hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest 

XR or CT that persist when stable) or weight for length <10th percentile 

For the Benefits and Harms domain question regarding whether the desirable effects outweigh 

the undesirable effects, the MEDLEY study57 included CHD and CLD cohorts that for the first 

season had a 2:1 randomization of nirsevimab to palivizumab. For the second season, the 

nirsevimab group continued to receive nirsevimab and the palivizumab group was randomized 

1:1 to receive nirsevimab or second-season palivizumab. Based on these data, the WG was 

able to evaluate only 2 outcomes, MA RSV LRTI and SAEs. MEDLEY was a safety and 

pharmacokinetics (PK) study. It did not evaluate efficacy and efficacy data for children entering 

their second RSV are not available. The PK data from the trials in infants in their first RSV 

season were analyzed using modeling. An area under the curve (AUC) was derived using 

individual estimates as a measure of exposure to nirsevimab and then correlated to efficacy for 

prevention of the first episode of MA RSV LRTI in infants <12 months of age from the Phase 2b, 

Phase 3, and MEDLEY trials. Based on these data, an AUC PK threshold of 12.8 day mg/mL 

56 https://publications.aap.org/pediatrics/article/134/2/415/33013/Updated-Guidance-for-Palivizumab-ProphylaxisAmong?autologincheck=redirected 57 Domachowske et al. https://www.nejm.org/doi/full/10.1056/NEJMc2112186, https://clinicaltrials.gov/ct2/show/NCT03959488 

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was established. As a surrogate of efficacy, a predetermined threshold was that 80% of 

MEDLEY participates needed to be above that AUC PK criteria, and 95.8% of infants receiving 

200 mg of nirsevimab for their second RSV season were above that AUC criteria. The WG had 

very serious concerns about the evidence for protection against MA RSV LRTI because of 

indirectness with PK being used as a surrogate outcome and because the AUC PK threshold 

was determined in the first season, while the indication is for the second RSV season. In 

addition, the population was limited to children with CHD and CLD, while other conditions are 

being considered as proposed indications for nirsevimab dose for children entering their second 

RSV season. The evidence type was low certainty (type 3). 

For safety, no SAEs were reported for the group who received palivizumab in both seasons. 

Among groups who received nirsevimab in the second season, approximately 9% to 10% 

experienced an SAE. None of these SAEs were deemed by trial investigators to be related to 

the product, and no deaths were reported. The relative risk of having an SAE among those who 

received nirsevimab in their second RSV season compared with those who received 

palivizumab in their second RSV season was 8.4 (95% CI: 0.52-135.50) but with a wide 

confidence interval. Serious concerns were raised about indirectness because the comparison 

group was palivizumab recipients rather than placebo. Additionally, there were serious concerns 

about imprecision because of the small number of participant in the trial. Combined, there was 

very low certainty in the evidence (type 4). 

In summary of GRADE for a nirsevimab dose for the second season, nirsevimab might be 

effective in preventing MA RSV LRTI but with low certainty. SAEs may not be more common in 

recipients of nirsevimab compared with children receiving no nirsevimab, but there is very low 

certainty. No data were available for other outcomes. Overall, the evidence rating was very low 

certainty (type 4). The WG felt the desirable anticipated effects were moderate and undesirable 

anticipated effects were minimal. However, some WG members felt that they did not know or 

that the undesirable anticipated effects were small to moderate. For palivizumab-eligible 

children, the WG felt that the desirable effects outweigh the undesirable effects and favors 

nirsevimab. 

In terms of the Values, Acceptability, and Feasibility domains, no additional data were available 

for values or acceptability specific to high-risk populations. The WG felt that the target 

population feels that the desirable effects are probably large relative to the undesirable effects 

and that there is probably not important uncertainty or variability. For palivizumab-eligible 

children, the WG felt that nirsevimab is acceptable or probably acceptable to key stakeholders. 

An additional consideration for feasibility is that an additional visit to a provider might be needed 

for administration of nirsevimab prior to the beginning of a second RSV season, either at a 

specialist clinic or a primary care provider. The WG felt that it was probably feasible to 

implement nirsevimab to palivizumab-eligible children <20 months of age entering their second 

RSV season. 

For the Resource Use domain question regarding whether nirsevimab use among all high-risk 

children aged <20 months of age entering their second RSV season would be a reasonable and 

efficient allocation of resources, at $600 per child, the WG felt it was probably a reasonable and 

efficient allocation of resources. However, at $1,000 per child, the WG was split if it probably 

was or was not a reasonable and efficient allocation of resources. 

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For the Equity domain, equity issues are different by chronic condition among infants and young 

children. For example, non-Hispanic Black populations experience higher rates of preterm birth 

than non-Hispanic white populations.58 The majority of children with cystic fibrosis are from nonHispanic white populations.59 Hispanic populations may have a higher prevalence of Down 

syndrome than non-Hispanic white populations.

60 Hispanic and non-Hispanic AI/AN populations 

may have higher prevalence of neuromuscular disorders than non-Hispanic White 

populations.61 

There was no consensus on the impact of equity. Many WG members felt that it would have no 

impact among palivizumab-eligible children, but several felt it could increase or reduce equity or 

did not know. The primary concern was that it is unknown whether this will be included in VFC. 

After reviewing the totality of the data and acknowledging uncertainties around aspects of the 

data, the WG felt that the desirable consequences probably outweigh the undesirable 

consequences. The WG proposed to ACIP to recommend the intervention for palivizumabeligible children as defined by the AAP guidance. However, additional conditions will be 

reviewed. 

In summary for the first RSV season, the WG recommended nirsevimab a) at birth for all infants 

born during October to March and b) when entering first RSV season and <8 months of 

age for all infants born during April through September. However, many members expressed 

concerns about feasibility and equity, particularly because inclusion in VFC is unknown. Some 

WG members expressed concern that at higher prices, nirsevimab may not be a reasonable 

and efficient allocation of resources. For the second RSV season, the WG would like more time 

to consider which infants and children would be sufficiently high-risk to warrant nirsevimab in 

their second RSV season. There are limited efficacy and safety data available at this time in this 

population, and there are little data to measure the risk of severe disease in the second RSV 

season by chronic condition. At this time, the WG recommended nirsevimab for those who are 

eligible for palivizumab in their second RSV season per AAP guidance. Because nirsevimab is 

assumed to cost less than palivizumab and to be of noninferior efficacy, this was assumed to be 

cost-effective. The WG will continue to evaluate other conditions. 

If licensed by FDA, the 2 policy questions ACIP will be asked to vote on are as follows: 

 Should one dose of nirsevimab be recommended a) at birth for all infants born during 

October to March and b) when entering first RSV season and <8 months of age for all 

infants born during April through September? 

 Should one dose of nirsevimab be recommended for children <20 months of age entering 

their second RSV season who are eligible for palivizumab in their second RSV season? 

(Note: the second question may have other conditions added). 

58 https://www.cdc.gov/reproductivehealth/maternalinfanthealth/pretermbirth.htm 59 McGarry Pediatr Pulmonol 2021 Jun;56(6):1496-1503 60 Mai Birth Defects Res 2019 Nov 1;111(18):1420-1435 

61 Mai Birth Defects Res 2019 Nov 1;111(18):1420-1435 

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Clinical Considerations for Nirsevimab 

Jefferson Jones MD, MPH, FAAP, CDR USPHS (CDC/NCIRD) presented draft Interim Clinical 

Considerations and explained that the goals of the WG were to develop simple, uniform 

recommendations that apply to most US healthcare providers, and provide flexibility for specific 

situations. For the first indication for infants born during or entering their first RSV season, there 

were some important considerations for the WG when developing recommendations. In terms of 

timing and administration considerations, nirsevimab efficacy against MA RSV LRTI and 

hospitalization in the RCTs was assessed through 150 days after administration, so the efficacy 

beyond 150 days is unknown. Only 1 dose of nirsevimab is recommended per season, even if 

given early in the season. If the nirsevimab dose is given too early before the season such as in 

May or June during the peak of the RSV season, the infant could be beyond 150 days after the 

dose and have waning protection. Thus, nirsevimab administration should be timed to maximize 

protection during the RSV season when infants are most at risk of exposure to RSV. For infants 

born during October─March before the start of most RSV seasons and during the months with 

the highest RSV activity, the optimal timing of nirsevimab dosing is at birth. For infants born 

during April─September in months typically with low RSV circulation, the ideal timing for 

nirsevimab dosing is just before or near the start of the RSV season. Typically, this is midOctober to early December. The 150-day period after administration includes the months of 

peak RSV circulation, December─February when the infant is most at risk of exposure to RSV. 

Therefore, for infants born during October─March, nirsevimab is recommended shortly after 

birth or as soon as possible afterwards. Administration in the hospital prior to discharge is 

recommended to ensure protection. If this is not possible, administration at the first visit to the 

primary care provider, ideally within 1 week of discharge, can be considered. However, not all 

infants are taken to their provider in the first week after discharge. For infants born 

April─September, nirsevimab is recommended to be administered during October─November 

such as during regularly scheduled 2-, 4-, or 6-month well-child visits. 

Regarding additional considerations, during the COVID-19 pandemic interseasonal RSV 

transmission has occurred. The WG has expressed that it is important to allow for flexibility of 

timing in nirsevimab administration during periods of significant interseasonal RSV transmission. 

However, for the upcoming 2023-2024 season, nirsevimab may not be available prior to 

October 2023. As a reminder, the incidence of RSV-associated hospitalization is substantially 

higher during the first 2 months of life and decreases with each month of life.

62 This needs to be 

balanced. The recommended timing of administration previously presented should serve as a 

uniform recommendation. If increased RSV transmission is occurring locally in August or 

September, nirsevimab could be administered earlier than October if available. The NREVSS 

data could be used as one factor in decision-making. Census division-level or HHS regionallevel data is recommended to be used as some state-level data may not be representative. 

Specific to NREVSS data, and not local hospital or other data sources, greater than 3% 

positivity of PCR tests for 2 consecutive weeks can indicate an increased rate of RSV 

detection.63 To determine if nirsevimab should continue to be administered to newborns shortly 

after birth beyond March, local jurisdictions can alter administration schedules based on local 

transmission conditions with clear evidence of ongoing increased transmission. Local data may 

be a best indicator, but the WG recommended establishing an evidence-based threshold. As 

noted earlier, NREVSS data at the Census division-level or HHS regional-level could be used as 

62 2000-2005: Adapted from Hall et al, Pediatrics 2013; 2016-2020: CDC unpublished data 63 https://www.cdc.gov/surveillance/nrevss/index.html 

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one factor in decision-making. For NREVSS data, <5% positivity of PCR tests for 2 consecutive 

weeks can indicate decreasing transmission. 

There are some particular geographic considerations. Tropical climates (e.g., Hawaii, Guam, 

and the US-affiliated Pacific Islands) may have RSV seasonality that differs from the majority of 

the continental US or is unpredictable. Providers in these areas are recommended to administer 

nirsevimab to newborns shortly after birth throughout the year to maximize protection in the first 

150 days of life—the age at which infants are at the highest risk of hospitalization with RSV. 

Some specific jurisdictions such as Puerto Rico are recommending nirsevimab during 

August─March. Providers can consult with local state or territorial health departments for 

recommendations. In Alaska, RSV seasonality is less predictable and the duration of RSV 

activity is often longer than the national average. Similar to palivizumab guidance from the AAP, 

providers are recommended to use RSV laboratory surveillance data generated by the State of 

Alaska to assist in determining the appropriate timing of nirsevimab. The Alaska Department of 

Health will continue to provide clinicians with updated Alaska-specific guidance. Infants residing 

in remote areas who travel long distances to receive well-child care (e.g., those who require 

medical evacuation by air for severe disease) can be given nirsevimab outside the normal 

schedule if there is concern that the infant may not have access to nirsevimab at the 

recommended time. 

For the second RSV season indication, the same groups who are currently eligible for 

palivizumab when entering their second RSV season per AAP recommendations64 are 

recommended for nirsevimab when entering their second RSV season. These groups include 

the following, with other conditions under review: 

 Children with chronic lung disease of prematurity if require medical support (chronic 

corticosteroid therapy, diuretic therapy, or supplemental oxygen) during the 6-month period 

before the start of the second RSV season 

 Children who are profoundly immunocompromised 

 Children with cystic fibrosis with manifestations of severe lung disease (previous 

hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest 

XR or CT that persist when stable) or weight for length <10th percentile 

In terms of the timing of nirsevimab administration for the second RSV season, nirsevimab 

should be administered during October─November when children are normally entering the 

RSV season. Nirsevimab is not recommended to be used after the second RSV season. 

Safety and Efficacy of RSV Bivalent Prefusion F (PreF) Maternal Vaccine 

Iona Munjal, MD (Pfizer) presented data from Pfizer’s ongoing maternal vaccine program for its 

bivalent RSVpreF candidate. They believe that this is the first time a maternal vaccine for infant 

efficacy has been presented in this forum, which brings them great joy regarding the future of 

maternal vaccines. The proposed indication Pfizer is seeking is the prevention of lower 

respiratory tract disease (LRTD) and caused by RSV in infants from birth through 6 months of 

age by active immunization of pregnant individuals. The dose level is 120 μg without an 

adjuvant. Each dose contains 60 μg of each prefusion protein antigen A and B in a 0.5 mL 

injection. The presentation is a lyophilized vial with water for injection in a prefilled syringe. The 

vaccine is to be stored at 2°C to 8°C. 

64 American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Updated guidance 

for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus 

infection. Pediatrics. 2014 A ug;134(2):415-20. 

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The target of Pfizer’s RSVpre-F vaccine is the surface F protein. The F protein is anchored on 

the surface of the virus. It undergoes a change from its metastable prefusion conformation to a 

stable post-fusion conformation, causing it to fuse with the host cell membrane and facilitate cell 

entry. The Pfizer vaccine targets the prefusion form to induce antibodies that are most effective 

at blocking viral infection. This graphic provides an overview of Pfizer’s RSVpreF maternal 

clinical development program: 

During this session, Dr. Munjal focused on 2 maternal studies including the Phase 2b dosefinding and immunogenicity study and the Phase 3 efficacy study. Both studies were conducted 

in pregnant women who were between 24 and 36 weeks gestation at the time of vaccination. 

The Phase 2b study was a proof-of-concept study. In terms of immunogenicity results in a 

subset of participants who received the 120 μg dose from a total of 562 enrolled maternal 

participants following vaccination, the neutralizing GMTs were robust at 1 month after 

vaccination and remained high at delivery and at 6 months postpartum. The RSVpre-F 

antibodies were found to be efficiently transferred to the infant based on maternal serology at 

delivery and contemporaneous infant cord blood samples. At the 120 μg unadjuvanted selective 

dose, transplacental transfer ratios were > 1 overall and were high by geography and in each 

maternal gestational age category at vaccination. 

Looking at the kinetics of the antibody responses following transplacental transfer in infant 

participants at birth, 1, 2, 4, and 6 months after birth, the RSVpre-F group remained higher than 

placebo at all time points. Although there is no correlative protection, for comparison, a 

reference titer of 100 ug/mL palivizumab was demonstrated to be efficacious in preventing infant 

RSV-associated ICU admission.

65 

65 Forbes ML, Kumar VR, Yogev R, et al. Hum Vaccin Immunother 2014;10:2789-94 

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The Phase 3 efficacy study, Maternal Immunization Study for Safety and Efficacy (MATISSE), 

was conducted in 18 countries globally (3 North American countries, 3 South American 

countries, 4 countries in Europe, 2 African countries, and 6 countries in the Asia-Pacific region). 

Women were enrolled if they met qualifying criteria and were less than ≤49 years of age and 

between ≥24 and ≤36 weeks gestation at the time of enrollment. Over 7,000 vaccinated mothers 

and their infants were included in this analysis. The study began in June 2020 and follow-up 

with the cohort is ongoing until the last infant completes the study in the fourth quarter of 2023. 

This study covered 4 seasons, 2 in the Southern Hemisphere and 2 in the Northern 

Hemisphere. Women were randomized 1:1 to receive either the study vaccine or placebo. The 

participants randomized to the RSVpre-F group received a single dose of the 120 μg bivalent 

vaccine, which contains equal amounts of each prefusion F antigen from RSV subgroups A and 

B. The vaccine does not contain any adjuvant. Maternal participants were screened, including 

with an ultrasound, if not already performed, as standard of care prior to vaccination. 

Safety was monitored with a self-reported e-diary mobile device soliciting AEs for 7 days 

following vaccination. All AEs were collected for a month as delivery was a variable time period 

that may have occurred at any time after vaccination. Most participants’ deliveries occurred 

outside of the AE 1-month period. AESIs, including preterm delivery, and SAEs were collected 

throughout the study period. In these maternal participants, surveillance for respiratory tract 

illnesses was conducted through chart reviews, but swabs were not taken. For the infants born 

to those vaccinated mothers, AEs collected from their first 5 breaths to 1 month after birth. 

AESIs, SAEs, and newly diagnosed chronic medical conditions were collected throughout the 

study period. The infants enrolled in the first year of the study were followed for 2 years, which 

was approximately half the infants. The remaining infants were enrolled for 1 year. Respiratory 

tract illness surveillance was conducted throughout the study period, with swabs being 

performed for all MA respiratory events in the first 6 months and for hospitalization and severe 

illness respiratory events throughout the study period. All cases were adjudicated by an 

independent event adjudication committee. 

In terms of demographics, the maternal characteristics reflected the diverse study population 

and were similar between the RSVpre-F and placebo groups. The average age at vaccination 

for maternal participants was 29 years, with participants ranging from 14 to 47 years overall. 

Data were generated in adolescent participants, and Pfizer will propose to include them in the 

indication. The average gestational age at vaccination was 30 weeks, with a substantial number 

of participants vaccinated early in the qualifying 24─36-week gestational window. Infant 

participants also represented a diverse population. There were approximately equal numbers of 

male and female participants. Demographics were similar between the RSVpre-F and placebo 

groups. 

The primary objective for the Phase 3 study was to describe the safety profile of RSVpreF in 

maternal and infant populations. For efficacy, there were 2 equal primary endpoints which were 

prevention of RSV MA-LRTI within 180 days after birth and prevention of RSV severe MA-LRTI 

within 180 days after birth. The secondary efficacy endpoints include prevention of RSV MALRTIs within 360 days after birth, prevention of RSV hospitalization within 360 days after birth, 

and prevention of MA-LRTIs due to any cause within 360 days after birth. 

Beginning with the safety data for maternal participants and reactogenicity that was solicited in 

those vaccinated women in their e-diaries, solicited local reactions were mostly mild or 

moderate and were higher in the vaccinated group. The most commonly reported local reaction 

was injection site pain. The solicited e-diary systemic events by maximum severity, again from 

maternal participants following vaccination, were mostly mild or moderate. There were 2 fevers 

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reported overall and were similar between the vaccine and placebo groups. The most commonly 

reported event, fatigue, was similar between the vaccine and placebo groups. Headache 

incidence was slightly higher in the RSVpre-F group compared to the placebo group. Muscle 

pain was reported more frequently in the RSVpre-F group compared to the placebo group. In 

terms of AEs by type in the maternal participants within one month after vaccination, overall AEs 

were common. This was expected from known background rates, and this was a maternal study 

that included a delivery period. In each category, the events were similar between the RSVpre-F 

and placebo groups, including the category of SAEs. There have been 5 related SAEs reported 

in the study to date, all of which were in maternal participants. There were 4 related SAEs in the 

RSVpre-F group and 1 in the placebo group. All of the events were reported as having been 

resolved. 

Among infant participants, the rates of AEs overall in the first month after birth were higher in 

the maternal participants. This too was expected from known background rates for a study 

covering the neonatal period. The events were similar, with no statistically significant differences 

seen between the RSVpre-F and placebo groups in all categories, including AESIs and in 

congenital anomalies. Focusing on AESIs include terms of prematurity, low birth weight, and 

events of developmental delay. These were collected throughout the student period and were 

similar in the RSVpre-F and placebo groups. Global estimates put infant prematurity at 

approximately 10% of all births. The rate of prematurity in the study was low, at a little over 5% 

for all infant participants. This likely reflects the maternal eligibility criteria in the study, including 

the inclusion of singleton pregnancies only. 

With respect to all of the deaths and fetal losses reported in the trial, all events were deemed 

unrelated by the investigator and sponsor. These data, along with safety information in the 

ongoing study, are reviewed by an external data monitoring committee. The External 

Adjudication Committee (EAC) reviews all deaths related to respiratory illnesses of any etiology. 

Maternal deaths were rare. There was a single maternal death, which occurred in a woman in 

the Philippines who had an unexpected home birth and died of hypovolemic shock secondary to 

post-partum hemorrhage approximately 2 months after vaccination. The majority of pregnancies 

in RSVpre-F vaccinated mothers resulted in live births. Still births and fetal deaths were rare 

and were reported in no more than 0.3% of participants in each group, or 10 in the RSVpre-F 

group and 8 in the placebo group. The incidence rate of fetal demises in maternal participants 

who received RSVpre-F was lower than estimated background rates globally and by country. 

There were 17 deaths overall at the time of the analysis, 5 in infants born to RSVpre-F 

vaccinated mothers and 12 in infants born to placebo recipients. There was only 1 infant 

associated with RSV, which was in an infant from Japan in the placebo group. 

The efficacy data in the pivotal Phase 3 MATISSE study were based on an interim analysis 

conducted in October 2022, which was successful and resulted in a final analysis of all of the 

infant efficacy data. Infant participants were followed regularly by weekly e-diary response or 

phone contacts to determine if they had ever sought care in that past week for a respiratory tract 

illness. Each time they did, a study swab was taken for RSV and vital signs were systematically 

collected by the study site. All data collected from the study sites, physicians, and hospital visits 

were collated for a combined review of data by an independent adjudication committee to 

determine if it was a case. All cases had to have a valid molecular swab positive for RSV. Case 

definitions used by the adjudication committee are listed here: 

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Primary Endpoint Criteria 

Medically-Attended RSV LRTI Medically attended visit and ≥1:

• Tachypnea (RR ≥60 (<2 m [60 days]) or ≥50 (≥2 to 12 

m) 

• Peripheral capillary oxygen saturation (SpO2) 

measured in room air <95% 

• Chest wall indrawing 

Medically Attended Severe RSV LRTI Medically attended visit and ≥1:

• Tachypnea (RR ≥70 (<2 m [60 days]) or ≥60 (≥2 to 12 

m) 

• SpO2 measured in room air <93% 

• High-flow nasal cannula or mechanical ventilation 

• ICU admission for >4 hours; unresponsive/ 

unconscious 

Based on the successful interim efficacy analysis at 90 days, the full analysis of infant efficacy 

endpoints was conducted on the infant available efficacy population. For severe medically 

attended LRTI, the statistic criterion for success with a lower bound of 20% was met with 39 

cases within 90 days after birth. VE of 81.8% was similarly met with 69.4% efficacy at 180 days 

with 81 total cases. Cases are cumulative at each time point. For medically attended LRTI, the 

interim analysis results based on 80 cases at 90 days did not meet the statistical criterion for 

success with the lower bound of 20%. Because that interim analysis required the use of the very 

stringent 99.5% confidence level, it is notable that the confidence interval for VE at later time 

points analyzed after the successful interim analysis all had a lower bound greater than 20%, 

with point estimates comparable to the 90-day result. Medically attended LRTI to 180 days 

included 174 total cumulative cases of RSV-positive events, with an observed VE of 51.3%. 

In terms of the secondary endpoint of the efficacy of RSV-positive medically attended LRTI 

within 360 days after birth with 240 reported cases, the cumulative VE met the statistical 

criterion for success of a confidence interval lower bound more than 0% at all timepoints, 

corresponding to an observed VE between 40% and 45%. For the secondary endpoint of RSVpositive hospitalizations within 360 days after birth, all infants were included who had confirmed 

RSV that resulted in an admission to a hospital. Although severity criteria were not applied, 

more than half of these cases also meet the criteria for severe medical attended LRTI. With 63 

cases of hospitalization with confirmed RSV, VE was met for the predefined criterion within 180 

days. 

Regarding the exploratory endpoint of RSV-positive MA-RTIs confirmed by the EAC, there were 

no prespecified criteria for success on the exploratory endpoint, so a 95% confidence interval 

was used for presentation purposes. This endpoint looked at all RSV-positive MA-RTI infants 

who had respiratory tract illness symptoms (e.g., an infant who was taken to the physician or for 

whom other healthcare was sought who were confirmed to have a valid RSV test within 6 

months of birth). Similar to the hospitalization endpoint, severity criteria were not applied. VE 

was approximately 38% to 39% through the 6-month period, with confidence intervals above 

zero for all time points, showing that VE was demonstrated across the spectrum of RSV disease 

even down to milder presentations. With regard to efficacy across MA-LRI by RSV subgroup A 

or B, for demonstration purposes a 95% confidence interval was used to evaluate the efficacy of 

A and B as there is no prespecified lower-bound criterion for an exploratory endpoint. 

Nonetheless, efficacy for RSV A and B was largely consistent with the overall analysis. For RSV 

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A, there were lower cases overall. Interestingly, this was seen in each year of the study and in 

each season. This resulted in overlapping but wider confidence intervals. 

In summary, the Phase 3 trial demonstrated that the RSVpre-F investigational vaccine was welltolerated with a favorable benefit-risk profile. The totality of the data demonstrates that efficacy 

in infants born to mothers vaccinated at 24 to 36 weeks was met for the severe MA-LRTI 

endpoint through 6 months. Clinically meaningful efficacy was observed for the MA-LRTI 

endpoint through 6 months. When combined with the secondary endpoint, efficacy was 

demonstrated through a year. 

Workgroup Considerations 

Katherine Fleming-Dutra, MD FAAP (CDC/NCIRD) presented the WG’s considerations 

regarding maternal RSV vaccine. The policy question being considered by the WG is: 

 Should the Pfizer RSV bivalent prefusion F vaccine be recommended for all pregnant 

people as a single dose given at 24─36 weeks gestation? 

This maternal vaccine has targeted prevention of RSV disease in infants. Therefore, should this 

vaccine be licensed by FDA, this recommendation would be considered in the context of the 

current standard of care for prevention of RSV in infants at the time of ACIP vote. 

To highlight a few key considerations regarding this vaccine, including what the data from the 

trial show regarding the timing of dose within pregnancy, as stated by the manufacturer, the 

dosing window in the trial was 24─36 weeks gestation. Currently, no data are available on 

efficacy stratified by gestational age at time of administration. It is important to note that the 

majority of infants in the Phase 3 trial were born at term, meaning ≥37 weeks gestation, and 

most doses in the Phase 3 trial were given at ≥28 weeks gestation. This means that the efficacy 

data from the Phase 3 trial largely reflects doses given in the third trimester. Data regarding 

efficacy in infants born preterm are limited. 

Regarding the number of total lifetime doses, all pregnant people in the trial received their first 

and only doses of RSV vaccine. Currently, there are no data available on the efficacy of the first 

lifetime dose during subsequent pregnancies or the safety of additional doses given in 

subsequent pregnancies. 

In terms of the proposed tentative timeline for future ACIP presentations regarding this vaccine, 

during the June 2023 ACIP meeting, the WG plans to present a summary of the GRADE 

evidence, a cost-effectiveness analysis, and the EtR framework. An ACIP vote could be held in 

October 2023 if the product is licensed by that time. 

ACIP Discussion Points, Observations, Suggestions on Pediatric/Maternal RSV Vaccines 

Following Dr. Hutton’s Presentation 

• The theoretical uptake assumption of 100% in the base-case seems unlikely. There are 

parents who refuse vitamin K and hepatitis B vaccine. Dr. Hutton agreed that there 

probably would not be 100% uptake, but with lower uptake, the ICER would be the same 

because there would be a lower cost of giving nirsevimab. 

• Given that nirsevimab dosing is weight-based, it was not clear what the thinking was 

behind the $300 assumption. Dr. Hutton clarified that weight was not taken into 

consideration in the model, but they had to pick some numbers. $300 was thought to be 

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reasonable, but the sensitivity analysis was run because the manufacturer has a 

different cost in mind. It also is important to keep in mind that the price the manufacturer 

sets may not be the price payers pay. The current understanding is that the price will be 

identical for the lower and higher doses. 

• Regarding a question about whether consideration was given to recommending 

nirsevimab for breast-fed babies who are exclusively human milk-fed and would have 

significant protection against RSV already, Dr. Hutton indicated that this was not taken 

into account and it was assumed for the analysis that there would not be a differential for 

breast-fed versus non-breast fed newborns receiving nirsevimab. 

• In terms of whether information would be provided on non-medically-attended RSV 

infections, Dr. Hutton indicated that the initial model leaned toward making conservative 

assumptions until additional data become available, at which time adjustments will be 

made to the model. 

• Concern was expressed that high-risk children born outside of an RSV season could be 

placed at risk of infection for some period of time based on the administration schedule. 

Following Dr. Ortega-Sanchez’s Presentation 

• While the idea of giving nirsevimab to all infants seems to be that this would postpone 

their first RSV infection until they are older when infections seen in children 2 to 3 years 

of age are typically reinfections and are milder, clinicians are seeing a lot more RSV in 

children 2 to 3 years of age who have never had infection and it is more prevalent. It 

would be beneficial to try to capture additional information through existing surveillance 

systems to provide more insight on this. 

• There is no evidence that this monoclonal antibody will prevent infection, so it may not 

be putting off infection and instead may be making the first infection less likely to be 

symptomatic. 

• Regarding a question about whether there are second-year data to show that the 

immune responses post-antibody infusion are not aberrant and are actually helpful, to 

comment on what the company is doing, rates of RSV MA or LRTI and hospitalization for 

the second season were presented in October 2022. The Phase 3 trial did not show 

increased rates among those who received nirsevimab versus placebo. NSVN data will 

allow for assessment in these age groups. 

Following Dr. Jones’s Presentations 

• While the burden of RSV and its impact on young children and families are huge, there 

are numerous logistical challenges that ACIP needs to think about carefully (e.g., 

potential to worsen disparities, timing, cost, billing, who can administer, bundled 

insurance payments for birth hospitalizations, cost, the need to know what a child has 

received, coadministration with other vaccines, AE reporting to FAERS and VAERS, et 

cetera). 

• Dr. Jones indicated that in terms of bundled payments, CDC is in discussion with 

multiple agencies to try to address some of the many challenges so that if nirsevimab is 

licensed, there will be as smooth as possible a process going into the upcoming RSV 

season. They have heard that while there may not be initial reimbursement, if ACIP 

recommends nirsevimab and it is widely used, bundled payments would be updated to 

reflect the increased cost from its use. 

• Dr. Sarah Meyer from CDC’s Immunization Services Division (ISD) emphasized that 

ensuring equitable access is one of the highest priorities. CDC wants to ensure that all 

children have access if nirsevimab is licensed and recommended. The VFC program has 

been very effective in helping to reduce disparities for childhood vaccines. There are a 

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lot of complexities with this being characterized as a therapeutic and not vaccine, many 

of which have been highlighted in his talk. This is another example of there being a few 

additional issues that need to be worked through, but those discussions are underway. 

CDC is working closely with other federal agencies, including CMS, to explore all options 

to make sure that equitable access of this product can be achieved if it is approved and 

recommended. Further updates will be shared with the WG and ACIP as soon as 

possible. 

• In terms of coverage, Dr. Romero added that current analyses based on Census data 

suggest that approximately 5.7% of all children <3 years of age are not covered by 

private insurance, Medicaid, or CHIP. 

• Regarding adverse reporting, Dr. Jones explained that FAERS differs from VAERS. 

Many providers are familiar with the CDC VAERS platform. Colleagues from FDA’s 

Center for Biologics Evaluation and Research (CBER) have been informing CDC about 

the system. The current understanding is that AEs following receipt of nirsevimab would 

be reported to VAERS and reports would be forwarded to FAERS. The hope is to 

present further information on the FAERS system during a future ACIP meeting. 

• Dr. Shimabukuro added that nirsevimab is regulated by CBER as it is a CBER product, 

so it is monitored by FAERS. There are processes in place for VAERS and FAERS to 

redirect to reports that are submitted the wrong system. If VAERS receives reports, there 

will be a process for redirecting those to FAERS and vice versa. Many of the monitoring 

issues may be related to coordinating with FDA to make sure that CDC is aware of 

safety findings. CDC also plans to monitor nirsevimab in the VSD, planning for which is 

underway. While it is challenging to monitor safety when multiple vaccines or products 

are being administered, CDC will have the data to assess co-administration. CDC also 

has the Clinical Immunization Safety Assessment (CISA) Project that provides 

consultations for US healthcare providers of complex AEs associated with a product or 

when the product is given with other vaccines. In addition, CDC is in the process of 

developing the next generation v-safe, which also could be used to monitor the safety of 

this product. 

• In terms of coadministration, Dr. Jones conveyed that the consensus of the WG was 

there is a lack of data but that theoretically, adding passive immunization to regular 

childhood vaccines poses a low risk. 

• CDC’s Dr. Melissa Coughlin and Dr. Natalie Thornburg agreed that while there are no 

data, the theoretic risk that providing an antibody in conjunction with a vaccine for any 

AE is low. The best source of information is to look at palivizumab administration for 

safety signals. Palivizumab has been used for a very long time, though in a small 

population, but no safety signals have been observed thus far. Direct and indirect data 

could be provided during a future ACIP meeting. 

• In terms of the birth dose, many institutions already have infrastructure in place for the 

hepatitis B dose. It might be beneficial for ACIP to understand that process and how to 

expand it, as well as birth dose coverage. 

• ACIP members expressed concern that nirsevimab may be considered a drug rather 

than a vaccine. While it is not technically a vaccine, it confers passive immunization in 

the same way that most other vaccines do that are given to children. If it is not covered 

under the VFC program, there will be numerous problems. Leaving this up to individual 

states almost certainly will lead to inequities of delivery. From a feasibility standpoint, it is 

unclear what would happen in practices if nirsevimab is classified as something other 

than a vaccine. The bottom line is that if this product is licensed, it should be made 

available for all children without regard to the ability to pay. It is not clear how that would 

happen beyond inclusion in the VFC. 

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• Dr. Rebecca Coyle, Executive Director of the American Immunization Registry 

Association (AIRA), highlighted some of the known issues that exist with regard to IISs. 

They are aware that there are going to be challenges implementing nirsevimab using the 

routine systems in terms of the clinical decision-making perspective, given that 

forecasting has to account for seasonality and locality. There also are likely to be issues 

with how data would be submitted to IISs because there are uniform code sets that all 

EHRs and IISs use, and it could be costly to modify systems because this product is not 

considered a vaccine. While many partners are working through these challenges, it is 

unlikely that operationalization would take effect immediately when the product goes live. 

• There are lessons learned from Evusheld, which could be used as a model. It would be 

beneficial for standardization of what products ACIP considers. ACIP did not review 

Evusheld, nor is that information logged into IISs. 

• Dr. Long, WG Chair, emphasized that it will be imperative for the WG and ACIP to better 

understand the actual cost of nirsevimab, including administration costs. When the WG 

asked the manufacturer and they presented $500, the WG had assumed a lower cost of 

$300 and had modeled that. Giving this to a birth cohort could cost a billion dollars, not 

even considering the administration fee. Given that the VFC’s budget is $5 billion, other 

important vaccines could be dropped. It would be difficult for the WG or ACIP to say that 

there would be a recommendation regardless of cost. There was a sense in the WG that 

at a cost of $200 to $300, this could be doable. However, there was considerable 

trepidation among WG members for anything more than that. The WG also felt that there 

would have to be a decision about the VFC and how this product would be provided in 

order to make an ACIP recommendation. 

• In the era of vaccine hesitancy, there will need to be considerable education that this 

medication is not a vaccine per se. There have been horrific issues with palivizumab in 

terms of conflicting recommendations at the local level and parental acceptance. 

Following Dr. Munjal’s Presentation 

• Data on whether maternal participants were breastfeeding or not would help to 

differentiate the impact of breastfeeding on the antibody response in the infant. Dr. 

Munjal indicated that Pfizer studies are collecting data on breastfeeding in terms of 

exclusivity and duration, which will be analyzed in the future. However, they do not have 

data on breastmilk composition or antibodies in breastmilk in either of the studies. 

• It would be beneficial to have more granular data at some point on maternal outcomes 

(e.g., mode of delivery, preeclampsia, preterm labor, gestational hypertension, et 

cetera). Dr. Munjal indicated that Pfizer does have data on pregnancy-related events for 

which they can provide additional data. 

• Regarding coadministration questions, Dr. Munjal reported that Pfizer has 2 published 

trials. One characterized coadministration with influenza in nonpregnant patients and the 

other was a noninferiority study assessing Tdap coadministration in women. The 

influenza coadministration was a descriptive not a noninferiority study. Among the 

nonpregnant participants in the lower age groups, there was a trend toward lower titers 

to influenza overall. Therefore, coadministration was not recommended in the Phase 3 

study. The 120 μg RSVpre-F vaccine is being studied in the older adult population, and 

there is a study ongoing that is assessing noninferiority of coadministration in the older 

adult population. For the maternal population, there would be no additional clinical 

studies. Pfizer would analyze that in a larger post-marketing cohort. 

• Regarding a request for further details about congenital malformations in the vaccine 

and placebo cohorts, Dr. Munjal indicated that congenital anomalies are collected in all 

of Pfizer’s clinical studies throughout the study period. In order to have the most 

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complete and consistent reporting, investigators are asked to follow guidance by the 

CDC’s Metropolitan Atlanta Congenital Defects Program (MACDP). A systematic list of 

congenital anomalies were collected throughout the study. The rates of congenital 

anomalies were 5.9 in the placebo group and 4.8 in the RSV pre-F group, so there was 

no difference between the groups. Background rates are complicated because there is 

variable reporting on congenital anomalies in terms of WHO rates versus US rates. 

Pfizer anticipated a similar background rate, but that was based on comparable maternal 

studies not other studies of background rates because this population is quite unique in 

that it self-selects for women who have had required screening ultrasounds. Those 

whose infants have congenital defects identified by screening ultrasound are excluded. 

Following Dr. Fleming-Dutra’s Presentation 

• Prior to making a decision, ACIP would appreciate having information on 

coadministration with influenza, RSV, COVID, and Tdap vaccination that include 

antibody levels. 

• Thinking about the potential for a combined platform of nirsevimab and this vaccine, 

consideration needs to be given to: 

− Integrating these from a decision-making perspective with regard to benefits and 

risks 

− Having a monoclonal antibody available to pregnant persons who deliver early 

and may not have an opportunity to be vaccinated 

− Understanding the biological implications and safety of maternal vaccination 

followed by passive immunization of the infant 

− Contemplating how to address pregnant persons who receive scant prenatal care 

− Understanding how pregnant people feel about acceptability, values, and 

preferences with regard to receiving a vaccine after pregnancy or having their 

infant receive nirsevimab 

RSV VACCINES: ADULT 

Introduction 

Camille Kotton, MD (Chair, Adult RSV WG) introduced the adult RSV vaccines session. She 

reminded everyone that the October 2022 sessions included a manufacturer safety and efficacy 

presentation by GSK regarding the adjuvanted candidate RSV vaccine for older adults 

(RSVpreF3); a manufacturer safety and efficacy presentation by Pfizer regarding bivalent 

candidate RSV vaccine for older adults (RSV pre-F); and a WG presentation on interim 

considerations regarding novel RSV vaccines for older adults. Recent WG discussions have 

focused on cost-effectiveness of RSV vaccination among US older adults, GRADE and EtR for 

GSK adjuvanted RSVpreF3 and Pfizer bivalent RSVpreF, and CDC vaccine safety surveillance 

systems. The WG’s recent discussions have focused on possible policy recommendations for 

RSV vaccines of US older adults including whether RSV vaccines should be recommended for 

US adults ≥65 years of age or if RSV vaccines should be recommended for US adults ≥60 years 

of age. GSK and Pfizer have submitted BLAs to the FDA for use of these products in adults ≥60 

years of age. The FDA’s target action for a regulatory decision is in May 2023. ACIP 

recommendations would be made only if the vaccines are approved and licensed by FDA. This 

session included presentations on the cost-effectiveness of RSV vaccination among US older 

adults; a comparison of RSV vaccination economic analyses performed by the University of 

Michigan/CDC, GSK, and Pfizer; the EtR framework for GSK and Pfizer candidate vaccines; 

and vaccine policy options. 

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Cost-Effectiveness of the GSK and Pfizer Vaccines: Main CDC Model 

David W. Hutton, PhD, MS (University of Michigan) presented the results of the University of 

Michigan/CDC (UM-CDC) economic analysis of RSV vaccination in older adults. The overall 

goal was to evaluate the cost-effectiveness of RSV vaccination in the US population ≥60 years 

of age. Vaccine policy was evaluated for several age groups (≥60 years, ≥65 years, ≥70 years, 

and ≥75 years). The outcomes examined included resource utilization, cases, costs, deaths, 

and QALYs lost from RSV with or without vaccination. The ICER of vaccination was compared 

to no vaccination and scenario analyses were performed that examined key areas of uncertainty 

related to these questions. Intervention with GSK and Pfizer vaccines were examined. Each 

vaccine was individually compared to a no vaccination strategy. The base-case assumed an 

age-based RSV vaccination recommendation for adults ≥65 years of age. Other potential age 

groups were examined in the sensitivity analysis. The vaccination intervention was examined 

over a time period of 1 year, but a lifetime analytic horizon was used to look at outcomes that 

might last beyond a year, such as years of life lost to deaths. 

This analysis used a decision-tree model that incorporated several elements. With no 

vaccination, individuals can become infected. Infection can lead to hospitalization, ED visits, 

outpatient visits, or none of these. Individuals who are hospitalized potentially could die. 

Vaccination may involve AEs such as systemic reactions, injection site reaction, SAEs, or none 

of these. Individuals could become infected as well. Of course, the RSV outcomes are less likely 

to happen with vaccination. This decision tree was used to calculate the numbers of events, 

costs, QALYs, and numbers needed to vaccinate (NNV) for the various outcomes and cost per 

QALY gained. Because this was a decision tree model, it did not take into account any 

reductions in RSV transmission. Therefore, the results were not dependent upon vaccine 

uptake. Infections that were not medically attended were not taken into account. One of the key 

epidemiological parameters was the incidence of RSV. It is important to keep in mind that 

reported incidence might be under-reported because of imperfect PCR sensitivity. For the basecase, it was assumed that sensitivity was 95%, and that was adjusted for to estimate the true 

cases of RSV. A scenario analysis examined what the results would be if the sensitivity was 

lower, meaning the actual cases of RSV were even higher. 

The estimates for RSV hospitalization incidence came from CDC RSV-NET in the season 

starting in 2015 and ending in 2019. The rates were slightly lower for the younger age groups 

and were higher for those over 75 years of age. As mentioned earlier, there was considerable 

uncertainty surrounding these rates. The incidence estimates of ED and outpatient visits related 

to RSV came from a study by McLaughlin, et al. published in 2022, which was a Pfizersponsored meta-analysis.66 Similar to the hospitalization incidence, the incidence of ED and 

outpatient RSV visits also increased with age. The UM-CDC model was estimated for RSV 

mortality linked to hospitalization. These numbers also came from RSV-NET.

67 Notably, the 

probability of dying from hospitalized RSV increased with age. 

The model incorporated seasonality to account for incidence of RSV, timing of RSV vaccination, 

and waning immunity. In terms of the fraction of annual infections occurring in each month, most 

infections occurred from November through April. Seasonality data came from NREVSS 

2015─2019. The model assumed that vaccine uptake follows a seasonal pattern similar to 

66 McLaughlin JM, Khan F, Begier E, Swerdlow DL, Jodar L, Falsey AR. Rates of Medically Attended RSV Among US Adults: A 

Systematic Review and Meta-analysis. Open forum infectious diseases 2022 Jul (Vol. 9, No. 7, p. ofac300). 67 CDC RSVnet data includes the following RSV seasons: 2015-16, 2016-17, 2017-18, and 2018-19. Ranges incorporate a 20% 

increase/reduction from the base case value 

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influenza vaccination uptake. It also is important to understand the efficacy of RSV vaccines. 

This table shows estimates of RSV VE from the GSK and Pfizer Phase 3 trials: 

Efficacy was split into 2 components, 1 against ED visits and hospitalizations, and the other 

against outpatient visits. Efficacy was based on how the trials evaluated RSV LRTI (efficacy 

against ED visits and hospitalizations) and all ARIs (efficacy against outpatient visits). The 

efficacy preventing the more severe outcomes was higher than the efficacy preventing 

outpatient visits. 

Given that definitive information was not available on the long-term efficacy of these vaccines, 

the decision was made to model efficacy with an exponential decay in the efficacy over time. 

Efficacy over the first 6 months was based on the average efficacy seen in the trials. There was 

slightly different efficacy against hospitalization compared to outpatient visits. 

The estimates for RSV medical costs (e.g., hospitalization, ED visits, outpatient visits) were 

taken from a variety of sources that have estimated cost of RSV, which all were inflated to 2022 

dollars using the Gross Domestic Product (GDP) Price Deflator. The hospitalization cost 

estimates came from a study by Ackerson in 2020 that studied the cost of inpatient 

hospitalization but did not include costs of follow-on care that might occur subsequent to 

hospitalization, such as rehabilitation care. Given that the vaccines are new, the precise vaccine 

costs were not known. A cost of $100 was used as the base-case for the price per vaccine 

dose. This may not be the exact number payers ultimately will pay for the vaccines, so a range 

of $50 to $200 was used in the sensitivity analysis. In addition, $16.96 was included for vaccine 

administration costs. Productivity costs also were included for an individual’s time to go get the 

vaccine. 

Health-related QALY losses from RSV were included for outpatient visits, ED visits, and 

hospitalization for RSV. These estimates came from a study that surveyed people with QALY 

lost for medically attended RSV infections. Additional inputs related to RSV illness also were 

included, such as productivity costs for individuals when they are sick with RSV, productivity 

costs associated with vaccination, and vaccination AEs and associated quality of life medical 

and productivity costs associated with them. Several analyses of uncertainty were conducted, 

including one-way and two-way sensitivity analyses, several potential age-based 

recommendations for RSV vaccination (≥60 years, ≥65 years, ≥70 years, ≥75 years), a variety 

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of vaccine costs from $50 to $200, and some scenario analyses examining higher RSV 

incidence. 

In terms of the results, the base-case assessed at a hypothetical cohort of 100,000 individuals. 

It was assumed that 20% of them would get vaccinated based on the assumption that RSV 

vaccine uptake would be slightly lower than the influenza vaccination uptake. The base-case 

assumed vaccination of individuals ≥65 years of age with a $100 vaccine cost over a 1-year 

time horizon. In terms of resulting health outcomes, vaccination with GSK or Pfizer vaccines 

would lead to reductions in outpatient visits, ED visits, hospitalizations, ICU stays, deaths, 

inpatient days, and ICU days. While the reductions might seem small, only 20,000 of the 

100,000 people in the cohort were assumed to be getting vaccines in this analysis. 

The NNV to avert 1 of these events for the GSK of Pfizer vaccine were typically lower when 

vaccinating older age groups. The cost would be about $8,000 to $9,000 to avert 1 outpatient 

visit and about $2 million to avert a death. In terms of the overall cost-effectiveness summary 

measures, it is anticipated that the GSK vaccine would increase costs by $1.84 million and 

reduce QALY lost from RSV by 11, leading to an ICER of $180,720 per QALY gained. It is 

anticipated that the Pfizer vaccine would increase costs by $1.92 million and reduce the QALY 

lost from RSV by 11, leading to an ICER of $189,407 per QALY gained. 

In terms of the sensitivity analyses, recalling that the base-case ICER was about $180,000 per 

QALY gained, if the vaccine costs for the GSK vaccine were lower at $50 per dose, the ICER 

would drop to approximately $83,000 per QALY. If the vaccine costs were higher at $200 per 

dose, the ICER would increase to about $375,000 per QALY. For many of the other parameters, 

if the value is higher, the ICER would drop. For example, if the incidence of RSV hospitalization 

was much higher, the ICER would drop to about $32,000 per QALY. The most important 

parameters are those related to vaccine costs, incidence, VE, and the costs of RSV. For the 

Pfizer vaccine, the top parameter was VE effectiveness at preventing LRTD. The bar was very 

wide because the Pfizer VE effectiveness had such a wide confidence interval. Vaccine cost 

was an important parameter. If the Pfizer vaccine had a cost of $200 per dose, the ICER would 

be about $384,000 per QALY. If the vaccine costs were only $50 per dose, the ICER would drop 

to about $92,000 per QALY gained. Similar parameters were important for the Pfizer vaccine as 

for the GSK vaccine in terms of the ICER. For instance, VE, vaccine cost, and incidence were 

important parameters. 

For the sensitivity analysis looking at how vaccine cost and changing the population vaccinated 

would affect the cost-effectiveness of the GSK vaccine, vaccinating older age groups would be 

more cost effective and a lower-cost vaccine would be more cost-effective. The same analysis 

for the Pfizer vaccine was similar. In terms of the scenario analyses with higher incidence, it is 

important to recall that there is uncertainty about what the precise incidence of RSV is, 

particularly given some uncertainty in how precise available tests are at detecting RSV. In the 

base case, sensitivity was assumed to be 95%, which suggests that not too many cases of RSV 

are being missed. However, if actual sensitivity were lower as suggested by a 2016 study by 

Zhang, et al. and a 2022 study by McLaughlin, et al.,68 more cases of RSV might be being 

missed than assumed. That is, actual RSV cases might be about 40% to 50% higher than 

reported. Using higher incidence for the GSK vaccine, if the vaccine were to cost $100 per 

68 Zhang Y, et al. Serology Enhances Molecular Diagnosis of Respiratory Virus Infections Other than Influenza in Children and 

Adults Hospitalized with Community-Acquired Pneumonia. J Clin Microbiol. 2016 Dec 28;55(1):79-89. doi: 10.1128/JCM.01701-

16. PMID: 27795341; PMCID: PMC5228265; and McLaughlin JM, et al. Rates of Medically Attended RSV Among US Adults: A 

Systematic Review and Meta-analysis. Open Forum Infect Dis. 2022 Jun 17;9(7):ofac300. doi: 10.1093/ofid/ofac300. PMID: 

35873302; PMCID: PMC9301578. 

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dose, the ICER would drop in half to about $91,000 per QALY gained. With higher incidence 

and $100 cost per vaccine dose for the Pfizer vaccine, the ICER would drop to about $104,000 

per QALY gained. 

To highlight some limitations of this analysis, the structure did not contain varying risk groups 

besides age and was for a general older aged population. The model did not include dynamic 

transmission, so there is no estimate of vaccine impact on population transmission or indirect 

effects of RSV. No direct post-discharge medical costs were included (e.g., rehabilitation). 

Additionally, models like this are a function of the underlying parameter assumptions, and this 

model has many uncertain inputs (e.g., actual vaccine costs for payers, imperfect information 

about RSV incidence, long-term efficacy). 

To summarize, the cost-effectiveness of RSV vaccination depends upon many factors. The 

vaccine cost could cause the ICER to vary substantially between approximately $80,000 to 

$385,000 per QALY gained. VE also could cause the ICER to vary between $150,000 and 

$575,000 per QALY gained. The ages recommended for vaccination also could cause the ICER 

to vary substantially between about $100,000 to $230,000 per QALY gained. In addition, the 

incidence of hospitalization could cause the ICER to vary between about $30,000 and $250,000 

per QALY gained. Under certain conditions, RSV vaccination may be cost-effective. However, 

under other conditions it might seem like an expensive intervention. 

Comparison of Cost-Effectiveness Results of the Main CDC Model and Each 

Manufacturer Model (GSK & Pfizer)

Ismael R. Ortega-Sanchez, PhD (CDC/NCIRD) compared and summarized the key elements 

and findings of the UM-CDC, GSK (RSVpreF3 vaccine), and Pfizer (RSVpreF vaccine) 

economic studies that were discussed by the WG. The starting point of the 3 economic models 

was the policy question regarding potential recommendations for the use of RSV vaccine in 

older adults populations, “Should adults ≥60 years of age (or ≥65 years of age) receive one 

dose of Respiratory Syncytial Virus (RSV) vaccine (GSK or Pfizer product) for the prevention of 

RSV disease and its complications?” To consider the policy question, the question also must be 

answered, “Is vaccinating adults aged ≥65 years (or ≥60 years) against RSV cost-effective?” 

The 3 models use the same comparator to address this question, unvaccinated older adults ≥65

years of age (or ≥60 years of age). 

The policy question also defines key elements in the 3 economic models, including the modeling 

approach; inputs for RSV disease burden, VE, and costs; and some influential assumptions that 

need to be defined carefully because of the policy question under consideration. In general, the 

3 models followed similar designs. They all used a static analytical decision-making approach, 

relied on sensitivity analyses and probabilistic simulation to manage various data uncertainties, 

modeled hypothetical cohorts of US adults ≥60 years of age or ≥65 years of age in order to align 

with the policy questions, used reasonable timeframe analytical horizons and discount rates, 

and accounted for loss of income associated with temporary productivity loss and premature 

RSV-associated deaths. Once the models were set, they were fed by various types of input data 

(e.g., clinical, epidemiological, economic, quality of life, candidate vaccine characteristics, et 

cetera. Across models, the source of specific values and assumptions of the parameters have 

some overlaps, but there were marked differences. This table delineates the standard outcomes 

estimated and reported by the 3 models, ratios of incremental cost per QALY saved, and the 

NNI to prevent a health outcome: 

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The CDC model reported cost per QALY saved estimates for GSK and Pfizer vaccines 

differentiated by age at which the vaccination program would begin. Although the cost per QALY 

saved were slightly higher for Pfizer relative to GSK, they were basically in the same ballpark for 

each age at which the potential vaccine program would be recommended to start. However, the 

main outcomes of the manufacturers’ models compared to those of the CDC model show 

significant discrepancies. Even though the CDC model assumes a lower vaccine cost per dose 

for both vaccines, the resulting cost per QALY are much higher than those of GSK and Pfizer. 

Specifically, the CDC estimates are about 3 times higher than those of GSK and 4 times higher 

than those of Pfizer for either the adults ≥60 years of age or adults ≥65 years of age strategies. 

To understand these discrepancies, an effort was made to try to identify and present the key 

differences. The CDC model provided a one-way sensitivity analysis for each vaccine with a 

base-case of age ≥65 years and $180,720/QALY (GSK) and $189,407/QALY (Pfizer). The most 

influential input variables in the GSK model were vaccine cost, incidence of RSV hospitalization, 

and outpatient QALYs lost. In the Pfizer model they were VE against LRTD, vaccine cost, and 

incidence of RSV hospitalization. In a similar fashion, the GSK model reported the most 

influential variables in a tornado diagram. While cost was the first or second most influential in 

the CDC model, it ranked 6th in the GSK model. The base-case for the GSK model was age ≥60 

years and $ 78,971 /QALY saved. Pfizer also reported one-way sensitivity analysis identifying 

the most influential variables. Again, medical costs were in 6th place. Aside from the cost of the 

vaccine dose, the common influential variables identified could group this into these 3 

categories: 

 RSV-hospitalization rate 

− GSK: Proportion of MA RSV hospitalized cases identified by PCR, differentiated by 

age (Belongia, 2018) 

− Pfizer: Differentiated by age and comorbidity profile (Pfizer data on file) 

− CDC: Differentiated by age (four RSV seasons in CDC RSV-NET data) 

 Unitary medical cost of RSV outcomes 

− GSK: Age- and outcome-specific cost for symptomatic RSV LRTD & URTI cases (MA 

and non-MA) (CMS) 

− Pfizer: Age-, outcome-, and comorbidity-specific cost for MA RSV 

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− CDC: Age- and outcome-specific cost for MA RSV

 Initial VE & waning over time

− GSK: Phase 3, monthly waning: ARI (5.36%), LRTD (2.63%) until 12 months, then to

0%

− Pfizer: Phase 3, flat 7 months, then linear decay to 0% at 24 months

− CDC: GSK’s & Pfizer’s Phase 3, flat 6 months, exponential decay until 12 months,

then to 0%

There were marked difference in the rates of hospitalization, outpatient illness, and unitary 

medical cost of hospitalization as shown in this table: 

The hospitalization rates and medical costs as input data points using the Pfizer model were on 

the high end while those using the CDC model were on the lower end, with GSK input values 

somewhere in the middle. The committee should bear in mind that the higher these input values 

are in the models, the lower the ICERs or the incremental cost per QALY would be. Particularly 

influential was the rate of hospitalization, which also was the input parameter with more 

uncertainty recognized by the manufacturing models. The GSK model showed an inverse 

relation between the cost per QALY and RSV hospitalization rates. The GSK base-case fell 

somewhere in the middle within most scenarios. GSK’s base-case parameters were mostly from 

peer-review publications in the last 10 years, while others relied on secondary sources that were 

used as inputs in some cost-effectiveness analyses as well. It could be argued that considering 

these uncertainties, the quality of data may be higher for the peer-reviewed publication input. 

Likewise, Pfizer reported a similar correlation between the incidence rate of hospitalization and 

the cost per QALY. However, all of the alternative scenarios were based on similar published 

sources used by GSK and were high compared to the base-case scenario. An important detail 

is that the data source of the base-case scenario in Pfizer model relied upon an ongoing, 

unvetted, and published prospective study with adjusted RSV detection rates. The source was 

reported as “Pfizer Inc. data on file.” The Pfizer data were not available yet for independent 

review. The input value of 300 per 100,000 population rate of RSV hospitalization was selected 

for their base-case. 

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In an analogous way, the CDC model also reported this correlation. For adults ≥65 years of age, 

the cost per QALY saved for each vaccine was reported as approximately $180,000 for GSK 

and approximately $189,000 for Pfizer for $1,000 per QALY saved. To consider the uncertainty 

about the rate of hospitalization in the CDC model, the range in the model relied on those 

reported in the peer-review sources. 

The 3 models showed similar, if not equal, input values for initial or early peak of VE variables 

are shown in this table: 

This will help to understand where to start and what comes next, which is duration of protection. 

Although it is important how well the VE starts at the beginning of the RSV season, it is much 

more significant how it performs during the whole season. The 3 models relied on duration of 

protection data from both vaccines trials that covered the first 6 to 7 months. However, after this 

initial period, the residual protection was basically an assumption. Both the GSK and CDC 

models assumed no residual protection after month 12. Although the GSK model used an initial 

peak and linear decay, the CDC used an exponential decay to fit the initial VE and the 

presumed residual after 6 to 7 months to drop later to zero protection after month 12. Unlike the 

GSK and CDC models, after the initial period, Pfizer model assumed a linear decay to 0% 

effectiveness at 24 months after vaccination. 

Looking at Pfizer’s different scenarios for duration of protection and data sources for RSVassociated disease outcomes, if waned to 0% at 12 months, the cost per QALY would increase 

from $44,000 per QALY to more than $106,000 per QALY. Moreover, with different data 

sources for the RSV-associated disease outcome rates (e.g., the data from CDC inflated to 1.4), 

the cost per QALY would increase to $171,000 per QALY. This is very close to what the CDC 

model calculated, although other caveats need to be considered. 

Comparison of GSK and Pfizer vaccines base-case and scenario cost per QALY results using 

UM-CDC using only the CDC model, if the vaccine costs $200 per dose, with only one-year 

timeframe, the cost per QALY for GSK would be almost 100% higher than the base-case 

scenario. Basically, the same happens in the Pfizer scenario. Compared to the base-case, the 

cost per QALY would be 15% higher in vaccinated adults start at age 60 instead of 65. If the 

lower bound of medical cost for hospitalization is used, the increase would be only 10% higher. 

On the other hand, RSV incidence adjusted outward for increased diagnostic yield reveal that a 

year from testing in addition to RT-PCR on a respiratory specimen will decrease the cost per 

QALY to approximately 50% of the value that is considered in the base-case scenario. Similarly, 

when reducing the vaccine price per dose to $50 per dose, the cost per QALY would be 

reduced considerably to less than 50% compared to the base-case scenario. 

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There are a number of limitations to this analysis. Factors not considered in the model may 

result in underestimating the cost-effectiveness of vaccination or over-estimate the ICERs. None 

of the 3 models included RSV-related medical costs incurred after discharge from an RSVassociated hospitalization or ED visit (e.g., stay in long-term care or rehabilitation facility, 

assisted living at home, productivity losses incurred by caregivers whose support is needed 

post-discharge). All 3 of the models assumed no indirect effects of vaccination (i.e., no 

protection against RSV transmission). VE beyond clinical trial follow-up time (6–7 months) is 

unknown. All 3 models assumed non-zero declining efficacy beyond 6–7 months (UM-CDC: 12 

months, GSK: 12 months, Pfizer: 24 months). 

In conclusion, differences in key inputs among the GSK, Pfizer, and UM-CDC models explain 

differences in the results. The 4 variables to be more influential were incidence of 

hospitalization, duration of VE, medical costs, and vaccine costs. The GSK and Pfizer models 

used less conservative estimates and the CDC model used more conservative estimates. 

Assumptions and selection of input data were crucial in difference in ICERs as well (e.g., 

adjustment approach of incidence rates of hospitalization, ED, and outpatient) and the selection 

of medical costs sources and data extraction approach. Yet in general, in general, the basecase in the 3 models suggested that vaccination would reduce the RSV disease burden 

significantly in older adults. VE clinical trials data and assumptions supported the impact on 

disease reduction. However, the economic value of RSV vaccines appears to be costly and 

could be cost-effective. Factors such as RSV incidence, related healthcare costs, initial VE, and 

duration, combined with reasonable vaccine price, would determine the cost-effectiveness value 

of RSV vaccination. 

EtR/GRADE for 2 Vaccines (GSK & Pfizer)

Michael Melgar, MD (CDC/NCIRD) presented the EtR frameworks for the 2 candidate RSV 

vaccines for use in older adults manufactured by GSK and Pfizer. The 2 policy questions 

considered by the WG for each vaccine were as follows: 

 Should vaccination with GSK RSVpreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose 

IM), rather than no vaccine, be recommended in persons aged ≥65 years?

 Should vaccination with GSK RSVpreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose 

IM), rather than no vaccine, be recommended in persons aged ≥60 years?

 Should vaccination with Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM), 

rather than no vaccine, be recommended in persons aged ≥65 years?

 Should vaccination with Pfizer bivalent RSVpreF vaccine (120μg antigen, 1 dose IM), 

rather than no vaccine, be recommended in persons aged ≥60 years?

For simplicity, Dr. Melgar explained that he would present the EtR framework from the 

perspective of vaccination policy for adults ≥65 years of age and at the end of the presentation 

would summarize the WG’s thoughts regarding the pros and cons of selecting a ≥60 years of 

age versus a ≥65 years of age threshold. In terms of the EtR framework used by ACIP to make 

policy decisions within 7 domains, he noted that as he described the WG’s interpretations, some 

components would be the same for both manufacturers and would be presented once while 

others would be manufacturer-specific. The Public Health Problem domain focused on RSV in 

older adults broadly. The Values, Acceptability, and Equity domains focused on RSV vaccines 

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broadly. Manufacturer-specific data were presented for Benefits and Harms, Feasibility, and 

Resource Use domains. 

For the Public Health Problem domain regarding whether RSV among older adults is of public 

health concern, RSV is recognized by pediatricians but there is a lower awareness of RSV in 

adults among HCP and the public. Even though it is not often recognized as a cause of illness in 

adults, and there is substantial uncertainty in RSV epidemiology and the burden of disease in 

older adults is significant. Among adults ≥65 years of age in the US, RSV is estimated to cause 

approximately 1 million medical encounters;

69 60,000 to 160,000 hospitalizations,70 and 6,000 to 

10,000 deaths per year.71 

CDC’s RSV-NET provides active population-based surveillance of laboratory-confirmed RSVassociated hospitalizations at sites in 12 US states. The combined catchment area is estimated 

to account for almost 9% of the US population. Looking at seasonal rates of RSV-associated 

hospitalizations among adults stratified by age, hospitalization rates were substantially higher 

among adults 70─79 and ≥80 years of age compared with younger age groups. Focusing on the 

potential age thresholds of interest, adults 60─64 and 65─69 years of age experienced 

intermediate rates of hospitalization.72 

Among adults hospitalized with RSV, a large proportion are severely ill as measured by the 

proportion admitted to ICU and the proportion who died. In RSV-NET data from 3 seasons, 

mortality was highest in those ≥65 years at 5%. However, the proportion admitted to the ICU 

was over 20% even in younger patients 18─49 and 50─64 years of age. This likely reflects the 

fact that younger patients hospitalized with RSV have underlying medical conditions that make 

them more vulnerable to severe outcomes. RSV-NET data reflect only patients hospitalized with 

laboratory-confirmed RSV and more severely ill patients are probably more likely to be tested 

for RSV. Therefore, these data may overestimate the proposition with severe illness. 

Regardless, it is clear that RSV can cause severe disease in hospitalized adults of any age. 

Turning back to the published literature, there is evidence that adults with certain underlying 

medical conditions are at higher risk of RSV illness, particularly hospitalization.73 The list of 

medical risk factors has not been as well-documented as that for influenza, but adults with 

immune compromise, especially those with hematopoietic stem cell transplant (HSCT) or solid 

organ transplant (particularly lung transplant) and those with cardiovascular disease (CVD), 

diabetes, chronic obstructive pulmonary disease (COPD), and asthma have been shown to 

have higher risk of RSV hospitalization than adults without those conditions. 

69 McLaughlin et al, Open Forum Infect Dis (2022): https://doi.org/10.1093/ofid/ofac300 70 Widmer et al, JAMA Network Open (2012): https://doi.org/10.1093/infdis/jis309; McLaughlin et al, Open Forum Infect Dis (2022): 

https://doi.org/10.1093/ofid/ofac300; Zheng et al, Pneumonia (2022): https://doi.org/10.1186/s41479-022-00098-x; Branche et al, 

Clinical Infect Dis (2022): https://doi.org/10.1093/cid/ciab595; and CDC RSV-NET data 2016–2020 (unpublished) 71 Thompson et al, JAMA (2003): https://doi.org/10.1001/jama.289.2.179; Matias et al, Influenza Other Respi Viruses (2014): 

https://doi.org/10.1111/irv.12258; and Hansen et al, JAMA Network Open (2022): 

https://doi.org/10.1001/jamanetworkopen.2022.0527 72 RSV-NET: unpublished data; https://www.cdc.gov/rsv/research/rsv-net/overview-methods.html. Rates are adjusted for the 

frequency of RSV testing during recent prior seasons and the sensitivity of RSV diagnostic tests 73 Anderson et al, Diagn Microbiol Infect Dis (2016): https://doi.org/10.1016/j.diagmicrobio.2016.02.025; Prasad et al, Clin Infect Dis 

(2020): https://doi.org/10.1093/cid/ciaa730; Kujawski et al, Plos One (2022): https://doi.org/10.1371/journal.pone.0264890; and 

Branche et al, Clin Infect Dis (2022): https://doi.org/10.1093/cid/ciab595 

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In summary, RSV is a frequent and often unrecognized cause of severe respiratory illness in 

older adults. A high proposition of adults across the age spectrum who are hospitalized with 

RSV are admitted to the ICU. Death is more common with increasing age. The WG felt that 

RSV disease was indeed of public health importance among adults ≥65 years. 

Dr. Melgar approached the Benefits and Harms domain one candidate vaccine at a time starting 

with GSK’s adjuvanted RSVpreF3 vaccine. He presented the GRADE summary reviewed by the 

WG followed by a NNV analysis. He then presented the same for the Pfizer bivalent RSVpreF 

vaccine. For the PICO question and outcomes, both manufacturers enrolled adults ≥60 years of 

age in their large Phase 3 trials. Data from all participants in this age group were included in the 

GRADE analysis. The intervention was either of the 2 vaccines under consideration. The 

comparison was no RSV vaccine and the outcomes included RSV LRTI or LRTD, MA LRTI or 

LRTD, hospitalization for RSV respiratory illness, severe RSV respiratory illness requiring 

supplemental oxygen or other respiratory support, death due to RSV respiratory illness, SAEs, 

inflammatory neuropathy (e.g., GBS), and severe reactogenicity (e.g., Grade ≥3). 

Beginning with the GSK RSVpreF3 candidate vaccine, the CDC calculated VE estimates over 1 

RSV season of follow-up for the outcomes can be considered benefits of vaccination. GSK’s 

pivotal Phase 3 trial was the source of data for all outcomes. The efficacy against RSV LRTD, a 

critical outcome, was 82.5%. However, the WG was concerned about indirectness because 

adults ≥80 years of age who are at greatest risk of severe RSV disease were underrepresented 

in the trial relative to the US population of adults ≥60 years of age. Additionally, persons with 

immune compromise were excluded all together. The efficacy against MA RSV LRTD was 

87.5%. The WG was concerned about indirectness for the same reasons. Efficacies against 

hospitalization, severe RSV respiratory illness, and death were not calculated due to no or few 

events recorded in the trial. These outcomes were considered important but not critical by the 

WG. 

In terms of the outcomes that are potential harms of vaccination, in additional to the pivotal 

Phase 3 trial, an early phase dose selection study also reported these outcomes. The pooled 

relative risk of SAEs of critical outcome was 1.03. The WG had no serious concerns in the 

certainty assessment. The pooled relative risk for severe reactogenicity events was 4.1, with a 

confidence interval that did not include 1.0. The WG had no serious concerns in the certainty 

assessment either. The outcome of inflammatory neuropathy was not formally evaluated in 

GRADE because there were no events in the included studies. However, 1 case of GBS was 

recorded in a recipient of the investigational vaccine in an open-label trial without a placebo 

arm. This trial was not included in GRADE due to lack of an unvaccinated comparator group. 

Across all trials, there was a total of 1 case of inflammatory neuropathy among approximately 

15,000 investigational vaccine recipients. 

In summary, the GSK RSV vaccine likely reduces RSV LRTD with moderate evidence. The 

GSK vaccine also likely reduces MA RSV LRTD with moderate evidence. The investigational 

vaccine results in little to no difference in SAEs when all organ classes and types of SAEs are 

considered. The vaccine increases severe reactogenicity events with high certainty. There were 

insufficient data to evaluate the outcomes of RSV hospitalization, severe illness requiring 

respiratory support, death due to RSV respiratory illness, and inflammatory neuropathy. The 

overall certainty of evidence was considered moderate. 

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In terms of the NNV analysis performed by CDC colleagues at the University of Michigan as part 

of the cost-effectiveness analysis, 84 adults ≥65 years of age would need to be vaccinated to 

prevent 1 outpatient visit over a single year. Over 1,000 would need to be vaccinated to prevent 

1 hospitalization, and over 21,000 would need to be vaccinated to prevent 1 death due to RSV. 

The numbers are larger for adults ≥60 years of age. That is primarily because there is less 

existing RSV disease in that group at baseline for the vaccine to prevent. Notably, the time 

horizon matters here. If the vaccine is assumed to have non-zero efficacy during the second 

year, even if it waned substantially, the NNV could be smaller if the analysis were extended for 

a second year. 

In terms of how substantial the desirable anticipated effects of GSK’s candidate are among 

adults ≥65 years of age, the WG determined that they were moderate or large. Regarding 

undesirable effects, the WG’s majority opinion was that they were minimal or small. However, a 

minority opinion was that the magnitude of these effects was unknown. These WG members 

were concerned about the case of Guillain-Barre syndrome (GBS) in the cross-trial safety 

dataset. It is difficult to know from a single case if this was a true safety signal or a random 

event. Regarding the balance of desirable and undesirable effects, the WG’s majority opinion 

was that the comparison favors the intervention. There was a minority opinion that the balance 

was unclear in light of the single observed case of inflammatory neuropathy. 

Turning now to the Pfizer investigational vaccine, the CDC calculated VE estimates for the 

outcomes that could be considered benefits of vaccination. Pfizer’s pivotal Phase 3 trial was the 

source of data for all outcomes. The efficacy against RSV LRTI, a critical outcome, was 85.7%. 

However, as was the case for the other candidate vaccine, the WG was concerned about 

indirectness because of under-representation of adults ≥80 years of age and because persons 

with immune compromise were excluded. The efficacy against MA RSV LRTI was 80%. Again, 

the WG was concerned about indirectness for the same reasons. Counts of RSV-associated 

hospitalization and severe RSV respiratory illness were not provided by the manufacturer, so 

efficacy was not calculated. There were no RSV-associated deaths reported in the trial. Again, 

these outcomes were considered important but not critical. 

In terms of the outcomes that are potential harms of vaccination. In addition to the pivotal Phase 

3 trial, an early-phase formulation selection study also reported these outcomes. The pooled 

relative risk of SAEs of critical outcome was 1.01, and the WG had no serious concerns in the 

certainty assessment. The pooled relative risk for severe reactogenicity events was 1.47. The 

WG had concerns about imprecision because the confidence interval for a measure of absolute 

risk included the potential for both benefit and harm. Two events of GBS or a variant thereof 

occurred among recipients of the investigational vaccine compared with no events among 

placebo recipients. Due to the small number of events, measures of relative and absolute risk 

were not calculated. In total, these were the only 2 cases of inflammatory neuropathy that 

occurred among approximately 26,000 recipients of the investigational vaccine across all clinical 

trials. 

In summary, the Pfizer RSV vaccine likely reduces RSV LRTI with moderate evidence. The 

Pfizer vaccine also likely reduces MA RSV LRTI with moderate evidence. The investigational 

vaccine results in little to no difference in serious adverse events when all organ classes and 

types of SAEs are considered, and the vaccine likely increases severe reactogenicity events 

with moderate certainty. There was insufficient data to formally evaluate the outcomes of RSV 

hospitalization, severe illness requiring respiratory support, death due to RSV respiratory illness, 

and inflammatory neuropathy. The overall certainty of evidence was considered moderate. 

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In terms of the NNV analysis for the Pfizer vaccine, 95 adults ≥65 years of age would need to be 

vaccinated to prevent 1 outpatient visit over a single year. Almost 1,300 would need to be 

vaccinated to prevent 1 hospitalization. Almost 25,000 would need to be vaccinated to prevent 1 

death due to RSV. Again, the numbers are larger for adults ≥60 years of age because there is 

less baseline RSV disease in that group for the vaccine to prevent. 

When asked how substantial the desirable anticipated effects of Pfizer candidate vaccine are 

among adults ≥65 years of age, the WG responded that they were moderate or large. 

Regarding the undesirable effects, the WG’s majority opinion was that they were minimal or 

small. However, the minority opinion again was that the magnitude of these effects was 

unknown. These WG members were concerned about the 2 cases of inflammatory neuropathy 

observed in the main Phase 3 trial as it is hard to know from 2 cases if this is a true safety signal 

or random events. When asked about the balance of desirable and undesirable effects, the WG 

majority opinion was that the comparison favors the intervention. There was a minority opinion 

that the balance was unclear in light of the 2 observed cases of inflammatory neuropathy. 

Data for the Values domain drew upon unpublished results from an online survey developed by 

CDC in collaboration with the University of Iowa and the Rand Corporation. The survey was 

designed to assess vaccination intentions for a hypothetical RSV vaccine among US adults ≥60 

years of age. The final sample consisted of 586 respondents. Overall, 68% of respondents said 

they definitely or probably would choose to get vaccinated if a safe and effective FDA-approved 

RSV vaccine was available. That proportion increased to 77% if it was recommended by a HCP. 

Among those expressing hesitancy to accept the vaccine, the most common reasons included 

lack of knowledge about RSV and long- and short-term safety concerns about the vaccine. The 

WG consensus was that older adults do or probably do feel that the desirable effects of RSV 

vaccination are large relative to the undesirable effects. However, the WG also believed that 

there was or probably was important uncertainty or variability in how much older adults value 

these main desirable and undesirable outcomes of vaccination. 

Data informing the Acceptability domain related to whether an RSV vaccine recommendation 

would be acceptable to stakeholders came from a survey of physicians conducted in 

February─March of 2017.74 Surveys were administered to a national network of 930 primary 

care physicians who agreed to participate in surveys about vaccine policy and who spent at 

least half of their time practicing primary care. Two-thirds (620; 67%) completed the survey. 

Among those respondents, 317 (51%) reported taking care of an adult patient who they thought 

had RSV in the last 12 months, and they were included in the final analysis. A majority (57%) of 

physicians believed that RSV was a very important pathogen in adults of any age with an 

immune-compromising condition and in adults ≥65 years of age with cardiopulmonary disease. 

By comparison, approximately one-third (56%) of physicians believed that RSV was a very 

important pathogen in adults 50─64 years of age with cardiopulmonary disease and in adults 

≥65 years of age without cardiopulmonary disease. 

The WG felt that generally recommending RSV vaccines for adults ≥65 years of age would or 

probably would be acceptable to stakeholders. However, some WG members noted that a 

limitation of these published results was that only physicians were surveyed. Other clinicians, 

including pharmacists, who order or administer vaccines may have responded differently. 

74 Hurley LP, Allison MA, Kim L, et al. Primary care physicians’ perspectives on respiratory syncytial virus (RSV) disease in adults 

and a potential RSV vaccine for adults. 2019 Vaccine 37(4): 565-570. ISSN 0264-410X. 

https://doi.org/10.1016/j.vaccine.2018.12.031. 

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Regarding the Feasibility domain, feasibility barriers might arise from vaccine storage and 

handling requirements, the increasing complexity of the adult immunization schedule (including 

coadministration) and from financial barriers. In terms of the storage and handling requirements 

for the 2 products under consideration, both vaccines require reconstitution of powder and liquid 

components, both of which will come supplied in the purchased kit. Both vaccines require 

refrigeration at 2°C–8°C in the original container and with protection from light. Both vaccines 

should be administered within 4 hours and otherwise discarded. 

To illustrate that the older adult routine schedule is becoming more complex, here is CDC’s 

older adult routine immunization schedule with the potential addition of a regularly scheduled 

COVID-19 vaccine as discussed at VRBPAC in January: 

The immunization schedule is becoming more complex, and vaccination is not the only age- and 

risk-based preventive healthcare that adult clinicians must provide. If an RSV vaccine is added, 

clinicians likely will face competing priorities at each patient appointment. Different age cutoffs 

may also add to the complexity. Harmonizing age recommendations with those of other older 

adult vaccines may improve feasibility and may increase uptake. At age 65, all adults are 

recommended to receive pneumococcal vaccination, and there are specific influenza vaccine 

formulations licensed for adults ≥65 of age. Finally, recipient feasible barriers include time and 

financial consideration. Older adults without health insurance coverage may experience 

financial hardship obtaining an RSV vaccine. Financial hardship also may arise if vaccine 

recipients need to take off from work to be vaccinated or due to post-vaccination reactogenicity 

events. 

The WG felt that overall, both the GSK and Pfizer candidate RSV vaccines are feasible to 

implement among adults ≥65 years of age. 

For the Resource Use domain, rather than repeating the content presented by Drs. Hutton and 

Ortega-Sanchez, Dr. Melgar presented the WG’s interpretation of the cost-effectiveness 

analyses. The WG felt that RSV vaccination for older adults could be a cost-effective 

intervention, but that the cost-effectiveness would depend on several factors around which there 

is substantial uncertainty. WG members felt that the uncertainty is chiefly driven by uncertainty 

in the annual incidence of severe RSV illness (particularly hospitalization), uncertainty in 

vaccine acquisition cost, and duration of protection resulting from RSV vaccination in this 

population. The WG was concerned about the net societal costs resulting from scenarios in 

which the vaccine acquisition costs were those assumed by the manufacturers. On the other 

hand, although the net societal costs in some modeling results were high, the WG noted that 

none of the 3 models incorporated medical costs resulting from longer-term sequelae of RSV 

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infection. For instance, inclusion of costs of admission to skilled nursing facilities (SNF) among 

adults discharged from RSV hospitalizations might lower the net societal costs estimated in the 

analyses. The WG also noted that vaccination of older age groups would be more cost-effective 

than vaccination of younger age groups. All evidence taken into account, the WG responded 

that yes or probably yes both candidate vaccines could be reasonable and efficient allocations 

of societal resources if recommended for adults ≥65 years of age compared with no RSV 

vaccine. 

With respect to the Equity domain, it is known that RSV disease does not impact all US adults 

equally. Incidence rates of RSV hospitalization published in 2022 from 3 US states75 showed 

that at every age group beginning at ≥45 years of age, incidence was highest among adults 

living in low-income zip codes and lowest among those living in high-income zip codes. In 

addition to differences by income level, RSV has differing impact by race and ethnicity. Data on 

median age of adults hospitalized with RSV reported in CDC’s RSV-NET stratified by race and 

ethnicity over the seasons spanning 2015─2020, Black, Hispanic, AI/AN, and Alaska Native 

adults hospitalized with RSV were younger than adults overall. In fact, at least 50% of adults in 

these age groups would not have qualified for RSV vaccination if there had been a 

recommendation for adults ≥65 years of age. As discussed in the Public Health Problem 

domain, certain chronic medical conditions increase the risk of severe RSV illness. Adults who 

are Black, AI/AN, and Hispanic have higher prevalence of many of these conditions, including 

CVD, diabetes, and asthma when compared with non-Hispanic White adults. The same is true 

of adults with lower income or socioeconomic status (SES). In these demographic groups, these 

conditions are also diagnosed at earlier ages, often before age 60, increasing the risk of severe 

RSV disease earlier in life. 

Like most medical interventions, access to a new RSV vaccine may be determined by health 

insurance coverage. It is known that lack of health insurance is more common among adults 

younger than 65 years of age.

76 However, even this disparity is not evenly distributed in the US 

population. AI/AN and Hispanic persons 55─64 years of age are substantially more likely to be 

uninsured than their same age peers in other racial and ethnic groups. Depending upon the age 

at which an RSV vaccine is recommended, this may exacerbate existing health inequities 

among older adults. Similar to the relationship between race, ethnicity, and health insurance 

coverage, insurance coverage also differs by household income. Especially below age 65, the 

proportion of adults without health insurance is much higher among those with a household 

income that is below 3 times the poverty threshold than it is among those above that threshold. 

Depending upon the age at which and RSV vaccine recommendation is made, this may 

exacerbate health inequities among adults. 

Overall, the WG felt that recommendation for RSV vaccination among adults ≥65 years of age 

would or probably would increase health equity. 

In summary of the WG’s overall interpretation, both candidate vaccines demonstrated significant 

efficacy against LRTI caused by RSV among older adults. However, the trials were 

underpowered to show efficacy against RSV hospitalization and demographic groups at highest 

risk of severe illness with RSV, including adults ≥80 years of age, were under-represented in the 

trials. At least 1 case of inflammatory neuropathy has been observed among recipients of each 

investigational vaccine. The WG felt that if either vaccine is licensed, post-licensure surveillance 

75 Zheng Z, et al. Estimated incidence of respiratory hospitalizations attributable to RSV infections across age and socioeconomic 

groups. Pneumonia (Nathan). 2022 Oct 25;14(1):6. doi: 10.1186/s41479-022-00098-x 76 U.S. Census Bureau, 2021 American Community Survey 1-year estimates: https://data.census.gov/table 

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for both safety and effectiveness will be critical. The WG identified the pros and cons to the 

choice of age cut-off for an age-based recommendation, which are summarized in this table: 

If a recommendation is made for adults ≥65 years of age, the target population would be at 

greater risk of severe RSV disease. Therefore, the balance of risks and benefits of vaccination 

would be more favorable. The WG was concerned about the possible risk of inflammatory 

neuropathy, particularly in light of the low observed RSV hospitalization rates and the trials 

impacting that balance. It also would align with the age-based cutoff for certain influenza 

vaccines and pneumococcal vaccination. On the other hand, this selection would exclude adults 

60─64 years of age among whom certain racial and ethnic groups are impacted by RSV at 

earlier ages. If a recommendation is made for adults ≥60 of age, there is the potential to prevent 

a greater total burden of RSV disease and it would increase access to persons 60─64 years of 

age with medical risk factors for severe RSV illness. Conversely, persons 60─64 years of age 

who are uninsured would have more difficulty obtaining vaccination, counteracting some of 

these potential gains in equity. Clinicians also may be less willing to adopt a recommendation 

among adults younger than 65 years of age. Such a recommendation would be a less efficient 

allocation of collective societal resources. 

To summarize the WG summary interpretation regarding GSK’s candidate vaccine, for an age 

threshold of ≥65 years of age and one of ≥60 years, the WG felt that the desirable 

consequences of a vaccine recommendation probably outweigh the undesirable consequences 

in most settings. However, when considering a recommendation at ≥60 years of age, there were 

substantial minority opinions that the desirable and undesirable consequences were closely 

balanced or that there was insufficient evidence to make a determination. The majority opinion 

was in favor of recommending that GSK candidate vaccine for adults ≥65 years of age, but was 

not in favor of a broader recommendation for adults ≥60 years of age. There was a substantial 

minority opinion not to recommend this product based on currently available evidence. These 

WG members were concerned about the balance of risks and benefits considering the single 

case of inflammatory neuropathy observed in a recipient of the investigational vaccine and the 

under-representation in the clinical trials of adults older than 80 who are at greatest risk of 

severe RSV illness. They felt that it is imperative to demonstrate efficacy in this age group prior 

to making a recommendation. Further, they felt that a post-implementation safety signal for 

inflammatory neuropathy, even if caught early, could undermine confidence in RSV vaccines 

and in vaccines more generally. Among WG members who did support a recommendation 

among adults ≥65 years of age, there also was a minority opinion to include a recommendation 

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for individual adults 60─64 years of age based on shared clinical decision-making intended to 

facilitate access to the vaccine among adults with medical conditions placing them at high risk of 

severe RSV disease. 

To summarize the WG summary interpretation regarding the Pfizer candidate vaccine, for an 

age threshold of ≥65 years of age and one of ≥60 years of age, the WG felt that the desirable 

consequences of a vaccine recommendation probably outweigh the undesirable consequences 

in most settings. However, when considering a recommendation at age 60, there were 

substantial minority opinions that the desirable and undesirable consequences were closely 

balanced or that there was insufficient evidence to make a determination. The majority opinion 

was in favor of recommending the Pfizer candidate vaccine for adults ≥65 years of age but was 

not in favor of a broader recommendation for adults ≥60 years and older. However, as with the 

other candidate vaccine, there was a substantial minority opinion among WG members not to 

recommend this vaccine based on currently available evidence. Similar to the considerations for 

the other candidate vaccine, these WG members were concerned about the balance of risks 

and benefits considering the 2 observed cases of inflammatory neuropathy and the 

underrepresentation of the very oldest adults in the clinical trials. Among WG members who did 

support a recommendation among adults ≥65 years of age, there was a minority opinion to 

include a recommendation for adults 60─64 years of age based on shared clinical decisionmaking intended to facilitate access to the vaccine among adults with medical conditions that 

place them at high risk of severe RSV disease. 

GSK Statement 

Leonard Friedland, MD (GSK) thanked the members of the ACIP for giving GSK the 

opportunity to make a brief statement. He said that he and his GSK colleagues are proud to 

have developed the GSK RSV candidate vaccine for older adults being discussed by the ACIP. 

He focused his remarks on the policy consideration regarding whether adults 60─64 years of 

age should be included in routine RSV vaccine recommendations. RSV results in considerable 

clinical and economic burden among all adults ≥60 years of age, including adults 60─64 years 

of age. GSK’s cost-effectiveness model, which uses burden of disease estimates that align to 

the current body of published scientific evidence, estimates that vaccinating adults 60─64 years 

of age would result in roughly 260,000 fewer symptomatic RSV cases in adults 60─64 years of 

age, including over 100,000 fewer output visits and around 7,400 fewer hospitalizations each 

year. The model found that GSK’s RSV vaccine is cost-effective across a range of price points, 

indicating that the vaccine would be considered a good public health value for adults ≥60 years 

of age. In addition to reducing the burden of RSV, including adults 60─64 years of age in RSV 

vaccine recommendations would have health equity benefits. Studies have demonstrated that 

certain racial and ethnic minority groups are more likely to have underlying risk factors for 

severe RSV outcomes, are more likely to be diagnosed with risk factors for severe RSV at 

younger ages, and are more likely to have undiagnosed risk factors—particularly at younger 

ages before they are eligible for Medicare. Studies also have found that certain racial and ethnic 

minorities are more likely to have severe RSV-related outcomes, including a study being 

presented by the CDC at the ReSViNET Conference that demonstrates that a higher proportion 

of younger adults hospitalized for RSV were Black, Hispanic, or AI/AN. Excluding adults 60─64 

years of age from age-based routine recommendations would be detrimental to the racial and 

ethnic groups who develop risk factors for severe RSV at younger ages. Additionally, shared 

clinical decision-making recommendations at any age would be detrimental to racial and ethnic 

groups who have undiagnosed risk factors. Age-based RSV vaccine recommendations for 

adults ≥60 years of age would ensure equitable access across all older adults. To spend a 

moment on GSK’s candidate vaccine, the vaccine is highly efficacious in adults with one or 

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more underlying comorbidities of interest. Data on co-administration with high-dose influenza, 

adjuvanted influenza vaccines, and VE through 2 RSV seasons will become available in the 

second to third quarter of 2023. GSK appreciates all of the work that CDC and ACIP are doing 

to improve the lives of older adults and to improve health equity and looks forward to continuing 

collaborative discussions. 

Pfizer Statement 

Dr. Alejandro D. Cané (Pfizer) thanked the ACIP for the opportunity to provide Pfizer’s 

comments, emphasizing that Pfizer was very proud to share its vaccine. The RSVpreF vaccine 

represents Pfizer’s commitment to developing a targeted prevention measure to address an 

important amendment for RSV illness, which has been largely unrecognized and under 

diagnosed. Pfizer recognizes that there are many unanswered questions such as duration of 

protection, need for future revaccination, and underdiagnosis of RSV. As such, economic 

modeling is necessary based on uncertain inputs and assumptions. While vaccine price plays a 

role in the evaluation, it also is important to know that the burden of disease is a critical aspect 

to be considered. In fact, the University of Michigan/CDC model that was presented earlier in 

the day used a hospitalization incidence rate of 108 per 100,000 persons per year among adults 

≥65. This is the main input difference in the vastly disparate cost-effectiveness results for the 

CDC model versus either the Pfizer or GSK models. Pfizer used a base-case incidence of 300 

and 256 cases per 100 adults per year, respectively. That is fully aligned with recent CDC 

published data that reports on hospitalizations incidence rates among adults ≥65 years of age of 

240 to 356 cases per 100 persons per year. Pfizer remains committed to developing vaccines 

as a public health strategy and has a goal of eliminating barriers to vaccine access and uptake. 

Pfizer looks forward to working with the CDC in the coming months to continue to collect data 

and inform this important question to further support policy discussion on RSV vaccine use in 

the adult population. 

ACIP Discussion Points, Observations, Suggestions on Adult RSV Vaccines 

Following Dr. Hutton’s Presentation 

• Regarding a question about scenarios in which such a vaccine would be cost-neutral or 

cost-saving, Dr. Hutton indicated that they did not find many scenarios in which the 

vaccine would be cost-saving. There would have to be a scenario in which several things 

were occurring simultaneously. Higher incidence or much lower vaccine cost could get 

closer to cost-savings. They did look at a scenario with a 3-year time horizon, assuming 

that the VE decays at an exponential rate and found that with higher incidence over a 

longer time period, potentially this scenario could be cost-saving. 

• In terms of a question regarding standard cost-effectiveness thresholds per QALY 

gained, Dr. Hutton said there is not necessarily a clear threshold in the US. Anything 

less than $50,000 per QALY is typically seen as highly cost-effective in the US, but a lot 

of people would argue that there should be a willingness to spend $100,000 to $150,000 

or more per QALY gained. There is not necessarily a right answer in the US, unlike in 

the UK where there are very specific thresholds. 

• Dr. Ortega-Sanchez added that there have been many discussions about what 

constitutes a good threshold. For many years, $50,000 per QALY has been used, but 

that proved not to be substantiated by theoretical principles/concepts or data. It was then 

raised to $100,000 per QALY that was corrected to address inflation. Other thresholds 

have been suggested by international organizations, such as the WHO, which said it 

should be 3 times the GDP per capita. In the case of the US, that would be 

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approximately $180,000 per QALY at 3 times the $60,000 GDP per capita. That is only a 

suggestion and CDC usually does not adopt that kind of threshold. 

Following Dr. Ortega-Sanchez’s Presentation 

• Regarding the models seeming to vary depending upon the RSV hospitalization rate and 

the hospitalization rates seeming to vary depending upon the study, Dr. Melgar 

acknowledged that surveillance for RSV disease has not been as robust as surveillance 

for influenza over the last 10 to 20 years, for example. In all 3 of the models by Dr. 

Ortega-Sanchez, the incidence of RSV hospitalization happens to be one of the most 

influential parameters that determines how cost-effective it would be to vaccinate against 

RSV in this age group. As Dr. Ortega-Sanchez showed, even within CDC-derived 

estimates of RSV epidemiology, there is a tremendous amount of uncertainty in the per 

population incidence of RSV hospitalization. That is reflected in the charts showing the 

sensitivity of the ICER by the model input of the number of RSV hospitalizations year-toyear. While CDC continues to work on its surveillance systems to update these 

estimates, the uncertainty interval continues to be very wide. 

• It would be beneficial to know what proportion of the study population in the Phase 3 

trials were 70 and older, 75 and older, and 80 and older. Dr. Melgar noted that he would 

discuss this further during the EtR framework presentation, but one of the key factors 

and considerations the WG discussed was the fact that adults ≥80 years of age were

substantially under-represented in the clinical trials. 

Following Dr. Melgar’s Presentations 

• Concern was expressed about GBS being observed in 1 out of 15,000 in the GSK openlabel trial in 2 of the RSV recipients out of 26,000 in the Pfizer clinical trial, meaning that 

there is a possibility that this could be a side effect in 1 in 13,000 to 1 in 15,000. More 

information was requested about this and specifics about the cases. Dr. Melgar noted 

that the distinction may be somewhat subtle in terms of the trials in which these cases 

occurred. The GSK case occurred in a Phase 3 open-label trial. While this trial was 

randomized but did not include a placebo arm, which is why it was not included in the 

GRADE evaluation. The intent of that trial was to evaluate different revaccination 

schedules, which is where the randomization took place. There were 1,650 adults ≥60

years of age enrolled. Among them, around 4% reported at least 1 SAEs and 2 of those 

was a case of GBS that occurred 9 days after vaccination. That case was in a 78-yearold female in Japan. The level of certainty of the diagnosis of GBS was a Brighton 

Collaboration Level 3. It led to hospitalization lasting 179 days, and the patient 

recovered. This was the only case of inflammatory neuropathy that occurred in GSK’s 

safety database that spans all of their clinical trials in which there were a total of 

approximately 15,000 RSV vaccine recipients. The Pfizer cases of GBS both occurred in 

the Pfizer pivotal Phase 3 trial in which there was a placebo arm. Both occurred in adults 

in their 60s, a male in the US and a female in Japan. The patient in the US initially 

suffered a Non-ST-Elevation Myocardial Infarction (NSTEMI) 7 days after vaccination 

with the investigational vaccine and developed new-onset weakness the next day. A 

nerve conduction study diagnosed Acute Inflammatory Demyelinating Polyneuropathy 

(AIDP) in the lower extremities. This was diagnosed as Brighton Collaboration Level 1 as 

GBS. The other case was diagnosed retrospectively as the Miller Fisher syndrome 

(MFS) variant. The onset was 11 days after vaccination with the RSVpreF vaccination 

and certainty was Brighton Collaboration Level 4. This was the level of detail that was 

provided by the manufacturers. Summed across all of Pfizer’s clinical trials, there were 

approximately 26,000 RSVpreF vaccine recipients and a total of 2 cases of inflammatory 

neuropathy. While the summary of 1 in 13,000 to 15,000 is correct for both 

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investigational vaccines, it is important to realize that 1 or 2 is very sparse to actually 

calculate a rate, which is why this was not done. 

• Data are needed on: prevention of hospitalization for RSV, coadministration with other 

vaccines (especially COVID and influenza), VE and safety in nursing home patients 

where morbidity and mortality are highest from RSV disease, VE and safety in adults 

≥75 years of age who have the highest morbidity and mortality behind those in nursing 

homes, longer-term outcomes, and GBS and other inflammatory neuropathies that result 

from infection with RSV (particularly because natural baseline incidence of inflammatory 

neuropathy increases with age). 

• In the cost-effectiveness modeling, it would be helpful to see explicit incorporation of 

hospitalization for outcomes other than RSV and costs associated with post-discharge, 

as well as modeling with the actual cost of the vaccine. 

• Clarification is needed about whether this vaccine would be covered under Medicare 

Part D. It is possible for physicians to implement Medicare Part D vaccines and be 

reimbursed, but it is difficult. CMS has made some changes that has made this easier in 

2023. 

• There is concern about risk-based vaccination because many patients will not perceive 

themselves as being at risk. Shared clinical decision-making would make 

implementation more complicated for physicians, which may result in missed 

opportunities to vaccinate at-risk patients who do not see themselves as being at risk. 

• The survey conducted among physicians was done in 2017, but physicians may be more 

knowledgeable now about RSV. 

• Equity could be better addressed. 

• A recurring theme about this and all adult vaccines is that a VFA program like the VFC is 

needed. 

CHIKUNGUNYA VACCINE

Introduction 

Beth Bell, MD, MPH (Chair, ACIP Chikungunya Vaccines WG) introduced the chikungunya 

vaccine session. By way of background, the FDA recently accepted Valneva’s BLA application 

for their chikungunya vaccine and granted priority review with licensure possible as early as 

August 2023. No Chikungunya vaccine has ever been licensed in the US or globally, and there 

are no existing ACIP chikungunya vaccine recommendations. To address this, the Chikungunya 

Vaccine WG was formed in May 2022 to develop policy options for ACIP’s consideration for use 

of chikungunya vaccine among US persons at risk of chikungunya, including travelers; residents 

of US territories and states with, or at risk of, transmission; and laboratory workers. 

The Terms of Reference (TOR) for the Chikungunya Vaccines WG are to: 1) review information 

on chikungunya disease, including outcomes; 2) review data on chikungunya epidemiology and 

burden among US residents, including travelers and persons living in areas at risk for local 

transmission; 3) review data on safety, immunogenicity, and effectiveness of chikungunya 

vaccines; 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 

a chikungunya vaccine MMWR Recommendations and Reports document. 

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As a reminder, previous WG presentations to ACIP on this topic provided during the October 

2022 meeting included an overview of chikungunya virus disease and vaccines and a 

discussion about the immunogenicity and safety of Valneva’s chikungunya vaccine. Building 

upon that, presentations during this session focused on the global epidemiology of chikungunya, 

chikungunya in US travelers, persistent arthralgia following chikungunya, and WG 

considerations. 

Global Epidemiology of Chikungunya 

Susan Hills, MBBS, MTH (CDC/NCEZID) presented some information on chikungunya virus 

transmission to provide some background on the overall global patterns and the risk of the 

disease. As a reminder, chikungunya is a mosquito-borne disease with the virus primarily 

transmitted in an ongoing cycle between humans and mosquitos. The main mosquitos involved 

are Aedes aegypti and Aedes albopictus, which are the same mosquitos that transmit some 

other arborviruses such as dengue virus (DENV) and Zika virus (ZIKV). Chikungunya disease is 

clinically characterized by the acute onset of fever and often severe polyarthralgia. Groups at 

risk for more severe disease include adults ≥ 65 years of age, people with underlying medical 

conditions (e.g., hypertension, diabetes, and heart disease), and neonates infected through 

intrapartum transmission. 

This map is useful to illustrate the dramatic spread of chikungunya virus that began in 2004 and 

lasted for about 12 years: 

After chikungunya virus was first detected in Tanzania in the 1950s, for about 5 decades it 

caused sporadic cases and occasional outbreaks in parts of Africa and Asia. In 2004, the 

epidemiology changed dramatically, beginning with a large outbreak in Kenya followed by rapid 

spread of the virus to Indian Ocean islands and beyond, causing numerous outbreaks as it 

expanded across the globe. Ultimately in late 2013, the virus was introduced into the region of 

the Americas, initially spreading throughout the Caribbean and then broadly throughout South 

and Central America. Because the populations in the Americas were largely immunologically 

naïve to chikungunya virus (CHIKV), there was a very large outbreak. More than 2.4 million 

suspected or confirmed cases were reported during the outbreak period. Subsequently, the 

outbreak subsided. 

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During the last 6 years, while there has been some variability in case numbers reported from 

year-to-year, typically fewer than about 200,000 cases have been reported annually from the 

Americas. This map77 shows all countries and territories with past or current transmission of 

Chikungunya virus: 

Transmission is known to have occurred in the past, albeit occurring currently in over 110 

countries worldwide. This map is readily available and is often referenced, but it is sometimes 

misinterpreted because it just shows countries and territories that have ever had chikungunya 

virus transmission, but these locations did not necessarily have any current transmission. In 

fact, understanding the current patterns of chikungunya virus transmission can be challenging. 

There are some sources of data such as Ministry of Health websites, WHO websites, and data 

on traveler cases that are collected by national authorities or published in journal articles. 

However, the available information on chikungunya virus transmission is usually incomplete and 

typically not available in a timely manner. 

When considering the current patterns of chikungunya virus transmission, there are some 

general overall features of note. The disease occurs in tropical and subtropical regions with very 

rare outbreaks reported in temperate areas. It is often seen in the same locations where similar 

Aedes mosquito-borne diseases are found such as dengue and Zika. Transmission can be 

impacted by several factors, including weather, environmental conditions, pre-existing 

population immunity, population density, and the type of Aedes vectors present. 

Patterns of chikungunya virus transmission vary in different locations. In Africa, Asia, and 

Central and South America, the general pattern is ongoing 1-level transmission with periodic 

outbreak activity. This reflects a cycle where immunologically susceptible individuals continue to 

acquire infection and propagate human-mosquito-human transmission cycles. Outbreaks are 

unpredictable in terms of timing and size. Typically, after high incidence outbreaks, low-level 

transmission continues for many years. Complete cessation of transmission after outbreaks is 

common in island nations because they are geographically isolated and often have small 

populations that develop herd immunity during outbreaks. It is more feasible for interruption of 

77 https://www.cdc.gov/chikungunya/geo/index.html 

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transmission to occur compared with large countries with contiguous borders. Currently, there is 

no evidence of chikungunya virus transmission in most Pacific Island and Caribbean countries 

and territories. Nonetheless, there is ongoing potential for reintroduction of virus in island 

settings without transmission. The risk increases over time as population immunity wanes. Once 

there is low population immunity, the possibility of reemergence and then an explosive outbreak 

is high. 

Periodic outbreaks are a key feature of chikungunya virus transmission. In terms of location, 

outbreaks are more likely in regions with no or mild outbreaks in the recent past. However, this 

is unlikely to accurately predict the location of any future outbreaks as other factors also 

contribute. Sometimes outbreaks are localized and sometimes they are widespread. Once an 

outbreak begins, it can increase rapidly in size. About 30% to 60% of the susceptible population 

can be infected within a few months. Huge outbreaks like those that occurred in the 

immunologically naïve population in the Americas from 2014–2016 are unlikely in future. 

However, there is likely to be continued reporting of large outbreaks on an ongoing basis. For 

example, there is currently an ongoing outbreak in Paraguay with over 50,000 suspect cases. In 

regard to the timing of outbreaks, most occur during the rainy season and abate during the dry 

season, but outbreaks can occur in the dry season. In terms of duration, the period of intense 

transmission is typically short, often only about 3 to 6 months. 

The interval between outbreaks is unpredictable and variable. There can be 20 years or more 

between outbreaks in any particular location. Various factors likely impact the interval between 

outbreaks, including pre-existing population immunity, build-up of non-immune population over 

time, environmental conditions, and other factors. Some countries regularly report outbreaks, 

but these are typically in different locations of the country. 

In summary, the key points of the global epidemiology of chikungunya are that the disease 

mainly occurs in tropical and subtropical areas. Currently, most countries with chikungunya virus 

activity have low-level ongoing transmission. However, chikungunya is an outbreak-prone 

disease. The impact of outbreaks when they occur is important because they often can result in 

intense transmission. In general, the duration of any outbreak is short. 

Chikungunya in US Travelers 

Nicole Lindsey, MS (CDC/NCEZID) noted that as mentioned earlier, the WG will be 

considering recommendation options for chikungunya vaccine use among various groups. The 

first group the WG will be considering is travelers to areas at risk. Therefore, she summarized 

the data on chikungunya in US travelers based on data from national surveillance for US 

travelers, including confirmed and probable cases in residents of US states reported to CDC. All 

of these cases have laboratory evidence of infection based on either molecular or serologic 

testing. Cases reported from US territories and associated states were excluded due to 

difficulties in differentiating travel-associated and locally-acquired cases. Prior to 2006, 

chikungunya was very rarely reported in US travelers, so the data included here are for cases 

reported for 2006─2021. Overall, 4,590 traveler cases were reported during this timeframe. 

Because chikungunya was not a notifiable disease until 2015, we expect that reporting may 

have been more incomplete during the earlier years. 

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From 2006─2013, cases were rare with an average of 7 cases reported annually. All of these 

cases reported travel to areas in Asia, Africa, or the Indian Ocean that were known to have 

chikungunya activity. There was a large increase in reported cases concurrent with explosive 

outbreaks in the Americas, with more than 3,700 cases reported in 2014 and 2015 together. 

Annual numbers of cases have declined steadily since the Americas abated. Overall, 35% of 

reported cases were male and 65% were female. This predominance of female cases was 

consistent by year and by age group. A predominance of female cases has been reported in the 

literature fairly consistently. Some authors have hypothesized that the difference could be due 

to greater healthcare-seeking behaviors among women, as most seroprevalence studies have 

not shown a significant difference in infection rates by sex. The majority of cases occurred in 

persons 40─59 years of age. There were relatively few cases in the very young and older age 

groups. This age distribution is likely reflective of the age of the traveler population, given that 

infection rates are not expected to different by age. The age distribution was consistent over 

time. 

Although cases occurred in all months of the year, 61% occurred during June through 

September. This likely reflects popular times of travel as well as the timing of seasonal 

outbreaks and locations of travel. Because 2014 accounted for such a high proportion of the 

total cases, the WG wanted to see if there was any difference in seasonality for that year 

compared to other years. When the 2014 cases are removed, there is still a peak in the summer 

months, but the curve is flatter. There is more of a discernable peak in January. 

In terms of clinical outcomes, about 18% were hospitalized. In the literature, the reported 

frequency of hospitalization of chikungunya-infected patients ranges from about 0.5% to 11% 

and may be affected by access to medical care, local clinical practices, reporting and testing 

practices, and frequency of comorbidities and coinfections in the population. The hospitalization 

rate among cases reported to CDC is high and is likely artificially inflated due to biases of 

identification and reporting of more severe disease cases in travelers. There were 4 reported 

deaths. While causes of death were not available, these deaths were among older adults with a 

mean age of 77 years. No deaths occurred during the acute illness. The mean time from illness 

onset to death was about 2 months. Hospitalization rates were highest among young children 

and adults ≥60 years of age. Infants were most likely to be hospitalized. Of the 17 cases 

reported, 7 were in children under 2 years of age who were hospitalized. 

More than half of the cases (~54%), were reported to have been infected in locations in the 

Caribbean. More than 80% were reported to have acquired infection in one of the Americas 

regions. Because this was heavily influenced by the 2014-2015 outbreak in the Americas, the 

WG looked at region of infection just in the past 5 years. Among the 532 cases reported during 

that time, 60% were infected in locations in Asia. About 27% were infected in 1 of the 4 

Americas regions, and about 8% were infected in Africa. The 10 most common countries or 

territories of infection for cases reported since 2006 were in the Americas with the exception of 

India, which accounted for approximately 9% of cases overall. By far the highest number of 

cases, over 1,000, originated from the Dominican Republic. Looking at trends in more recent 

years without the influence of the Americas outbreaks, the most common location of infection in 

the last 5 years was India, which accounted for about 37% of cases. Most cases originated from 

Asian countries, although a fair number are still being identified related to travel in the Americas 

locations. 

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There are several limitations of national surveillance data. Reported cases are likely an 

underestimate of the true incidence of disease among US travelers. More severe cases are 

more likely to be identified and reported, leading to an inflated proportion of severe outcomes 

such as hospitalization and death. The data provided through national surveillance are often 

incomplete, particularly for travel history. There is no information available on duration of travel 

or activities during travel that might be associated with an increased risk of infection. 

Additionally, there is no information on the duration of specific symptoms or long-term sequelae. 

In summary, outside of the time of the unprecedented outbreaks in the Americas, relatively few 

chikungunya disease cases in US travelers are reported annually. Reported cases likely 

underestimate the true incidence of disease and overestimate the proportions of severe 

outcomes. Very young children and older adults have the highest hospitalization rates. Cases 

have occurred among travelers to all regions with chikungunya risk and can occur year-round, 

with case numbers reflecting levels of chikungunya virus activity in and numbers of travelers to 

destinations with risk. 

Persistent Arthralgia Following Chikungunya 

Nicole Lindsey, MS (CDC/NCEZID) next discussed chronic arthralgia, an important sequela of 

chikungunya infection. It often is reported that the acute symptoms of chikungunya typically 

resolve in 7 to 10 days and that mortality is rare. However, a significant proportion of patients 

have continued to recurrent arthralgia in the months and years following their acute illness. 

Other long-term complications have been reported less frequently (e.g., fatigue, depression, 

alopecia, impaired memory, sleep disorders, and lowered quality of life). Although other sequela 

have been reported, chronic arthralgia is clearly the most significant of these. Therefore, 

understanding disease burden in relation to this outcome is very important in understanding the 

potential benefits of vaccination. 

Multiple studies that have been published reported on chronic joint symptoms following 

chikungunya infection. There is variability in these studies in terms of methodology, symptoms 

assessed, definitions and ascertainment of symptoms, self-report versus assessment by a 

clinician, duration of follow-up, and characteristics of the cohort of patients. Meta-analyses have 

been published, but these also varied in the specific outcomes analyzed and the criteria used to 

evaluate studies for inclusion. After reviewing the published meta-analyses, the WG determined 

that none used the outcome and inclusion criteria that would be most useful in guiding the 

vaccination recommendation process and therefore decided to perform its own review and 

meta-analysis. 

The primary objective of the WG’s review and analysis was to estimate the percentage of 

patients with chronic arthralgia defined as ≥3 months following chikungunya infection. A 

literature search was conducted in Medline for articles describing primary data on arthralgia 

following chikungunya infection published from January 1, 2000─October 24, 2022. Articles 

were excluded if the investigators did not confirm all chikungunya infections by serologic or 

molecular testing. Studies where only a clinical diagnosis was made were not included. Studies 

also were excluded in which cases were from specific subgroups that might affect disease 

severity or duration or duration of symptoms (e.g., children, people with coinfections, 

abnormally large proportion of cases hospitalized for acute disease). Non-English language 

articles also were excluded. These accounted for less than 5% of all articles identified in the 

original search. 

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The original search identified 1,167 publications and all titles and abstracts were reviewed. Of 

those, only 80 required a full text review to determine whether they met the WG’s criteria. Of 

those, 27 met the inclusion criteria and a data extraction was completed using a standardized 

spreadsheet tool. The 27 included articles accounted for a total of 4,079 chikungunya infected 

persons. Most of the studies were clustered in 1 of 2 time periods, 2005─2006 during the 

outbreaks in the Indian Ocean and 2014─2015 during the initial outbreaks in the Americas. 

Overall, 23 studies were conducted among local populations during outbreaks. Of these, 4 

studies were among travelers to outbreak locations, 14 included patients infected in countries in 

the Americas, 8 were in countries in the Indian Ocean, 4 were in Asia, and 1 was in Europe. 

Only 4 of the 27 studies included a control group of non-infected persons. There was a range of 

severity of illness among populations included in the studies (0%–33% hospitalized) and varied 

demographics of included participants. 

There were more than 27 datapoints because some studies reported estimates from multiple 

timepoints. The WG chose 3 timepoints to generate summary estimates at 3, 6, and 12 months. 

There were 7 studies that evaluated arthralgia at 3 months after acute infection, accounting for 

733 patients. All studies included patients who sought healthcare for their acute symptoms. 

There were 2 studies among travelers, 1 among travelers to locations in the Indian Ocean and 1 

with travelers to locations in the Americas. There were 5 cohorts from communities with 

outbreaks in Brazil, French Guinea, Martinique, St. Maarten, and Thailand. In all studies, there 

was a predominance of females. The studies included patients of varying ages. The mean or 

median ages ranged from a low of 35 years to a high of 51 years. There also was a range of 

disease severity from no hospitalizations to 17%. Among the 7 studies, the reported proportion 

of patients with chronic arthralgia at 3 months ranged from 42% to 86%. The summary estimate 

for this timepoint was 51%, with a 95% confidence interval from 44% to 58%. 

There were 9 studies that evaluated arthralgia at 6 months, accounting for 961 patients. All 

studies included patients who sought healthcare for their acute symptoms. There were 3 studies 

among travelers, all among Indian Ocean travelers, and 6 in communities with outbreaks in 

Bangladesh, French Guinea, Martinique, Mexico, Suriname, and Thailand. Again, there was a 

predominance of females in a range of ages. The mean ages ranged from a low of 32 years to a 

high of 60. Hospitalization rates ranged from 0% to 33%. The reported proportion of patients 

with chronic arthralgia at 6 months ranged quite widely from 13% to 70%. The summary 

estimate for this timepoint was 35%, with a confidence interval from 24% to 47%. 

There were 10 studies that evaluated arthralgia at 12 months, accounting for 1,539 patients. Of 

these studies, 9 included patients who sought healthcare for acute symptoms and 1 was a 

population-sample obtained from persons testing positive during a serosurvey who were asked 

about symptoms at the time of the blood draw. All studies were conducted in communities with 

outbreaks occurring, including Aruba, Bangladesh, Brazil, Grenada, Italy, Malaysia, Martinique, 

Reunion Island, and the US Virgin Islands). Again, there was a predominance of females and a 

range of ages and hospitalization rates. The reported proportion of patients with chronic 

arthralgia at 12 months also ranged widely from a low of the 19% to a high of 61%. The 

summary estimate for this timepoint was 38%, a 95% confidence interval from 29% to 46%. 

Among the 9 studies that assessed arthralgia at multiple timepoints, in general there was a 

decrease in the proportion over time. 

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As noted earlier, the first task of the WG is to develop recommendations for travelers. This table 

presents results of the 4 studies that were among travelers specifically: 

These 4 studies had relatively small sample sizes. Due to the methods of patient identification, 

they tended to include more older person and skew toward those with more severe acute 

disease. The Simon study included 47 French travelers who acquired illness in locations in the 

Indian Ocean. A very high percentage, 85%, reported arthralgia at 3 months and 48% had 

arthralgia at 6 months. Another study of French travelers identify from a different facility reported 

almost 60% with arthralgia at 2 years. Notably different results were reported by a small study of 

16 German travelers from the same general outbreak location and time period. Only 13% of 

cases had arthralgia at 6 months. There was 1 study of Spanish travelers from the outbreak in 

the Americas. In that group, 50% reported arthralgia at 3 months. 

To highlight some limitations of this work, there is substantial variability among the studies the 

WG included in terms of case definitions, populations included, and the findings. Almost all of 

the studies that have been completed are among persons who sought healthcare for their 

disease symptoms and are not representative of all infected persons. There are only a few 

studies that included a control group to account for background rates of arthralgia in the 

population. For the meta-analysis, the crude estimates were used from all studies to calculate 

the summary estimates. 

To summarize the 4 studies that did include a control group of uninfected persons, the first 2 

were conducted following the Reunion Island outbreak. The Soumahoro 2009 study (Reunion 

2005-2006) included 199 cases and 199 controls. At 17 months after onset, the chikungunya 

cases reported significantly more joint pain than was reported in the control group at 53% 

compared to 28%. It was estimated that 47% of pain in the cases was attributed to chikungunya 

infection. The Gerardin 2011 (Reunion 2005-2006) study was larger, with 512 cases and 582 

controls. At 16 months, cases were more likely to report musculoskeletal pain than controls at 

43% compared to 17%. It was estimated that 60% of pain in the cases was attributed to 

chikungunya infection. 

The 2 studies with controls were conducted following the outbreak in the US Virgin Islands. The 

Feldstein 2017 (USVI 2014-2015) study included 165 cases and 167 controls. At 6 months, the 

difference in arthralgia between case patients and controls was 32% after adjusting for age, sex, 

and history of arthritis. At 12 months, the adjusted difference was 19%. The Hennessey 2018 

(USVI 2014-2015) study included 171 cases and 338 controls. At 12 months, 31% of case 

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patients and 26% of controls reported joint pain. The study estimated that only 23% of joint pain 

in the case patients was attributed to chikungunya infection. 

To review the key points, this meta-analysis that included patients who almost universally 

sought healthcare during their acute infection showed that a substantial proportion had chronic 

arthralgia following infection. There was variability among studies at all timepoints, but it is 

estimated that about half of patients have arthralgia at 3 months after illness onset. The 

proportion with arthralgia decreased over time, and just over a third were estimated to have 

arthralgia after a year. It is very important to understand that these proportions of persons with 

chronic arthralgia are likely over-estimates when the broader population is considered. First, 

they reflect almost exclusively the healthcare-seeking population who are likely to have more 

severe disease compared to those who do not seek healthcare. Among the population as a 

whole, rates almost certainly would be lower. Second, the rates do not account for underlying 

rates of arthralgia in the population. The small number of studies that did include a control group 

provided variable results, but overall suggested when this background rate of arthralgia was 

taken into consideration, 20% to 60% of reported arthralgia after chikungunya might be 

attributable to the prior chikungunya virus infection. 

In summary, it is difficult to provide a precise estimate of incidence of long-term joint pain after 

chikungunya. In addition, the percentages of patients with long-term joint pain are likely variable 

based on several factors, including the severity of acute illness and patient age, sex, and 

comorbid conditions, particularly pre-existing joint conditions. However, long-term joint pain after 

infection is an important complication of chikungunya that could be prevented by vaccination. 

Workgroup Considerations 

Nicole Lindsey, MS (CDC/NCEZID) concluded the session by briefly reviewing the WG plans 

and timelines. As Dr. Bell mentioned earlier, FDA recently accepted Valneva’s BLA for 

chikungunya vaccine and granted priority review. Therefore, licensure is possible as early as 

August 2023. The WG is initially focusing on developing recommendations for ACIP’s 

consideration for travelers and laboratory workers and plans to present the EtR Framework 

during the October 2023 ACIP meeting. A vote on these recommendations would follow at the 

February 2024 meeting. The WG then plans to continue its discussions to consider 

recommendations for adults living in US territories and states at risk for outbreaks. During the 

next few months, the WG plans to comprehensively review the vaccine immunogenicity and 

safety data as a part of the GRADE assessment. The WG anticipates making further 

presentations to ACIP on topics relevant to consideration of vaccine use in territories and US 

states with risk of transmission in the future. Additionally, the WG anticipates that over time 

there will be additional data on the use of Valneva’s vaccine among younger age groups. 

Additional chikungunya vaccines may be submitted for licensure in the US, and those data will 

be presented to the ACIP as they become available. 

ACIP Discussion Points, Observations, Suggestions on Chikungunya Vaccines 

Following Dr. Hill’s Presentation 

• Regarding an inquiry about whether there are any data on acquisition of chikungunya 

infection among residents of the US who have not left the country, Dr. Hills indicated that 

there has been limited evidence of transmission in the US in just 2 states, Florida and 

Texas in 2014. There were 12 cases of local transmission in Florida and there was 1 

case of local transmission in Texas. There was a large outbreak of chikungunya in 

Puerto Rico that began in 2014. The last clear evidence of transmission in Puerto Rico 

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was in mid-2017. One of the questions that the WG is going to consider is the use of 

chikungunya vaccine in US territories and affiliated states with risk of transmission and in 

states in the US with evidence of transmission. The first questions the WG plans to 

tackle relate to US travelers and laboratory workers. The WG does plan to present some 

additional data in the future in relation to US states and territories. 

Following Dr. Lindsey’s Presentation (Travelers) 

• No questions or comments. 

Following Dr. Lindsey’s Presentation (Arthralgia) 

• No questions or comments. 

Following Dr. Lindsey’s Presentation (WG Considerations) 

• Regarding an inquiry about whether there will be any consideration of pregnant and 

lactating women, Ms. Lindsey indicated that pregnancy will be a contraindication since 

this is a live-attenuated vaccine. Discussions have not yet started in the WG, but various 

factors will be considered over the next couple of months. The WG would be happy to 

discuss lactating women in the future. 

• Regarding how confident the WG is that climate change will impact the dynamics of the 

epidemiology in the coming years, Ms. Lindsey indicated that the WG is struggling with 

the availability of surveillance data. While some Ministry of Health websites post data, 

they are often not complete or timely. There are various sources of data such as WHO 

and traveler data, but overall the data tend to be incomplete and not timely. The WG will 

discuss a variety of issues in depth over the next couple of months, including 

considerations about how to make recommendations in the context of limited and 

potentially untimely data. 

DENGUE VACCINE 

Introduction 

Wilbur Chen, MD, MSc (ACIP Member and WG Chair) emphasized that DENV infections are 

so extensive, they put approximately half of the global population at risk. There are 4 genetically 

distinct DENV serotypes: DENV-1, 2, 3, 4. Infection with 1 serotype provides life-long typespecific immunity, but only short-term cross-protection of approximately 1 to 2 years against the 

other 3 serotypes. Importantly, it is with the second dengue infection that there is increased risk 

of severe dengue illness. This is due to a phenomenon called antibody-dependent 

enhancement (ADE). 

ACIP already discussed and voted on DengvaxiaTM. Clinical trials found different outcomes with 

DengvaxiaTM vaccination among children with and without previous dengue infection. Children 

without previous dengue infection had a higher risk of hospitalization and severe dengue if they 

were vaccinated and subsequently had a natural DENV infection, which basically mimics the 

second dengue infection. Children with previous dengue infection were protected from 

hospitalization and severe dengue when they were vaccinated with DengvaxiaTM. 

DengvaxiaTM was recommended by the ACIP during the June 2021 meeting. Three doses of 

DengvaxiaTM are indicated for the prevention of dengue disease caused by serotypes 1, 2, 3, 

and 4 in children 9─16 years of age with the provisions that they should have laboratory 

confirmation of prior dengue virus infection and be living in endemic areas. 

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Since the June 2021 ACIP meeting, the WG took a hiatus and then reconvened in August 2022 

when the WG restarted its meetings to discuss the Takeda product, TAK003, the focus of this 

session in terms of efficacy, immunogenicity, and safety from Takeda and the WG’s 

interpretation. During the June 2023 ACIP meeting, the WG plans to present the GRADE and 

cost-effectiveness analysis. During the October 2023 ACIP meeting, the WG plans to present 

the EtR framework and draft recommendations and hopes to have a vote ready for the ACIP at 

that time. The WG will continue to review efficacy, immunogenicity, and safety data through the 

GRADE process; review the EtR domains and cost-effectiveness analysis; and develop policy 

options to present for an ACIP vote. 

This session included presentations on the efficacy, safety, and immunogenicity of TAK-003; 

and the WG’s summary and interpretation of the TAK-003 efficacy, safety, and immunogenicity 

data. 

Takeda Dengue Vaccine (TAK-003) Safety and Efficacy 

Shibadas Biswal, MD (Takeda Vaccines) noted that TAK-003 is an investigational compound 

that has not been approved by the US FDA for use in the US. Currently, this vaccine is 

approved for use in UK, Europe, and Indonesia for use regardless of prior dengue exposure 

status. That is, it can be used in both dengue-naïve and pre-exposed individuals. Takeda is 

seeking an indication for this vaccine in the US for prevention of dengue in individuals 4─60 

years of age regardless of prior dengue exposure. This presentation focused on the construct of 

the vaccine, its immune response profile, the clinical development process, efficacy profile from 

the pivotal efficacy trial, safety profile from an integrated analysis of placebo-controlled trials, 

and immunogenicity data from the pivotal efficacy trial. 

To describe the construct of this vaccine, TAK-003 is a live, attenuated tetravalent vaccine 

constructed using DENV-2 as the backbone. A dengue-based vaccine was expected to have a 

better chance of protection against the disease. The serotype 2 component has a TDV-2 

attenuated structure. In constructing the other 3 components, the pre-membrane and envelope 

protein genes from DENV-2 are replaced with those from the other 3 serotypes, DENV-1, 3, and 

4. That leads to 4 virus components corresponding to each of the 4 Dengue serotypes. The 

primary mechanism of action is to replicate locally and induce immune response against all 4 

serotypes. This includes humoral-mediated immunity, cell-mediated, and innate immunity. For 

Dengue, an immune correlate of protection has not been established. The broad spectrum of 

immune responses are likely to contribute to protection against infection, virus clearance, and 

prevention of severe disease.78 

Turning to an overview of the clinical development of this vaccine, the vaccine has been 

evaluated in 19 completed or ongoing clinical trials in 13 dengue-endemic and non-endemic 

countries. Over 28,000 children and adults 1.5─60 years of age participated in Phase 1─3

clinical studies. Clinical development included both baseline seronegative and seropositive 

participants. Approximately 20,000 participants received at least 1 dose of TAK-003 in clinical 

development programs. 

78 Biswal S, et al. Lancet 2020;395:1423–1433; Tricou V, et al. Lancet 2020;395:1434–1443; Sharma M, et al. J Infect Dis 

2020;221:867–877; Michlmayr D, et al. J Infect Dis 2021;233:247–257; Tricou V, et al. Vaccine 2022;40:1143–1151 

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The pivotal efficacy trial was a randomized double-blind placebo-controlled trial that was 

designed in accordance with WHO guidelines and was conducted in 8 dengue-endemic 

countries. The trial included more than 20,000 participants 4─16 years of age. This age range 

was selected to ensure inclusion of both seronegative and seropositive individuals. Also 

importantly, dengue incidences tend to be higher in this age group in endemic areas. 

Participants received either TAK-003 or placebo by subcutaneous injection into the upper arm. 

Two-thirds received vaccine and one-third received placebo in a 2:1 randomization ratio. 

Baseline samples were collected from all participants to assess baseline serostatus. Active 

surveillance with weekly contact was in place throughout the study to detect all symptomatic 

dengue cases. Dengue cases were confirmed through RT-PCR. After 2 doses 3 months apart, 

the trial had a follow-up period of approximately 4.5 years. Toward the end of this follow-up 

period, a booster dose was administered to a subset of participants and is currently ongoing. In 

this presentation, Dr. Biswal described only data from the pre-booster part of the trial. 

Overall demographics were similar between placebo and vaccine groups. Nearly 28% were 

dengue seronegative at baseline. The mean age at enrollment was 9.6 years. Slightly more 

participants were enrolled in Latin America than in Asia. The trial was conducted in a wide 

geographic area to maximize chances of detecting all 4 dengue serotypes. At the Asian site, all 

4 serotypes were reported with DENV-2 being the most common. At the Latin American sites, 

the serotypes were mostly DENV-1 and DENV-2, with DENV-1 being the most common. DENV4 was generally infrequently reported in the trial, which is also in line with known dengue 

epidemiology. 

In terms the key efficacy data starting with the primary and secondary efficacy endpoints, the 

trial metrics primary endpoint demonstrated 80% efficacy in the symptomatic dengue at the end 

of the past 12 months after vaccination. It also met the key secondary endpoint demonstrating 

efficacy against dengue leading to hospitalization at the end of 18 months after vaccination. The 

trial met all additional secondary efficacy endpoints for which there were sufficient cases to 

evaluate. This includes efficacy in baseline seropositive and baseline seronegative participants, 

efficacy by each serotype, Dengue Case Adjudication Committee (DCAC)-defined virologically 

confirmed dengue (VCD). Two endpoints were not met due to low numbers of cases. Those 

were efficacy against DENV-4 serotype and efficacy against severe VCD. 

Looking at the exploratory analysis beginning with the long-term VE by baseline dengue 

serostatus, TAK-003 continued to reduce incidence of dengue fever during the 57 months of 

surveillance. TAK-003 was efficacious soon after the first dose with early separation of placebo 

on maximum curves and it remained efficacious through the whole 57 months in both 

seronegative and seropositive participants. The cumulative efficacy during this time from the 

first dose was 61% overall, 54% in seronegative participants, and 64% in seropositive 

participants. Looking at the similar curves for dengue hospitalizations, TAK-003 also reduced 

hospitalizations over 57 months. The cumulative efficacy during this timeframe was 84% overall, 

79% in seronegative participants, and 86% in seropositive participants. Overall, the vaccine 

demonstrated protection against symptomatic dengue and those leading to hospitalization, 

irrespective of prior exposure to dengue over 57 months of follow-up. 

Turning to further exploratory analysis looking at the profile of the vaccine stratified by baseline 

serostatus at each serotype level for all symptomatic cases, efficacy was clear for 6 out of 8 of 

the subgroups in this analysis. In seropositive participants, efficacy was seen against all 4 

serotypes. In seronegative participants, efficacy was shown against DENV-1 and DENV-2. The 

data for DENV-3 in seronegative participants suggested a lack of efficacy with a marginally 

negative point estimate. For DENV-4. there are too few cases in seronegative participants to 

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assess the efficacy profile. Looking at similar data for hospitalized cases, the first thing notable 

is that the efficacy was consistently higher against hospitalizations than it was against any 

dengue. Again, the efficacy profile was clear for the 4 serotypes in seropositives and for DENV1 and DENV-2 in seronegatives. Looking specifically at DENV-4 in seronegatives, the only case 

of hospitalization was in a placebo recipient. For DENV-3 hospitalizations in seronegatives, the 

case counts were small so VE was inconclusive, but the point estimate was negative. 

Looking deeper into data in a country-by-country analysis, it is important to know that the 

surveillance methodology was the same across sites and clinical management of febrile 

illnesses was according to local standards of care. In other words, rates for hospitalizations 

were not defined in the drug protocol and trial centers were able to hospitalize according to local 

standards. As a result, there were considerable barriers in hospitalization rates looking 

specifically at the placebo group. Cases were proactively hospitalized based on local dengue 

testing regardless of clinical condition. In all countries other than Sri Lanka, hospitalization was 

due to clinical need. As a result, 68% of cases in Sri Lanka were hospitalized compared to an 

average of 16% across all other countries. 

In terms of the sensitivity analysis, excluding the data from Sri Lanka, seropositive participants 

had high efficacy against hospitalized dengue across all 4 serotypes. That is not affected by 

hospitalization practices in Sri Lanka. In seronegative participants, DENV-1, 2, and 4 results 

also were not impacted by hospitalization practices in Sri Lanka. Only DENV-3 was the 

exception, and therefore requires further interpretation. There were numerically more 

hospitalized cases in the vaccine group compared to placebo group, although case counts were 

small. Excluding the Sri Lanka data, the case counts were proportionate and there was no 

difference between the 2 groups. These data must be considered in the context of a number of 

factors. While detections were the same across all sides, the hospitalization approach was 

unique in Sri Lanka. More than 85% of all DENV-3 cases in seronegative participants appeared 

outside Sri Lanka, but there was no evidence of increased hospitalization. DENV-3 cases in 

seronegative participants in Sri Lanka were reported from one site during Year 3. In summary, 

there is little evidence that vaccination increases the risk of hospitalization in seronegative 

recipients infected by DENV-3. This will be further monitored and studied in the post-marketing 

setting. 

Now to review safety data from an integrated analysis of placebo-controlled trials. Solicited 

reactions occurred more frequently in the vaccine group than the placebo group. Unsolicited AE 

had similar incidence in both the vaccine and placebo groups. The most frequent vaccinerelated unsolicited AE were injection site pruritus, bruising, and pyrexia. In an integrated 

analysis of SAEs in the placebo-controlled trials, the rates of SAEs were 8% in the vaccine 

group and 9.6% in the placebo group. None of the deaths reported were related to the 

investigational vaccine. There were also no deaths caused by dengue in the development 

program. 

In terms of immunogenicity, the primary immunological endpoint of all studies in the program 

was based on neutralizing antibodies. In the pivotal efficacy trial, TIDES, seropositivity rates in 

seronegative participants were used to measure the proportion of responders to the vaccine. 

The vaccine was found to be immunogenic against each of DENV-1, 2,3, and 4 serotypes. This 

was based on achieving the lowest detectable level of antibody response. To clarify, this is not 

synonymous with correlate of protection. Seropositivity rates after 1 dose of TAK-003 were 

greater than 90% for each serotype, with 85% of vaccines having a tetravalent response. After 

the second dose, nearly 100% of the participants had a tetravalent response among those who 

were seronegative. Regarding the GMTs of antibody response over time, titers increased after 

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the first dose for all serotypes, with highest levels against DENV-2. Titers against Dengue-1, 3, 

and 4 were similar. Persistence of antibody titers were seen out to 51 months after the first 

vaccination in the seronegative participants. 

To summarize, TAK-003 has been evaluated in 19 clinical course trials in 13 countries. Data 

from the pivotal trial showed long-term efficacy in both baseline seronegative and seropositive 

participants. TAK-003 is immunogenic against all 4 serotypes. Data from the pivotal trial 

suggested varying efficacy profiles by serotype. It was efficacious against all 4 serotypes in 

seropositive participants. In seronegative participants, it was efficacious against Dengue-1 and 

Dengue-2, the serotypes most commonly seen in the trial. In baseline seronegative participants, 

the data suggested lack of efficacy against Dengue-3 and did not allow assessment of Dengue4 due to low incidence. However, the long-term follow-up did not conclude a high risk of 

hospitalized or severe forms of Dengue associated with TAK-003. The totality of the data did not 

indicate harm. Safety data from the integrated analysis of placebo-controlled trials showed that 

TAK-003 had an acceptable safety profile. To conclude, TAK-003 represents a new tool that can 

have a critical role in reducing dengue burden globally and in the US. 

Workgroup Considerations 

Gabriela Paz-Bailey, MD, PhD, MSc (CDC/NCEZID) presented a summary of the WG’s 

interpretation of TAK-003 efficacy, safety, and immunogenicity data. Takeda’s trial was a 

double-blinded placebo control study. Participants were enrolled and randomized to vaccine or 

placebo at a 2:1 ratio. The study included children 4─16 years of age. The study was conducted 

across 5 countries in Latin America and 3 countries in Asia. It has a follow-up time of 57 months 

after the first dose. The safety set included about 20,000 participants of whom 28% were 

seronegative at baseline. The primary endpoint was virologically confirmed dengue or VCD due 

to any serotype measured at 1 year after the second dose in the series. The secondary 

endpoints were stratified by the participants’ serostatus and by dengue serotype. The secondary 

outcomes included the outcome VCD, hospitalizations for dengue, dengue hemorrhagic fever 

(DHF), and a trial-specific severe dengue definition. 

Dr. Paz-Bailey summarized the data for the follow-up time of 57 months and included data from 

all the trial sites, including VE for the outcome of VCD for all serotypes and serostatus combined 

and then stratified by serostatus and then stratified by serotype. Starting with an overall vaccine 

efficacy for all serotypes and all serostatuses combined for VCD of 61%, stratified by serostatus 

VE was 64% in seropositives and 54% in seronegatives. When stratified by individual serotype, 

there was efficacy against all serotypes in seropositives. However, VE for seronegatives was 

negative with 95% confidence interval crossing zero for DENV-3 and DENV-4. The WG’s 

interpretation for the outcome of VCD was that there is evidence of protection against all 4 

serotypes for seropositives. For seronegatives, there is significant protection against DENV-1 

and DENV-2 but not for DENV-3 or DENV-4. There are insufficient data to rule out an increased 

risk of VCD for these 2 serotypes. 

Similar trends were observed for the outcome of hospitalizations. There was VE of 84% against 

hospitalizations for serostatuses and serotypes combined. Stratified by serostatus, there was 

significant protection in both seropositives and seronegatives. Stratified by serotype, there was 

significant protection for seropositives against serotypes 1, 2, and 3 and a calculated VE of 

100% against DENV-4. However, there were only 3 events for these serotypes and they were 

all in the placebo arm. For seronegatives, there was significant protection for DENV-1 and 

DENV-2 and a negative VE for DENV-3 of 88% with confidence intervals crossing zero. There 

was only 1 hospitalization event for DENV-4 in the placebo arm. While the negative VE for 

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DENV-3 among seronegatives suggested a higher rate of hospitalization in the vaccinated 

participants compared to placebos. It is important to emphasize that the hospitalization rate for 

the serotype was overall low for both the vaccine and the placebo arms in the trial. For DENV-3, 

there were 3 hospitalizations in the placebo arm and 11 in the vaccine arm, which had twice as 

many participants as the placebo arm. That equals a hospitalization rate of 0.04 per 100 person 

years for the placebo and 0.07 for 100 person years for vaccinated participants. For DENV-4, 

there was only 1 case in the placebo arm. 

The WG interpretation of these data was that in seropositives, there is protection against all 

serotypes, although there were very few hospitalizations for DENV-4. For seronegatives, there 

was protection for DENV-1 and DENV-2. Once again, there were few hospitalizations for DENV4. There was no efficacy for DENV-3 against hospitalization and there were insufficient data to 

rule out the possibility of an increased risk of hospitalization among vaccinated children. 

Looking at the outcome of severe dengue for the outcomes of DHF based on the 1997 WHO 

definition and the trial-specific definition for severe dengue, Dr. Paz-Bailey showed VE by 

serostatus but not by serotype since there were very few events. There was VE of 70% overall 

against DHF for serostatuses and serotypes combined. When stratified by serostatus, there was 

VE of 81% in seropositives and −3.4 in seronegatives. There are only 5 DHF cases in the 

vaccine arm and 13 cases in the placebo arm for seropositives. In seronegatives in the placebo 

arm, which had half as many participants as the vaccine arm, there were only 2 diastolic heart 

failure cases,1 due to DENV-1 and 1 due to DENV-3. There were 4 DHS cases in the vaccine 

arm, and they were all due to DENV-3. For the trial-specific definition of severe dengue, VE was 

70% for serostatuses combined, with a confidence interval ranging from -24.7 to 92.9%. When 

stratified by serostatus, the VE was 90% in seropositives. For seronegatives, there were only 2 

cases, both of which occurred in the vaccine arm and were due to DENV-3. 

The WG interpretation of these data was that overall, it is difficult to draw conclusions, 

particularly stratifying by serotype, due to the small number of events. For seropositives, there 

was protection against DHF and trial-defined severe dengue. For seronegatives, there was no 

efficacy for either outcome. 

The immunogenicity data for the vaccine was evaluated in a subset of participants. Among 

seronegative vaccine recipients, the GMTs (calculated using PRNT50) were highest for DENV-2. 

GMTs were stable over 51 months after the first dose for DENV-1, 3, and 4 and decreased over 

time for DENV-2. However, DENV-2 titers remained higher than the other serotypes at 51 

months. Solicited AEs were higher among recipients of the vaccine compared to placebo, and 

unsolicited AE were similar between the vaccine and placebo. SAEs were similar among the 

vaccine and placebo arms. Only 1 of the SAEs was deemed to be related to the vaccine and 4 

were related to the placebo. The most common SAEs were dengue fever and DHF, which were 

both higher in the placebo group compared to the vaccine group. There were 16 deaths in the 

vaccine arm and 10 in the placebo arm, none which were related to the vaccine. 

In summary, the WG had 5 conclusions they believed to be clear based on the data presented. 

TAK-003 protects seropositive recipients against VCD and hospitalization due to any serotype. 

Additionally, TAK-003 protects seronegative recipients against VCD and hospitalization for 

DENV-1 and DENV-2. However, the vaccine does not protect seronegative recipients against 

VCD and hospitalizations for DENV-3. DENV-4 efficacy assessment is limited by a low number 

of events. The data suggests that there is no protection against VCD for DENV-4, and there was 

only 1 DENV-4 hospitalization. Finally unsolicited, SAEs and deaths were similar in the vaccine 

and placebo arms. 

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The WG identified 3 observations that they are still working through. First, the WG is discussing 

the implications for the unknown VE against DENV-4 hospitalization among seronegative. 

Second, there is no efficacy against VCD or hospitalization for DENV-3 among seronegative 

recipient in the vaccine compared to placebo groups. The data are insufficient to rule out an 

increased risk among those who are vaccinated. Finally, the WG is still debating the significance 

of the immunogenicity data because there is no clearly defined correlate of immune protection 

for the dengue vaccine. 

ACIP Discussion Points, Observations, Suggestions on Dengue Vaccines 

Following Dr. Biswal’s Presentation 

• Regarding an inquiry about why efficacy was not observed in seronegatives, Dr. Biswal 

indicated that they have looked into a number of factors sch as immunological basis and 

genotype, but still do not have a definitive answer. 

• In terms of a question about whether there were other discrepancies between the 

immunologic response and clinical efficacy in the hospitalization data, Dr. Biswal 

explained that there was a negative point estimate for DENV-3 hospitalizations. After the 

Sri Lanka data were removed, this negative point estimate was not seen. 

• Given what has been learned about dengue disease and dengue vaccination, continuing 

evidence of absence of harm is going to be important. While it is understood that there 

were differences in hospitalization rates in Sri Lanka, that did not necessarily mean that 

the data are invalid. More information is needed about whether the data should or should 

not be included from Sri Lanka, because otherwise it seemed like the data should be 

included as intended in the WG’s interpretation of whether there is absence of harm or 

no absence of harm. Dr. Biswal emphasized that the sensitivity analysis had a negative 

point estimate when Sri Lanka was included that was not there when Sri Lanka was 

removed. The intent was not to remove the data, but to understand what was occurring. 

Sri Lanka had 6 cases in 1 site in the vaccine group and none in the placebo group. The 

cases were not adjudicated as severe, so in the investigators’ view, they do not 

represent an increase in the severity of cases in the vaccine group. This is mostly likely 

by chance due to the varying hospitalization practices. 

Following Dr. Paz-Bailey’s Presentation 

• ACIP expressed gratitude for the excellent summation of a considerable amount of 

confusing information. 

VARICELLA 

Public Health Impact of 25 Years of Varicella Vaccination in the United States

Mona Marin, MD (CDC/NCIRD) presented on the public health impact of 25 years of the 

varicella vaccination program in the US. Historically, varicella was considered a disease of little 

consequence, of rite of passage during childhood, too mild to warrant prevention. That 

misconception started to change after the first cases of fatal varicella were reported in mid1950s in children treated with newly introduced immunosuppressive therapy that cured several 

serious diseases but unmasked the lethal potential of the varicella-zoster virus (VZV).79 

79 Cheatham et al. Am J Pathol 1956; 32:1015-35 

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In the late 1960s through early 1970s, immunosuppressive treatment was increasingly used as 

systemic steroid therapy for organ transplantation or childhood cancers. Leukemia, previously 

almost always fatal, was cured in about 80% of children only to have many of them die of 

varicella before immune reconstitution. Varicella no longer seems too inconsequential to justify 

the development of a vaccine. In 1974, research from Japan announced the varicella vaccine 

that contained an attenuated strain of VZV after studies showed impressive results on small 

numbers of healthy children and adults and children with leukemia in remission.80 In the US, 

there initially was controversy about the use of a varicella vaccine, with important concerns 

being the risk for latency and persistence of immunity. 

However, fear of varicella in leukemic and other immunocompromised children led to trials in the 

US in the early 1980s in children with leukemia that demonstrated VE and safety.

81 Subsequent 

studies in healthy people also showed that the vaccine was safe and effective in children and 

adults. In 1995, the varicella vaccine was licensed and recommended in the US. The US 

became the first country with a routine varicella vaccination program. ACIP made a scientifically 

informed, yet bold decision in recommending varicella vaccination. There was debate around 

the time of the vaccine recommendations about whether the health burden of varicella justified a 

vaccination program, whether the vaccine would be accepted by parents and providers, whether 

the varicella program would shift the burden of varicella from children who had milder disease to 

adults who had more severe presentations, whether there was a risk during pregnancy, and 

whether the program would increase herpes zoster (HZ) incidence. 

Before vaccine, varicella represented a significant medical and societal health burden in the US 

that assumed more importance once other preventable causes of health burden and mortality, 

such as polio and measles had been controlled. In the US, approximately 4 million cases of 

varicella occurred every year pre-vaccine, approximating the birth cohort and resulting in 11,000 

to 13,000 hospitalizations and 100 to 150 deaths. The greatest health burden occurred in 

children, with more than 90% of cases, 70% of hospitalizations, and about half the deaths from 

varicella.82 

As mentioned, the US varicella program started in 1995 when 1 dose was recommended for 

routine vaccination of children 12─18 months of age and catch-up vaccination for older children 

and other susceptible persons. In 2007,83 the policy was changed to a routine 2-dose childhood 

program with the first dose at 12─15 months of age and the second at 4─6 years of age, catchup vaccination of persons who had received 1 dose, and vaccination of all eligible susceptible 

persons. The main rationale for the policy change was continuing low-level community 

transmission, with outbreaks in highly 1-dose vaccinated elementary school populations 

although these were smaller and less frequent than pre-vaccine. 

Regarding acceptability, varicella program implementation was highly successful.84 High 

coverage was attained among young children of 89% by the end of the 1-dose program in 2006 

and has remained around 91% since then, with coverage levels similar to those of MMR, a more 

mature program. There was rapid uptake of the second dose after the 2-dose recommendation 

in 2007, with coverage reaching a median of 93% by 2020 in 6 states—again approaching the 

coverage of 2-dose MMR. The second vaccine characteristic that influences vaccine impact is 

80 Takahashi et al. Lancet 1974 81 Gershon at al. JID 2021 82 Wharton et al. 1996; Galil et al. 2001; Davis et al 2004; Meyer et al. 2000; Nguyen et al. 2005; Enders and Miller. 2000 83 MMWR 2007;56(RR-4):1–39 . Available at www.cdc.gov 84 Elam-Evans et al. JID 2022 

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the performance of the vaccine.85 One dose of varicella vaccine is moderately effective in 

preventing varicella of any severity at 82% and highly effective in preventing moderate or severe 

varicella at more than 97%. The second dose adds 10% or more improved protection against 

varicella of any severity. 

In terms of the impact of the program on varicella, in 4 states that consistently reported varicella 

cases to the NNDSS since before vaccine introduction, incidence declined by more than 97% 

from the pre-vaccine period through 2018.86 The decline was impressive during the 1-dose 

program at more than 86%. During the 2-dose program from 2007─2019, incidence declined 

further by 90% from the end of the 1-dose program. Incidence declined in all age groups during 

the 2-dose program, indicating additional control added by the second dose and no increase in 

disease in other ages. The greatest decline was in children 5─9 and 10─14 years of age, who 

were the primary recipients of the second dose. Additionally, in 7 states with consistent outbreak 

reporting, the number of outbreaks declined by 82%.87 

Moving to varicella hospitalizations,88 varicella hospitalization rates declined 90% by 2019 

compared with the pre-vaccine period. Hospitalization rates continued to decline during the 2-

dose program. Absolute numbers are instructive to define the burden in a population. Dramatic 

declines were observed in hospitalization rates of over 94% in all age groups younger than 50 

years of age, with the greatest declines in children and adolescents. More than 10,500 varicella 

hospitalizations are now prevented annually, including more than 1,250 among infants and more 

than 4,200 among children 1─4 years of age. 

Large declines occurred for deaths as well. The overall varicella mortality rate declined 89% 

from the pre-vaccine period to 2017─2019. Most of this decline occurred during the 1-dose 

program. Similar to hospitalizations, the mortality rates declined in all age groups in persons 

younger than 50 years of age. Deaths declined from an annual average of 84 deaths prevaccine with varicella as the underlying cause to 3 deaths in 2018─2019 with deaths practically 

eliminated among those younger than 20 years of age with a 99.4% reduction.89 In 5 of the last 

9 years, no underlying or contributing deaths were reported in this age group.90 

To summarize HZ trends during the US varicella vaccination program, before the routine 

varicella vaccination program was adopted, some experts were concerned that decreased 

circulation of VZV and therefore implicit bias boosting would lead to an increase in HZ in adults. 

In persons aged ≥30 years, HZ incidence increased during the earlier study years, with

decelerations in later years. There was no acceleration following introduction of the varicella 

vaccine and deceleration in later years starting in 2007 with the oldest age groups. Among 

children and young adults, age-specific HZ incidence declined in a step-wise pattern once each 

age group was comprised mostly of persons born during the varicella program and therefore 

likely vaccinated. Incidence among children 1─14 year of age is converging at the lowest 

levels.91 

85 Marin et al. Pediatrics 2016 and Son et al. JID 2010. 86 Marin et al. JID, 2022 87 29 states and the District of Columbia reported age data during 2005–2006 (end of 1-dose program) and 38 during 2018–2019 

(mature 2-dose program); National Notifiable Diseases Surveillance System data; Marin et al. JID 2022. §Outbreak: ≥5 varicella 

cases; Leung et al. JID 2022. 88 Marin et al. JID 2022. Data: HCUP National Inpatient Sample (NIS). 89 Marin et al. JID 2022. 90 2011, 2013, 2014, 2017, 2018. Data: National Center for Health Statistics 91 Leung et al. JID 2022. MarketScan 1998–2019. 

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To conclude, the US varicella vaccination program has been successfully implemented, 

resulting in substantial disease prevention and societal savings over the last 25 years. The 

varicella vaccine has shown good effectiveness that has been maintained to date and has a 

favorable safety profile. High vaccine coverage was reached and maintained. The program 

prevented morbidity and mortality with large declines. Approximately 91 million varicella cases; 

238,000 hospitalizations; and 1,900─ to 2,400 deaths have been prevented over the 25 years of 

the program. The program is highly cost-savings with $23.4 billion net societal savings to date. 

US data do not support prior predictions that the varicella vaccination program would increase 

HZ incidence among adults and documented reduced herpes zoster incidence among children 

and adolescents born in the vaccine era, with reduction due to the varicella program likely to 

extend to the entire population over time. Details of the program can be found in the article 

titled, “The Varicella Vaccination Program in the United States: 25 Years of Saving Lives and 

Preventing Illness” was included in a Journal of Infectious Diseases (JID) supplement released 

on November 1, 2022.

92 

ACIP Discussion Points, Observations, Suggestions on Varicella Vaccines 

Following Dr. Marin’s Presentation 

• ACIP members, ex officios, and liaisons applauded the tremendous work the Varicella 

Vaccine Program has done over the last few decades, emphasizing the importance of 

highlighting what is not seen, given that what is not seen can be forgotten. It is important 

to demonstrate the profound impact of this program and all those involved in it. 

• It also is important to recognize all of the states that got varicella vaccine included in 

school immunization laws. These laws have been very important in establishing high 

immunization rates and maintaining them over the years. This has been true not only for 

varicella, but also for many other vaccinations. 

FRIDAY: FEBRUARY 24, 2023 

COVID-19 VACCINES 

Introduction 

Matthew F. Daley, MD (WG Chair) introduced the COVID-19 vaccines session on behalf of the 

ACIP COVID-19 Vaccine WG. Bivalent booster authorization was extended to children 6 months 

of age and older. On December 8, 2022, the FDA granted Emergency Use Authorization (EUA) 

for use of Moderna bivalent COVID-19 booster in children 6 months─5 years of age and use of 

Pfizer BioNTech bivalent COVID-19 vaccine as a third primary series dose for children 6 

months─4 years of age.93 The following day, CDC expanded the use of updated bivalent 

COVID-19 vaccines for children 6 months─5 years of age.94 

92 https://academic.oup.com/jid/issue/226/Supplement_4 93 https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-updated-bivalent-covid-19-

vaccines-children-down-6-months 94 https://www.cdc.gov/media/releases/2022/s1209-covid-vaccine.htm 

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Since the last ACIP meeting, the WG has been very active reviewing and discussing numerous 

topic areas, including the following: 

 Epidemiology of COVID-19, including multisystem inflammatory syndrome in children (MISC) and hospitalization data 

 VE updates 

 COVID-19 among persons with immunocompromise, including VE and Evusheld 

 Inputs for cost-effectiveness analyses 

 COVID-19 vaccine safety updates 

 Updated benefit/risk analyses 

 Updates to COVID-19 vaccine use in children 6 months through 5 years of age, including 

Moderna COVID-19 vaccine booster doses 

 Ongoing work to increase uptake of bivalent COVID-19 vaccines 

 Considerations for the transition to a bivalent primary series 

 Future directions for the COVID-19 vaccination program overall 

The agenda for this session including presentations on the following: 

 Plan to End the COVID-19 Public Health Emergency (PHE) on May 11, 2023 

 COVID-19 vaccine safety updates from CDC 

 COVID-19 vaccine safety updates from FDA 

 VaST summary 

 WG interpretation and summary 

 Updates on COVID-19 hospitalizations in the US 

 Updates on COVID-19 VE in the US 

 Considerations for transitioning to a bivalent primary series 

 NCIRD Director’s Remarks 

 WG interpretation and summary 

 Updated benefit-risk analysis for COVID-19 vaccines 

 COVID-19 vaccines in terms of future directions for the program 

Plan to End the COVID-19 Public Health Emergency (PHE) on May 11, 2023 

Sarah A. Meyer, MD, MPH (CDC/NCIRD) provide information about the federal government’s 

plans to end the COVID-19 PHE on May 11, 2023. CDC has been receiving many questions 

about what this means and does not mean for the vaccination program. CDC remains dedicated 

to preventing severe illness and death from COVID-19, with particular concern for populations 

who are at higher risk of adverse outcomes. CDC is actively working with other federal agencies 

and offices to maintain access to vaccines, testing, and therapeutics to the extent possible. 

Much of the current COVID-19 vaccine program will remain unchanged after the PHE ends in 

May. The primary impact of the PHE ending on the vaccination program is the possibility of 

reduced submission of vaccine administration data from some jurisdictions. This is because the 

Data Use Agreements (DUAs) for COVID-19 vaccine administration were established with 

termination provisions that referenced the PHE. However, state and territorial public health 

jurisdictions have been asked to extend this DUA through the end of 2023. Thus far, the 

majority of jurisdictions have done so. It is important to note that the end of the PHE does not 

equate to the end of the current national vaccine distribution program or the transition to 

commercialization. This has been one of the biggest points of confusion CDC has heard about. 

The end of the PHE does not mean the end of the federal vaccine program. CDC also has 

received many questions regarding commercializing COVID-19 vaccines and continues to work 

with HHS on this process. CDC is collecting questions to help ensure the agency addresses the 

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needs of jurisdictions and partners moving toward commercialization in the future. Further 

information will be shared with the ACIP as soon as possible. 

COVID-19 Vaccine Safety Updates: CDC 

Tom T. Shimabukuro, MD, MPH, MBA (CDC/NCEZID) described: 1) CDC’s VSD Rapid Cycle 

Analysis (RCA) monitoring methods and assessment processes for statistical signals; 2) VSD 

RCA signal detection and signal assessment for ischemic stroke after Pfizer-BioNTech COVID19 mRNA bivalent booster dose vaccination in the age group 65 years and older; and 3) rates of 

myocarditis and pericarditis following COVID-19 mRNA vaccination. 

By way of background, bivalent COVID-19 mRNA booster vaccinations first became available in 

the US in September 2022. As of February 2023, 52.5 million bivalent booster doses have been 

administered to people ages 5 years and older in the US. This includes 22.3 million doses in 

people ≥65 years of age. CDC and partners monitor the safety of licensed and authorized US 

vaccines using multiple complementary systems.

95 Safety data support CDC recommendations 

that everyone eligible for a COVID-19 mRNA bivalent booster get vaccinated. 

As a reminder, the VSD was established in 1990. It is a collaboration between CDC and 9 

integrated healthcare organizations throughout the US and includes EHRs on approximately 

12.5 million individuals. The strengths of VSD rapid cycle analysis include its population of 12.5 

million people, which is about 4% of the US population across the VSD data sites. The VSD 

data sites are geographically, racially, and ethnically diverse. The VSD RCA uses near real-time 

data, with analyses updated weekly. The VSD RCA has access to comprehensive medical 

records, including exposures of vaccinations and outcomes. This allows rapid chart reviews to 

obtain additional clinical information as needed. The VSD employs innovative methods for RCA. 

The vaccinated concurrent comparative method is the primary analysis. Recent vaccinees as 

comparators are expected to be more similar to current vaccinees than unvaccinated 

individuals, with the advantages that the potential biases associated with calendar time, site, 

and demographic factors can be adjusted for carefully. In addition, these analyses can begin 

sooner than alternative methods. Supplemental analyses are conducted weekly. Unvaccinated 

or un-boosted comparators also would be available to provide context in real-time. Using 

vaccinated concurrent comparators with supplemental analyses offers substantial benefits 

compared to either unvaccinated or historical comparators. 

The primary methodology for RCA for the primary analysis is the vaccinated concurrent 

comparator method. This has been used for bivalent boosters and the primary series and for the 

primary series and monovalent boosters. Pre-specified outcomes were assessed during weekly 

sequential monitoring after bivalent vaccination. The risk of pre-specified outcomes 1─21 days 

following a bivalent vaccination is compared with bivalent vaccinated individuals who were 

22─42 days following the bivalent dose. That is the comparison interval. All analyses are 

adjusted for age, sex, race, ethnicity, VSD site, calendar time in days, and seasonality. The 

signaling thresholds is a 1-sided p-value <0.01.

96 To illustrate, this schematic depicts a 

hypothetical vaccinee with the outcome in the risk interval and a concurrent comparator 

“bivalent vaccinated individuals only:” 

95 https://www.cdc.gov/vaccinesafety/index.html 96 Rapid Cycle Analysis (RCA) to monitor the safety of COVID-19 vaccines in near real-time within the Vaccine Safety Datalink. 

Available at: Rapid Cycle Analysis (RCA) to monitor the safety of COVID-19 vaccines in near real-time within the Vaccine Safety 

Datalink (cdc.gov) 

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Using the methods described, the VSD conducted RCA for the prespecified outcomes shown 

here: 

In COVID-19 bivalent booster vaccine monitoring for these pre-specified outcomes, VSD RCA 

detected a statistical signal for ischemic stroke after Pfizer-BioNTech bivalent booster 

vaccination in the age group ≥65 years. No other VSD RCA pre-specified surveillance outcomes 

have signaled in any age groups for either of the mRNA COVID-19 bivalent booster vaccines or 

when data for the 2 mRNA vaccine types are combined/pooled. 

To look in more detail at the VSD COVID-19 RCA preliminary analyses for the ischemic stroke 

signal after Pfizer-BioNTech bivalent booster among people ≥65 years of age to assess whether

it reflects a real effect of vaccination on an outcome, substantially more Pfizer bivalent boosters 

(580,000) were administered in the VSD compared to Moderna boosters (309,000). Then there 

were substantially more Pfizer bivalent boosters administered in this age group early in the 

bivalent booster program. The peak of bivalent booster vaccination, most of which was Pfizer in 

this age group, was occurring at the same time as peak influenza vaccination. 

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This is the VSD RCA ischemic stroke definition with inclusion/exclusion criteria: 

In terms of the main findings for the bivalent RCA concurrent comparator analysis of ischemic 

strokes during the risk interval versus the comparison interval, Pfizer bivalent booster met the 

threshold for a statistical signal in the sequential analysis. Since then, it has attenuated for an 

adjusted rate ratio of 1.36, with a nominal confidence interval of 1.05 to 1.76, which did not meet 

the sequential statistical threshold for a statistical signal. More specifically, the signal for 

ischemic stroke following Pfizer bivalent occurred on November 27, 2022 in persons ≥65 years 

of age. At that point, the rate ratio was 1.92. The statistical signal persisted for 8t weeks, 

although it attenuated slightly. In the past several weeks, it has intermittently met the signaling 

criteria. At this time, the rate ratio was 1.36 and did not meet the signaling criteria. The caveat is 

that in VSD RCA, once there is a signal, it always signals. Weekly sequential analyses are 

continued because they are informative and shows when a signal drops below the signaling 

threshold. 

Looking at a temporal scan analysis of ischemic stroke by day after the Pfizer bivalent boosters 

in people ≥65 years of age, and older, a statistically significant cluster of cases was detected on 

days 13─22 following vaccination. As a reminder, the pre-specified risk interval was Days 1─22. 

This clustering is more subtle and not as well-defined compared to the prominent clustering 

observed for myocarditis several days after vaccination. Nonetheless, it was statistically 

significant clustering. Comparing the rate preceding the statistical clustering for ischemic stroke 

on Days 13─22, the rate appeared to be lower. This implies that there may be lower than 

expected counts in the comparison interval. 

CDC’s colleagues at the Kaiser Permanente Northern California Vaccine Study Center 

conducted a chart review of a subset of 24 cases from the initial cluster, which was slightly 

different at 11─21 days. Of these, 22 were incident stroke or transient ischemic attack (TIA) 

cases for a positive predictive value (PPV) of 92%. None had any history of stroke or TIA. The 

median age was 77.5 years. Symptom onset rarely shifted from the electronic date. Of the 22, 5 

(23%) had a known history of SARS-CoV-2 infection, only 1 of which within the last 6 months. 

None had a mention of recent exposure to SARS-CoV-2 in the chart notes. A total of 14 (64%) 

of these cases had influenza vaccine co-administered on the same day. Of those 14, 13 were 

high-dose influenza vaccines and 1 was adjuvanted. In terms of outcomes among the 22 

verified cases, 13 (59%) were discharged home, 18 were discharged home with home health, 

9% were discharged to a SNF, and 3 (14%) died. One death was in a male 75─79 years of age 

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approximately 1 month after the stroke, and the death was likely related to the stroke. Another 

was in a female 65─69 years of age noted after craniotomy, although the relationship to surgery 

was unclear. This death was due to cardiac arrest about 2.5 months later. The last case was in 

a male 70─74 years of age during hospitalization for metastatic cancer, with subsequent death 

due to cancer-related complications during hospitalization. A random sample of risk and 

comparison interval cases across VSD sites are currently being reviewed. 

One of the supplemental analyses focused on ischemic strokes during the 1─21 day interval 

comparing bivalent booster versus un-boosted concurrent comparators (but eligible for a 

bivalent booster). This is essentially a vaccinated versus unvaccinated analysis, but the 

unvaccinated individuals are likely to be fairly similar to boosted individuals because they are 

highly vaccinated and are eligible for a booster. In this analysis, the adjusted rate ratio was 1.07 

0.89–1.28 and was not statistically significant. The supplemental analysis did not signal for 

ischemic stroke. An additional supplemental analysis focused on ischemic strokes during the 

22─42 day interval comparing bivalent boosted versus un-boosted concurrent comparators (but 

eligible for booster). The investigators essentially performed the same analysis using a different 

interval. They found an adjusted rate ratio of 0.76 (0.6 to 0.95), which suggested a protective 

effect or reduced rate of stroke in the comparison interval. 

Given that a fairly high percentage of the cases in the chart review noted simultaneous highdose or adjuvanted influenza vaccines, an additional post-signal analysis was performed to 

assess simultaneous vaccination. Among those ≥65 years of age who received bivalent Pfizer + 

same-day high-dose or adjuvanted influenza vaccine, there were 43 cases in the risk interval of 

1─21 days and 26 cases in the comparison interval of 22–42 days. The adjusted rate ratio was 

1.65 (1.02 – 2.72), which just met statistical significance for the lower bound of the 95% 

confidence interval. Among those ≥65 years of age who received a bivalent Pfizer booster 

without any same-day influenza vaccine, the adjusted rate ratio was 1.19 (0.87 – 1.62), which 

was not statistically significant. 

A follow-on to that analysis was done to assess expected cases after bivalent booster + highdose or adjuvanted influenza vaccine based on ischemic stroke incidence in un-boosted people 

eligible for a booster among the older age groups in 5-year increments. The total expected was 

38.7 cases in a 3-week interval. Observed cases in the 1─21-day risk interval was 43. Observed 

cases in the comparison interval was 26, substantially below the expected background of 38.7. 

Again, these findings suggest a reduced rate of stroke in the comparison interval. 

To summarize the statistical signal for ischemic stroke following bivalent Pfizer-BioNTech 

COVID-19 mRNA booster vaccination in people ≥65 years of age, the statistical signal persisted 

for 8 weeks. The rate ratio has slowly attenuated from 1.92 to 1.36 and intermittently met 

signaling criteria. Temporal clustering evaluation found a significant cluster 13─22 days after 

vaccination. Supplemental analyses using un-boosted concurrent comparators showed a rate 

ratio of 1.07(95% CI 0.89–1.28), which was non-statistically significant. Of the small subset of 

charts reviewed, most confirmed cases had co-administered high-dose or adjuvanted influenza 

vaccine. Analyses evaluated simultaneous high-dose or adjuvanted influenza vaccine showed a 

rate ratio of 1.65 (95% CI 1.02–2.72, which was statistically significant. Separate analyses did 

not detect an elevated rate ratio for stroke after influenza vaccine alone, and supplemental 

analyses suggests the comparison interval rates were lower than expected. 

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Some additional considerations include a small number of strokes and precise rate ratios limit 

some analyses. There was reduced follow-up time after Moderna booster doses due to 

distribution delays. Simultaneous influenza vaccine analyses were limited by small numbers. It 

is difficult to interpret temporal clustering during risk and comparison intervals. There is possible 

unmeasured confounding. The results may be influenced from confounders that vary over time. 

There is a question regarding whether early adopters of bivalent booster vaccination have 

greater risk of near-term cardiovascular events, although the same trend has not been observed 

for acute myocardial infarctions. There is a potential impact of differential vaccine availability 

after the EUA. There are simply more Pfizer doses available and administered in VSD than 

Moderna doses. There is also the possible role of SARS-CoV-2 infection before the booster. 

Background incidence of SARS-CoV-2 infection was rapidly changing during bivalent booster 

uptake. The analyses excluded cases with COVID-19 diagnosis or positive laboratory tests in 

the prior 30 days, although asymptomatic infections and home antigen tests are not consistently 

documented in EHRs. However, chart reviews did not find recent SARS-CoV-2 infection or 

exposure. 

In terms of further evaluation and key next steps, weekly monitoring will continue along with 

exploration of potential data-related explanations for this statistical signal in VSD. Chart review 

of a random sample of 100 cases across VSD sites is in process. CDC will consult with other 

surveillance systems to better understand the possible role of simultaneous high-dose or 

adjuvanted influenza vaccination with COVID-19 vaccination and the possible decreased rate of 

stroke in the 3─6 weeks following vaccination. 

To touch on some data from other systems and programs, there have been no unusual or 

unexpected reporting patterns observed and no evidence of a safety concern detected for 

ischemic stroke with either bivalent booster in VAERS. FDA monitoring in CMS data and VA 

monitoring in the VA system have not detected any safety signals using the historical 

comparator designs. Surveillance conducted by international regulatory and public health 

partners has not detected a safety concern for ischemic stroke following bivalent booster 

vaccination. There has been no evidence of a safety signal for ischemic stroke in Pfizer’s global 

monitoring, nor were any safety signals detected for ischemic stroke for the primary series or 

monovalent boosters for Pfizer or Moderna vaccines in the US and global monitoring. Notably, 

these surveillance activities did not include analyses to evaluate the effect of simultaneous 

influenza vaccination. CDC continues to recommend that everyone eligible for a COVID-19 

MRNA bivalent booster or influenza vaccine get vaccinated. CDC and FDA are engaged in 

epidemiologic analyses regarding co-administration of bivalent booster and influenza vaccines. 

Regarding myocarditis and pericarditis following COVID-19 mRNA vaccination in the VSD, 

approximately 135,000 Moderna and 431,000 bivalent boosters have been administered for a 

total of approximately 566,000 booster doses administered. Based on VSD incidence rates of 

verified myocarditis or pericarditis in the 0–7 days after Pfizer-BioNTech vaccination in people 

12–39 years of age, there have been no new or unusual findings. There has been only 1 case in 

a male in the 18─29 years of age group.

97 The highest incidence rates have been among 

adolescent and young adult males after Dose 2 of the primary series. Rates were somewhat 

lower after the monovalent booster dose and lowest after the bivalent booster, with a caveat that 

the bivalent booster dose data are sparse. Little difference has been seen across Dose 2 and 

the first monovalent dose for females, particularly in females 30─39 years of age.

97 Primary series and 1st monovalent booster data through August 20, 2022, bivalent booster data through January 29, 2023; 

Source: Goddard K, et al. Incidence of Myocarditis/Pericarditis Following mRNA COVID-19 Vaccination Among Children and 

Younger Adults in the United States. Ann Intern Med. 2022;175:1169-1771 

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VSD incidence rates of verified myocarditis or pericarditis in the 0–7 days after Moderna 

vaccination was assessed in people 18–39 years of age. Given that such few doses were 

administered among those 12─17 years of age, it was not informative and not included. The 

data among those 18─29 years of age and 30─39 years of age showed the same general trend. 

The highest incidence rates were in males after Dose 2, although there were wide confidence 

intervals on these point estimates. There were lower incidence rates after the monovalent 

booster dose, with the lowest rates after bivalent boosters with the caveat that the number of 

doses was limited. There was not much difference in the incidence for the females 18─29 years 

of age, with no substantial differences across the monovalent and bivalent booster doses in 

those 30─39 years of age. 

COVID-19 Vaccine Safety Updates: FDA 

Richard Forshee, PhD (FDA/CBER/OBPV) presented COVID-19 vaccine safety updates 

based on FDA’s active surveillance on bivalent COVID-19 vaccines. The following data sources 

are available to the FDA CBER Biologics Effectiveness and Safety (BEST) System from multiple 

research partners with whom the FDA is working as part of this initiative, which includes data on 

hundreds of millions of patients: 

For this sequential analysis of the COVID-19 bivalent vaccines, the FDA worked with 3 of its 

commercial research partners and the CMS Medicare data to determine the various age ranges 

that were included in the analysis. Given the finding that was discussed by Dr. Shimabukuro, Dr. 

Forshee noted that he would focus on FDA’s Medicare analysis with persons ≥65 plus of whom 

36 million were enrolled in the Medicare private fee-for-service (PFFS) system. One of the 

concerns that everyone working in COVID-19 safety surveillance has had is that the claims 

data, and in some cases the EHR data, have not always reliably captured all the COVID-19 

vaccinations, especially early in the pandemic when the vaccines were first rolling out. Many 

vaccinations were delivered in mass vaccination clinics and not all of that vaccination data made 

its way back into the healthcare claims systems. 

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In order to try to address the concern of under-capture of COVID-19 vaccines, extensive efforts 

have been made to reach out to IISs. These are confidential population-based, computerized 

databases that report immunization doses administered by participating providers to persons in 

US public health jurisdictions. This had to be done jurisdiction-by-jurisdiction and data sourceby-data source. This resulted in the ability to obtain substantially more information about the 

COVID-19 vaccination status of individuals. 

As discussed in the previous presentation, there are different phases of vaccination active 

surveillance. The earliest stage is descriptive monitoring in which descriptive statistics of 

vaccine doses and selective AEs are provided while waiting for sufficient doses to accumulate in 

order to move to more statistically rigorous approaches. The next approach is the signal 

detection phase during which sequential testing is being performed while vaccine doses 

accumulate in order to identify potential safety risks early. It is important to note that this 

approach does not prove a causal relationship. The current approach is moving into a signal 

evaluation phase in which more robust study designs are used to evaluate any potential safety 

signals that have been identified. 

In terms of the BEST Initiative specifically, this table summarizes the vaccinations that have 

been observed in the systems the FDA is using: 

The red box at the bottom of the table highlights that most of the vaccinations observed have 

been among the population ≥65 of age, with more than 7 million total vaccinations (over 4 

million Pfizer and over 3 million Moderna). The numbers are smaller for the younger age 

groups. 

For the FDA sequential analysis, near real-time surveillance was used. Again, this design 

cannot establish a causal association. The study population included several age ranges: 6 

months─4/5 years, 5/6─17 years, 18─64 years, and ≥65 years. For the myocarditis/pericarditis 

outcome, the study population was additionally split into 18─35 years of age and 36─64 years 

of age. The exposure was either the Moderna (mRNA-1273.222) or Pfizer (BNT162b2) COVID19 bivalent boosters containing the original SARS-CoV-2 virus and Omicron variants BA.4 and 

BA.5. The statistical method used was MaxSPRT, which is a sequential probability ratio test. 

The comparator was historic rates. The FDA is monitoring a number of AEs in adult and 

pediatric populations. Among these, the closest for the particular analysis of ischemic stroke 

was non-hemorrhagic stroke. The difference between the definitions is that the FDA’s nonhemorrhagic stroke definition does not include transient ischemic attack or TIA, whereas the 

ischemic stroke that Dr. Shimabukuro discussed did include TIA. 

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The only signal the FDA has detected thus far was for myocarditis/pericarditis in the young adult 

population 18─35 years of age that was detected for the Pfizer BioNTech bivalent vaccine. This 

is consistent with what was seen with the earlier mRNA COVID-19 vaccines. Relevant to the 

discussion in this session, the FDA has not seen a signal for non-hemorrhagic stroke in any of 

the populations, including the Medicare population ≥65 years of age. Several of FDA’s AEs 

have completed their surveillance period at this point. Most relevant to this discussion is that 

non-hemorrhagic stroke is that the maximum length of the pre-defined surveillance has been 

reached without a signal. As of the last observation period in 2019 comparing non-hemorrhagic 

stroke for Pfizer bivalent vaccine compared to historical rates, the risk ratio was 0.76. This 

means that the rate that observed after the Pfizer COVID-19 bivalent vaccine is less than what 

would be expected based on the historic rate. 

There was some discussion in the earlier presentation about concomitant influenza vaccination. 

Among the 4.25 million doses of Pfizer BioNTech bivalent vaccine in the CMS database, 38% of 

those Medicare recipients who received the Pfizer bivalent booster also received a seasonal 

influenza vaccination on the same day, 78% received a seasonal influenza vaccine within +/- 42 

days. More than 90% of the concomitant and influenza vaccines were either high-dose or 

adjuvanted vaccines. No signal has been seen to date for non-hemorrhagic stroke, even though 

a large number of individuals received the influenza vaccine at the same time or at close to the 

same time as their bivalent COVID-19 vaccine. 

In summary, this was a large-scale signal detection study of the 2 COVID-19 mRNA bivalent 

vaccines conducted in multiple claims databases. RCA surveillance detected a signal for 

myocarditis/pericarditis following the Pfizer BNT162b2 bivalent vaccine among adults 18─35 

years of age. Among adults ≥65 years of age, several AEs already have completed the 

surveillance period without a signal. It is important to emphasize again that signal detection 

studies do not establish a causal relationship, and further evaluation of signals is required in 

more robust studies. Surveillance is ongoing and will be expanded to children <5 years of age 

as more doses accumulate in younger age groups. 

As Dr. Shimabukuro discussed in his presentation, it is important to consider the totality of 

evidence about the potential safety risk of ischemic stroke or non-hemorrhagic stroke. No 

excess reports of stroke have been seen in VAERS. The CMS database did not show any 

increase in non-hemorrhagic stroke or hemorrhagic stroke among approximately 4.25 million 

doses administered. The VA database has not shown an increase in stroke in their preliminary 

analyses. Various countries in Europe and Israel have not identified an increased risk of stroke 

reported in their surveillance systems. Pfizer notes no increase in the signal in their global 

safety database or when comparing the monovalent to bivalent vaccines. However, the FDA is 

launching a formal epidemiologic study in order to prepare for potential vaccine coadministration 

in 2023-2024. This will be a self-controlled study in which the individual beneficiary serves as 

his or her own control and will assess the occurrence of non-hemorrhagic stroke in different time 

periods of risk in a control window. Specific analyses will examine coadministration of 

adjuvanted or high-dose influenza vaccines as part of this more formal epidemiological study. 

Work is underway on the protocol for that analysis. 

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VaST Summary 

H. Keipp Talbot, MD MPH (VaST Chair) reminded everyone that the objectives of VaST are to: 

1) review, evaluate, and interpret post-authorization and approval of COVID-19 vaccination 

safety and data; 2) serve as the central hub for technical subject matter expertise from federal 

agencies conducting post-authorization and approval safety monitoring; 3) advise on analyses, 

interpretation, and presentation of vaccine safety data; and 4) provide updates to the ACIP 

COVID-19 Vaccines WG and the entire ACIP on COVID-19 vaccine safety. Between December 

21, 2020 through February 24, 2023, VaST has had 71 independent meetings to review vaccine 

safety data and 17 joint meetings with the ACIP COVID-19 Vaccines WG. In addition, VaST has 

presented or given reports during 22 ACIP meetings. During this session, Dr. Talbot described 

the VaST assessment of the statistical signal for ischemic stroke in the VSD following the 

bivalent COVID-19 booster vaccination and myocarditis pericarditis following mRNA COVID-19 

vaccination. 

The statistical signal among persons ≥65 years of age for ischemic stroke/TIA following bivalent 

Pfizer, BioNTech COVID-19 booster vaccination is based on limited data and has been 

attenuating over time. A signal has not been observed in 2 other US active vaccine safety 

monitoring systems98 or in data from other countries.99 The US systems differ from each other. 

The VSD and VA analyses included TIA with ischemic stroke, while the FDA CMS analyses did 

not. VSD is the only US system that uses concurrent comparator groups. The VA and FDA CMS 

analyses have not evaluated simultaneous administration with influenza vaccination. 

There is no increased rate ratio for ischemic stroke/TIA following bivalent Moderna COVID-19 

booster vaccination. Previous surveillance in VSD and other US systems found no evidence of 

increased risk of ischemic stroke/TIA after the primary series or monovalent COVID-19 booster 

vaccination for either Pfizer-BioNTech or Moderna products. The cause of the increased rate 

ratio is unclear. Potential contributing factors include simultaneous administration of bivalent 

COVID-19 booster and influenza vaccines or unmeasured confounding or bias. Most VSD 

participants ≥ 65 years of age received high-dose influenza vaccine in 2022-2023 season. VaST 

would like to review additional data on simultaneous administration of bivalent COVID-19 

booster and influenza vaccination. VaST highlighted the following areas for further exploration, 

which are to: 1) assess the impact of recent respiratory viral illness on the risk of ischemic 

stroke and TIA; and 2) analyze in VSD the potential reasons for the lower rate of ischemic 

stroke/TIA in the vaccinated comparator group that could be contributing to the increased rate 

ratio. 

VaST also has reviewed data on myocarditis and pericarditis following COVID-19 vaccination 

since April 2021 and has provided several assessments during ACIP meetings. Rates after the 

monovalent primary series, monovalent booster series, and bivalent booster doses have been 

assessed. Rates have been highest in adolescent and young adult males following primary 

series Dose 2 and the first monovalent booster dose. Outcomes after the monovalent primary 

series and monovalent booster doses also have been assessed. Data on rates after bivalent 

COVID-19 booster vaccinations are limited, primarily due to the limited use of the bivalent 

COVID-19 booster. Current data in the VSD do not raise additional concerns about myocarditis 

following the bivalent COVID-19 booster vaccination. 

98 FDA analysis of Centers for Medicare and Medicaid Services (CMS) data, and Department of Veterans Affairs (VA) rapid cycle 

analyses

99 Israel and European countries 

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In terms of future plans, VaST is preparing to transition review of vaccine safety data to the 

ACIP COVID-19 Vaccines WG. 

WG Interpretation and Summary 

Evelyn Twentyman, MD, MPH (CDC/NCIRD) discussed the WG’s interpretation of the data on 

ischemic stroke, COVID-19, and influenza in adults ≥65 years of age in terms of the statistical 

signal reviewed in-depth earlier in the session; important new and published contextual 

evidence regarding ischemic stroke, COVID-19, and influenza in adults ≥65 years of age; the 

WG’s interpretation and next steps. 

To briefly review the statistical signal for ischemic stroke identified in the highly sensitive VSD 

RCA system following Pfizer COVID-19 mRNA bivalent booster vaccination, the rate ratio has 

attenuated over time based on comparison rates of ischemic stroke in an early interval after a 

booster receipt with rates in a later interval. The supplemental analysis, which compared rates 

after booster among boosted people with rates over the same period with un-boosted people, 

did not show an elevated rate ratio. As Dr. Shimabukuro mentioned earlier, there were fewer 

cases of stroke among the bivalent boosted than the eligible but un-boosted in the later interval. 

Additionally, while stratified analysis evaluating people with co-administration of high-dose or 

adjuvanted influenza showed a rate ratio of 1.65, the rate ratio was not elevated. People who 

received Pfizer bivalent mRNA booster without simultaneous influenza vaccine and a separate 

analysis did not detect an elevated rate ratio for ischemic stroke after influenza vaccine alone. 

Moreover, the statistical signal has not been identified in any other age groups following other 

vaccines or combination of vaccines in the VSD RCA or in any other vaccine safety monitoring 

systems in the US (VAERS, CMS, VA, VA EHR) or around the world (Canada, EU. Israel). 

While it is important to note that these other systems generally did not have the ability to 

investigate co-administration with influenza vaccine, such analyses are planned. 

The put this information in the context of what is known and what has been learned recently 

from new data regarding relationships of ischemic stroke, COVID-19, influenza, it is known that 

COVID-19 disease is associated with increased risk of acute ischemic stroke (AIS). Among 

Medicare beneficiaries ≥65 years of age, incidence of AIS hospitalizations was 10 times higher 

during the 3 days post-COVID diagnosis compared with control periods.

100 COVID cohort 

estimated incidence of AIS is 2.10% (1.97—2.23) within 6 months after COVID diagnosis,101 

though stroke and COVID symptoms present concomitantly in >80% of cases.102 A recently 

completed analysis on COVID identified an incidence of stroke of 2.2% overall among patients 

≥65 years of age who were hospitalized with COVID-19 between March 2020 and October 

2022. COVID-19 patients who develop stroke are more likely to be of older age, have more 

severe COVID-19 disease, and are more likely to have hypertension, diabetes, and coronary 

artery disease than those who do not.

103 In terms of who may be at greater risk, it is known that 

those who develop stroke are more likely to be of older age, have more severe COVID-19 

disease, and more likely to have hypertension, diabetes, and coronary artery disease than those 

who do not develop stroke. In terms of who may be at lower risk, it has been observed that 

COVID-19 vaccination is associated with a reduced risk of ischemic stroke after COVID-19, 

including for those ages ≥65 years of age. 

100 Yang Q et al. Neurology 2022; 98(8): e778-789 101 Taquet M et al. Lancet Psychiatry 2021; 8(5): 416-427 102 Nannoni S et al. International Journal of Stroke 2021;16(2): 137-149 103 Nannoni S et al. International Journal of Stroke 2021;16(2):137-149 

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In terms of influenza, influenza vaccination, and stroke, an association between recent 

respiratory infection and increased stroke has been noted in some observational studies.

104 

While 2 small randomized studies did not note a significant effect of influenza vaccination on 

stroke risk,105 decreased risk of stroke with influenza vaccination has been reported in several 

observational studies.106 Additionally, a benefit of influenza vaccination has been noted in some 

studies examining major cardiovascular outcomes, some including stroke within composite 

outcomes.107 The hope is to learn more about COVID-19 and influenza and their relationship to 

stroke and to better understand potential protective effects of vaccination given the limitations 

that potential reduction in stroke risk varies and is not seen in all studies; populations, study 

designs, outcome definitions, and analytic methods vary across studies; observational data are 

more subject to bias; and overall data are limited concerning specific influenza vaccines and 

stroke-specific risk. 

In the collective effort to interpret the ischemic stroke safety signal, there was a particular 

interest in these outcomes within the population of people ≥65 years of age. CDC was able to 

initiate pursuit of these questions through 2 large healthcare data sources, the National PatientCentered Clinical Research Network (PCORnet©) and HealthVerity. PCORnet© is comprised of 

EHR data from ambulatory, ED, and inpatient settings. It covers all patients with and without 

insurance in participating health systems, or about 10% of the US population including those 

≥65 years of age. There is almost no lag in these data because it comes directly from 

participating PCORnet© sites following structured inquiries and does not have external 

dependencies, such as processing of claims. CDC used these data to rapidly assess incidents 

of stroke across this diverse population among those with recent COVID-19 or influenza and 

incidence overall in this population. 

HealthVerity is a massive healthcare data source that includes medical claims from closed 

payor systems related to ambulatory, ED, and inpatient settings. These data are linked to 

vaccination data from the Federal Retail Pharmacy Program (FRPP) using health verities prior 

to say preserving record linkage technology. It covers patients insured through Medicare 

Advantage or about 25% of the US population ≥65 years of age. There is an approximate 3-

month lag in data when using closed claims. These data were to assess incidence of stroke 

across the insured US population with recent COVID-19 or influenza vaccination and incidence 

overall in this population. 

Methods used in each of these datasets were designed to capture incident strokes. Patients 

with a history of stroke were intentionally excluded to avoid over-estimation of incidence but 

may have resulted in under-capture of history of stroke and TIA associated with risk of stroke. 

ICD-10 codes were generally chosen to align with the definitions of stroke used in the VSD. It is 

known that stroke and COVID symptoms often present simultaneously, as do stroke and 

influenza symptoms. Stroke is frequently an early complication of respiratory disease. While 

healthcare data can identify the exact date and time of the administration of a vaccine, that is 

not true for the onset of COVID or influenza infection or their symptoms. Use of the interval of -3 

to 28 days around diagnosis allows for the identification of patients who were admitted with 

acute stroke, get tested for COVID-19, and have a positive test that results on Day 1 or 2 of 

their hospital stay. 

104 Smeeth L et al, N Engl J Med 2004; 351: 2611-8; Zurrú MC et al, Stroke 2009; 40:1986-90 105 Loeb M et al, Lancet Global Health 12 2022; 10: e1835-e1844; Phrommintikul A et al, Eur Heart J 2011; 32: 1730–1735 106 Holodinsky JK et al, Lancet Resp Health 2022; 7: e914-e922; Rodriguez-Martin S et al, Neurology 2022; 00: e2199-e2160; 

Asghar Z et al, Vaccine 2015; 33: 5458-5463; and Chiang MH et al, Am Heart J 2017;193:1-7 107 Phrommintikul A et al, Eur Heart J 2011; 32: 1730–1735; Chiang MH et al, Am Heart J 2017;193:1-7 

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There was a high incidence of stroke following COVID-19 or influenza diagnosis in the 

PCORnet© data over the late Omicron period of 2022. In the -3 days prior to COVID diagnosis to 

28 days post-diagnosis, there was an incidence of approximately 8,800 incident strokes per 

million over these days. Although there is not a current estimate of incident strokes in the US, it 

is possible to calculate an average incidence of stroke in this population using this healthcare 

data. Incidence within -3 to 7 days of COVID-19 disease was 93.5% per million among adults 

≥65 years of age with COVID-19 (N=77,981) and 90.9% in adults ≥65 of age with influenza 

(N=11,396). Average stroke incidence among adults ≥65 years of age in the HealthVerity 

population over 28 days was slightly less than 1,400 strokes per million over this time period. In 

contrast, a very low incidence of stroke was observed in the recently vaccinated population. 

Notably, the groups in this analysis for both PCORnet© and HealthVerity are of the same age 

category and adjusted time at risk. Crude incidence within these groups is not otherwise 

adjusted for underlying medical conditions or older age groups. While attributable risk was not 

presented and causality was not assessed in any way, these are helpful observations. 

With regard to the WG’s interpretation and next steps, the WG believes that the review of safety 

data is reassuring and must continue. The priorities identified by the WG are to: 1) continue to 

closely follow the intermittently statistically significant signal and VSD, with continued review by 

VaST and colleagues; 2) continue performing supplementary analyses to clarify the relationship 

between the signal and any specific vaccine, co-administration of vaccines, and/or confounding; 

and 3) continue the most intensive vaccine safety surveillance in US history. While the data 

pertaining to vaccine safety is reassuring, in contrast, the data pertaining to COVID-19 disease 

and influenza were not so reassuring. Based on the review of healthcare data demonstrating 

high incidence of stroke with COVID-19 or influenza, the priorities include increasing awareness 

of the risk of stroke with COVID-19 disease and influenza and continuing to encourage uptake 

of the bivalent COVID-19 boosters. 

In summary, the COVID-19 ACIP WG remains confident in current COVID-19 vaccine 

recommendations and does not recommend any changes to the current recommendations, 

including those regarding coadministration of vaccines. CDC and partners anticipate the 

opportunity to review and consider upcoming analyses prior to the 2023-2024 influenza season. 

Updates on COVID-19 Hospitalizations: COVID-NET 

Christopher A. Taylor, PhD (CDC/NCIRD) provided updates on population-based rates of 

COVID-19-associated hospitalizations from COVID-NET. All hospitalizations captured in 

COVID-NET from March 2020─February 2023 had a positive SARS-CoV-2 test during 

hospitalization or within 14 days prior to admission. Rates of older adults 65─74 years of age 

and ≥75 years of age respectively have been highest throughout the pandemic. For both the 

Delta and early Omicron peaks in January 2021 and January 2022, rates among adults ≥75 

years of age were about 2 times as high as those in the next youngest age group of adults 

65─74 years of age. For the 6 months from August 2022–February 2023, rates among adults 

≥75 years of age were 3 times as high relative to adults 65─74 years of age. Rates among 

children <6 months of age remained elevated relative to older children and adolescents. 

From March 2020─February 2023, the proportion of hospitalizations comprised of adults ≥75 

years of age increased steadily since Summer 2021. For the 6 months from August 2022– 

February 2023, about 40% of all adult COVID-19 hospitalizations were among adults ≥75 years 

of age. In terms of hospitalizations among pediatric age groups from March 2020─February 

2023, hospitalizations comprised of infants <6 months of age increased steadily and in the most 

recent 6 months from August 2022–February 2023 showed that infants <6 months of age 

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comprised more hospitalizations than all other pediatric age groups, with 25% to 30% of all 

COVID-19-associated hospitalizations in this age group. 

To assess the proportion of hospitalizations for which COVID-19 was a likely reason for 

admission by age group and period of COVID variant predominance for June 2020─November 

2022, trained COVID-NET surveillance officers used an established algorithm. As a reminder, 

all COVID-NET hospitalizations have a laboratory-confirmed positive SARS-CoV-2 test during 

hospitalization or within 14 days before hospital admission. Hospitalizations for which admission 

was noted as likely due to trauma, obstetrics, labor and delivery, psychiatric admissions 

requiring acute medical care, and inpatient surgery or procedures were categorized as such. 

Hospitalizations for which the chief complaint included fever, respiratory illness, COVID-like 

illness (CLI), or suspicion for COVID-19 were classified as having COVID-19 as the likely 

reason for admission. Hospitalizations for which the medical chart specifically indicated that 

COVID-19 was an incidental finding but that the admission was likely not COVID-related were 

categorized as such. For hospitalizations for which another reason for admission was specified 

in free text, COVID-NET clinicians examined the specified reasons and further classified. 

For the period June 2020─November 2022, about 80% to 90% of COVID-19-associated 

hospitalizations among children ≤4 years of age had COVID-19 as a likely reason for admission 

across all variant periods. For older children 5─11 years of age, the range was between 

70%─95%. Adolescents 12─17 years of age had the lowest proportion of hospitalizations with 

COVID-19 as a likely reason for admission at 50%─60% for the Omicron-predominant period 

beginning in December 2021. Among this group, many admissions were psychiatric admissions 

requiring acute medical care, with more than 25%─35% of hospitalizations in some months. 

Adults 18─49 years of age had a similarly low proportion of hospitalizations with COVID as a 

likely reason for admission at 50%─70% during the Omicron period. Among this group, many 

admissions were due to labor and delivery, with more than 25%─30% of hospitalizations 

attributed to that in some months. Among adults ≥50 years of age, between 80%─90% of 

hospitalizations included COVID as a likely reason for admission across all variant periods 

examined. 

Looking at underlying medical conditions among non-pregnant adults ≥18 years of age in 

COVID-NET from June 2022–November 2022 in which COVID-19 was a likely reason for 

admission, the most common underlying medical conditions were chronic lung disease, 

cardiovascular disease, obesity, diabetes, and neurologic disorders. Chronic lung disease was 

prevalent and more than two-thirds of all adult COVID-19-associated hospitalizations. 

Cardiovascular disease present in more than half; diabetes, obesity, and neurologic disorders in 

about one-third; and renal disease in about one-quarter. A total of 96% of hospitalized adults 

had at ≥1 underlying medical condition.

Regarding the prevalence of underlying medical conditions in COVID-19-associated 

hospitalizations among children and adolescents ≤17 years of age from June 2022─November 

2022, the most recent 6 months for which complete data were available, the data were limited to 

hospitalizations for which COVID-19 was the likely primary reason for admission. The most 

common underlying medical conditions are asthma, prematurity, feeding tube dependence, and 

obesity. It is important to note that asthma and prematurity were underlying medical conditions 

in more than 10% of these pediatric cases. In contrast to adults, 49% of COVID-19-associated 

hospitalizations among children and adolescents had no recorded of underlying medical 

conditions. There were some notable differences between younger and older pediatric age 

groups. Among children <2 years of age, prematurity was by far the most common underlying 

condition recorded in nearly 20% of all hospitalizations. The next most common was feeding 

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tube dependence at 5%. Among the 3 older pediatric age groups, the most common underlying 

medical conditions differed. While the order of these most common conditions varied by age 

group, the most common are asthma, feeding tube dependence, obesity, immunocompromising 

conditions, and chronic lung disease not including asthma and not related to prematurity. 

With regard to vaccination status by age group among non-pregnant adults ≥18 years of age 

and older in COVID-NET from October 2022–November 2022, the 2 months of data available 

after the updated bivalent booster dose was approved, more than half of hospitalized children 

5─17 years were unvaccinated. One-third of adults 18─49 years of age remain unvaccinated, 

with less than 25% for adults ≥50 years of age. Very small proportions of hospitalizations 

occurred among persons vaccinated with the updated bivalent booster. Looking at age-adjusted 

rates of COVID-19-associated hospitalizations by vaccination status for adults ≥18 years of age 

from January 2021─December 2022, in December 2022, compared to adults who received an 

updated bivalent booster dose, the monthly rates of hospitalization were 16 times higher among 

unvaccinated adults and 2.6 times higher among vaccinated adults who had not received an 

updated bivalent booster dose. 

Updates to COVID-19 Vaccine Effectiveness in the United States 

Amadea Britton, MD, SM (CDC/NCIRD) presented a summary of VE data available from CDC 

studies, including VE of the original monovalent vaccines against symptomatic infection in 

children aged 6 months–4 years (Pfizer-BioNTech) and 6 months–5 years (Moderna); VE of 

bivalent vaccines against symptomatic infection in children and adolescents aged 5-17 years 

and adults aged ≥18 years; and bivalent vaccines against severe disease in adults, with a 

focus on adults ≥65 years of age. 

Beginning with data on VE against symptomatic infection in young children 6 months─5 years of 

age for Moderna and 6 months─4 years of age for Pfizer-BioNTech as presented in the 

previous week’s MMWR. For children 6 months─5 years receiving Moderna, the recommended 

primary series is 2 doses given 4 to 8 weeks apart. Given that dosing interval and the initial 

authorization date of June 18, 2022, August 1, 2022 was the earliest date that a child could 

have been included in analysis for the complete series. In other words, the earliest a child 

receiving the vaccine could have been at least 2 weeks out from completion of their second 

dose. For children 6 months─4 years of age receiving the Pfizer-BioNTech vaccine, the 

recommended primary series is 3 doses, with the first and second doses separated by 3 to 8 

weeks and the second and third doses separated by at least 8 weeks. Since this series required 

an extra dose, the earliest date a child could have been included in analyses of the complete 

primary series was September 19, 2022. For Pfizer-BioNTech, the recommended third dose 

was changed from a monovalent to a bivalent dose on December 9, 2022, but this analysis was 

restricted to VE of monovalent doses because uptake of the bivalent dose in his age group 

remains too low at this time to estimate VE. 

For background, national coverage estimates from CDC’s COVID Data Tracker show that young 

children 2─4 years of age have the lowest coverage for either a single dose or a completed 

primary series, with just over 10% for 1 dose and just over 5% for the complete primary series. 

Coverage is even lower among children <2 years of age. Children vaccinated early may be 

meaningfully different from those who remain unvaccinated, which may impact VE estimates. 

These estimates should therefore be considered preliminary.108 

108 https://covid.cdc.gov/covid-data-tracker/#vaccination-demographics-trends 

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The Increasing Community Access to Testing (ICATT) Program includes community-based 

testing data from pharmacies and partners nationwide. It uses a test-negative design with selfreported vaccine history at the time of test registration. For this analysis, only children whose 

caregivers reported symptoms and who were between 3─5 years of age for the Moderna 

analysis and 3─4 years of age for the Pfizer-BioNTech analysis were included. Children with 

immunocompromising conditions were excluded. These data are for tests from July 4, 

2022─February 5, 2023, although the analysis start date varied depending on dose analyzed. 

This was a period when the Omicron BA.4 and BA.5 sub-lineages predominated, but included 

some time when XBB and related sub-lineages were circulating. 

Looking at preliminary estimates of VE for primary series monovalent Moderna vaccine among 

children 3–5 years of age against symptomatic infection from July 4, 2022 – February 5, 2023, 

VE was 40% for 1 dose or a partial series during the interval between the first and second dose. 

VE for the complete 2-dose primary series of Moderna, VE was 60% during the 2 weeks to 2 

months after the second dose. This decreased to 36% after 3 to 4 months, though the 

confidence interval was wide and had some overlap with the earlier estimate.109 Looking at the 

same data for the Pfizer BioNTech among children 3─4 years of age, VE for a 1-dose partial 

series was 19%, with a confidence interval that just crossed the null. For 2 doses, which for 

Pfizer is also a partial series, VE was 48% in the interval between Doses 2 and 3. For 3 doses, 

the complete Pfizer primary series, VE was 31% in the 2 weeks to 4 months after the dose. 

There are a number of limitations for this analysis. First, as noted earlier, vaccine coverage is 

low in children <5 years of age. When coverage is low, vaccinated children may be meaningfully 

different than unvaccinated children, potentially biasing early VE estimates and making the 

estimates less stable over time. Second, the prevalence of prior infection among children is 

high. Based on CDC’s seroprevalence data through December 2022, more than 87% of children 

6 months─4 years of age have had a prior infection.110 If unvaccinated children have protection 

from prior infection, it may lead to underestimation of VE. However, as the prevalence of prior 

infection is so high, these estimates are likely to represent the current situation among young 

children in the US. Lastly, while the goal of the US COVID-19 vaccination program is to prevent 

severe disease and hospitalization, the ICATT platform estimates VE for symptomatic infection 

only. Low vaccination coverage in this age group has, to date, prevented estimation of VE 

against more severe disease in other platforms and may impact future ability to estimate VE in 

this age group, including against severe outcomes. Given this context, VE against symptomatic 

infection can provide important insight into vaccine protection. 

In summary, a complete monovalent primary vaccination series helped provide protection for 

children 3─5 years of age against symptomatic SARS-CoV-2 infection for at least the first 4 

months after vaccination. Some waning of the monovalent Moderna primary series might occur 

by 3 to 4 months after the second dose based on point estimates, although confidence intervals 

overlapped. This is similar to patterns observed in older children and adults in the first months 

after vaccination. Waning of monovalent Pfizer-BioNTech VE against symptomatic infection 

could not be assessed, but it is also likely based on analyses in older children and adults. CDC 

recommends that children should stay up to date with COVID-19 vaccines, including completing 

the primary series. Those who are eligible should receive a bivalent vaccine dose. CDC will 

continue to monitor VE in this age group, including against severe disease and for recently 

authorized bivalent doses. 

109 Fleming-Dutra, Ciesla, Roper, et al. MMWR February 16, 2023 110 https://covid.cdc.gov/covid-data-tracker/#pediatric-seroprevalence 

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Moving to updated estimates of VE against symptomatic infection among children and 

adolescents 5–17 years of age and adults ≥18 years of age for a bivalent booster dose against 

symptomatic infection, Dr. Britton first reviewed the concepts of “absolute” and “relative” VE. 

Absolute VE compares the frequency of health outcomes in vaccinated and unvaccinated 

people, such as comparing outcomes in people who received an updated bivalent booster 

versus no vaccine at all. Relative VE compares the frequency of health outcomes in people who 

received one type of vaccine to people who received a different vaccine or by comparing people 

who received more vaccine doses to those who received fewer doses, such as comparing 

outcomes and people vaccinated with an updated bivalent booster versus monovalent vaccine 

only. In this analysis, relative VE can be interpreted as the additional protection provided by an 

updated bivalent booster among people who already received monovalent COVID-19 vaccines. 

This analysis again used the FRPP data through ICATT. Looking at children and adolescents 

5─17 years of age and adults ≥18 years of age with CLI, individuals with the last monovalent 

dose less than 4 months previously were excluded. Persons with immunocompromising 

conditions also were excluded. Tests in this analysis were completed between December 1, 

2022 and February 13, 2023. This includes periods of both BA5-related sub-lineage 

predominance and XBB/XBB.1.5 related sub-lineage predominance. Because previously 

published work from this platform demonstrated that VE against symptomatic disease for these 

2 groups was similar, these time periods were combined. 

In terms of the results for relative VE for children and adolescents 5─17 years of age. Relative 

VE in the month after vaccination was 65% for children 5─11 years of age and 68% for 

adolescents 12─17 years of age. An early indication of slight waning as was observed with the 

monovalent vaccine. Notably, a Pfizer BioNTech bivalent booster was first authorized for 

adolescents ≥12 years of age on September 1, 2022 and for children 5─11 on October 12, 

2022. Moderna was authorized for children and adolescents 6─17 on October 12th as well. This 

means that there is less follow-up time for children 5─11 years of age, so it was not possible to 

estimate VE 4 to 5 months after the bivalent dose in children 5─11 years of age. 

Looking at the same analysis adult age groups with individuals who received a bivalent booster 

compared to individuals who received only 2 to 4 doses of monovalent vaccine, similar waning 

patterns were observed across age groups. Estimates of waning among adults ≥65 years of age 

appeared to be slightly lower than in younger individuals. The pattern of waning against 

symptomatic infection was very similar to what was observed after monovalent booster doses, 

with VE against symptomatic infection decreasing to minimal protection by around 5 to 6 

months. 

Now moving to updated estimates of VE against ED/UC encounters and hospitalizations among 

adults ≥18 years of age in the VISION Network, the VISION Network is a multistate network 

based on EHRs. Like ICATT, it uses a test-negative design with cases having CLI and a positive 

PCR and controls having CLI with a negative PCR. For this analysis, VE was adjusted for age, 

sex, race, ethnicity, geographic region, calendar time, and local rates of SARS-CoV-2 

circulation. Vaccination was determined via EHRs and state and city registries. 

In terms of absolute VE of ≥2 monovalent doses against ED/UC encounters and hospitalizations 

among adults ≥18 years of age and adults ≥65 years of age from September 2022 – January 

2023, it is important to note that the median time since last monovalent dose was almost a full 

year for both age groups. What was observed was that residual protection against ED/UC 

encounters was minimal for both age groups. However, it remained somewhat higher against 

hospitalization, with residual protection of 19% for adults 18─64 years of age and 28% for those 

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≥65 years of age. Understanding that there is likely some residual protection from monovalent 

vaccines against hospitalization is important context to understand the relative contributions of 

bivalent vaccines. Also observed was that protection appeared to be slightly higher for both 

outcomes in adults ≥65 years of age, which may be due to behavioral differences and lower 

infection-induced immunity among older individuals. 

Preliminary estimates of VE against hospitalizations among adults aged ≥65 years show relative 

VE of the bivalent booster against ED-UC visits and hospitalizations. The reference groups in 

this analysis were the individuals from the VISION Network analysis who received only 

monovalent doses, with their last dose at least 2 months previously. Note again that most 

individuals in this group were almost a full year from their last dose. Among these individuals, a 

bivalent booster offered an additional 50% protection against ED-UC visits in the first 7─59 days 

after boosting, which declined to 36% after 60 days. The median time since the last dose was 

76 days. Relative VE against hospitalization was similar at 52% and 31% at 7─59 and 60─119 

days, respectively. Although the relative trends were similar for both outcomes, residual 

protection prior to the booster was higher against hospitalization than for ED-UC visits, so it is 

likely that total protection against hospitalization also was higher. There also may have been 

some hospitalizations captured by the VISION Network platform that represent less severe 

COVID-19 disease comparable to that of an ED or UC visit. 

To provide an update on data published by CDC in December 2022 looking at the effectiveness 

of the bivalent boosters against hospitalization in adults ≥65 years of age through the IVY 

Network, the IVY Network is a multistate VE platform that uses a prospective test-negative 

design. For this analysis, participants were from 24 hospitals in 19 states with hospitalization 

between September 8, 2022 and January 30, 2023. This analysis included data beyond what 

was published in the MMWR in December. Participants included in this analysis were adults ≥65 

years of age who were hospitalized with CLI. Cases had a SARS-CoV-2 positive PCR or 

antigen test, and controls were negative for SARS-CoV-2 and influenza by PCR. Models were 

adjusted for age, sex, race and ethnicity, admission date, and HHS Region. Looking at the 

updated IVY results among adults ≥65 years of age, comparing people with at least 2 

monovalent doses but no bivalent dose, to unvaccinated people, VE was 17% with a confidence 

interval crossing the null. This is consistent with limited to no residual protection. The relative VE 

of a bivalent booster, comparing individuals who received a bivalent booster with individuals 

with at least 2 monovalent doses but no booster, the additional protection offered by a bivalent 

booster was 52%. Note that the median time since last dose was almost a year at 352 days. In 

terms of absolute bivalent VE, comparing individuals who received a bivalent booster to 

unvaccinated individuals who never received even monovalent vaccine, the estimate is almost 

identical to the relative VE of the bivalent booster. This is consistent with the finding that the 

monovalent vaccine is providing limited to no protection after 1 year. 

To share some information on the COVID-19 hospitalizations included in this analysis, all cases 

included in the analysis met the CLI definition. Patients with incidentally detected SARS-CoV-2 

infections with no CLI were not included. However, of all included hospitalized cases, 59% had 

hypoxemia (e.g., low oxygen levels) and 16% required ICU-level care. This suggests that, as 

with VISION, there may have been some cases included that, while a result of COVID-19 

disease, did not represent severe COVID-19 disease. Inclusion of less severe cases may result 

in lower estimates of VE against hospitalization, as VE tends to be higher against more severe 

outcomes. 

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There are several limitations for the data on older children, adolescents, and adults. First, for 

estimates of absolute VE, if unvaccinated individuals are meaningfully different than vaccinated 

individuals, these estimates may be biased. Second, for interpretation of estimates of relative 

VE, residual protection from prior doses is an important consideration. This is likely to be 

particularly important for severe disease, for which residual protection from prior doses may be 

higher than protection for symptomatic infection. In addition, interpreting waning relative VE for 

bivalent doses is challenging because relative estimates also are dependent on the underlying 

patterns of waning protection of prior monovalent doses. This means that if relative VE 

decreases, it does not necessarily mean the total protection on individual experiences has 

decreased by that same amount. Third, there is limited information on prior infection. Although, 

just as with young children, it is known that rates of prior infection in adults and older children 

are high. VE estimates presented during this session are therefore a snapshot of how well the 

vaccine is working under current conditions. Lastly, VE against COVID-19-associated 

hospitalization from the platforms presented represents COVID-19 disease requiring 

hospitalization but may underestimate protection against more severe disease, such as that 

requiring respiratory support and ICU level care. 

In summary, current data from CDC VE platforms demonstrate that bivalent booster doses 

provide added protection compared to earlier monovalent doses against symptomatic infection 

in children and adolescents 5─17 years of age and in adults ≥18 years of age. However, there 

may be early evidence of waning consistent with patterns previously observed from monovalent 

vaccines against symptomatic disease. Updates to VE of bivalent booster doses against ED/UC 

visits and hospitalization in adults confirm that the bivalent vaccines are providing protection 

against ED/UC visits and hospitalization compared to people who received 2, 3, or 4 doses of 

the monovalent vaccine and no bivalent dose. For most people who received monovalent doses 

and are eligible for a bivalent booster, more than a year has elapsed since their last monovalent 

dose and they may have limited remaining protection. All eligible people should stay up to date 

on COVID-19 vaccinations, including receiving a primary series and a bivalent dose if eligible. 

Considerations for Transitioning to Bivalent Primary Series 

Sara Oliver, MD, MSPH (CDC/NCIRD) discussed considerations for a bivalent primary series 

for which ACIP thoughts were being requested on harmonizing the vaccine strain composition 

for mRNA COVID-19 vaccines across both primary series and booster doses. At this point, 

logistically that would mean changing the primary series from the monovalent vaccine 

(original/ancestral strain) to bivalent (original/ancestral plus Omicron BA.4/5 strains) for all ages. 

The current recommendation is for people ≥6 months of age to receive a 2-dose monovalent 

vaccine and a bivalent booster dose. The proposal for future recommendations would be for 

people ≥6 months of age to receive a 2-dose bivalent primary series and a bivalent booster 

dose in most ages. While a later presentation would discussion simplifying the primary series 

and booster approach for some ages, this presentation focused specifically on using the existing 

vaccine framework, but potentially using a bivalent vaccine for all recommended doses. Policy 

on any bivalent primary series will be coordinated with FDA for regulatory action and CDC for 

recommendations for use. Therefore, Dr. Oliver noted that these discussions were predecisional and there would not be a vote specifically on this. 

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The summarize the public health problem for the primary series, the eligible persons would be 

those who are unvaccinated currently, which predominantly is a pediatric population.111 Looking 

at weekly population-based rates of COVID-19-associated hospitalizations among children and 

adolescents ≤17 years of ages in COVID-NET from March 2020–February 2023, the highest 

rates are among children ≤6 months of age. Hospitalization rates have varied over the last 

several years, with an increase during the larger BA.1 Omicron surge in early 2022, especially 

among children 6 months─2 years of age. Half of hospitalized children had no underlying 

medical conditions. Looking at COVID-19 hospitalizations by vaccination status, across all ages 

of children 5─11 years of age and adolescents 12─1 years of age between December 2021 -

December 2022, hospitalization rates were higher for unvaccinated children and adolescents.112 

Given low uptake of the bivalent boosters in the pediatric population, it is not yet possible to 

estimate hospitalization rates for children and adolescent with a bivalent booster. The lowest 

hospitalization rates are among the vaccinated individuals, so hopefully data in coming months 

will be able to include the bivalent population. 

In terms of COVID-19 deaths in children and adolescents by year of age over the course of the 

pandemic, over 1,500 children have died from COVID since early 2020. The highest numbers of 

death have been in the youngest children and in older adolescents. While analyses on death 

rates by vaccination status cannot be limited to just the pediatric population at this time, the 

lowest rates of death have been among those with the updated or bivalent booster.113 

To summarize, children and adolescents can develop severe COVID. While the rates in children 

are lower than adults, nearly 1,500 children and adolescents have died from COVID since the 

beginning of the pandemic, and it is not possible to predict which children will have severe 

disease. Half of the hospitalized children and adolescents had no underlying medical condition. 

During all time periods, COVID hospitalizations and mortality were consistently higher among 

unvaccinated persons than among persons who had completed a primary series and/or an 

updated booster. In spite of this, many children remain unvaccinated for COVID. 

In terms of the data on benefits and harms, data are available to evaluate a bivalent vaccine as 

a primary series for Moderna using their BA.1 bivalent vaccine given as a primary series to 

children 6 months─5 years of age. These data were presented during the VRBPAC meeting in 

January 2023. There were 179 children who received a 25 ug bivalent vaccine who were 

compared to nearly 5,000 children who received a monovalent ancestral vaccine previously. 

The median follow-up time for the 2 groups varied slightly. For the original ancestral vaccine, the 

follow-up time was just over 100 days, whereas for the bivalent vaccine, it was 85 days. An 

important note is that the 2 studies were conducted during different timeframes, so the 

seropositivity of the participants was different. For the study with the original vaccine, 8% of 

children were baseline SARS-CoV-2 seropositive. Among children who received a bivalent 

primary series, over 60% were baseline seropositive. This likely reflected the impact of Omicron 

infections over the past year. 

111 Source: https://covid.cdc.gov/covid-data-tracker/#vaccination-demographics-trends Updated February 10, 2023 112 CDC COVID Data Tracker. https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalizations-vaccination Accessed February 

10, 2023 113 Source: https://data.cdc.gov/NCHS/Provisional-COVID-19-Deaths-Counts-by-Age-in-Years/3apk-4u4f/data. Accessed February 

16, 2023 

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Comparing the immunogenicity of the original monovalent vaccine and the BA.1 bivalent 

vaccine, the GMT for the BA.1 neutralizing antibodies for the bivalent compared to the 

monovalent had a GMR of 25.42 (20.14, 32.07). This clearly met the prespecified superiority 

criteria. The BA1 bivalent vaccine provided a boost, but the ratio was below 1.0. However, the 

ratio of 0.83 (0.67, 1.02) did meet the prespecified noninferiority criteria with a lower bound of 

the confidence interval of 0.67. 

For the available safety data of a bivalent primary series, there were 142 children who received 

both doses and were included in the safety analysis. Overall, the percentage of patients 

reporting a solicited local or systemic event was similar to or less than percentages seen after 

the original vaccine. However, this may be a result of the larger seropositive participants in that 

bivalent group. The AEs seen after a bivalent primary series were similar to what was reported 

after the original vaccine in this age group. No Grade 4 solicited AE were reported. There was 1 

SAE of asthma exacerbation after the first dose that was assessed as unrelated to vaccination 

by the investigator. In terms of local reactions for the BA.1 bivalent vaccine compared to the 

original vaccine, rates were the same or lower in the bivalent group. Injection site pain was the 

most common local reaction. Regarding systemic reactions among children 6─36 months of age 

37 months─5 years of age, similar patterns were seen overall. Irritability was most common in 

the younger children and fatigue in the older children.114 

Thinking through other considerations for a bivalent primary series, Dr. Oliver addressed some 

concerns pertaining to imprinting. As a reminder, imprinting is the concern that the initial 

exposure to 1 virus strain may prime the B-cell memory and limit the development of memory B 

cells and neutralizing antibodies against new strains. As there are now 3 years of experience 

with this virus, it is known that prior infection and/or vaccination history likely have some impact 

on the subsequent immune response and that the risk of reinfection can vary by somebody’s 

previous infection or exposure.115 This can be impacted by a variety of factors (e.g., continued 

virus evolution of SARS-CoV-2, time since last vaccination, prior infection, imprinting). Affinity 

maturation that can occur. This is the ability of memory B cells to mature over time, especially 

when exposed to newer strains.116 Affinity maturation also is likely improved with more time 

between doses. While somewhat limited, several studies have shown that variant-specific 

vaccines can not only boost, but also initiate new variant-specific immune responses. However, 

most of these studies are focused on laboratory-based assays.117 The clinical impact of different 

immune responses by prior exposure or how it may differ by vaccination and infection, requires 

additional research. What is known is that vaccines continue to be able to provide a broad boost 

in antibody response and continue to provide important protection against severe COVID. It also 

is important to note that imprinting concerns relate to the incremental benefit of updated variantspecific vaccine. 

114 From Jan 26, 2022 VRBPAC meeting: https://www.fda.gov/media/164810/download 115 Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure | Science; Imprinted SARS-CoV-2 

humoral immunity induces convergent Omicron RBD evolution (nature.com); and Protective Effect of Previous SARS-CoV-2 

Infection against Omicron BA.4 and BA.5 Subvariants | NEJM 116 Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations – 

ScienceDirect; and The germinal centre B cell response to SARS-CoV-2 | Nature Reviews Immunology 117 SARS-CoV-2 Omicron boosting induces de novo B cell response in humans | bioRxiv; and Molecular fate-mapping of serum 

antibody responses to repeat immunization (nature.com) 

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To review the available data that compare monovalent and bivalent vaccines, the only available 

data for a primary series already have been reviewed. Several studies compared antibody titers 

with recent Omicron sub-lineages for both the bivalent and monovalent vaccines. Studies 

ranged from approximately 21─42 days after the bivalent vaccine. For this interpretation, assays 

differed by laboratory and the exact level of titers could not be compared across different 

laboratories. The most meaningful outcome for this is the ratio of antibody titers from bivalent to 

monovalent vaccines, which is depicted in this figure: 

1. https://www.biorxiv.org/content/10.1101/2022.10.22.513349v1.full.pdf

2. https://www.nejm.org/doi/full/10.1056/NEJMc2213948

3. https://www.nejm.org/doi/full/10.1056/NEJMc2214314

4. https://www.biorxiv.org/content/10.1101/2022.10.31.514636v1

5. https://www.nature.com/articles/s41591-022-02162-x

In the figure, a ratio of 1, highlighted with a red line, would mean the 2 vaccines are equal. A 

ratio of over 1 would mean an improvement with a bivalent vaccine, and a ratio of less than 1 

would be better titers in the monovalent vaccine. The figure also differentiates by type of assay 

done. The studies done with a pseudo-virus neutralizing assay have green text and the live 

virus neutralization assays have blue text. The bars are also slightly different shades of blue 

based on which Omicron sub-lineage was tested. BA.4/5 is in the lighter blue and the XBB is 

shown in a darker blue. Overall, most studies show an improvement in neutralizing antibodies 

for Omicron sub-lineages with a BA.4/5 bivalent vaccine, where that ratio would be over 1. 

There are differences noted in the ratios of type of assays where the improvement in the 

bivalent vaccines seemed to be more noted when the assay was the live virus assay. However, 

the clinical impact is unknown for any specific ratio or antibody level. Notably, neutralizing 

antibodies at a single point in time cannot convey the entirety of the immune response. 

To highlight the clinical data, the outcomes for monovalent and bivalent vaccines must be 

compared. It was not possible to do head-to-head comparison of studies comparing clinical 

outcomes directly in the US due to timing of the authorizations. However, these data were 

shown during the VRBPAC January 2023 and are published in a preprint.

118 A study in the UK 

found an approximately 10% increase in relative VE for the prevention of COVID infections for a 

bivalent BA.1 vaccine. However, no COVID hospitalizations were noted at the time, so it was 

not possible to estimate the differential impact for the prevention of severe COVID. 

118 https://www.fda.gov/media/164810/download A Randomized Trial Comparing Omicron-Containing Boosters with the Original 

Covid-19 Vaccine mRNA-1273 | medRxiv 

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Overall, bivalent COVID-19 vaccines are able to induce an immune response when given either 

as a primary series or as a booster. There are limited data to directly compare COVID-19 

outcomes after receipt of a monovalent or bivalent vaccine, especially against the prevention of 

severe disease. COVID-19 vaccines have a high degree of safety. Initial safety data from a 

bivalent primary series trial are encouraging, but the study was not powered to assess rare AEs. 

To highlight some feasibility and implementation considerations with a transition to a bivalent 

primary series, there are currently 11 total mRNA COVID-19 vaccine products (5 Moderna and 

6 Pfizer-BioNTech) between monovalent, bivalent, and different doses and formulations by age. 

While the final number of products ultimately will depend upon what is authorized in transitioning 

from primary series to bivalent, it is possible to reduce from 11 to 5 total products (2 Moderna 

and 3 Pfizer-BioNTech). Importantly, this would eliminate look-alike vials for Pfizer and 

Moderna. In terms of feasibility and implementation, a transition to a bivalent primary series 

could improve storage space. Providers have limited storage space. In addition to monovalent 

and bivalent products, the VFC program stock is required to be duplicate and separate. It also 

reduce errors, by eliminating look-alike vials. Currently, one of the most common administration 

errors reported is providers giving a bivalent vaccine as a primary series dose in error. It also 

would allow for continued access to primary series. While the dates vary by product and age 

group, the majority of current monovalent vaccine stock in the US expires within the next few 

months. There would be a possibility that access to primary series could be more limited without 

transitioning to a bivalent option. Regarding resource use, work is ongoing to evaluate costeffectiveness in preparation for transition to commercialization of COVID-19 vaccines. For this 

particular question, vaccines are already purchased, delivered, and available. Transition of a 

primary series recommendation for monovalent to bivalent is unlikely to have a significant 

impact on resource use. 

In summary, receiving a COVID-19 vaccine primary series continues to be important for the 

prevention of COVID-19 severe disease, hospitalization, and death. In spite of this, many 

children and adolescents remain unvaccinated for COVID-19. COVID-19 vaccine 

recommendations that are simple to implement may remove some barriers to uptake. 

Harmonizing the primary series and booster doses could simplify the presentation, reduce 

administration errors, and allow for continued access to primary series for unvaccinated 

populations. Overall, the WG was supportive of this transition of the mRNA COVID-19 vaccine 

primary series from monovalent (original) to bivalent (original plus Omicron BA.4/5). 

In closing, Dr. Oliver requested feedback from the ACIP on the following: 

 Transition to bivalent primary series can occur only after FDA regulatory action and updates 

to CDC recommendations. There is no vote. It is pre-decisional, but ACIP’s discussions can 

help inform actions for the future. 

 What are ACIP’s thoughts on a transition of the mRNA COVID-19 vaccine primary series 

from monovalent (original) to bivalent (original plus Omicron BA.4/5)? 

Notably, “monovalent” and “bivalent” designations are based on the currently authorized 

products. For future vaccines, the focus would be on harmonization of products across primary 

series and booster doses. 

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NCIRD Director Remarks 

José R. Romero, MD (CDC, Director NCIRD) indicated that before the committee began the 

next series of presentations, he wanted to take a moment to reinforce the importance of the 

ACIP’s input as plans are made for the future use of COVID-19 vaccines and potential updates 

to the nation’s COVID-19 vaccination efforts. These initial discussions by the ACIP voting 

members, ex officious, and liaisons, were occurring at a time when there are still limited data 

and several unanswered questions. However, it is essential that ACIP’s discussions are not 

paralyzed by these uncertainties and limitations. The information previously and to be presented 

to the ACIP would allow them to assess what is now several years of viral and vaccine data. 

Nevertheless, it is important to acknowledge multiple uncertainties and unknowns that exist. 

Hopefully, the information presented will begin to help ACIP plan for the best path forward in 

terms of the use of available COVID-19 vaccines. CDC is encouraged to hear of ACIP’s support 

for tentative plans to harmonize COVID-19 vaccine efforts and shift from the original monovalent 

primary vaccine formulation to a formulation used for updated bivalent boosters. While this 

would not happen until the appropriate FDA authorizations, it is clear that concurrence on a 

single vaccine composition for primary and booster doses would help streamline and simplify 

CDC’s recommendations, reduce complexity, and allow for clearer communication and 

guidance to HCP and to the public. CDC recognizes that the previous 3 years have been very 

difficult for the ACIP as they have crafted their recommendations. Dr. Romero emphasized that 

he knew this firsthand, having occupied a seat at the inner-table during the initial 18 months of 

the SARS-CoV-2 pandemic. He and ACIP have often been asked to make difficult decisions 

without all of the information desired in order to quickly respond to this evolving, unprecedented 

global pandemic and public health emergency. This has led to the crafting of incremental 

vaccine policies that have at times added complexity to COVID-19 vaccinations and schedules. 

Despite the previously mentioned challenges, the ACIP has helped shape vaccine policies that 

ultimately have helped protect millions of people across the US and save millions of lives. CDC 

and the American public are grateful for the ACIP’s contributions and leadership. CDC remains 

committed to the efforts to ensure optimal vaccine recommendations moving forward. CDC will 

continue to monitor the SARS-CoV-2 evolution, COVID-19 disease levels, and vaccine safety 

and effectiveness in the months ahead and looks forward to hearing the ACIP’s thoughts and 

insights as they discuss the future direction of the COVID-19 vaccine program. 

Benefit-Risk for COVID-19 Vaccines 

Megan Wallace, DrPH, MPH (CDC/NCIRD) further discussed the benefit and risk assessment 

for COVID-19 vaccine with respect to benefits of COVID-19 vaccine by age for the primary 

series; the incremental benefits of COVID-19 vaccine by age and time since the last dose for a 

bivalent booster dose, with sensitivity analyses modeling high and low points in the pandemic; 

and the benefit-risk assessment for the bivalent booster dose focused on individuals 12─17 

years of age and 18─49 years of age. 

To review the methods used, an assessment was performed for both primary series and 

bivalent booster doses with the results presented in per million primary series or per million 

bivalent booster doses. The COVID-NET COVID-19-associated hospitalization rates were used 

from December 2022, which were the most recently available rates by vaccination status.119 

Sensitivity analyses were used to model high and low points in the pandemic. The time horizon, 

the period over which benefits of vaccination were allowed to accrue, was 6 months. VE 

119 https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalizations-vaccination. Rates among unvaccinated used for primary 

series assessment. Rates among those vaccinated with monovalent doses only used for bivalent booster dose assessment. 

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estimates were used from VISION,120 with the assumption of waning by 10% each month 

starting after Month 2. VE for the primary series assessment was based on the absolute VE for 

a bivalent dose.121 The VE for the bivalent booster assessment was based on the relative VE by 

interval from last monovalent dose to bivalent dose.122 

These are the monthly rates of COVID-19-associated hospitalization by vaccination status from 

COVID-NET (main driver of these assessments), rate among the unvaccinated (basis of the 

primary series assessment), and rate among the vaccinated (basis of the bivalent booster 

assessment), there were considerable differences in the hospitalization rates by age group:

123 

In terms of estimated COVID-19-associated hospitalizations prevented for every million mRNA 

COVID-19 primary series over a 6-month period, there are still significant benefits to primary 

series vaccination. The benefits are the most striking in the older adults, with nearly 16,000 

hospitalizations prevented per million doses given. Even for children, nearly 250 hospitalizations 

were prevented per million doses given. For those age groups for which there were sufficient 

data, the benefits of the bivalent booster were added. These were the additional benefits one 

would expect from a bivalent booster beyond the benefits they already are receiving from any 

previous monovalent doses. Not surprisingly, the expected benefits were smaller for the bivalent 

booster than the primary series but were still substantial in the older adults, with nearly 2,500 

hospitalizations prevented per million doses. For adolescents, these numbers were smaller than 

seen in the past, with an estimated 53 hospitalizations prevented among adolescents 12─17 

years of age per million doses over 6 months. 

Dosing interval refers to the time between the most recent monovalent dose and a bivalent 

dose. Dosing interval has a noticeable impact on the benefits, with longer intervals showing 

greater benefit. Because benefits of a bivalent booster dose were smallest in adolescents 

12─17 years of age and because the benefit assessment is so strongly impacted by 

hospitalization rates, sensitivity analyses were used to explore what the benefits would look like 

in this age group under different epidemiologic scenarios. Focusing on the time since the 

Omicron surge and hospitalization rates in adolescents 12─17 years of age by vaccination 

120 https://www.cdc.gov/mmwr/volumes/71/wr/mm715152e1.htm?s_cid=mm715152e1_w. 121 Absolute VE of bivalent booster dose (57%) used as the estimated primary series VE. Absolute VE from the bivalent booster was 

used as an estimate of primary series VE because current VE of monovalent primary series is unknown. 122 Relative VE of bivalent booster dose used in booster dose assessment (5-7 month interval: 38%; 8-10 month interval: 42%; 11+ 

month interval 45%). Relative VE for ED/UC visit was used for 2-4 month interval (31%) because VE against hospitalization was 

not available 123 https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalizations-vaccination 

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status, benefits were calculated from a low hospitalization rate scenario from March 2022 and a 

high hospitalization rate scenario from July 2022. For both the low and high scenario, the rate 

was steady for the 6-month time horizon.124 The benefits were driven strongly by hospitalization 

rates. In the high incident setting, approximately 120 hospitalizations would be prevented per 

million doses over 6 months depending on the dosing interval. The dosing intervals have been 

different from monovalent and bivalent booster doses. Among adolescents who received a 

monovalent booster, nearly half received the monovalent booster at an interval less than 8 

months after their primary series. Among adolescents who received a bivalent booster dose, 

over 90% received a bivalent booster ≥8 months after their previous dose.

125 

In terms of the potential myocarditis risk following the bivalent booster dose in this age group, 

there are limited data to inform the myocarditis risk following a bivalent booster dose. 

Preliminary VSD myocarditis rates following bivalent booster dose in adolescent and young 

adult males are lower than first monovalent boosters, but this is limited by small numbers of 

doses administered. Myocarditis risk is lower with longer time between doses. Rates of 

myocarditis were lower with an extended interval between Dose 1 and Dose 2 for the primary 

series.126 A longer interval between doses for bivalent boosters compared to monovalent 

boosters also may impact myocarditis rates. Most individuals with myocarditis or pericarditis 

have fully recovered at follow-up.127 In previously published analyses, the risk of adverse 

cardiac outcomes were 1.8 to 5.6 times higher after SARS-CoV-2 infection than after mRNA 

COVID-19 vaccination among males 12─17 years of age.

128 

Looking at myocarditis rates from the VSD shown in Dr. Shimabukuro earlier by age and sex for 

Pfizer-BioNTech for Dose 2 of the primary series, the monovalent booster dose, and the 

preliminary data for the bivalent booster dose, few bivalent doses have been captured in the 

VSD. However, there has been only 1 myocarditis case reported in any of these age groups. 

Looking at the incidence rates by dose, the risk might be trending downward, with bivalent 

boosters having the lowest risk. Again, these are small numbers and wide confidence 

intervals.129 In terms of Moderna myocarditis rates from the VSD, no myocarditis cases have 

been reported. Again, there have been few bivalent booster doses captured.130 

With regard to estimated COVID-19 hospitalizations prevented versus potential myocarditis 

cases for every million bivalent mRNA COVID-19 booster doses among adolescents 12─17 

years of age, it would be expected that 31─136 hospitalizations, 9─40 ICU admissions, and 1 

death would be prevented. Based on the preliminary data on myocarditis following bivalent 

booster in VSD, zero myocarditis cases have been observed in nearly 50,000 males who have 

received a bivalent booster dose and no cases in females with a similar number of doses.131 

Applying a correction to account for the potential incidental SARS-CoV-2 infections among 

hospitalized patients that Dr. Taylor discussed in the COVID-NET presentation, it was estimated 

124 https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalizations-vaccination 125 IZ Data Lake: Accessed 2/7/2023 126 https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-02-04/11-COVID-Moulia-508.pdf 127 https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-02-04/04-COVID-Kracalic-508.pdf 128 https://www.cdc.gov/mmwr/volumes/71/wr/mm7114e1.htm?s_cid=mm7114e1_w 129Primary series and 1st monovalent booster data through August 20, 2022, bivalent booster data through January 29, 2023; 

Source: Kristin Goddard, Kayla E. Hanson, Ned Lewis, et al. Incidence of Myocarditis/Pericarditis Following mRNA COVID-19 

Vaccination Among Children and Younger Adults in the United States. Ann Intern Med. [Epub 4 October 2022]. doi:10.7326/M22-

2274 

130 Primary series and 1st monovalent booster data through August 20, 2022, bivalent booster data through January 29, 2023; 

source: Goddard K, et al. Incidence of Myocarditis/Pericarditis Following mRNA COVID-19 Vaccination Among Children and 

Younger Adults in the United States. Ann Intern Med. 2022;175:1169-1771. 131 Based on preliminary Pfizer-BioNTech bivalent booster safety data from VSD (incident rate/million doses): 0 (95% CI: 0-62) in 

males and 0 (95% CI: 0-60) in females 

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that among adolescents 12─17 years of age,132 it would be expected that 17─75 

hospitalizations, 5─22 ICU admissions, and 0─1 death would be prevented. Again, zero 

myocarditis cases have been observed in nearly 50,000 males who have received a bivalent 

booster dose and no cases in females with a similar number of doses.133 

Looking at the benefit risk assessment for adults 18─49 years of age per million doses over 6 

months, it would be expected that 117─376 hospitalizations, 21─69 ICU admissions, and 4─11 

deaths would be prevented. Among adults 18─39 years of age in the VSD, 1 myocarditis case 

was identified in a male with over 180,000 bivalent booster doses given. No cases have been 

reported in females who over 270,000 doses recorded.134 While 18─49 is a fairly wide age 

group for benefits, it was not possible to stratify it further for rates by vaccine status. However, 

looking at hospitalization rates overall, adults 18─29 years of age had lower rates than adults 

30─49 years of age, but higher rates than the adolescents. Adults 18─29 years of age likely 

would have lower numbers for benefits, but probably still somewhat higher that what was 

observed for adolescents. If the correction for potential incidental SARS-CoV-2 infections 

among hospitalized patients is applied, it would be expected that 81─259 hospitalizations, 

15─48 ICU admissions, and 3─8 deaths would be prevented. 

There are several important limitations to the benefit risk assessment that should be noted. The 

benefits of vaccination may continue to accrue beyond the time horizon used. Stable 

hospitalization rates were assumed for the duration of the time horizon, which may not 

represent what will happen in the future. The underlying complexity of vaccine histories and 

previous infections could not be accounted for. COVID-NET hospitalization rates included 

hospitalizations for which COVID-19 was not a primary reason for admission. The extent to 

which COVID-19 hospitalization rates include incidental findings is the extent to which benefits 

may be overestimated. Current COVID-19 epidemiology reflects the impact of both prior 

vaccination and prior infection. It is not possible to account for possible future increases in 

COVID-19 hospitalization rates or a new variant. Myocarditis rates following bivalent booster 

doses are uncertain. Studies are underway to assess the long-term impact of vaccineassociated myocarditis. 

In summary, significant benefits continue to outweigh risks for primary series vaccination in all 

age groups. The benefits of a bivalent booster dose vary by age, time since last dose, and 

COVID-19 incidence. The risk of myocarditis after COVID-19 vaccines is likely reduced by a 

longer interval since last dose. Additional data can better define risk after bivalent vaccines, but 

current data are encouraging. Changes in COVID-19 hospitalization rates would impact the 

benefit assessment. There are additional benefits of COVID-19 vaccines unable to be quantified 

in the benefit risk assessment, including likely prevention of post-COVID conditions, possible 

reduction in transmission, and increased confidence in social interaction. The benefit-risk 

assessment will continue to be monitored as new data are available. Receipt of primary series 

continues to be important in all ages and boosters remain an important option to improve 

protection against severe COVID-19, especially for higher risk populations. 

132 Results were adjusted to account for potential incidental findings of SARS-CoV-2 infection by multiplying the estimated 

hospitalizations, ICU admissions, and deaths prevented by the estimated percent of COVID-NET hospitalizations that are likely 

due to COVID-19 among 12 – 17-year-olds during on Omicron BA.5 predominant period (55%) 133 Based on preliminary Pfizer-BioNTech bivalent booster safety data from VSD (incident rate/million doses): 0 (95% CI: 0-62) in 

males and 0 (95% CI: 0-60) in females 134 2Based on preliminary bivalent booster safety data from VSD among persons ages 18-39 years. Among Pfizer-BioNTech 

recipients, rates per million doses were: 20 (95% CI: 1–53) in males ages 18–29 years; 0 (95% CI: 0– 37) in females ages 18–29 

years; 0 (95% CI: 0–36) in males ages 30–39 years and 0 (95% CI: 0–26) in females ages 30–39 years. Among Moderna 

recipients, rates per million doses were: 0 (95% CI: 0–162) in males ages 18–29 years; 0 (95% CI: 0– 101) in females ages 18– 

29 years; 0 (95% CI: 0– 85) in males ages 30–39 years and 0 (95% CI: 0–63) in females ages 30–39 years. 

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COVID-19 Vaccines: Future Directions 

Sara Oliver, MD, MSPH (CDC/NCIRD) presented COVID-19 considerations for future planning 

for COVID vaccines. For planning purposes, it is important to aware of and evaluate the current 

status of COVID-19 vaccine, where there are going, and how to get there. To flesh that out, Dr. 

Oliver reviewed the current recommendation, vaccination rates, and hospitalization rates for the 

program at large. The ultimately goal is clear, simple recommendations. In thinking through how 

to get there, ACIP was asked to focus on the following questions: 

 How frequently should people get a COVID-19 vaccine?

 Are there groups/populations who should have >1 vaccine per year?

This graphic of the current recommendations for COVID-19 vaccines illustrates the complexity 

of the recommendations: 

COVID-19 vaccine uptake is higher with older ages. However, uptake for bivalent boosters is 

only about 40% for adults ≥65 years of age.

135 While in general uptake has declined as the 

number of doses recommended have progressed, people tend to get vaccinated in waves 

shortly after recommendations.136 In terms of why vaccine coverage is lower than desired, 

recent studies reflect profound COVID-19 vaccine message fatigue,

137 a desire to end the use 

of mitigation measures,

138 and a common perception that immunity is sufficient without future 

vaccine doses.139 There are other reasons as well. Barriers to vaccine access still persist for 

135 https://covid.cdc.gov/covid-data-tracker/#vaccination-demographics-trends Updated February 10, 2023 136 IZ Data Lake 137 Guan et al. Health Communication 2022: COVID-19 Message Fatigue: How Does It Predict Preventive Behavioral Intentions and 

What Types of Information are People Tired of Hearing About? - PubMed (nih.gov) 138 CDC's State of Vaccine Confidence Insights Reports, Jan 26 2023: CDC’s State of Vaccine Confidence Insights Report 139 Sinclair et al. MMWR Jan 20 2023: MMWR, Reasons for Receiving or Not Receiving Bivalent COVID-19 Booster Vaccinations 

Among Adults — United States, November 1–December 10, 2022 (cdc.gov) 

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some populations, including but not limited to people who live in rural areas,140 people 

experiencing homelessness,141 and people with disabilities.142 Despite improvements in vaccine 

equity after primary series vaccination observed with the incredible efforts in 2021 to get people 

vaccinated with the primary series, disparities in booster coverage have emerged.143 

In addition, the virus continues to evolve. Looking at trends in weighted variant proportion 

estimates and Nowcast for the period November 6, 2022─February 11, 2023, nearly threefourths of isolates were projected to be XBB.1.5.144 It also is important to look at the estimated 

number of reported COVID-19 cases by variant.145 Even with newer variants, massive increases 

have not been seen as those that occurred in the winter of 2021 and 2022. Most adults have 

now had SARS-CoV-2 infection, vaccine, or both. Looking at seroprevalence by vaccine and 

infection history among adult US blood donors between January–June 2022, only 6% had 

neither infection nor vaccine.146 

Looking at weekly population-based rates of COVID-19-associated hospitalizations by age 

group in COVID-NET for the period March 2020–February 2023, the highest hospitalization 

rates continue to be among older adults. However, hospitalization rates among those <65 years 

of age have not mirrored the similar increases recently as they did earlier in the pandemic. 

Based on monthly age-adjusted rates of laboratory-confirmed hospitalizations by vaccination 

status among adults ≥18 years of age in COVID-NET for the timeframe January 2021– 

December 2022, hospitalization rates are the lowest among those who have received a bivalent 

vaccine. In December 2022, compared to adults who received an updated bivalent booster 

dose, the monthly rates of hospitalization were 16 time higher among unvaccinated and 2.6 

times higher in vaccinated adults without an updated booster dose. 

To summarize the present status, current COVID-19 vaccine recommendations are complex. 

Uptake of current bivalent vaccine is low. The SARS-CoV-2 virus continues to evolve, but recent 

virus evolution has not led to large population-level surges and cases or hospitalizations. Most 

adults have prior infection, prior vaccination, or both. Hospitalization rates are highest in older 

adults but remain low among people who have received a bivalent booster. 

In terms of future planning, the question of how frequently people should get a COVID-19 

vaccine needs to be considered. While the ability to capture COVID cases has changed over 

time with increasing utilization of the home antigen test, CDC continues to be able to closely 

monitor COVID hospitalizations. Increases in COVID-19 cases and hospitalizations have 

occurred during the winter months, due to the development of a new immune escape variant, 

and/or both as occurred during the BA.1 winter surge when both occurred. However, the most 

recent winter did not have the increases seen in either of the previous 2 winters.147 

140 Assessing barriers to access and equity for COVID-19 vaccination in the US - PMC (nih.gov) 141 McCosker et al. Vaccine May 2022: Strategies to improve vaccination rates in people who are homeless 142 Griffin-Blake et al. Barriers and facilitators of COVID-19 vaccine uptake among people with disabilities. Presentation to the 

COVID-19 Vaccine Innovation Team: Feb 8 2023 143 COVID-19 Vaccination Coverage, by Race and Ethnicity — National Immunization Survey Adult COVID Module, United States, 

December 2020–November 2021 | MMWR (cdc.gov) 144 https://covid.cdc.gov/covid-data-tracker/#variant-proportions Accessed Jan 20, 2023 145 Data sources: https://covid.cdc.gov/covid-data-tracker/#variant-proportions and https://covid.cdc.gov/covid-datatracker/#trends_newtestresultsreported_7daytestingpositive_00 146 https://covid.cdc.gov/covid-data-tracker/#nationwide-blood-donor-seroprevalence-2022 147 Cases from October 2021-February 2023 https://covid.cdc.gov/covid-data-tracker/#trends_weeklycases_select_00; and 

Admissions from October 2021 – February 2023 https://covid.cdc.gov/covid-data-tracker/#new-hospital-admissions 

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Looking at trends over time and number of doses for monovalent vaccines and VE against 

hospitalizations for the first part of 2022,

148 declines were seen over time with monovalent 

COVID-19 vaccines. This is likely impacted by both time since vaccine dose and continued virus 

evolution. Additional vaccine doses restored protection lost over time. While it is too soon to 

know the impact of waning and virus evolution on the VE of the bivalent vaccines over time, 

CDC continues to closely monitor the impact of waning and virus evolution on VE for bivalent 

doses and will present updates to ACIP when available. It is known that time since last dose 

impacts COVID-19 VE. Relative VE of bivalent boosters, meaning the additional benefits of a 

bivalent booster, are higher the longer it has been since the last monovalent dose. Safety also is 

likely improved with longer time between doses, with myocarditis risk appearing to be lower with 

longer time between doses.

149 

To summarize the data pertaining to how frequently people should get a COVID-19 vaccine, 

winter months and immune escape variants have impacted COVID-19 epidemiology. This past 

winter did not see the same level of increases in cases and hospitalizations as previous winters. 

Time since last COVID-19 vaccine dose may increase the incremental benefits of a COVID-19 

vaccine and decrease the risk of myocarditis. Vaccine protection likely declines over time. A 

plan for a fall booster dose could provide added protection, at a time when many would be 

approximately 1 year out from their last dose. Future epidemiology and SARS-CoV-2 virus 

evolution could help determine the need for continued annual boosters. 

In terms of the question regarding whether there are populations who still need a primary series, 

most adults have completed a primary series. However, most children 6 months─4 years of age 

remain unvaccinated (92.4% of children <2 years of age and 89.7% of children 2─4 years of

age). For most older children, adolescents, and adults, future doses will be an additional boost 

after prior infection, prior vaccination, or both. In addition, young children will continue to age 

into the vaccine recommendation at 6 months and could be SARS-CoV-2 naïve. Because of 

this, some population of young children likely still will need a prime and a boost to optimize 

immunity. 

Data from a CDC/University of Iowa/RAND survey show that among parents with an 

unvaccinated or under-vaccinated child 6–23 months of age, 38% intended to get their child 

vaccinated in the next month, 39.4% said they “definitely” or “probably” will not vaccinate their 

child, and 23% said they were unsure. Additionally, 38% of parents of children 2–4 years of age 

said they “definitely” or “probably” would get their child vaccinated in the next month, 43.2% said 

they “definitely” or “probably” would not, and 18.4% were unsure. Doctor’s offices and clinics 

were the most trusted place for parents to have their child receive a COVID-19 vaccine, as 

reported by 51.1% of parents of children 6–23 months of age and 52.5% of parents of children 

2– 4 years of age. Therefore, thinking through optimal strategies for primary series vaccination 

in this young pediatric population continues to be important. 

Looking at weekly population-based rates of COVID-19-associated hospitalizations among 

children 6 months─4 years of age in COVID-NET for the period March 2020–February 2023, 

pediatric hospitalization rates were higher among children 6 months to <2 years of age. Based 

on pediatric SARS-CoV-2 infection-induced and combined seroprevalence from US commercial 

laboratories for the time period March–December 2022, the youngest children 6─11 months of 

148 BA.2/BA.2.12.1 estimates: Link-Gelles et al. MMWR: https://www.cdc.gov/mmwr/volumes/71/wr/mm7129e1.htm BA.4/BA.5 

estimates: Link-Gelles et al. medRxiv: https://www.medrxiv.org/content/10.1101/2022.10.04.22280459v1. Individuals with prior 

infections excluded. Adjusted for calendar time, geographic region, age, sex, race, ethnicity, local virus circulation, respiratory or 

non-respiratory underlying medical conditions, and propensity to be vaccinated. 149 Tenforde et al. MMWR December 16, 2022: https://www.cdc.gov/mmwr/volumes/71/wr/mm715152e1.htm 

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age have the lowest both infection and combined immunity and it increases with age of the 

child.150 

To summarize whether there are populations who may still need a primary series, children <2 

years of age have higher COVID hospitalization rates than older children. Children <4 years of 

age are less likely to have both prior infection and prior vaccination. Children have frequent 

visits to HCP. According to the AAP’s recommended schedule for well-child visits, prior to 3 

years of age, children are recommended to go to the pediatrician at least every 6 months or 

more. The WG discussed continued primary series recommendations for young children 6 

months─2 years of age and 6 months─4 years of age.151 There was not a clear consensus from 

the WG for either age cut-off. Without a clear-cut off from the data, the WG thought feasibility 

also could be considered in thinking this through. 

The next population of interest is older adults. Based on weekly population-based rates of 

COVID-19 hospitalization among all ages from COVID-NET from March 2022─February 2023,

the highest hospitalization rates were among adults ≤75 years of age followed by adults 65─74 

years of age. Based on age-adjusted rates of COVID-19-associated hospitalization by 

vaccination status and receipt of booster dose in adults ≥65 years of age in COVID-NET from 

January 2021–December 2022,

152 in December 2022, adults ≥65 years of age who received a 

bivalent booster had a 12.8 times lower risk of hospitalization for COVID-19 compared to 

unvaccinated people and a 2.5 times lower risk of hospitalization compared to those vaccinated 

without a bivalent booster. Data from ICATT153 on relative VE of bivalent booster against 

symptomatic infection in adults ≥18 years of age from December 1, 2022–February 13, 2023 

demonstrate that immunity and vaccine response are different in older adults and patterns of 

VE, including waning, may be different in older adults. Waning for bivalent VE against 

hospitalization, including among older adults, is not yet known. 

To summarize whether older adults should be recommended for >1 vaccine annually, older 

adults have higher rates of hospitalization than younger adults, but the rates of vaccination 

among older adults who already have received their bivalent booster remain low. The WG 

emphasized the importance of older adults being up to date on current recommendations, 

including receiving a bivalent booster. The WG discussed more frequent COVID-19 vaccine 

doses for older adults and at this time felt that the data were insufficient to determine a 

conclusion on a need for frequent vaccines, and there was concern that it may not be feasible to 

implement a vaccine program in all adults ≥65 years of age. However, there was much 

discussion that these recommendations can be updated based on closely monitoring data in 

older adults, including hospitalization rates of older adults who have received a bivalent booster, 

bivalent VE and patterns of waning in older adults, and SARS-CoV-2 virus evolution and the 

possibility of future immune escape variants. 

150 https://covid.cdc.gov/covid-data-tracker/#pediatric-seroprevalence and unpublished data from CDC 151 https://www.healthychildren.org/English/family-life/health-management/Pages/Well-Child-Care-A-Check-Up-for-Success.aspx 152 CDC COVID Data Tracker. https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalizations-vaccination Accessed Feb 17, 

2023 

153 Unpublished CDC data. From ACIP presentation February 24, 2022 

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In terms of whether people with immunocompromising conditions should be recommended for 

more frequent vaccines, numerous studies154 have demonstrated that mRNA COVID-19 VE 

among immunocompromised persons is lower than that of immunocompetent persons, including 

within the period of Omicron. This has been demonstrated across a range of 

immunocompromising conditions and is particularly notable for organ or stem cell transplant 

recipients. Among people with immunocompromise, recommendations prior to the bivalent 

booster allowed for up to 5 monovalent doses of COVID-19 vaccine. VE studies are not yet 

sufficiently powered to evaluate the effectiveness of a bivalent booster among persons with 

immunocompromise. 

Looking at what is known, a published paper by Ferdinands, et al. compared VE among persons 

with an immunocompromising condition to people without immunocompromising conditions.155 

VE among immunocompromised persons is lower than that of immunocompetent persons at 

comparable time points after Dose 2 and Dose 3. VE wanes in both immunocompetent and 

immunocompromised people.156 

In summary for this population, immunocompromised adults can have a less robust immune 

response to COVID vaccines. While not necessarily the scope of ACIP’s work for now, it is 

important to note that there is not currently any authorized prophylactic monoclonal antibody 

products for populations at higher risk of COVID-19. The WG discussed more frequent COVID19 vaccine doses for people with immunocompromising conditions and felt that the data were 

insufficient at this time to determine a conclusion for definitive recommendations moving 

forward. However, the WG acknowledged that this population may continue to be more 

vulnerable to severe COVID and is likely to need flexibility with future COVID-19 vaccine 

recommendations. 

With respect to the future goal for simple recommendations, COVID-19 vaccines continue to be 

the most effective tool available to prevent serious illness, hospitalization, and death from 

COVID-19. While the goal of the COVID-19 vaccine program continues to be prevention of 

severe disease, prevention of post-COVID conditions, increased confidence in social 

interactions, and even a temporary protection against symptomatic disease can be important as 

well. As discussed throughout the day, the benefits of additional COVID-19 vaccine booster 

doses vary by age, time since last dose, and COVID incidence. A simplified annual 

recommendation could help reduce vaccine and message fatigue. A COVID vaccine framework 

that is similar to a well-understood influenza vaccine framework could be easy for COVID-19 

vaccine providers to implement and for the public to understand. 

154 Britton A, Embi PJ, Levy ME, et al. Effectiveness of COVID-19 mRNA Vaccines Against COVID-19–Associated Hospitalizations 

Among Immunocompromised Adults During SARS-CoV-2 Omicron Predominance — VISION Network, 10 States, December 

2021—August 2022. MMWR Morb Mortal Wkly Rep 2022;71:1335–1342. Embi PJ, Levy ME, and Patel P, et al. Effectiveness of 

COVID-19 Vaccines at Preventing Emergency Department or Urgent Care Encounters and Hospitalizations Among 

Immunocompromised Adults: an Observational Study of Real-World Data Across 10 US States from August—December 2021. 

Preprint. *Effectiveness of COVID-19 Vaccines at Preventing Emergency Department or Urgent Care Encounters and 

Hospitalizations Among Immunocompromised Adults: An Observational Study of RealWorld Data Across 10 US States from 

August-December 2021 (medrxiv.org) Ferdinands J M, Rao S, Dixon B E, Mitchell P K, DeSilva M B, Irving S A et al. Waning of 

vaccine effectiveness against moderate and severe covid-19 among adults in the US from the VISION network: test negative, 

case-control study BMJ 2022; 379 :e072141 doi:10.1136/bmj-2022-072141 155 Figure: Ferdinands J M, Rao S, Dixon B E, Mitchell P K, DeSilva M B, Irving S A et al. Waning of vaccine effectiveness against 

moderate and severe covid-19 among adults in the US from the VISION network: test negative, case-control study BMJ 2022 156 VISION: mRNA COVID-19 VE for hospitalizations among immunocompetent versus immunocompromised adults during Omicron 

predominance (mid-Dec. 2021—Jul. 2022) 

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In terms of the WG’s interpretation of considerations for future planning, simple 

recommendations are easier to communicate, which also may improve uptake. The WG was 

very supportive of simplified recommendations and planning for the future of COVID-19 

vaccines, which also could include additional updates to COVID-19 vaccines in the future. 

However, uncertainties remain for the ideal timing and populations for future booster doses, 

especially if new immune escape variants develop. The WG was supportive of a Fall or annual 

COVID-19 vaccine program, with the flexibility to adjust based on new data, especially for 

populations at higher risk. The WG will continue to review data to inform future deliberations 

including data on VE of bivalent vaccines over time; safety data of the bivalent vaccines, 

especially in terms of monitoring myocarditis rates as more doses are administered; costeffectiveness analyses; COVID-19 epidemiology, including hospitalization rates among the 

vaccinated and boosted people; SARS-Cov-2 genomic surveillance and virus evolution; and 

data from vaccine manufacturers as they continue to study these vaccines. As a reminder, 

discussions about future COVID-19 vaccine recommendations are pre-decisional and intended 

to inform planning and additional analyses. 

In conclusion, Dr. Oliver posed the following questions for the ACIP’s consideration and 

deliberation: 

 What are ACIP’s thoughts on a simplified framework for future COVID-19 vaccine 

recommendations? 

 What does ACIP think about children who may still need a primary series? 

 What does ACIP think about future recommendations for older adults? 

 What does ACIP think about future recommendations for people with immunocompromising 

conditions? 

ACIP Discussion Points, Observations, Suggestions on COVID-19 Vaccines 

Following Dr. Shimabukuro’s Presentation 

• Regarding an inquiry about whether there is specific surveillance in nursing homes, Dr. 

Shimabukuro said that while he was not aware of specific surveillance in nursing homes, 

the VSD analyses may include nursing homes. In addition, Dr. Forshee may be able to 

provide additional insight on nursing home residents from the CMS data. Dr. Forshee 

added that the Medicare sequential analyses did not include nursing home residents. 

They have performed some separate analyses on nursing home residents, but 

specifically for the outcome of ischemic stroke. 

• In terms of a question about the point at which these data would be widely publicized, 

Dr. Shimabukuro indicated that this information has been posted on the CDC website, 

presented during the last VRBPAC meeting, were presented to the ACIP during this 

session, and presumably would soon be published. He emphasized that the data he 

presented during this session were not sufficient to conclude that there is a safety 

problem with the Pfizer bivalent booster and ischemic stroke in adults ≥65 years of age 

or a safety problem with the Pfizer bivalent booster and co-administration with high-dose 

or adjuvanted influenza vaccines. There are other factors that could be the reason for 

the statistical signal, such unmeasured confounding or chance alone. Monitoring will 

continue and the recommendations for bivalent booster vaccination and influenza 

vaccination have not changed. 

• As a reminder for the public, Dr. Lee stressed that no safety signals were detected for 

ischemic stroke for the primary series or monovalent boosters for Pfizer-BioNTech or 

Moderna COVID-19 vaccines in US and global monitoring. 

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Following Dr. Forshee’s Presentation 

• With respect to a question about whether there is an opportunity to for the FDA to 

partner with CMS to assess nursing home data, Dr. Forshee emphasized that the FDA 

has done some work already on safety and effectiveness data among nursing home 

populations, but have not specifically looked at the ischemic stroke. He emphasized that 

he and Dr. Shimabukuro talk on a regular basis and their teams meet regularly, so they 

can continue this discussion as part of their ongoing conversations. 

• It would be beneficial to have data on how much coadministration of influenza vaccine 

occurs in other systems. Dr. Forshee indicated that he could speak only to what was 

observed in their CMS analysis. 

Following Dr. Talbot’s Presentation 

• Dr. Lee took a moment to express gratitude to Drs. Talbot, Hopkins, Wharton, and 

Markowitz for leading the very focused and specialized VaST WG. Because of the 

intensity and need for real-time safety surveillance and the need to coordinate and 

collaborate across federal agencies and with global colleagues, this particular WG has 

been highly impactful in response to the COVID-19 pandemic by focusing attention on 

safety. She thanked the VaST WG for its contributions as its activities transitions back to 

the COVID Vaccines WG. As evidenced by the 71 additional meetings of the VaST WG, 

it was possible to look closely at the data to ensure that the vaccines and the vaccination 

program were indeed considered safe and effective for the public. She emphasized that 

it is important to recognize that this was the phenomenal work behind the scenes of 

many unsung heroes including individuals, public and private partners, federal agencies, 

academia, health systems, and others. Behind the 71 meetings and under extremely 

difficult circumstances, this was a tremendous effort of too many colleagues to name 

who have brought information to the public as quickly as possible. 

• Dr. Poehling emphasized that the deliberate transfer of the VaST WG activities to the 

COVID Vaccines WG would ensure that due diligence would continue. 

Following Dr. Twentyman’s Presentation 

• It is clear that there is a risk of stroke following infections such as COVID-19 and 

influenza infections and a protective effect of vaccines has been observed against some 

of the complications of infections such as stroke. Balancing the risk of vaccination versus 

the risk of infection and the totality of the data, it is not convincing that the VSD signal 

was a true signal. Nevertheless, it deserves further investigation over time. 

• Some patients remain concerned about the potential long-term safety of COVID 

vaccines. 

• In terms of encouraging vaccine uptake among the public, it would be extremely 

beneficial to have some simple numbers to convey that one’s risk of stroke at ≥65 years 

of age is X times higher than having a stroke after getting vaccinated. 

Following Dr. Taylor’s Presentation 

• Regarding whether monthly age-adjusted rates of laboratory-confirmed hospitalizations 

by vaccination status were available for the pediatric population, Dr. Taylor indicated that 

the data for adults ≥18 years of age are posted publicly and were age-adjusted. He 

showed those data because they included data on the bivalent booster dose. There is a 

quality standard for the COVID-NET data that requires that a certain proportion of the 

underlying COVID-NET catchment population has to reach a certain level of vaccination 

in order for the rates to be considered stable. The most recent data analyzed for the 

pediatric groups had not yet reached the standard to be able to include them. 

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• These data highlight the importance of continuing to think about how to encourage 

vaccine acceptance. Given that the CICP working well is an important part of vaccine 

acceptance, expeditious review of claims are crucial as related to vaccination and the 

continued development of an Injury Table. 

• Given the 16-fold higher hospitalization rate among the unvaccinated in the context of 

the current transmissibility of COVID-19, it would be helpful to know the prevalence of 

natural infection rates among adults. Dr. Taylor noted that while there is immunity 

provided by infection, it is not possible to adjust for that because they do not have a 

variety of other data sources such as prior infection, home testing results, et cetera. As 

more people become vaccinated, perhaps this could be assessed in a seasonal manner 

similar to what is done for influenza. 

• Assuming that the bulk of the unvaccinated have been infected, these data suggest that 

prior infection does not confer much immunity and that what is conferred may be only 

against the variant to which one is exposed. If the data support that, it is important to 

send a clear message that prior infection is not adequate for protection against future 

hospitalization from COVID. 

• For the monthly age-adjusted rates of laboratory-confirmed hospitalizations by 

vaccination status and underlying condition, it would be beneficial to have a breakdown 

by race and age group. For instance, some chronic conditions are higher among African 

Americans, AI/AN, and Latinos. Dr. Taylor indicated that while there is not sufficient 

power to show the vaccination rates by race and ethnicity, they do see patterns of 

differences within groups. A publication has been submitted looking further at COVIDNET data by race and ethnicity because it is so important. Differences have been 

observed since the beginning of the pandemic, so it is clearly important to continue to 

describe them in the ways that are possible. 

Following Dr. Britton’s Presentation 

• Hopefully in the future when there are sufficient data, ACIP could see the ED/UC and 

hospitalizations among children, recognizing that their vaccination recommendations 

came later and those data probably are going to lag. Dr. Britton emphasized that this is a 

high priority and they are checking every available avenue. 

• It will be interesting to know whether these data may have implications for the future in 

terms of whether an additional booster dose might be added or might be given annually 

similar to influenza vaccines. 

Following Dr. Oliver’s Presentation #1 

• ACIP expressed appreciation for the systematic approach that was taken to share all of 

the available data. 

• Vaccine acceptance is critical, so processing CICP claims expeditiously is imperative 

and encourages vaccine acceptance. An update on the Vaccine Injury Table and an 

explanation to the public about why it takes time to develop that table is very important. 

Dr. Grimes acknowledged that HRSA wholeheartedly agrees that expeditious processing 

of claims is of paramount importance. A large volume of claims have been submitted to 

the CICP of over 11,000 alleged COVID-19 countermeasures injuries. Over 8,000 of 

those are COVID-19 vaccine-related. HRSA has been processing claims as 

expeditiously as possible and that effort will continue moving forward. For the CICP, 

HRSA promulgates Countermeasures Injury Tables. For a serious physical injury to be 

added to the Countermeasures Injury Tables, it must meet compelling, reliable, and valid 

medical and scientific evidence. To be promulgated, the alleged injuries must go through 

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the Federal Rulemaking process, which takes time. The Vaccine Injury table specific to 

the VICP is a separate process that currently does not cover COVID-19 vaccines. 

• There is major support from pediatricians, family medicine practitioners, and other 

vaccinators for harmonization of the number and look of the products. Look-alike 

products are a major source of safety concerns. Simplification will improve the logistics, 

feasibility, and confidence of families in receiving the vaccine. 

• Families are having a difficult time understanding why a bivalent vaccine is 

recommended for adults, but their young child is recommended to have 2 doses of 

monovalent before they can receive a bivalent. Given that this has been a very 

confusing message, moving to a bivalent would be easier to communicate. 

• Clarity is needed on what a transition to bivalents will mean for immunocompromised 

and immunosuppressed patients, given that it has become increasingly difficult for 

people to find monovalent vaccine. 

• In terms of the 2 options in front of the ACIP to continue to modify the authorizations for 

special cases or allow clinicians to have the ability to prescribe as they think it makes 

clinical sense to do so, Dr. Kaslow indicated that the FDA is working diligently on this 

topic as quickly as possible, but that this was all he could say at this time. 

• In addition to SARS-CoV-2’s miraculous ability to change and escape immune 

protection, the age groups affected and clinical disease observed also change. Given 

this, it is critical for the newer strain bivalents to be available for the primary series in 

individuals down to 6 months of age. 

• The CMS requirement for HCW/HCP to receive at least the primary series is causing 

some consternation and delay in bringing on new staff because of difficulty in finding 

vaccine. Flexibility in allowing the bivalent vaccine serve as the primary series could help 

to alleviate this issue. 

• It will be beneficial in terms of harmonizing to understand whether the primary series 

with Pfizer will continue to be 3 doses or both Pfizer and Moderna might eventually both 

be 2 doses. Pfizer indicated that as discussed in the recent VRPBAC meeting, Pfizer is 

currently enrolling for its dose-finding portion of a primary bivalent series with the 

bivalent Omicron BA.4/5. These data are anticipated to be available later in the fall. This 

trial has experienced the issue with low uptake in terms of enrollment in the clinical trial. 

As per the currently authorized vaccine, Pfizer is working on a 3-dose primary series. 

Phase 1 includes children 6 months to <2 years of age and 2─5 years of age, with 90 

participants in of those groups for a total of 180. 

• ACIP put forth a strong plea for simplification and more data to support confidence in the 

safety and the effectiveness of these vaccines that will help the ACIP and CDC translate 

this to the broader population. 

Following Dr. Wallace’s Presentation 

• It would be beneficial to better understand how much the risk for MIS-C, MIS-A, and 

long-COVID is decreased with vaccination. Dr. Wallace indicated that an MMWR was 

published about a year ago that looked at VE of the primary series in children and 

adolescents against MIS-C, which showed a high protective effect of primary series 

monovalent vaccination. An article in August 2022 in Clinical Infectious Disease (CID) 

that looked at a reduced likelihood of MISC in children 5─18 years of age showing that 

primary series vaccination was associated with reduced likelihood of MISC in children 

5─18 years of age. 

• It is important to better understand the full spectrum and burden of post-COVID 

conditions in general and to incorporate them into the information on the benefits and 

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risks of COVID-19 vaccination and the decision-making for the full spectrum of COVID19 prevention. 

• Dr. Lee recognized that there are multiple federal efforts in this space and the ACIP 

appreciates the continued collaboration across federal agencies to engage in information 

sharing to ensure that the understanding of the benefit-risk balance is optimized. She 

emphasized how much the ACIP appreciated the overall summary and summative 

statements demonstrating that the benefits continue to outweigh the risks for the primary 

series in all age groups. The committee will continue to think through what else can be 

done to mitigate risk via the schedule and how to simplify it over time and longer 

intervals as an important intervention that can be implemented in the context of 

individual risk, immunocompromised persons, et cetera. 

Following Dr. Oliver’s Presentation #2 

• There was extremely strong support for as much simplification as possible moving 

forward. 

• While there is a population of younger children who will continue to age in who have 

never had a primary series, this also could be true for someone 11 years of age, 23 

years of age, or some other age who has not had the primary series but wants to get it— 

even if they likely have had natural infection. Part of the conversation about who needs 

an annual booster regards what to do about people who never received the primary 

series and where they fit in. At this pivotal point, the idea that someone 18 years of age 

who has never gotten the primary series but has been infected and then gets a single 

dose in the Fall probably would have decent protection. While there is not a lot of data at 

this point and this is not known as an established fact, an assumption underlying this is 

that a recommendation might be that this individual who is 18 years of age might not get 

the 2 doses and would just get the annual dose to be considered “up to date.” 

• It seems like there should be enough data to say that someone who has a documented 

SARS-CoV-2 infection just needs a booster, although that might be more complicated 

than saying every child <5 years of age should get a primary series. Dr Oliver noted that 

they have heard from some of their implementation-minded colleagues that have 

vaccine recommendations that differ based on prior SARS-CoV-2 testing potentially 

would be difficult to implement. 

• There was no mention of pregnancy or pregnant women. For instance, should every 

pregnant woman receive a booster dose during each pregnancy to prevent infection in 

herself and her infant ≥6 months of age? This question should be raised in the WG. Dr. 

Oliver indicated that the WG looks forward to outlining the available data to answer this 

question and bring it to ACIP. It was not included here because it is a separate issue that 

needs a deeper dive. It is on the docket of items the WG will be tackling next. 

• There was no mention of the scheme of things with Novavax in all of this. Dr. Oliver 

responded that the WG was very intentional, especially in the last presentation when 

talking about the transition from monovalent to bivalent, that the primary series 

discussions focused on the mRNA vaccines. No changes are anticipated at this time. 

The primary series that is currently authorized and recommended for Novavax is 

monovalent. The understanding is that Novavax will continue to be available and 

recommended as is. She called on Novavax colleagues to speak to their planning for the 

future. Dr. Denny Kim from Novavax reported that they are in discussions with the FDA 

and anticipate that within the next 2 to 3 months, they will have more clarity on the future 

direction going forward for the 2023 Fall and Winter campaign and future vaccination 

regimens. While he was not at liberty to say more about their discussions with FDA, in 

the context of the ACIP discussions, the Novavax primary series regimen for individuals 

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≥12 years of age is already approved as a booster dose in the same dose and 

presentation. They are working on a bivalent formulation as well and will be prepared to 

deliver that based on what the FDA advises for the Fall and Winter campaign. They also 

have a de-escalation clinical trial that utilizes the same dose as the primary series for 

individuals ≥12 years of age. 

• Practitioners have heard from families that it would be beneficial to have one message 

across all age groups of children. A study showing the benefit and duration of 1 bivalent 

vaccine would enhance the confidence in making a change versus making inferences. 

• While very low rates of far less than 5% are being seen among well-vaccinated people 

who are immunocompromised and receive standard antiviral treatments, many 

immunocompromised individuals have not taken the opportunity to get the bivalent 

vaccine. Based on feedback from patients, this is primarily due to vaccine fatigue or not 

being fully aware of the opportunity. Moving forward, it is important to get the message 

out to people who are immunocompromised to get their bivalent dose. 

• It would be beneficial if the FDA would permit enhanced flexibility of recommendations, 

which would allow providers to give additional doses to individuals who are 

immunocompromised, and to be responsive to upcoming increases in disease activity or 

variants, et cetera. 

• Regarding an inquiry about whether the WG has discussed a role for shared clinical 

decision-making for the older adult population or people with immunocompromising 

conditions, Dr. Oliver indicated that the WG has talked about populations who may 

benefit from a more permissive recommendation for whom population-level 

recommendations for everyone would not be sufficient. For instance, timing of 

immunocompromising might be a factor. The WG did not feel like the epidemiology and 

duration data were sufficient to propose a structure for shared clinical decision-making at 

this point. 

• In terms of whether the WG had any concerns that inequities would result if certain 

groups or populations were recommended to have more than 1 dose per year, Dr. Oliver 

emphasized that the WG has reviewed the inequities that currently exist with the bivalent 

vaccines and is considering ways to address those such as simple recommendations 

that everyone can understand and removal of barriers. They have heard that sometimes 

people are identified as being vaccine-hesitant when in fact they simply face barriers to 

getting vaccinated. Dr. Twentyman added that whenever the complexity of 

recommendations increase to the point of compromising delivery in any way (e.g., 

through clinician frustration, public COVID-19 message fatigue, et cetera) those who 

have less strong access to the healthcare system who will be affected, regardless of 

whether they want to get the vaccine or not. 

• In terms of minoritized communities, equity is a particularly major concern in the 

pharmacy community. It is known that up to this point, Hispanic and Latino individuals in 

particular are more likely to get immunized in a pharmacy than in other points of care 

based upon recent data. 

• Concern was expressed regarding the influx of undocumented immigrant populations 

who have never received a vaccination. There was a presentation earlier in the session 

showing that 50% of children who are hospitalized have no known underlying medical 

conditions but are sick enough to be hospitalized. This raised questions about whether 

there could be issues other than lack of vaccination and underlying conditions that might 

impact immunity and contribute to more severe disease a (e.g., food insecurity, poor 

nutrition, living environment, post-traumatic stress, et cetera). Dr. Oliver did not know 

whether they had that level of data on social factors for children, but thought it was 

compelling. 

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• It seems that if children get the bivalent primary series, a bivalent booster may not be 

necessary and perhaps the number of vaccines provided to children could be reduced. 

Dr. Jones indicated that there are relatively little data in children compared with adults. 

Because many VE platforms can have difficulty identifying previous infection, particularly 

asymptomatic infection, a lot of the data come from laboratory studies looking at those 

who had a known previous infection and were subsequently vaccinated or had a 

breakthrough infection. At least among those studies, many of which were early in the 

pandemic, showed that 1 dose of a vaccine led to neutralizing and binding antibodies 

that were at least as high as or higher than those who received a primary series. Based 

on those laboratory studies among those who previously were infected,1 dose of a 

vaccine appears to give at least as robust a response as a primary series. VE studies, 

the majority of which are in adults, have shown that hybrid immunity does give superior 

protection compared to just infection-induced immunity. Although infection induced 

immunity does appear to give robust protection, particularly against severe disease, and 

there is limited waning over a long amount of time. There is less information available 

about 1 dose versus 2, but the vaccination appears to increase or restore immunity. 

• ACIP members pointed out how amazed they were with the work that CDC’s staff, 

professionals, and scientists perform, emphasized that they do not get enough credit for 

that, and wanted to make sure they were recognized appropriately during this forum. 

• There was a lot of support for a regular recommendation that everyone get an annual 

booster and a shared clinical decision-making recommendation for certain categories of 

people (immunocompromised, persons ≥65 years of age, et cetera) so they could decide 

with their provider about when and how many doses to get. 

• Heretofore, studies have been in healthy populations. While it is understood that studies 

occur in a stepwise manner, it seems prudent at this juncture to move forward quickly 

toward studying particularly vulnerable pediatric and adult populations. 

• If ethical, perhaps some RCTs could be conducted with co-administration of COVID 

vaccine and influenza vaccine in one arm and separate administration in the other arm. 

• Practically speaking, there is support for single dose presentations—preferably prefilled 

syringes. That would allow practices to purchase vaccine in small quantities and 

potentially could expand the number of locations across the country where vaccine 

would be available. There is a certain reluctance to go into a multi-dose vial if there is 

only one patient who needs the vaccine. On a related note, current supplies of bivalent 

vaccines are about to expire in some locations, so it would be beneficial to know whether 

there is going to be a recommendation for additional vaccine before those doses expire. 

• In closing, Dr. Lee recapped some of the important considerations that arose throughout 

this session: 

− Simplified messaging for the broader population would be beneficial because 

messaging has gotten so complex it can be barrier for people to understand how 

to best protect themselves. The challenge is that oversimplification of the 

message may not be helpful. 

− Flexibility for individual clinicians to work with their clients makes sense because 

there are always going to be various situations or circumstances. 

− Strong and continued updating of clinical considerations is important to ensure 

that the benefit-risk balance is retained over time. 

− It is clear from the data that hybrid immunity is both the strongest and the 

longest, but all immunity wanes over time. Dr. Lee noted that she was personally 

struggling with the need to acknowledge that immunity is a combination of both 

infection and vaccination, but that would not make messaging simple in any way. 

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− The least likely to be immune are going to be the youngest children 6 months─2 

years of age as a starting point. A simple recommendation for that age group, 

that they should get a primary series because they are less protected and have 

higher hospitalizations rates at this point, would be much more straightforward. 

Although some members respectfully disagreed and thought that with 

documentation of COVID-19, the fairly simple message would be that a primary 

series is not needed no matter what the age. More information about antibody 

levels could perhaps guide recommendations about who needs a booster when. 

− The oldest and immunocompromised persons are more likely to get very sick, 

even with full vaccination and/or prior infection. The gap in immunity needs to be 

addressed for these populations. 

− ACIP needs to be able to speak confidently about vaccines so that the public can 

have confidence. There are still many uncertainties that are going to make it 

difficult to develop a straightforward message, given all of the caveats that need 

to be explained. There are specific scientific questions in front of the ACIP, but 

there also is the balance of ensuring that the public’s confidence in vaccines is 

maintained. Realizing that these 2 are not always the same, it is time to start 

incorporating that thinking going forward. 

− There are challenges for which the data are uncertain (e.g., pregnant women, the 

youngest children, immunocompromised persons, the older adult population, et 

cetera). 

− Transparency about what plans are in place to address particular issues is 

crucial, especially with confidence issues as one of the end goals. If certain 

studies are going to be conducted or not, it is important to be transparent about 

the rationale. 

− It is important to reiterate that the goal of vaccines is to prevent severe disease 

and death. 

− There is a misconception that children get mild disease. While deaths among 

children are infrequent, they do occur. 

− There is an opportunity for tremendous disease prevention through COVID-19 

vaccination if people get vaccinated. In transitioning to commercialized products, 

uninsured or underinsured will not have the opportunity by-and-large to be 

vaccinated. Consideration should be given to the feasibility of establishing an 

adult vaccine platform modeled after the VFC. Dr. Meyer reminded everyone that 

this was included as part of the President’s Budget. In order for that to be 

enacted, it would have to be authorized by Congress. Dr. Romero added that he 

is actively working to convince the legislature and people in general of the need 

for such a program. While this would be an incremental program that is not fully 

funded in the beginning, it would grow over time. CDC is committed to this, 

believes it is very important, and will continue to champion it. 

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CERTIFICATION 

Upon reviewing the foregoing version of the February 22-24, 2023 ACIP meeting minutes, Dr. 

Grace Lee, ACIP Chair, certified that to the best of her knowledge, they are accurate and 

complete. Her original, signed certification is on file with the Management Analysis and Services 

Office (MASO) of CDC. 

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ACIP MEMBERSHIP ROSTER

CHAIR

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: 8/4/2021 – 6/30/2023 

EXECUTIVE SECRETARY 

WHARTON, Melinda, MD, MPH 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Atlanta, GA 

MEMBERS 

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 

CHEN, Wilbur H, MD, MS, FACP, FIDSA 

Professor of Medicine 

Center for Vaccine Development and Global Health 

University of Maryland School of Medicine 

Baltimore, MD 

Term: 12/23/2020 – 6/30/2024 

DALEY, Matthew F, MD 

Senior Investigator 

Institute for Health Research, Kaiser Permanente Colorado 

Associate Professor of Pediatrics 

University of Colorado School of Medicine 

Aurora, CO 

Term: 1/4/2021 – 6/30/2024 

KOTTON, Camille Nelson, MD, FIDSA, FAST 

Clinical Director, Transplant and Immunocompromised Host Infectious Diseases 

Infectious Diseases Division, Massachusetts General Hospital 

Associate Professor of Medicine, Harvard Medical School 

Boston, MA 

Term: 12/23/2020 – 6/30/2024 

186 
 

 

 

 

 

 

 

 

 

 

 

LOEHR, Jamie, MD, FAAFP 

Owner, Cayuga Family Medicine 

Ithaca, New York 

Term: 7/26/2021 – 6/30/2025 

LONG, Sarah S, MD 

Professor of Pediatrics 

Drexel University College of Medicine 

Section of Infectious Diseases 

St. Christopher’s Hospital for Children 

Philadelphia, Pennsylvania 

Term: 12/24/2020 – 6/30/2024 

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, MD 

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 

TALBOT, Helen Keipp, MD 

Associate Professor of Medicine 

Vanderbilt University 

Nashville, TN 

Term: 10/29/2018 – 6/30/2022 

187 
 

 

 

 

 

 

 

 

 

 

 

 

 

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 

Food and Drug Administration (FDA)

TBD 

Health Resources and Services Administration (HRSA)

GRIMES, Reed, MD, MPH 

CDR, USPHS 

Director, Division of Injury Compensation Programs 

Health Systems Bureau 

Health Resources and Services Administration 

Rockville, MD 

Indian Health Service (IHS)

CLARK, Matthew, MD, FAAP, FACP 

Physician 

Chair, IHS National Pharmacy & Therapeutics Committee 

Durango, CO 

Office of Infectious Disease and HIV/AIDS Policy (OIDP)

KIM, David, MD, MA 

Director, Division of Vaccines, OIDP 

Office of the Assistant Secretary for Health 

Department of Health and Human Services 

Washington, DC 

National Institutes of Health (NIH)

BEIGEL, John, MD 

Associate Director for Clinical Research 

Division of Microbiology and Infectious Diseases 

National Institute of Allergy and Infectious Diseases (NIAID) 

Bethesda, MD 

188 
 

 

 

 

 

 

 

 

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)

O’LEARY, Sean, MD, MPH 

Professor of Pediatrics 

Pediatric Infectious Diseases 

General Academic Pediatrics 

Children’s Hospital Colorado 

University of Colorado School of Medicine 

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) 

LEE, Sara, MD 

Assistant Vice President of University Health and Counseling Services 

Chief Health Officer 

Case Western Reserve University 

Cleveland, OH 

189 
 

 

 

 

 

 

 

 

 

 

 

 

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 

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 

America’s Health Insurance Plans (AHIP)

GRUBB, Jessica, MD 

Medical Director, Infectious Diseases 

Elevance Health Companies/Carelon 

Charleston, SC 

American Immunization Registry Association (AIRA)

COYLE, Rebecca, MSEd 

Executive Director, AIRA 

Washington, DC 

American Immunization Registry Association (AIRA) (alternate) 

LONDO, Courtnay, MA 

Senior Program Manager 

Washington, DC 

190 
 

 

 

 

 

 

 

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)

GOODE, Jean-Venable “Kelly” R., PharmD, BCPS, FAPhA, FCCP 

Professor and Director, PGY1 Community-Based Pharmacy Residency Program 

School of Pharmacy, Virginia Commonwealth University 

Richmond, VA 

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) 

ZIMMERMAN, Richard, MD, MPH 

Professor 

University of Pittsburgh School of Medicine 

Department of Family Medicine and Clinical Epidemiology 

Pittsburgh, PA 

Association of State and Territorial Health Officials (ASTHO)

JUTHANI, Manisha, MD 

Commissioner 

Connecticut Department of Public Health 

Hartford, CT 

Biotechnology Industry Organization (BIO)

ARTHUR, Phyllis A, MBA 

Senior Director, Vaccines, Immunotherapeutics and Diagnostics Policy 

Washington, DC 

191 
 

 

 

 

 

 

 

 

 

Council of State and Territorial Epidemiologists (CSTE)

HAHN, Christine, MD 

State Epidemiologist 

Office of Epidemiology, Food Protection and Immunization Idaho 

Department of Health and Welfare 

Boise, ID 

Canadian National Advisory Committee on Immunization (NACI)

DEEKS, Shelley, MD, MHSc, FRCPC, FAFPHM 

Deputy Chief Medical Officer of Health, Department of Health and Wellness, Nova Scotia 

Associate Professor, Dalla Lana School of Public Health, University of Toronto 

Chair, National Advisory Committee on Immunization 

Halifax, Nova Scotia 

Infectious Diseases Society of America (IDSA)

DUCHIN, Jeffrey, MD 

Health Officer, 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 

Infectious Diseases Society of America (IDSA) (alternate)

MCAULEY, James B., DTM&H, MD, MPH 

Clinical Director 

Whiteriver Indian Hospital 

Whiteriver, AZ 

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 

192 
 

 

 

 

 

 

 

 

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 Association of Pediatric Nurse Practitioners (NAPNAP) (alternate) 

DESHON, Dana, DNP, APRN, CPNP-PC 

Order of Saint Francis Medical Group 

Morton Pediatrics 

Morton, IL 

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 

Pediatric Infectious Diseases Society (PIDS) 

PAULSEN, Grant, MD 

Associate Professor of Pediatrics 

Pediatric Infectious Diseases 

Cincinnati Children’s Hospital Medical Center 

Cincinnati, OH 

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 

193 
 

 

 

 

 

 

 

 

 

 

 

 

Pediatric Infectious Diseases Society (PIDS) (alternate)

Shannon A. Ross, MD, MSPH 

Professor of Pediatrics 

University of Alabama at Birmingham 

School of Medicine 

Birmingham, AL 

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)

MEHROTRA, Preeti, MD, MPH 

Senior Medical Director 

Infection Control/Hospital Epidemiology 

Beth Israel Deaconess Medical Center 

Adult and Pediatric Infectious Diseases 

Harvard Medical School 

Boston, MA 

Society for Healthcare Epidemiology of America (SHEA) (Alternate) 

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 

194 
195 

 

ACRONYMS USED IN THIS DOCUMENT 

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics 

ABCs Active Bacterial Core Surveillance System 

ACA Affordable Care Act 

ACHA American College Health Association 

ACIP Advisory Committee on Immunization Practices 

ACOG American College of Obstetricians and Gynecologists 

ACP American College of Physicians 

ADE Antibody-Dependent Enhancement 

ADHD Attention Deficit Hyperactivity Disorder 

AE Adverse Event 

AESI Adverse Event of Special Interest 

AHIP America’s Health Insurance Plans 

AI/AN American Indian/Alaskan Native 

AIDP Acute Inflammatory Demyelinating Polyneuropathy 

aIIV Adjuvanted Influenza Vaccine 

AIM Association of Immunization Managers 

AIRA American Immunization Registry Association 

AMA American Medical Association 

AMETHST American Transformative HIV Study 

AMIS American Men’s Internet Survey 

AOA American Osteopathic Association 

AOM Acute Otitis Media 

APhA American Pharmacists Association 

AR Adverse Reaction 

ARI Acute Respiratory Illness 

ASPR Administration for Strategic Preparedness and Response 

ASTHO Association of State and Territorial Health Officers 

AUC Area Under the Curve 

BARDA Biomedical Advanced Research and Development Authority 

BEST System Biologics Effectiveness and Safety System 

BLA Biologics License Application 

CBER Center for Biologics Evaluation and Research 

CBO Community-Based Organization 

ccIIV4 Cell-Culture Based Vaccine 

CDC Centers for Disease Control and Prevention 

CHD Chronic Heart Disease 

CHIKV Chikungunya Virus 

CHIP Children’s Health Insurance Program 

CICP Countermeasures Injury Compensation Program 

CISA Clinical Immunization Safety Assessment Project 

CLD Chronic Lung Disease 

CLI COVID-Like Illness 

CMC Chronic Medical Conditions 

CMS Center for Medicare and Medicaid Services 
 

 

CMV Cytomegalovirus 

COI Conflict of Interest 

CONUS Continental United States 

COPD Chronic Obstructive Pulmonary Disease 

COVID-NET Coronavirus Disease 2019 (COVID-19) Hospitalization Surveillance Network 

CSF Cerebrospinal Fluid 

CSTE Council of State and Territorial Epidemiologists 

CVD Cardiovascular Disease 

cVDPV2 Circulating Vaccine-Derived Poliovirus Type 2 

DCAC Dengue Case Adjudication Committee 

DENV Dengue Virus 

DFO Designated Federal Official 

DM diabetes mellitus 

DoD Department of Defense 

DSMB Data Safety Monitoring Board 

DUA Data Use Agreement 

DVA Department of Veterans Affairs 

eCRF Electronic Case Report Form 

ED Emergency Department 

EIND Emergency Investigational New Drug 

EMA European Medicines Agency 

EMDS Enhanced Meningococcal Disease Surveillance 

EMR Electronic Medical Record 

ET Eastern Time 

EtR Evidence to Recommendation 

EU European Union 

EUA Emergency Use Authorization 

FAERS FDA Adverse Event Reporting System 

FAS Freely Associated States 

FDA Food and Drug Administration 

FluSurv-NET Influenza Hospitalization Surveillance Network 

FQHC Federally Qualified Health Centers 

FRN Federal Register Notice 

FRPP Federal Retail Pharmacy Program 

GACVS Global Advisory Committee on Vaccine Safety 

GBS Guillain-Barré Syndrome 

GDP Gross Domestic Product 

GISAID Global Initiative on Sharing All Influenza Data 

GMC Geometric Mean Concentrations 

GMT Geometric Mean Titers 

GPEI Global Polio Eradication Initiative 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

HCP Healthcare Personnel / Providers 

HD-IV High-Dose Influenza Vaccine 

HHS (Department of) Health and Human Services 

HIV Human Immunodeficiency Virus 

HRSA Health Resources and Services Administration 

HSCT Hematopoietic Stem Cell Transplant 

HZ Herpes Zoster 

196 
 

 

 

 

IC Immunocompromising Conditions 

ICERs Incremental Cost Effectiveness Ratios 

ICU Intensive Care Unit 

IDMC Independent Data Monitoring Committee 

IDSA Infectious Disease Society of America 

IHS Indian Health Service 

IIS Immunization and Infectious Diseases 

IIS Immunization Information System 

IIV Inactivated Influenza Vaccine 

ILINet Influenza-like Illness Surveillance Network 

IM Intramuscular 

IMD Invasive Meningococcal Disease 

IPD Invasive Pneumococcal Disease 

IPV Inactivated Polio Vaccine 

IRA Inflation Reduction Act of 2022 

ISD Immunization Services Division 

IV Intravenous 

IVIG Intravenous Immune Globulin 

IVWG Federal Interagency Vaccine Workgroup 

IVY Investigating Respiratory Viruses in the Acutely Ill 

LGBTQ+ Lesbian, Gay, Bisexual, Transgender, Queer or Questioning, or Other 

LRTD Lower Respiratory Tract Disease 

LRTI Lower Respiratory Tract Illness 

LTCF Long-Term Care Facilities 

MAAEs Medically Attended Adverse Events 

MACDP Metropolitan Atlanta Congenital Defects Program 

MATISSE Maternal Immunization Study for Safety and Efficacy 

MELODY Prevention of Medically Attended Lower Respiratory Tract Infection Due to 

Respiratory Syncytial Virus in Healthy Late Preterm and Term Infants 

MFS Miller Fisher Syndrome 

MICH Maternal, Infant, and Child Health 

MIS-C Multisystem Inflammatory Syndrome in Children 

MMWR Morbidity and Mortality Weekly Report 

MoH Ministry of Health 

MSM Men Who Have Sex with Men 

NACCHO National Association of County and City Health Officials 

NACI National Advisory Committee on Immunization Canada 

NAMCS National Ambulatory Medical Care Survey 

NAPNAP National Association of Pediatric Nurse Practitioners 

NBP Nonbacteremic Pneumonia 

NCCDPHP National Center for Chronic Disease Prevention and Health Promotion 

NCEZID National Center for Emerging and Zoonotic Infectious Diseases 

NCHS National Center of Health Statistics 

NCIRD National Center for Immunization and Respiratory Diseases 

NDC National Drug Code 

NDCMC Newly Diagnosed Chronic Medical Conditions 

NFID National Foundation for Infectious Diseases 

NHANES National Health and Nutrition Examination Survey 

NHP Non-Human Primate 

197 
 

NHSN National Healthcare Safety Network 

NIAID National Institute of Allergy and Infectious Diseases 

NICU Neonatal Intensive Care Unit 

NIH National Institutes of Health 

NIS National Immunization Survey 

NMA National Medical Association 

NNDSS National Notifiable Diseases Surveillance System 

nOPV2 Novel Oral Polio Vaccine, Type 2 

NP Nasopharyngeal 

NREVSS National Respiratory and Enteric Virus Surveillance System 

NSSP National Syndromic Surveillance Program 

NSTEMI Non-ST-Elevation Myocardial Infarction 

NVAC National Vaccine Advisory Committee 

NVPO National Vaccine Program Office 

NVSN New Vaccine Surveillance Network 

NVSS National Vital Statistics System 

NYS New York State 

OASH Office of the Assistant Secretary for Health 

ODPHP Office of Disease Prevention and Health Promotion 

OGC Office of General Council 

OIDP Office of Infectious Disease and HIV/AIDS Policy 

OP Oropharyngeal 

OPA Opsonophagocytic Activity 

OPV Oral Polio Vaccine 

PCP Primary Care Provider/Practitioner 

PCR Polymerase Chain Reaction 

PCV Pneumococcal Conjugate Vaccines 

PEP Post-Exposure Prophylaxis 

PFFS Private Fee-For-Service 

PHAC Public Health Agency Canada 

PHE Public Health Emergency 

PHEIC Public Health Emergency of International Concern 

PICO Population, Intervention, Comparison, Outcomes 

PIDS Pediatric Infectious Disease Society 

PK Pharmacokinetics 

POTS Postural Orthostatic Tachycardia Syndrome 

PPSV23 Pneumococcal Polysaccharide Vaccine 

PPV Positive Predictive Value 

PR Puerto Rico 

PrEP Pre-Exposure Prophylaxis 

QALY Quality-Adjusted Life Year 

QIV Quadrivalent Inactivated Influenza 

RCA Rapid Cycle Analysis 

RCT Randomized Controlled Trial 

RESP-NET Respiratory Virus Hospitalization Surveillance Network 

RSV-NET Respiratory Syncytial Virus Hospitalization Surveillance Network 

SAB Spontaneous Abortion 

SAE Serious Adverse Event 

SAHM Society for Adolescent Health and Medicine 

198 
SD-IIV Standard-Dose Unadjuvanted Influenza Vaccines 

SES Socioeconomic Status 

SHEA Society for Healthcare Epidemiology of America 

SME Subject Matter Expert 

SMFM Society for Maternal-Fetal Medicine 

SNF Skilled Nursing Facilities 

STIs Sexually Transmitted Infections 

SVD Sudan Virus Disease 

TIA Transient Ischemic Attack 

TOR Terms of Reference 

UK United Kingdom 

US United States 

USG United States Government 

USVI US Virgin Islands 

VAERS Vaccine Adverse Event Reporting System 

VDPV Vaccine-Derived Poliovirus 

VE Vaccine Efficacy 

VE Vaccine Effectiveness 

VEPP Vaccine Equity Pilot Program 

VFC Vaccines For Children 

VFIP Vaccines Federal Implementation Plan 

VICP National Vaccine Injury Compensation Program 

VNSP Vaccines National Strategic Plan 

VRBPAC Vaccines and Related Biological Products Advisory Committee 

VSD Vaccine Safety Datalink 

VZV Varicella-Zoster Virus 

WG Work Group 

WGS Whole Genome Sequencing 

WHO World Health Organization 

WPV Wild Poliovirus 

ZIKV Zika Virus 

199