04 Srinivasan covid 508

Updates to COVID -19 Vaccine Effectiveness
Advisory Committee on Immunization Practices
September 19, 2025National Center for Immunization and Respiratory Diseases

2•Vaccine effectiveness methods
•Estimates of COVID -19 Vaccine Effectiveness in Children
•Estimates of Maternal COVID -19 Vaccine Effectiveness
•Estimates of COVID -19 Vaccine Effectiveness in Adults
•ConclusionsAgenda –COVID -19 vaccine effectiveness (VE)
Vaccine effectiveness methods
3
Randomized clinical trials vs. real -world evidence
•Randomized clinical trials needed to demonstrate vaccine efficacy for licensure of
new vaccines : does vaccination prevent disease under ideal and controlled
conditions (i.e., placebo or vaccine comparator )?
•Observational studies provide real -world evidence of vaccine effectiveness : does
vaccination protect against disease in the population?
•Vaccine effectiveness measures benefit of current* vaccination in a population with
existing levels of protection due to prior infection, vaccination, or both.
4* Varies by pathogen. “Current” for COVID -19 or influenza would indicate this season’s vaccine.
Efficacy and effectiveness are population level
estimates.
•If a vaccine has an effectiveness of 80%:
-It does not mean that the vaccine will only work 80% of the time.
-It does mean that in a vaccinated population, 80% fewer people will have the
outcome of interest when they are exposed to the virus compared to an
unvaccinated population.
Vaccine effectiveness can be measured using study
designs across a spectrum
Case -control
Controls generally sampled from
the same population* that gave
rise to the casesTest -negative design (TND)
Controls can be sampled or include entire
eligible at -risk population.*
Sometimes referred to as a
“case -cohort” design.Cohort
Eligible at -risk population* are
followed to see who develops or
does not develop disease
•A vaccine effectiveness (VE) study measures the extent to which a vaccine reduces the incidence of a
specific disease or its severe outcomes in a vaccinated population compared to an unvaccinated
population, often expressed as a percentage reduction in disease occurrence.
•VE can be measured using risk ratio, rate ratio, hazard ratio, or odds ratio, usually after adjustment for
confounding.
* Population is generally chosen from geographic or hospital -based enrollment.
7
CaseControlPerson with acute
respiratory illness
SARS -CoV-2 test
COVID -19
vaccination status
For respiratory viruses, CDC primarily uses the test -negative design (TND), to
measure vaccine effectiveness (VE)
Effectiveness = 1 – (odds ratio ) x 100%    Odds ratio = 𝑂𝑑𝑑𝑠  𝑜𝑓 𝑣𝑎𝑐𝑐𝑖𝑛𝑎𝑡𝑖𝑜𝑛 𝑐𝑎𝑠𝑒𝑠
𝑂𝑑𝑑𝑠  𝑜𝑓 𝑣𝑎𝑐𝑐𝑖𝑛𝑎𝑡𝑖𝑜𝑛 𝑐𝑜𝑛𝑡𝑟𝑜𝑙𝑠
VE findings should be interpreted as the
added benefit provided by COVID -19
vaccination in a population with a high
prevalence of vaccine - and infection -induced
immunity.
8Vaccine effectiveness can be measured using study designs across a
spectrum
Case -control
Controls generally sampled from
the same population* that gave
rise to the casesTest -negative design (TND)
Controls can be sampled or include entire
eligible at -risk population.*
Sometimes referred to as a “case -cohort”
design.Cohort
Eligible at -risk population* are
followed to see who develops or
does not develop disease
* Population is generally chosen from geographic or hospital -based enrollment.Strengths
• More cost effective than cohorts
• Useful for rare outcomes
Limitations
• Retrospective nature can introduce
recall bias (specific to studies that
collect information ONLY through
interview)
• If controls are sampled from
community, misclassification bias can
be introduced (no test to confirm
negative status)
• Potential for confounding due to
health -seeking behaviors
• Residual confounding is possible
• Difficult to establish causalityStrengths
• Useful for rare outcomes
• Controls for health -seeking behavior
and exposure risk
• Efficient for assessing VE in real -world
settings, including against new variants
• Efficient use of resources , especially
when electronic health data are used
Limitations
• Requires accurate testing and
classification (as with all studies)
• Residual confounding is possible
• Difficult to establish causalityStrengths
• Allows for assessment of multiple
outcomes
Limitations
• Time -consuming and expensive
• If identification of outcomes requires
seeking medical care, misclassification
bias can be introduced
• Potential for confounding due to
health -seeking behaviors
• Residual confounding is possible
• Difficult to establish causality
9VISION Multi -Site Network of Electronic Health Records
>300 emergency departments and urgent cares clinics and >200 hospitals
▪Design: Test-negative design
▪Population: Persons visiting a participating emergency
department or urgent care or hospitalized with COVID -
19-like illness with a SARS -CoV-2 test result within 10
days before or 72 hours after encounter
−Cases : CLI with positive  NAAT or antigen for SARS -CoV-2
and no positive NAAT for RSV or influenza
−Controls : CLI with negative  NAAT for SARS -CoV-2 and no
positive NAAT for influenza or RSV (≥60 years)
▪Vaccination data: Documented by electronic health records and state and city registries
CLI = COVID -19-like illness; ED/UC = emergency department/urgent care; RSV = respiratory syncytial virus; NAAT = nucleic acid am plification test
CLI is defined based on the presence of specific discharge diagnosis codes. Additional methods available: Link -Gelles, et al. MM WR.
https://www.cdc.gov/mmwr/volumes/74/wr/mm7406a1.htm
10
•Case infants: hospitalized for COVID -19 as the primary reason
for admission and with a positive SARS -CoV-2 NAAT or antigen
test result
•Control infants: hospitalized for COVID -19-like illness and
negative SARS -CoV-2 NAAT result, matched to case infants by
site; hospitalized within 4 weeks of case infant admissionOvercoming COVID -19 Network
•Design: Case -control study to assess
effectiveness of maternal vaccination against
COVID -19-related hospitalizations in infants
<6 months of age
•Population: 26 pediatric hospitals in 20
states
•Data collection: Baseline demographic and
clinical characteristics obtained via chart
abstraction and parent interview
•Vaccination status: Maternal vaccination
status verified using state vaccination
registries, electronic medical records, or
other sources
10
11IVY Network —26 hospitals, 20 U.S. States
•Design : Test -negative, case -control design
•Population : Adults  ages  ≥18 years  hospitalized with COVID -19-
like illness* and SARS -CoV-2 test results within 10 days of
illness onset and 3 days of admission
–Cases: CLI and test  positive  for SARS -CoV-2 by NAAT or antigen
–Controls : CLI and test negative  for SARS -CoV-2, influenza (≥18
years) and RSV (≥60 years) by RT -PCR
•Vaccination data: Electronic medical records, state and city
registries, and plausible self -report
•Specimens: Nasal swabs  obtained on all patients for central
RT-PCR testing and whole genome sequencing
*COVID -19-like illness = CLI; CLI is defined as presence of any one of the following: fever, cough, shortness of breath, chest i maging consistent with pneumonia, or hypoxemia
NAAT = nucleic acid amplification test

12Measuring COVID -19 Vaccine Effectiveness (VE)
Measure Definition* Example
vaccinated
groupExample comparison group
Absolute VE Compares frequency of health outcomes in
vaccinated and unvaccinated people Received original
monovalent doseReceived no COVID -19 vaccines ever
Relative VE Compares frequency of health outcomes in
people who received one type of vaccine to
people who received a different vaccineReceived  bivalent
doseEligible for, but did not receive,
bivalent COVID -19 vaccine , but
received original monovalent dose
VE “seasonal”
COVID -19 vaccinesCompares people who received this
“season’s”  COVID -19 vaccine to people who
did not, regardless of past COVID -19
vaccinationReceived
 this “season’s”Eligible for, but did not receive, this
“season’s” , regardless of past COVID -
19 vaccination history
* Prior SARS -CoV-2 infection is not generally considered, as it is documented inconsistently in medical records.
Estimates of COVID -19 Vaccine
Effectiveness in Children
13
14Age group | COVID -19 vaccination statusTotal
encountersSARS -CoV -2-
test -positive, N (%)Median interval
since
last dose among
those vaccinated,
days (IQR) Adjusted vaccine effectiveness % (95% CI)
No updated 2023 -2024 COVID -19 vaccine dose*
9 months -4 years 43,246 1,886 (4) 367 (250 to 461) Ref
5-17 years 54,310 2,071 (4) 679 (491 to 810) Ref
≥18 years 279,733 31,167 (11) 756 (61 -189) Ref
2023 -2024 COVID -19 dose received 7 -59 days earlier
9 months -4 years 725 18 (2) 32 (20 to 46) 53 (24 to 70)
5-17 years 951 16 (2) 34 (19 to 47) 64 (41 to 78)
≥18 years 16,082 1,228 (8) 34 (21 -47) 49 (46 to 52)
2023 -2024 COVID -19 dose received 60 -299 days earlier
9 months -4 years 1,345 48 (4) 129 (91 to 178) 23 ( -4 to 43)
5-17 years 2,510 63 (3) 138 (100 to 185) 34 (14 to 49)
≥18 years 49,824 4,701 (9) 149 (100 -211) 12 (8 to 15)VE of 2023 –2024 COVID -19 vaccine  doses against emergency
department/urgent care encounters  — VISION
September 2023 – August 2024
-20 0 20 40 60 80 100
CDC, unpublished data
* Includes all individuals who did not receive a 2023 -2024 COVID -19 vaccine. For those aged ≥5 years, this includes unvaccinated  persons and persons who were vaccinated with ≥1 original
monovalent or bivalent COVID -19 doses. For those aged <5 years, children with a partial initial series were excluded. The 2023 -2024 dose could have been part of the initial series or in addition to
the initial series.
Vaccine effectiveness was calculated by comparing the odds of COVID -19 vaccination in case -patients and control -patients using t he equation: (1 – adjusted odds ratio) x 100%. Odds
ratios were estimated by multivariable logistic regression. The odds ratio was adjusted for age, sex, race and ethnicity, cal end ar day, and geographic region.
15Age group | COVID -19 vaccination statusTotal
encountersSARS -CoV -2-
test -positive, N (%)Median interval
since
last dose among
those vaccinated,
days (IQR) Adjusted vaccine effectiveness % (95% CI)
No updated 2024 -2025 COVID -19 vaccine dose*
9 months -4 years 31,060 809 (3) 392 (282 -662) Ref
5-17 years 38,870 926 (2) 972 (710 -1,116) Ref
≥18 years 200,933 12,927 (6) 1,068 (742 -1,224) Ref
2024 -2025 COVID -19 dose received 7 -179 days earlier
9 months -4 years 393 2 (1) 64 (30 -98) 79 (17 to 95)
5-17 years 2,208 22 (1) 81 (44 -122) 57 (33 to 72)
≥18 years 40,043 1,694 (4) 89 (50 -129) 34 (30 to 37)VE of 2024 -2025 COVID -19 vaccine  doses against emergency
department/urgent care encounters  — VISION
September 2024 – May 2025
-20 0 20 40 60 80 100
CDC, unpublished data
* Includes all individuals who did not receive a 2024 -2025 COVID -19 vaccine. For those aged ≥5 years, this includes unvaccinated  persons and persons who were vaccinated with ≥1 original
monovalent or bivalent COVID -19 doses. For those aged <5 years, children with a partial initial series were excluded . The 2024 -2025 dose could have been part of the initial series or in addition to
the initial series.
Vaccine effectiveness was calculated by comparing the odds of COVID -19 vaccination in case -patients and control -patients using t he equation: (1 – adjusted odds ratio) x 100%. Odds
ratios were estimated by multivariable logistic regression. The odds ratio was adjusted for age, sex, race and ethnicity, cal end ar day, and geographic region.
Estimates of Maternal COVID -19 Vaccine
Effectiveness
16
VISION: VE of 2023 -2024  COVID -19 vaccination against COVID -19–associated
emergency department/urgent care encounters among immuno competent
women aged 18 -45 years, by pregnancy status  — VISION
September 2023 – August 2024
VE=vaccine effectiveness; CLI = COVID -19-like illness
Vaccine effectiveness was calculated by comparing the odds of COVID -19 vaccination in case -patients and control -patients using t he equation: (1 – adjusted odds ratio) x 100%. Odds
ratios were estimated by multivariable logistic regression. The odds ratio was adjusted for: age, ethnicity, race, underlying  medical conditions, gestational age at encounter, site,
Medicaid status, day of encounter, site facility urbanicity
CDC unpublished data17Vaccine Dosage PatternTotal
testsSARS -CoV-2-
test-positive,
N (%)Median interval
since last dose,
days (IQR)Adjusted VE
(95% CI)
Pregnant at CLI encounter
No 2023 -2024 dose (ref) 5058 709 (14) 797 (648, 931) Ref
Most recent 2023 -2024 dose received 7 -179 days 229 13 (6) 77 (44, 120) 58 (24 -77)
Not pregnant at CLI encounter
No 2023 -2024 dose (ref) 76,636 8,052 (11) 794 (641, 931) Ref
Most recent 2023 -2024 dose received 7 -179 days 5,079 313 (6) 83 (45, 126) 37 (29 -44)
-20 0 20 40 60 80 100
Vaccine Effectiveness (%)
Overcoming COVID -19: Effectiveness* of maternal vaccination† in
prevention of COVID -19–associated hospitalization  among infants§
March 9, 2022 – May 31, 2023
Simeone & Zambrano et al., MMWR, 2023: https://www.cdc.gov/mmwr/volumes/72/wr/mm7239a3.htm .
* VE estimates were based on odds of maternal vaccination during pregnancy in case -patients versus control patients, adjusted fo r U.S. Census Bureau region, admission date (monthly), age (in months),
sex, and race and ethnicity (non -Hispanic Black or African American, non -Hispanic White, non -Hispanic other, Hispanic or Latino of any race, or unknown). Study site was included as a repeated effect. VE
was calculated as (1 – adjusted odds ratio) x 100%.
†Maternal vaccination status was based on the last date of a COVID -19 mRNA vaccine dose: unvaccinated was defined as mothers who  had not received any vaccine dose before or during pregnancy,
and vaccinated was defined as mothers who received their last dose of a COVID -19 mRNA vaccine between the first day of pregnancy  and 14 days before delivery. Among those vaccinated during
pregnancy, mothers could have received ≥1 dose during pregnancy. Mothers could receive 1 dose of Ad.26.CoV2.S (Janssen [Johns on & Johnson]) vaccine before or during pregnancy and 1 dose of an
mRNA vaccine during pregnancy. Mothers who received only 1 dose of an mRNA vaccine were considered partially vaccinated and w ere excluded from the analysis. Mothers whose last vaccine dose
occurred before pregnancy were excluded from the analysis.
§Infants were excluded from analysis if they were born to mothers who had received their most recent dose before pregnancy, re ceived only 1 dose of an mRNA vaccine, received their most recent
vaccine dose within 14 days of delivery, received only 1 dose of a viral vector vaccine, or whose vaccination status could no t be verified or whose timing of vaccination was unknown.18Age group of infantNo. vaccinated/Total no. (%)
Interval between last vaccine dose and infant
hospitalization, days (IQR)Effectiveness of Maternal Vaccination against Infant Covid -19
Hospitalization % (95% CI) Case -patients Control patients
0-5 months 82/377 (22) 94/339 (28) 236 (185 –300) 35 (15 –51)
0-2 months 43/227 (19) 63/214 (29) 219 (152 –264) 54 (32 –68)
0 20 40 60 80 100
Vaccine Effectiveness (%)
Estimates of COVID -19 Vaccine
Effectiveness in Adults
19
20Effectiveness of 2024–2025 COVID -19 vaccination against COVID -19–associated hospitalization
among immunocompetent  adults aged ≥65 years — VISION and IVY Networks
September 2024 – May 2025
Network/2024 -2025 COVID -19 vaccination status/days
since doseCOVID -19
case -
patients
N (Col %)COVID -19
control -
patients
N (Col %)Median interval since
last dose among
vaccinated*, days (IQR) Adjusted vaccine effectiveness % (95% CI)
VISION
No 2024 -2025 COVID -19 dose  (Ref) 2,943 (85) 34,900 (74) 958 (508 -1,187) Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 515 (15) 12,043 (26) 92 (51 -132) 44 (38 -50)
2024 -2025 COVID -19 dose , 7–59 days earlier 155 (4) 3,604 (8) 34 (20 -47) 46 (36 -54)
2024 -2025 COVID -19 dose , 60–119 days earlier 207 (6) 4,509 (10) 90 (75 -104) 50 (42 -57)
2024 -2025 COVID -19 dose , 120 –179 days earlier 153 (4) 3,930 (8) 147 (133 -162) 32 (19 -43)
IVY
No 2024 -2025 COVID -19 dose  (Ref) 822 (88) 1,824 (79) Not available Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 110 (12) 499 (21) 92 (55 –130) 46 (32 -58)
2024 -2025 COVID -19 dose , 7–59 days earlier 43 (5) 124 (5) 32 (20 –46) 42 (16 -60)
2024 -2025 COVID -19 dose , 60–119 days earlier 37 (4) 205 (9) 89 (73 –103) 53 (32 -68)
2024 -2025 COVID -19 dose , 120 –179 days earlier 30 (3) 170 (7) 146 (130 –161) 40 (9 -62)
0 20 40 60 80 100
Vaccine effectiveness (%)
Updated from: Link -Gelles, et al. MMWR: https://www.cdc.gov/mmwr/volumes/74/wr/mm7406a1.htm
Vaccine effectiveness was calculated by comparing the odds of 2024 –2025 COVID -19 vaccination in case -patients and control -patien ts using the equation: (1 – adjusted odds ratio) x 100%. Odds ratios
were estimated by multivariable logistic regression. For VISION, the odds ratio was adjusted for age, sex, race and ethnicity , calendar day, and geographic region. For IVY, the odds ratio was adjusted for
age, sex, race and ethnicity, geographic region (U.S. Department of Health and Human Services Region) and calendar time (biwe ekly intervals). The “no 2024 –2025 dose” group included all eligible
persons who did not receive a 2024 –2025 COVID -19 vaccine dose, regardless of number of previous COVID -19 vaccine doses. VISION data go through May 2025; IVY data go through April 2025.
*Time since vaccination is for most recent dose, which could have been an original monovalent, bivalent, 2023 -2024, or 2024 -2025  COVID -19 vaccine.
21Effectiveness of 2024–2025 COVID -19 vaccination against COVID -19–associated critical illness
among immunocompetent  adults aged ≥65 years — VISION and IVY Networks
September 2024 – May 2025
2024 -2025 COVID -19 vaccination status/days since
doseCOVID -19
case -
patients
N (Col %)COVID -19
control -
patients
N (Col %)Median interval since
last dose among
vaccinated*, days (IQR) Adjusted vaccine effectiveness % (95% CI)
VISION
No 2024 -2025 COVID -19 dose  (Ref) 558 (85) 34,900 (74) 961 (510 -1,189) Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 97 (15) 12,043 (26) 92 (51 -132) 45 (31 -56)
2024 -2025 COVID -19 dose , 7–59 days earlier 28 (4) 3,604 (8) 34 (20 -47) 46 (21 -64)
2024 -2025 COVID -19 dose , 60–119 days earlier 44 (7) 4,509 (10) 90 (75 -104) 45 (25 -60)
2024 -2025 COVID -19 dose , 120 –179 days earlier 25 (4) 3,930 (8) 147 (133 -162) 43 (13 -62)
IVY
Acute respiratory failure
No 2024 -2025 COVID -19 dose  (Ref) 158 (88) 1,817 (78) Not available Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 21 (12) 498 (22) 96 (59 -131) 44 (11 -67)
ICU admission or death
No 2024 -2025 COVID -19 dose  (Ref) 141 (91) 1,824 (79) Not available Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 14 (9) 499 (21) 96 (60 -133) 56 (23 -76)
Invasive mechanical ventilation or death
No 2024 -2025 COVID -19 dose  (Ref) 74 (94) 1,824 (79) Not available Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 5 (6) 499 (21) 97 (60 -133) 70 (35 -89)
0 20 40 60 80 100
Vaccine effectiveness (%)
Based on methods in: Link -Gelles, et al. MMWR: https://www.cdc.gov/mmwr/volumes/74/wr/mm7406a1.htm
Vaccine effectiveness was calculated by comparing the odds of 2024 –2025 COVID -19 vaccination in case -patients and control -patien ts using the equation: (1 – adjusted odds ratio) x 100%. Odds ratios were estimated by multivariable logistic regression. For VI SION, the
odds ratio was adjusted for age, sex, race and ethnicity, calendar day, and geographic region. For IVY, the odds ratio was ad justed for age, sex, race and ethnicity, geographic region (U.S. Department of Health and Human Services Region) and calendar ti me (biweekly
intervals). The “no 2024 –2025 dose” group included all eligible persons who did not receive a 2024 –2025 COVID -19 vaccine dose, r egardless of number of previous COVID -19 vaccine doses. VISION data go through May 2025; IVY data go through April 2025.
For VISION, critical illness is defined as admission to the intensive care unit or in -hospital death. For IVY, acute respiratory  failure was defined as new receipt of high -flow nasal canula, noninvasive ventilation, or invasive mechanical ventilation.
*Time since vaccination is for most recent dose, which could have been an original monovalent, bivalent, 2023 -2024, or 2024 -2025  COVID -19 vaccine.
ICU = intensive care unit
22Effectiveness of 2024–2025 COVID -19 vaccination against COVID -19–associated hospitalization
among immunocompromised  adults aged ≥65 years — VISION and IVY Networks
September 2024 – May 2025
Network/2024 -2025 COVID -19 vaccination status/days
since doseCOVID -19
case -
patients
N (Col %)COVID -19
control -
patients
N (Col %)Median interval since
last dose among
vaccinated*, days (IQR) Adjusted vaccine effectiveness % (95% CI)
VISION
No 2024 -2025 COVID -19 dose  (Ref) 719 (81) 10,035 (69) 882 (451 -1,166) Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 164 (19) 4,432 (31) 93 (53 -133) 38 (25 -48)
2024 -2025 COVID -19 dose , 7–59 days earlier 62 (7) 1,247 (9) 35 (20 -47) 25 (2 -43)
2024 -2025 COVID -19 dose , 60–119 days earlier 61 (7) 1,689 (12) 89 (75 -104) 47 (30 -60)
2024 -2025 COVID -19 dose , 120 –179 days earlier 41 (5) 1,496 (10) 147 (133 -163) 39 (14 -57)
IVY
No 2024 -2025 COVID -19 dose  (Ref) 214 (83) 670 (76) Not available Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 44 (17) 209 (24) 82 (48 -133) 36 (6 -57)
0 20 40 60 80 100
Vaccine effectiveness (%)
Updated from: Link -Gelles, et al. MMWR: https://www.cdc.gov/mmwr/volumes/74/wr/mm7406a1.htm
Vaccine effectiveness was calculated by comparing the odds of 2024 –2025 COVID -19 vaccination in case -patients and control -patien ts using the equation: (1 – adjusted odds ratio) x 100%. Odds
ratios were estimated by multivariable logistic regression. For VISION, the odds ratio was adjusted for age, sex, race and et hnicity, calendar day, and geographic region. For IVY, the odds ratio was
adjusted for age, sex, race and ethnicity, geographic region (U.S. Department of Health and Human Services Region) and calend ar time (biweekly intervals). The “no 2024 –2025 dose” group included
all eligible persons who did not receive a 2024 –2025 COVID -19 vaccine dose, regardless of number of previous COVID -19 vaccine do ses (if any) received. VISION data go through May 2025; IVY data
go through April 2025.
* Time since vaccination is for most recent dose, which could have been an original monovalent, bivalent, 2023 -2024, or 2024 -2025 COVID -19 vaccine.
23•For the respective year, compared to no in -season dose, COVID -19 vaccination provided additional protection
against:
-COVID -19-associated emergency department and urgent care* visits among children ; protection was similar across age groups.
-COVID -19-associated emergency department and urgent care visits among adults (data included in back -up).
-COVID -19-associated hospitalizations among adults aged ≥65 years with and without immunocompromising conditions .
-COVID -19-associated critical illness among adults aged ≥65 years ; protection appeared to be higher and more durable against
critical illness compared to less severe outcomes.
•VE should be interpreted as the added benefit of 2023 –2024 or 2024 –2025 COVID -19 vaccination in a population with
high levels of infection -induced immunity, vaccine -induced immunity, or both.
-Prior SARS -CoV-2 infection contributes protection against future disease, though protection wanes over time.
-An increase in SARS -CoV-2 circulation in the United States during late summer 2024, just before the 2024 –2025 COVID -19 vaccines
were approved and authorized, may have resulted in higher population -level immunity against JN.1 -lineage strains, which could
have resulted in lower measured VE than in a population with less recent infection.Conclusions: effectiveness of COVID -19 vaccines
* Due to lower baseline rates of severe disease and lower COVID -19 vaccine coverage, VE against hospitalization and critical ill ness in children could not be estimated.
24Data and analysis were provided by CDC and the
following CDC -funded network partners:
VISION Collaborators
IVY Collaborators
Overcoming Collaborators
Back -up
26
Conclusions: “TND provided
reliable inferences on COVID -19
vaccine effectiveness in health
care–seeking populations for
multiple vaccines and symptom
definitions”
Source: Andrews L et al, JAMA Network Open 2025
Evaluating the Test -Negative Design for COVID -19 Vaccine
Effectiveness Using Randomized Trial Data: A Secondary Cross -
Protocol Analysis of 5 Randomized Clinical Trials - PubMedEstimates based on RCT vs TND analysis
CCC = concordance correlation coefficient
Steps from vaccine licensure to recommendations and
post -licensure monitoring and evaluation
* Academic, private and public healthcare, non -profit partnersManufacturers
•Safety,
immunogenicity, and
efficacy
•Request to FDA for
Emergency Use
Authorization (EUA)
or Biologics Licensure
Application (BLA)FDA
•Review of evidence
for licensure
•Advised by VRBPACCDC
•Review of safety,
efficacy, disease
burden, risks,
benefits, costs
•Advised by ACIP
•Makes
recommendations for
use of vaccinations in
specific populationsCDC & others*
•Real -world evidence
•Safety monitoring
•Vaccine effectiveness
•Impact of vaccination
(effect on disease
burden)
Mix of pre -clinical and clinical data Primarily clinical data
Outcome Analysis Design Vaccine efficacy /effectiveness,  % (95% CI)
Symptomatic, RSV -
associated lower
respiratory tract
disease (LRTD)GSK trial (≥2 or 3 sx LRTD, primary endpoint)†RCT 83 (58 –94)
Pfizer trial (≥2 sx LRTI, co -primary endpoint) * RCT 67 (29 –86)
Pfizer trial (≥3 sx LRTI, co -primary endpoint) * RCT 86 (32 –99)
RSV -associated
hospitalizationIVY Network, adults ≥60 years§TND 75 (50 –87)
VISION, adults ≥60 years, immunocompetent TND 80 (71 –85)
VHA, adults ≥60 years§Cohort 82 (69 –89)
Medicare ESRD, otherwise immunocompetent, ≥65y Cohort 72 (41 -87)
VISION, immunocompromised TND 73 (48 –85)
Medicare ESRD, additional immunocompromise, ≥65y Cohort 83 (45 -95)Observational VE studies show RSV vaccines protect against severe RSV
disease, similar to results from trials, although endpoints differ
0 20 40 60 80 100
Vaccine effectiveness, % (95% CI)
† Papi  A, et. al. Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults. N Engl J Med . 2023;388:595 –608.  See slide 43 for detailed definitions.
* Walsh E, et. al. Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults. N Engl J Med . 2023;388:1465 –77.  See slide 43 for detailed definitions.
§ Includes patients with immunocompromising conditions in the displayed VE estimate.Abbreviations:  ESRD = End stage renal disease; LRTI = lower respiratory tract infection; LRTD = lower respiratory tract disease; sx = symptoms or signs;
y = years; RCT = randomized controlled trial; TND = test -negative design
Data originally presented at
June 2024 ACIP meeting.
Observational COVID -19 VE studies conducted pre -Delta (March -
April/May 2021) showed COVID -19 vaccines provided similar protection
to estimates from trials for symptomatic SARS -CoV-2 infection
Analysis Design Vaccine efficacy /effectiveness,  % (95% CI)
Pfizer, median 2 months after 2nd dose RCT 95.0 (90.3 -97.6)
Moderna, median 63 days after 2nd dose RCT 94.1 (89.3 -96.8)
ICATT Pfizer, 14 -60 days after 2nd dose TND 90 (89 -91)
ICATT Moderna, 14 -60 days after 2nd dose TND 95 (95 -96)
HEROES -RECOVER, median 69 days after 2nd dose Cohort 91 (76 -97)
ICATT = Increasing Community Access to Testing, which is a CDC -funded program to provide SARS -CoV-2 testing in retail pharmacies . ICATT uses a test -negative design.
Polack et al., NEJM, 2020: https://www.nejm.org/doi/full/10.1056/NEJMoa2034577
Baden et al., NEJM, 2020: https://www.nejm.org/doi/full/10.1056/NEJMoa2035389
Britton et al., JAMA, 2022: https://jamanetwork.com/journals/jama/fullarticle/2789294
Thompson et al., NEJM, 2021: https://www.nejm.org/doi/full/10.1056/NEJMoa2107058  0 20 40 60 80 100
Vaccine effectiveness, % (95% CI)
30COVID -19 Vaccination Coverage Among Children and Adolescents 6 Months -17
Years, by Season and Age Group, National Immunization Survey, 2023 -2025
Weekly estimates of COVID -19 vaccination coverage for vaccination among children through December 31, 2023, were calculated usin g data from the National Immunization Survey –Child COVID Module (NIS –
CCM) . The NIS –CCM was discontinued at the end of 2023 and questions regarding COVID -19 vaccination status and intent were added to t heNational Immunization Survey –Flu (NIS–Flu).
NIS–CCM and NIS –Flu are national random -digit dial cellular telephone surveys of households with children ages 6 months through 17 years; NIS –Flu is conducted during October -June. The respondent to a NIS –
Flu survey is a parent or guardian who said they were knowledgeable about the child's vaccination history. All estimates are based upon parental report of receipt of vaccination and month of that vaccination. More
information: https://www.cdc.gov/covidvaxview/weekly -dashboard/child -coverage -vaccination.html  0%25%50%75%100%
Sep Oct Nov Dec Jan Feb Mar AprCOVID -19 vaccine coverage (%)
Month6 months-4 years, 2023-2024
6 months-4 years, 2024-2025
5-17 years, 2023-2024
5-17 years, 2024-2025
31COVID -19 Vaccination Coverage Among Adults ≥18 Years, 2023 -2024 and
2024 -2025, NIS -ACM
National Immunization Survey -Adult COVID Module: Data from adults age ≥18 years are collected by telephone interview using a random -digit -dialed sample of cell telephone numbers  stratified by
state, the District of Columbia, five local jurisdictions (Bexar County TX, Chicago IL, Houston TX, New York City NY, and Phi ladelphia County PA), and Puerto Rico and the U.S. Virgin Islands. Data are
weighted to represent the non -institutionalized U.S. population and mitigate possible bias that can result from an incomplete sa mple frame (exclusion of households with no phone service or only
landline telephones) or non -response. All responses are self -reported. For more information about the survey, see https://www.cd c.gov/nis/about/index.html.0%25%50%75%100%COVID -19 Vaccination Coverage (%)
Week2023-2024 COVID-19 Vaccination Coverage 2024-2025 COVID-19 Vaccination Coverage
Medicare fee -for-service beneficiaries aged ≥65 years were more likely to receive a
2024 -2025 COVID -19 vaccine dose if they had an underlying medical condition
Fee-for-Service:  enrolled in Medicare Parts A/B (and not Part C) for 365 days prior to reporting period. Estimates are based on  data released by Medicare claims data through January 2025; data may be incomplete
after December 7, 2024, due to 6 -week reporting lag. Data on uptake by season, race, and ethnicity can be accessed at: https://www.cdc.gov/covidvaxview/weekly -dashboard/adults -65yrs -older -vaccination.html .
Data on uptake by underlying medical condition from internal, unpublished analyses.32%
29%
28%
24%
0%25%50%75%100%
08/25/24 -
09/07/2409/08/24 -
09/21/2409/22/24 -
10/05/2410/06/24 -
10/19/2410/20/24 -
11/02/2411/03/24 -
11/16/2411/17/24 -
11/30/2412/01/24 -
12/14/2412/15/24 -
12/28/2412/29/24 -
01/11/2501/12/25 -
01/25/25% with ≥1 2024 -2025 COVID -19 vaccine dose
Two -week periodWeekly cumulative COVID -19 vaccination coverage, by underlying medical condition status,
Medicare fee -for-service beneficiaries aged ≥65 years, August 2024 -January 2025
Any immunocompromising condition
Any underling medical condition
Overall
No underlying medical condition
Cumulative rates of COVID -19–associated hospitalizations for the
2024 –2025 season are lower compared to 2023 -2024 season.
33020406080100120
Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May JunHospitalizations per 100,000 population
Hospitalization monthCumulative Rates of COVID -19-Associated Hospitalizations among children and adolescents aged ≤17 years,
by Surveillance Season* — COVID -NET, July 2023 –May 2025
≤4 years, 2023 –2024 5–17 years, 2023 –2024
≤4 years, 2024 –2025 5–17 years, 2024 –2025
* Seasons are defined as July through June. The 2024 –2025 season shows data from July 2024 –April 2025 and is ongoing.
Data source: https://www.cdc.gov/resp -net/dashboard/
Note that rates are not adjusted for testing or limited to admissions where the respiratory infection is the likely primary r eason for admission.
Accounting for correlated vaccination behaviors
•Pivotal assumption (when estimating VE against ARI causing pathogens):  risk of alternative causes
of ARI (e.g., influenza infection) is independent  of exposure status (i.e., COVID -19 vaccination)
-If violated, VE estimates may be biased
Doll MK et al. 2022 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9129127/  34•Three key considerations
-When is this assumption violated?
• When controls are positive for other vaccine preventable
illness (e.g., influenza) → due to the correlation between
vaccination behaviors, influenza infection is not
independent of exposure (COVID -19 vaccination)
-How might it impact VE estimates?
• Over representation of unvaccinated controls and
underestimation of COVID -19 VE
• Magnitude of bias depends on
– Proportion of controls positive for alternative
vaccine preventable ARI
– Vaccination coverage
– True VE
-What can be done to mitigate?
• Design: Exclude influenza positive controls
• Analysis:  Adjust for influenza vaccinationVaccination
Motivation
(Unmeasured) Influenza
Vaccination
COVID -19
VaccinationInfluenza
Infection
SARS -CoV -2
Infection
SARS -CoV -2 + SARS -CoV -2 -
Vaccinated a b
Unvaccinated c dOR = a ÷ c / b ÷ d
VE = (1 - OR) x 100%
VE = vaccine effectiveness | ARI = acute respiratory infection
Accounting for correlated vaccination behaviors
•COVID -19 VE estimates are robust
-Little variation in VE estimates,
regardless of accounting for
correlated vaccination behaviors
CDC Unpublished Data; Payne AB et al. 2023 https://pmc.ncbi.nlm.nih.gov/articles/PMC11823735/  35Vaccination Status Model TotalAdjusted VE*,
% (95% CI)
No 2023 -2024 dose
A 33,935 Ref
B 33,935 Ref
C 20,355 Ref
D 22,989 Ref
E 30,810 Ref
2023 -2024 dose, 7 -179 days
A 9,182 46 (41 -50)
B 9,182 49 (44 -54)
C 6,179 49 (44 -53)
D 6,963 47 (43 -52)
E 8,314 47 (43 -52)
2023 -2024 dose, 7 -59 days
A 3,848 56 (50 -61)
B 3,848 58 (52 -63)
C 2,498 58 (52 -63)
D 2,785 57 (51 -62)
E 3,535 57 (51 -62)
2023 -2024 dose, 60 -119 days
A 4,375 38 (30 -45)
B 4,375 41 (34 -48)
C 3,007 41 (34 -48)
D 3,442 39 (32 -46)
E 3,897 39 (32 -46)
2023 -2024 dose, 120 -179 days
A 959 28 (5 -45)
B 959 32 (11 -48)
C 674 34 (13 -50)
D 736 31 (9 -47)
E 882 29 (8 -46)
0 50 100
Adjusted VE*Model Description
A Ignore potential correlation
B Control for influenza and RSV vaccination status in model
C Limit to controls confirmed influenza - and RSV -negative
D Limit controls to tested for SARS -CoV -2, influenza, and RSV
E Limit to controls presumed influenza - and RSV -negative
VE = Vaccine Effectiveness
*VE against COVID -19-associated hospitalization among adults aged ≥60 years was calculated as
(1-odds ratio) x 100%, estimated using a test -negative case -control design, adjusting for age, sex,
race and ethnicity, VISION site ID, and calendar time (days since July 1, 2023).  The reference group
for all models was no 23/24 vaccine recipe regardless of prior vaccination history.
Absolute VE of COVID -19 original  monovalent and bivalent doses received prior to  or during
pregnancy against COVID -19–associated emergency department/urgent care encounters among
immuno competent  pregnant women aged 18 -45 years  — VISION
June 2022 – August 2023
Vaccine effectiveness was calculated by comparing the odds of COVID -19 vaccination in case -patients and control -patients using t he equation: (1 – adjusted odds ratio) x 100%. Odds ratios were estimated by
multivariable logistic regression. The odds ratio was adjusted for a ge, ethnicity, race, underlying medical conditions, gestational age at encounter, site, Medicaid status, day of encounter, site  facility
urbanicity.
Pregnant women were classified as (1) unvaccinated (no COVID -19 vaccine doses) or (2) vaccinated with the last COVID -19 vaccine dose ≥7 days before the index date (including the original
monovalent and/or bivalent vaccines). The index date was defined as (1) the collection date of a respiratory specimen associa ted with the most recent positive or negative SARS -CoV-2 test result
before the ED/UC encounter or (2) the encounter date, if testing occurred only after the encounter. COVID -19 vaccination dates a nd vaccine types were identified by electronic medical records.
Original monovalent COVID -19 vaccines (11 December 2020 –31 August 2022) include Moderna, Pfizer -BioNTech, and Janssen (Johnson &  Johnson), and bivalent COVID -19 vaccines include Moderna
and Pfizer -BioNTech. Bivalent vaccines (1 September 2022 –10 September 2023) contain components from the SARS -CoV-2 ancestral and  Omicron BA.4/BA.5 strains.
Ciesla et al., OFID 2024, https://academic.oup.com/ofid/article/11/9/ofae481/7743292  36Vaccine Dosage PatternTotal
testsSARS -CoV-2-
test-positive,
N (%)Median interval
since last dose,
days (IQR)Adjusted VE
(95% CI)
Absolute VE
Unvaccinated (ref) 2991 403 (13) -- Ref
Most recent monovalent or bivalent dose received:
≥6 months before pregnancy 3014 365 (12) 483 (393,579) 6 (-11, 21)
<6 months before pregnancy 1203 143 (12) 267 (204, 325) 28 (11, 42)
During pregnancy 469 35 (7) 91 (45, 158) 52 (29, 67)
-20 0 20 40 60 80 100
Vaccine Effectiveness (%)
37Context for interpreting COVID -19 VE across age groups: high infection -
induced seroprevalence in children and adults
* Data on persons aged 0 -17 years from nationwide commercial laboratory testing of residual serum specimens from ~27,000 childre n and adolescents originally submitted for routine screening or clinical management,
https://covid.cdc.gov/covid -data -tracker/#pediatric -seroprevalence
** Data on persons aged ≥16 years from a longitudinal, national cohort of ~35,000 blood donors, https://covid.cdc.gov/covid -data -tracker/#nationwide -blood -donor -seroprevalence -2022 89%
92%
87%
76%16-29 years
30-49 years
50-64 years
≥65 years
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Percent with infection -induced immunityPercent of persons with infection -induced immunity, based on anti -nucleocapsid results from blood donors,
adolescents and adults , October – December 2023**
VE findings should be interpreted as the added benefit provided by COVID -19 vaccination in a
population with a high prevalence infection -induced immunity.91%
93%0-11 years
12-17 yearsPercent of persons with infection -induced immunity, based on anti -nucleocapsid results from residual specimens from commercial l aboratories,
children and adolescents , November – December 2022*Age at blood draw
38Age group/2023 -2024 COVID -19 vaccination
status/days since doseTotal
encountersSARS -CoV -2-
test -positive,
N (%)Median interval since
last dose among
vaccinated, days (IQR) Adjusted VE (95% CI)
≥18 years
No 2023 -2024 COVID -19 dose (ref) 279,733 31,167 (11) 756 (543 -920) ref
2023 -2024 COVID -19 dose , 7-299 days earlier 65,906 5,929 (9) 117 (61 -189) 24 (21 to 26)
2023 -2024 COVID -19 dose , 7-59 days earlier 16,082 1,228 (8) 34 (21 -47) 49 (45 to 52)
2023 -2024 COVID -19 dose , 60-119 days earlier 17,653 1,521 (9) 88 (73 -103) 26 (22 to 30)
2023 -2024 COVID -19 dose , 120 -179 days earlier 13,815 875 (6) 147 (133 -163) 18 (12 to 24)
2023 -2024 COVID -19 dose , 180-299 days earlier 18,356 2,305 (13) 231 (204 -261) -7 (-13 to -2)
18-64 years
No 2023 -2024 COVID -19 dose (ref) 200,443 21,053 (10) 789 (624 -934) ref
2023 -2024 COVID -19 dose , 7-299 days earlier 23,655 1,893 (8) 116 (59 -187) 22 (18 to 26)
2023 -2024 COVID -19 dose , 7-59 days earlier 5,952 360 (6) 34 (20 -47) 55 (49 to 59)
2023 -2024 COVID -19 dose , 60-119 days earlier 6,285 436 (7) 88 (74 -104) 29 (22 to 36)
2023 -2024 COVID -19 dose , 120 -179 days earlier 4,971 256 (5) 147 (133 -163) 22 (11 to 31)
2023 -2024 COVID -19 dose , 180-299 days earlier 6,447 841 (13) 230 (203 -260) -24 ( -34 to -14)
≥65 years
No 2023 -2024 COVID -19 dose (ref) 79,290 10,114 (13) 669 (436 -868) ref
2023 -2024 COVID -19 dose , 7-299 days earlier 42,251 4,036 (10) 117 (62 -190) 25 (22 to 28)
2023 -2024 COVID -19 dose , 7-59 days earlier 10,130 868 (9) 34 (21 -47) 46 (41 to 50)
2023 -2024 COVID -19 dose , 60-119 days earlier 11,368 1,085 (10) 88 (73 -103) 25 (20 to 30)
2023 -2024 COVID -19 dose , 120 -179 days earlier 8,844 619 (7) 148 (133 -163) 19 (11 to 26)
2023 -2024 COVID -19 dose , 180-299 days earlier 11,909 1,464 (12) 232 (204 -262) 2 (-5 to 8)VISION: VE of 2023 -2024 COVID -19 vaccine against COVID -19-associated emergency
department/urgent care encounters among immunocompetent adults aged ≥18 years, by age group
September 2023 – August 2024
Link-Gelles et al., JAMA Network Open. VE was calculated as (1 − odds ratio) x 100%, estimated using a test -negative case -control design, with the odds ratio adjusted for age, sex, race and ethnicity, geographic
region, and calendar time. A VE estimate less than zero is possible due to the waning protection from COVID -19 vaccines coupled with the existing infection -induced immunity in unvaccinated participants. As
protection from vaccination wanes, and unvaccinated people accumulate protection from repeated infections, this may yield neg ative VE. -40 -20 0 20 40 60 80 100
39VISION: VE of 2023 -2024 COVID -19 vaccine against COVID -19-associated
hospitalization among immunocompetent adults aged ≥18 years, by age group
September 2023 – August 2024
Age group/2023 -2024 COVID -19 vaccination
status/days since doseTotal
encountersSARS -CoV -2-
test -positive,
N (%)Median interval since
last dose among
vaccinated, days (IQR) Adjusted VE (95% CI)
≥18 years
No 2023 -2024 COVID -19 dose (ref) 87,718 8,480 (10) 733 (507 -918) ref
2023 -2024 COVID -19 dose , 7-299 days earlier 24,213 1,900 (8) 123 (63 -193) 29 (25 to 33)
2023 -2024 COVID -19 dose , 7-59 days earlier 5,618 417 (7) 34 (21 -47) 51 (46 to 56)
2023 -2024 COVID -19 dose , 60-119 days earlier 6,231 486 (8) 88 (74 -104) 36 (30 to 42)
2023 -2024 COVID -19 dose , 120 -179 days earlier 5,275 306 (6) 149 (134 -164) 22 (12 to 31)
2023 -2024 COVID -19 dose , 180-299 days earlier 7,089 691 (10) 230 (203 -260) -4 (-14 to 5)
18-64 years
No 2023 -2024 COVID -19 dose (ref) 35,303 2,229 (6) 788 (606 -940) ref
2023 -2024 COVID -19 dose , 7-299 days earlier 4,249 234 (6) 120 (62 -188) 15 (2 to 27)
2023 -2024 COVID -19 dose , 7-59 days earlier 1,005 60 (6) 33 (21 -46) 31 (10 to 47)
2023 -2024 COVID -19 dose , 60-119 days earlier 1,113 52 (5) 89 (75 -104) 33 (11 to 50)
2023 -2024 COVID -19 dose , 120 -179 days earlier 936 33 (4) 148 (135 -164) 21 ( -12 to 45)
2023 -2024 COVID -19 dose , 180-299 days earlier 1,195 89 (7) 229 (201 -259) -31 ( -66 to -4)
≥65 years
No 2023 -2024 COVID -19 dose (ref) 52,415 6,251 (12) 698 (467 -899) ref
2023 -2024 COVID -19 dose , 7-299 days earlier 19,964 1,666 (8) 123 (63 -194) 31 (27 to 35)
2023 -2024 COVID -19 dose , 7-59 days earlier 4,613 357 (8) 34 (21 -47) 54 (49 to 59)
2023 -2024 COVID -19 dose , 60-119 days earlier 5,118 434 (8) 88 (73 -104) 36 (29 to 42)
2023 -2024 COVID -19 dose , 120 -179 days earlier 4,339 273 (6) 149 (134 -164) 21 (10 to 31)
2023 -2024 COVID -19 dose , 180-299 days earlier 5,894 602 (10) 230 (204 -261) 0 (-10 to 10)
-80 -60 -40 -20 0 20 40 60 80 100Link-Gelles et al., JAMA Network Open. VE was calculated as (1 − odds ratio) x 100%, estimated using a test -negative case -control design, with the odds ratio adjusted for age, sex, race and ethnicity, geographic
region, and calendar time. A VE estimate less than zero is possible due to the waning protection from COVID -19 vaccines coupled with the existing infection -induced immunity in unvaccinated participants. As
protection from vaccination wanes, and unvaccinated people accumulate protection from repeated infections, this may yield neg ative VE.
40Characteristics of emergency department and urgent care encounters and hospitalizations
among adults aged ≥18 years with COVID -19-like illness, by COVID -19 case status and CDC
vaccine effectiveness network — VISION and IVY Networks
September 2024 –May 2025
CharacteristicVaccine effectiveness network and setting, no. (column %)
VISION
ED/UC encounters,
all adults aged ≥18 yearsVISION
hospitalizations,
all adults aged ≥65 yearsIVY
hospitalizations,
all adults aged ≥65 years
TotalCOVID -19
case -
patientsCOVID -19
control -
patients TotalCOVID -19
case -
patientsCOVID -19
control -
patients TotalCOVID -19
case -
patientsCOVID -19
control -
patients
Total 240,976 14,621 226,355 65,751 4,341 61,410 4,392 1,190 3,202
Median age 52 [34, 71] 57 [36, 74] 52 [34, 71] 78 [71, 84] 79 [73, 86] 78 [71, 84] 75 [70, 82] 77 [71, 84] 75 [69, 81]
Age group
18-64 years 158,028 (66) 8,688 (59) 149,340 (66) -- -- -- -- -- --
≥65 years 82,948 (34) 5,933 (41) 77,015 (34) 65,751 (100) 4,341 (100) 61,410 (100) 4,392 (100) 1,190 (100) 3,202 (100)
Immunocompromised* -- -- -- 15,350 (23) 883 (20) 14,467 (24) 1,137 (26) 258 (22) 879 (28)
Updated from Link -Gelles, et al. MMWR: https://www.cdc.gov/mmwr/volumes/74/wr/mm7406a1.htm
ED/UC = emergency department/urgent care; VISION data go through May 2025; IVY data go through April 2025
* Immunocompromised status is not evaluated for ED/UC encounters due to a higher likelihood of incomplete discharge diagnosis  codes in this setting.
41Effectiveness of 2024–2025 COVID -19 vaccination against COVID -19–associated emergency
department/urgent care  encounters by age group — VISION
September 2024 – May 2025
Updated from: Link -Gelles, et al. MMWR: https://www.cdc.gov/mmwr/volumes/74/wr/mm7406a1.htm . Vaccine effectiveness was calculated by comparing the odds of 2024 –2025 COVID -19 vaccination in case -patients and control -patients using the equation: (1 – adjusted odds
ratio) x 100%. Odds ratios were estimated by multivariable logistic regression. The odds ratio was adjusted for age, sex, rac e and ethnicity, calendar day, and geographic region. The “no 2024 –2025 dose” group included all eligible persons who did not recei ve a 2024 –2025 COVID -19
vaccine dose, regardless of number of previous COVID -19 vaccine doses (if any) received.  * Time since vaccination is for most r ecent dose, which could have been an original monovalent, bivalent, 2023 -2024, or 2024 -2025 COVID -19 vaccine.Age group/2024 -2025 COVID -19 vaccination
status/days since doseCOVID -19
case -patients
N (Col %)COVID -19
control -patients
N (Col %)Median interval since
last dose among
vaccinated*, days (IQR) Adjusted vaccine effectiveness % (95% CI)
≥18 years
No 2024 -2025 COVID -19 dose  (Ref) 12,927 (88) 188,006 (83) 1,068 (742 -1,224) Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 1,694 (12) 38,349 (17) 89 (50 -129) 34 (30 -37)
2024 -2025 COVID -19 dose , 7–59 days earlier 572 (4) 11,763 (5) 34 (21 -47) 36 (30 -42)
2024 -2025 COVID -19 dose , 60–119 days earlier 695 (5) 14,685 (6) 89 (74 -104) 35 (29 -40)
2024 -2025 COVID -19 dose , 120 –179 days earlier 427 (3) 11,901 (5) 147 (133 -162) 28 (20 -35)
18-64 years
No 2024 -2025 COVID -19 dose  (Ref) 8,212 (95) 136,067 (91) 1,105 (866 -1,245) Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 476 (5) 13,273 (9) 86 (48 -127) 32 (25 -38)
2024 -2025 COVID -19 dose , 7–59 days earlier 156 (2) 4,244 (3) 33 (20 -46) 39 (29 -49)
2024 -2025 COVID -19 dose , 60–119 days earlier 199 (2) 5,155 (3) 89 (74 -104) 32 (21 -41)
2024 -2025 COVID -19 dose , 120 –179 days earlier 121 (1) 3,874 (3) 147 (132 -163) 20 (4 -34)
≥65 years
No 2024 -2025 COVID -19 dose  (Ref) 4,715 (79) 51,939 (67) 907 (448 -1,166) Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 1,218 (21) 25,076 (33) 91 (51 -131) 35 (30 -39)
2024 -2025 COVID -19 dose , 7–59 days earlier 416 (7) 7,519 (10) 34 (21 -47) 36 (29 -43)
2024 -2025 COVID -19 dose , 60–119 days earlier 496 (8) 9,530 (12) 90 (75 -105) 36 (29 -42)
2024 -2025 COVID -19 dose , 120 –179 days earlier 306 (5) 8,027 (10) 147 (133 -162) 30 (21 -39)
0 20 40 60 80 100
Vaccine effectiveness (%)
IVY: Number of COVID -19 case -patients by hospital admission week and
SARS -CoV-2 lineage
September 1, 2024 –April 27, 2025
Dates are for the start of the admission week.

43IVY: Effectiveness of 2024–2025 COVID -19 vaccine against hospitalization
among adults aged ≥18 years by SARS -CoV-2 lineage using viral whole -
genome sequencing
•Population
•Cases:  COVID -like illness (CLI) and test positive for SARS -CoV-2*;restricted to patients with sequence -
confirmed†KP.3.1.1 lineage (Nextstrain  clade 24E)  or XEC lineage (Nextstrain  clade 24F)
•Controls: CLI and test negative forSARS -CoV-2, influenza viruses, and RSV (≥60 years) byRT-PCR
•Analytic Period: September 1, 2024 –April 27, 2025
•VE§ against hospitalization was calculated separately using case -patients with sequence -confirmed SARS -
CoV-2 KP .3.1.1 and XEC lineage infections
* Case patients who were co -infected with influenza viruses or RSV were excluded.
† Identification of a SARS -CoV-2 lineage through viral whole -genome sequencing was successful for 49% of case -patients during the  analysis period.
§ Vaccine effectiveness was calculated by comparing the odds of 2024 –2025 COVID -19 vaccination in case -patients and control -patie nts using the equation: (1 – adjusted odds ratio) x 100%. Odds ratios
were estimated by multivariable logistic regression.  The odds ratio was adjusted for age, sex, race and ethnicity, geographic region (U.S. Dep artment of Health and Human Services Region) and calendar
time (biweekly intervals).
Lineage and 2024 -2025 COVID -19
vaccination statusCOVID -19 case -patients COVID -19 control -patients
Vaccine Effectiveness§% (95% CI)  N (Col %)Median interval
since last dose
among vaccinated,
days (IQR) N (Col %)Median interval
since last dose
among vaccinated,
days (IQR)
KP.3.1.1
No 2024 -2025 COVID -19 dose (Ref) 309 (91) Not available 5,202 (84) Not available Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 29 (9) 56 (33 –75) 1,027 (16) 94 (57 –133) 45 (19 –64)
XEC
No 2024 -2025 COVID -19 dose (Ref) 173 (84) Not available 5,202 (84) Not available Ref
Received 2024 -2025 COVID -19 dose 7–179 days earlier 32 (16) 87 (52 –112) 1,027 (16) 94 (57 –133) 34 (2 –57)
* These results include both immunocompetent and immunocompromised persons.
† KP.3.1.1 lineage was defined by Nextstrain  clade 24E and XEC lineage was defined by Nextstrain  clade 24F.
§ Vaccine effectiveness was calculated by comparing the odds of 2024 –2025 COVID -19 vaccination in case -patients and control -patien ts using the equation: (1 – adjusted odds ratio) x 100%. Odds ratios were
estimated by multivariable logistic regression.  The odds ratio was adjusted for age, sex, race and ethnicity, geographic region (U.S. Department of Health and Human Services Re gion) and calendar time
(biweekly intervals).-20 0 20 40 60 80 100Vaccine  Effectiveness (%)IVY: Effectiveness of 2024–2025 COVID -19 vaccine against hospitalization
among adults aged ≥18 years* by SARS -CoV-2 lineage †
September 1, 2024 – April 27, 2025
45*Data sources included Medicare Enrollment Database (EDB) and Common Medicare Environment (CME), Common Working File (CWF) an d Shared System Data (SSD) Medicare Parts A/B claims data, Minimum Data Set (MDS), and CDC/ATSDR Social
Vulnerability Index (SVI)
**Hazard ratios adjusted for age group, sex, race, long/short nursing home stay status, social vulnerability index, state, ru ral/urban classification, number of underlying medical conditions, 2022 -2023 influenza vaccination status, and bivalent
COVID -19 vaccination status.Medicare data
• Design: Retrospective cohort
• Data source:  Medicare fee -for-service claims data*
• Population:  Persons aged ≥65, recent nursing home
stay
• Censoring events:
– COVID -19-associated thromboembolic event (TE)
– Death
– Disenrollment in Medicare Parts A/B
– Enrollment in Medicare Part C
– Admission to hospice facility
– Dialysis encounter
– Receipt of a 2023 -2024 COVID -19 vaccine dose <60 days from
bivalent COVID -19 vaccine dose
– Receipt of a second 2023 -2024 COVID -19 vaccine dose <120 days
from first 2023 -2024 COVID -19 vaccine dose
– Receipt of a third 2023 -2024 COVID -19 vaccine dose
– End of study period
• VE = (1 - adjusted hazard ratio**) x 100%
where adjusted hazard ratio = 𝑟𝑎𝑡𝑒  𝑜𝑓 𝐶𝑂𝑉𝐼𝐷 −19−𝑎𝑠𝑠𝑜𝑐𝑖𝑎𝑡𝑒𝑑  𝑇𝐸𝑣𝑎𝑐𝑐𝑖𝑛𝑎𝑡𝑒𝑑
𝑟𝑎𝑡𝑒  𝑜𝑓 𝐶𝑂𝑉𝐼𝐷 −19−𝑎𝑠𝑠𝑜𝑐𝑖𝑎𝑡𝑒𝑑  𝑇𝐸𝑢𝑛𝑣𝑎𝑐𝑐𝑖𝑛𝑎𝑡𝑒𝑑
COVID -19 TEOther Censoring Event
Unvaccinated person -time
Vaccinated person -time
Start Follow -up End Study Period
46Age group/2023 -2024 COVID -19 vaccination
status/days since doseNumber of
Beneficiarie
sNumber of
OutcomesMedian Follow -up Time
Contributed to Category
(Days) Adjusted VE (95% CI)
≥65+ years
No 2023 -2024 COVID -19 dose (ref) 516,176 4,335 142 Ref
2023 -2024 COVID -19 dose , ≥ 7 days earlier 209,228 726 161 31% (25%, 36%)
2023 -2024 COVID -19 dose , 7-59 days earlier 26,646 198 53 50% (42%, 56%)
2023 -2024 COVID -19 dose , 60-119 days earlier 37,426 238 60 29% (20%, 38%)
2023 -2024 COVID -19 dose , 120 -179 days earlier 23,558 138 60 15% (0%, 28%)
2023 -2024 COVID -19 dose , ≥ 180  days earlier 121,598 152 65 0% ( -17%, 14%)
65-74 years
No 2023 -2024 COVID -19 dose (ref) 116,278 1,025 176 Ref
2023 -2024 COVID -19 dose , ≥ 7 days earlier 40,719 132 178 29% (16%, 39%)
2023 -2024 COVID -19 dose , 7-59 days earlier 5,029 34 53 47% (36%, 57%)
2023 -2024 COVID -19 dose , 60-119 days earlier 6,646 55 60 26% (11%, 39%)
2023 -2024 COVID -19 dose , 120 -179 days earlier 4,984 22 60 12% ( -9%, 29%)
2023 -2024 COVID -19 dose , ≥ 180  days earlier 24,060 21 64 -5% ( -29%, 15%)
≥75+ years
No 2023 -2024 COVID -19 dose (ref) 399,898 3,310 135 Ref
2023 -2024 COVID -19 dose , ≥ 7 days earlier 168,509 594 157 31% (25%, 37%)
2023 -2024 COVID -19 dose , 7-59 days earlier 21,617 164 53 50% (42%, 57%)
2023 -2024 COVID -19 dose , 60-119 days earlier 30,780 183 60 30% (20%, 39%)
2023 -2024 COVID -19 dose , 120 -179 days earlier 18,574 116 60 16% (1%, 29%)
2023 -2024 COVID -19 dose , ≥ 180  days earlier 97,538 131 65 1% ( -17%, 16%)VE of 2023 -2024 COVID -19 vaccine against COVID -19 related thromboembolic events among immunocompetent
Medicare fee -for-service beneficiaries residing in a nursing home, by age group and time since vaccination
September 2023 – July 2024
-40 -20 0 20 40 60 80 100
CDC, unpublished data
Models are adjusted for age group, sex, race, long/short NH stay status, social vulnerability index (SVI), state, rural/urban classification, number of UMC categories, 2022 -2023 influenza vaccination status, and bivalent COVID -19 vaccination status.
Infection -induced SARS -CoV-2 seroprevalence among U.S.
children — September 2021 – December 2022
47
Infection -induced (nucleocapsid
antibody) seroprevalence
Month and Year
Shaded ranges depict 95% confidence intervals for the estimated seroprevalence shown by the dark line in the corresponding co lor.
Source: https://covid.cdc.gov/covid -data -tracker/#pediatric -seroprevalence
Accessed: March 20, 20256-11 months
Population SARS -CoV -2 spike antibody over time by the cumulative
number of combined infections and vaccinations - U.S. blood donors
ages ≥16 years, September 2021 -December 2023
Solid lines represent mean anti -spike IgG levels; dotted lines represent model based 25th-75th% percentiles
Higher number of cumulative SARS -CoV-2 infections and COVID -19 vaccinations leads to higher antibody
levels, but with smaller incremental increases in antibodies with each exposure
Spike IgG BAU/mL
Source: https://covid.cdc.gov/covid -data -tracker/#nationwide -blood -donor -seroprevalence -2022 , CDC unpublished data 9
491. Yousaf AR, Mak J, Gwynn L, et al. COVID -19 Vaccination and Odds of Post –COVID -19 Condition Symptoms in Children Aged 5 to 17 Years. JAMA Netw Open. 2025;8(2):e2459672.
2. Mak J, Khan S, Britton A et al. Association of Messenger RNA Coronavirus Disease 2019 (COVID -19) Vaccination and Reductions i n Post COVID Conditions Following Severe Acute Respiratory Syndrome
Coronavirus 2 Infection in a US Prospective Cohort of Essential Workers, The Journal of Infectious Diseases, Volume 231, Issu e 3, 15 March 2025, Pages 665 –676COVID -19 mRNA vaccination associated with reduced occurrence
of Long COVID following COVID -19: June 2021 -September 2022
Among children aged 5 – 17 years:
Completion of the primary vaccine
series prior to infection associated
with reduced likelihood of Long
COVID symptoms1
•57% for 1 or more symptoms
•73% for 2 or more symptoms
•72% for respiratory symptomsAmong adults:
3 doses of original monovalent vaccine
prior to infection associated with
reduced likelihood of Long COVID
symptoms2
•63% for gastrointestinal symptoms
•44% for neurological symptoms
•52% for other non -specific
symptoms
•Data that explicitly quantifies vaccine effectiveness against transmission is ideal,
but it is often not feasible.
•Other data can help us understand the impact of COVID -19 vaccination on
transmission, vaccine effectiveness against infection and infectiousness
-COVID -19 vaccines provide moderate protection against infection in older children and adults.1,2,3
-COVID -19 vaccines may provide less protection against infection in young, infection -naïve
children.4
-COVID -19 vaccines moderately reduce infectiousness in individuals after they are infected with
SARS -CoV-2 (see next slides).5
•Preventing infections further reduces transmission by stopping future transmission
chains. COVID -19 vaccine impact on transmission
1 Feldstein L, et al. Effectiveness of mRNA COVID -19 Vaccines and Hybrid Immunity in Preventing SARS -CoV-2 Infection and Symptomatic COVID -19 Among Ad ults in the United States.
https://academic.oup.com/jid/article/231/4/e743/7945315
2 Feldstein L , et al. Effectiveness of Bivalent mRNA COVID -19 Vaccines in Preventing SARS -CoV-2 Infection in Children and Adolescents Aged 5 to 17 Yea rs. https://jamanetwork.com/journals/jama/fullarticle/2814536
3 Kirwan PD, et al. Protection of vaccine boosters and prior infection against mild/asymptomatic and moderate COVID -19 infection in the UK SIREN hea lthcare worker cohort: October 2023 to March 2024.
https://www.sciencedirect.com/science/article/pii/S0163445324002275?via%3Dihub
4 Feldstein L , et al. Protection From COVID -19 Vaccination and Prior SARS -CoV-2 Infection Among Children Aged 6 Months –4 Years, United States, Septemb er 2022 –April 2023
https://academic.oup.com/jpids/article/14/1/piae121/7917119
5 CDC. Respiratory Illness: Gauge of Household Transmission (RIGHT) Study, unpublished with manuscript in progress.
51COVID -19 Vaccine Effectiveness against SARS -CoV-2 (SCV2) Infectiousness
Respiratory Illness: Gauge of Household Transmission (RIGHT) Study
Prospective h ousehold transmission study of SARS -CoV-2, January 2024 –January 2025
Preliminary analysis (unpublished, manuscript in progress) from RIGHT Study shared by research teams at CDC, Vanderbilt Unive rsity Medical Center, University of Washington, and Columbia
University Irvin Medical Center.
Individuals with SARS -CoV-2 infection who had received a COVID -19
vaccination within prior 6 months had lower risk of transmitting to other
household contacts. Vaccine effectiveness at reducing transmission to others
was 45%.
Preliminary analysis (unpublished, manuscript is progress) from RIGHT Study Jan 2024 -Jan 2025 shared by research teams at CDC, V anderbilt University Medical Center, University of Washington, and
Columbia University Irvin Medical Center. *Adjusted for age of contact, COVID -19 vaccination status of contact, age of primary case, enrollment state, number of people in  the
home, enrollment timing, and clustering by household
† Vaccine effectiveness against infectionAdjusted* Risk of SARS -CoV-2 Infection in Household Contact by Primary Case Vaccination Status
†

Summary: Updates to COVID -19 Vaccine Effectiveness Advisory Committee on Immunization Practices September 19, 2025National Center for Immunization and Respiratory Diseases   2•Vaccine effectiveness methods •Estimates of COVID -19 Vaccine Effectiveness in Children •Estimates of Maternal COVID -19 Vaccine Effectiveness •Estimates of COVID -19 Vaccine Effectiveness in Adults •ConclusionsAgenda –COVID -19 vaccine effectiveness (VE) Vaccine effectiveness methods 3 Randomized clinical trials vs. real -world…


05 su covid 508

Vaccine safety signal detection and evaluation
John Su
Immunization Safety Office
Advisory Committee on Immunization Practices meeting
September 19, 2025

Outline
•Definitions
•Approach to signal detection and evaluation
•Example
-Previous statistical signals for ischemic stroke in the Vaccine Safety Datalink (VSD)
Definition:  adverse event following immunization (AEFI)
•Any untoward medical occurrence which follows immunization and which
does not necessarily have a causal relationship with the usage of the
vaccine. The adverse event may be any unfavorable or unintended sign,
abnormal laboratory finding, symptom, or disease.
Notes: “Immunization” as used in these definitions means the usage of a vaccine for the purpose of immunizing individuals. “Usage” i ncludes all processes that occur after a vaccine
product has left the manufacturing/packaging site, i.e. handling, prescribing and administration of the vaccine.
Source: Council for International Organizations of Medical Sciences. Definition and application of terms for vaccine pharmacovigilance: report of CIOMS/WHO Working Group on Vaccine
Pharmacovigilance. Geneva: CIOMS, 2012.
Definition:  signal
•Information that arises from one or multiple sources (including
observations and experiments) which suggests a new potentially causal
association, or a new aspect of a known association, between an
intervention and an event or set of related events, either adverse or
beneficial, that is judged to be of sufficient likelihood to justify
verificatory action.
Source: Council for International Organizations of Medical Sciences. Definition and application of terms for vaccine pharmacovigilance: report of CIOMS/WHO Working Group on Vaccine
Pharmacovigilance. Geneva: CIOMS, 2012
Vaccine safety signal pathway
*Adapted from: Practical Aspects of Signal Detection in Pharmacovigilance: Report of CIOMS Working Group VIII –CIOMS . (2010)Signal detection
(and assessment )
Signal Verified Signal Ruled OutHypothesis testing study for adverse event
risk after vaccine
Evaluate biologic mechanisms and prevention strategiesCommunication and education,
regulatory or public health action,
possible further studies
CDC’s Immunization Safety Office Monitors Vaccine Safety
Through Strong, Complementary Systems
VAERS VSD CISA Project V-safe
Systems work together to rapidly detect and assess potential
safety concerns to help inform public health actions 1990 1990 2001 2020

Evaluation following previous statistical signals for
ischemic stroke in the Vaccine Safety Datalink (VSD)
VSD •13 integrated healthcare organizations, covering >15.5
million people per year
•Active monitoring using electronic medical records (EMR)
and chart reviews
•Rapid monitoring for pre -specified events as well as
monitoring for unexpected events
•Can detect and assess safety signals
•Develops innovative methods for monitoring safetyVaccine Safety Datalink (VSD)
Collaborative Model for High -Quality Vaccine Safety Data

•Links vaccination data to health outcomes Vaccine Safety Datalink (VSD)
Vaccination recordsHealth care visits
•Hospital
•Emergency dept.
•ClinicPatient characteristics
Linked by study IDs
Data are linked and kept at each site, not at CDC
•Weekly sequential monitoring as data accrue
•Monitors a limited set of prespecified adverse events of special interest
-Potential cases identified using ICD -10 codes for healthcare encounters
•Designed to detect statistical signals
-A statistical signal is a finding from an analysis where a calculated value (i.e., the
test statistic) exceeds a specified statistical threshold
-A statistical signal does not necessarily represent a vaccine safety problem and requires further assessment before conclusions can be drawn.
•Since 2020, VSD has utilized a vaccinated concurrent comparator methodVaccine Safety Datalink (VSD)
Rapid Cycle Analysis (RCA) surveillance
Vaccinated Concurrent Comparator Method
COVID -19 vaccinated
Oct 30th
COVID -19vaccinated
Sept  20th Nov 3rd
1 21
43 63On each calendar day that an outcome
occurs in a vaccinee (e.g., Nov 3rd), we
compare vaccinees in their risk interval (1 -
21 days) with similar vaccinees in their
comparison interval (e.g., 43 -63 days).
‘Similar’ means that people were in the
same age group, sex, race/ethnicity, and
VSD site.
Inherently adjusts for calendar time.Risk interval 1 -21 days post -vaccination
Comparison interval 43 -63 days post -vaccination
Ref: Klein N, et al. Kaiser Permanente Northern California –
https://jamanetwork.com/journals/jama/fullarticle/2784015Nov 3rd
Vaccine Safety Datalink (VSD)
Statistical signal detection and evaluation
•Statistical signal detection:  RCA concurrent comparator analysis
-Intended to be rapid
-Might have residual bias
•Statistical signal evaluation:  self -controlled case -series (SCCS) analysis
-Requires waiting for complete accrual of follow -up time
-Less prone to bias
Core list of adverse events of special interest monitored by U.S. federal agencies, 2020 -2023
,
https://www.sciencedirect.com/science/article/pii/S0264410X2400224X?via%3Dihub

History of VSD RCA statistical signals for ischemic
stroke following mRNA COVID -19 vaccines
mRNA vaccine formulaVSD RCA
statistical signal for
ischemic stroke
2020 -21original, primary series No
2021- 22original,  booster dose No
2022- 23b ivalent (original and BA.4/BA.5) Yes
2023- 24XBB.1.5 Yes
2024- 25KP. 2 No
VSD RCA ischemic stroke after Pfizer -BioNTech bivalent booster,
age ≥65 years, counts and adjusted rate ratios,
Oct 16, 2022– April 8, 2023
This information was previously presented to the Advisory Committee on Immunization Practices (ACIP) meeting on April 19, 202 3
RR= 1.26 (95% CI 0.99– 1.60)
Red dot represents sequential signal: p- value <0.01 (1- sided)
Initial VSD statistical signal for ischemic stroke
January 13, 2023
May 31, 2023 update
•“Other safety monitoring systems have not observed similar findings.”
•“As time has passed and more safety data have accumulated, the initial
finding has decreased, and scientists believe factors other than vaccination might have contributed to the initial finding.”
•“The current evidence does not support the existence of a safety issue.”
CDC and FDA Identify Preliminary COVID -19 Vaccine Safety Signal for Persons Aged 65 Years and Older | FDA

History of VSD RCA statistical signals for ischemic
stroke following mRNA COVID -19 vaccines
•2022- 2023 (bivalent vaccine)
-Pfizer COVID -19 vaccine, age ≥65 years
•Question about effect of same day administration with influenza vaccine
•2023- 2024 (XBB.1.5 vaccine)
-Moderna COVID -19 vaccine, age ≥65 years
-Pfizer COVID -19 vaccine, age 50 -64 years
•Additional information that was previously pending
-A follow -up VSD analysis  using self- controlled case -series ( SCCS) analysis
-FDA’s 2023- 2024 COVID -19 vaccine safety surveillance using Medicare claims
database results
VSD SCCS analysis of ischemic stroke after Pfizer COVID -19
vaccine with or without influenza vaccine, 2022- 2023
No statistically significant increased risks found for either separate or
same day administrationIRR (95% Confidence Interval)
21-d ay risk interval 42-d ay risk interval
A ge groupCO VID -19
vaccination
without
influenza
vaccinationSam e -day
coad ministration
o f CO VID -19 and
influenza
vaccinationsCO VID -19
vaccination
without
influenza
vaccinationSam e -day
coad ministration
o f CO VID -19 and
influenza
vaccinations
PfizerOverall 0.87 (0.58–1.29) 1.14 (0.88–1.47) 0.83 (0.58–1.19) 1.12 (0.91–1.37)
12 - 64 years 0.92 (0.45–1.90) 0.88 (0.50–1.54) 0.93 (0.51–1.70) 1.06 (0.71–1.60)
65+ years 0.85 (0.53–1.37) 1.25 (0.94–1.68) 0.79 (0.51–1.23) 1.15 (0.91–1.45)
VSD SCCS analysis of ischemic stroke after mRNA COVID -19
vaccine with or without influenza vaccine, 2023- 2024
No statistically significant increased risks found for either separate or
same day administrationIRR (95% Confidence Interval)
21-d ay risk interval 42-d ay risk interval
A ge groupCO VID -19
vaccination
without
influenza
vaccinationSam e -day
coad ministration
o f CO VID -19 and
influenza
vaccinationsCO VID -19
vaccination
without
influenza
vaccinationSam e -day
coad ministration
o f CO VID -19 and
influenza
vaccinations
PfizerOverall 1.19 (0.65- 2.17) 0.90 (0.64- 1.28) 1.12 (0.67- 1.89) 1.08 (0.79- 1.46)
12 - 64 years 0.60 (0.08- 4.64) 1.17 (0.62- 2.21) 0.89 (0.24- 3.41) 1.23 (0.69- 2.17)
65+ years 1.34 (0.71- 2.53) 0.83 (0.55- 1.26) 1.20 (0.68- 2.11) 1.06 (0.73- 1.53)
ModernaOverall 2.11 (0.81- 5.53) 1.41 (0.35- 5.76) 1.29 (0.48- 3.46) 1.13 (0.33- 3.93)
12 - 64 years 2.73 (0.51- 14.52) 0.70 (0.05- 10.67) 1.53 (0.30- 7.80) 0.39 (0.01- 10.17)
65+ years 1.94 (0.60- 6.30) 1.96 (0.43- 9.03) 1.22 (0.36- 4.16) 1.56 (0.46- 5.24)
FDA surveillance:  Safety Monitoring of Multiple Health Outcomes Following
2023– 2024 COVID -19 Vaccination among Medicare Beneficiaries Aged 65
Years and Older in the United States
•Methods:
-Medicare Fee- for-Service (FFS) claims database from September 2023 to April 2024
-Self-controlled case series design
•Results:
-Approximately 7.6 million Medicare FFS beneficiaries received a 2023 –2024 COVID -19 vaccination
-Non -hemorrhagic stroke or transient ischemic attack
•Pfizer:   IRR: 1.03 [99% CI: 0.91, 1.17]
•Moderna:  IRR: 0.96 [99% CI: 0.85, 1.10]
•Novavax:   IRR: 0.98 [99% CI: 0.19, 5.13]
•Interpretation:  “we did not find evidence for an elevation in non- hemorrhagic stroke risk
following vaccination with any of the vaccine brands”
https://www.medrxiv.org/content/10.1101/2025.01.03.25319975v1
Summary
•The Vaccine Safety Datalink (VSD) rapid cycle analysis (RCA) surveillance
monitored a list of pre -specified adverse events of special interest after
COVID -19 vaccines, including ischemic stroke
•The VSD detected statistical signals for ischemic stroke during 2022- 2023
and 2023- 2024
•Signal evaluation using self -controlled case- series analyses in the VSD and
in other data sources have not confirmed an increased risk of ischemic stroke
For more information, contact CDC
1-800- CDC- INFO (232 -4636)
TTY:  1 -888- 232- 6348    cdc.gov
Follow us on X (Twitter) @CDCgov & @CDCEnvironment
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position
of the U. S. Centers for Disease Control and Prevention.

Summary: Vaccine safety signal detection and evaluation  John Su Immunization Safety Office Advisory Committee on Immunization Practices meeting September 19, 2025  Outline •Definitions •Approach to signal detection and evaluation •Example -Previous statistical signals for ischemic stroke in the Vaccine Safety Datalink (VSD) Definition:  adverse event following immunization (AEFI) •Any untoward medical occurrence which follows immunization and which  does not necessarily have a causal relationship with…


06 el deiry kuperwasser covid 508

Wafik El-Deiry , MD, PhD, FACP
Director, Legorreta Cancer Center
Associate Dean, Oncologic SciencesWarren Alpert Medical School, BrownUniversity
September 19, 2025
Workgroup Safety Uncertainties of mRNA
COVID Vaccines
Charlotte Kuperwasser, PhD
Director, Tufts Convergence Laboratory of
Biomedical, Physical, and Engineering SciencesProfessor Developmental, Molecular & Chemical Biology, Tufts University School of Medicine

TERMS OF REFERENCE # 6, 7 & 8
1.Immune Changes
2.Biodistribution
3.Frameshifting
4.ImpuritiesSummary of Workgroup Activities for
TORs

Immune Changes
COVID vaccination, especially multiple doses, can lead to the
following immune responses:
•IgG4 class switching 1
•Production of anti -idiotype antibodies 2,3
•Low long- term IgG Fc galactosylation and sialylation levels 4
•Persistent cytokine changes5,6
1)Irrgang et al. Sci Immunol (2023)
2) Murphy et al . N Engl J Med (2022).
3)Bellucci et al. Front Immunol. 2024
4)Buhre , et al. Front Immunol (2023)
5)Alghamdi  et al. Immun Inflamm Dis ( 2025)
6)Cabău et al. Vaccines (2024)
7) Bhattacharjee et al. & Iwasaki A medRxiv (2025)
8) Noé, A. et al. Front Immunol (2023).
9)Yamamoto, M. et al. J Cut Immun and Allergy (2022)
10)Park, H et al. Science Trans Med (2025).
•Reduction in circulating memory and effector CD4 T
cells, and increases in TNFα+ CD8 T cells 7
•Risk of more persistent and/or recurring infections 8-10
Immune Summary
•The persistence, clinical significance, and potential long- term
consequences of these immune changes is uncertain.
•More research is needed to understand vaccine non- specific
effects on innate and adaptive immunity and its ability to
reprogram innate and adaptive immune cells. Covid vaccine safety issues

Pfizer -Comirnaty
High levels detected in:
-Injection site
-LiverFDA Summary Basis for
Regulatory Action (SBRA)
Used a luciferase reporter mRNA (instead of spike mRNA) in mice and rats, delivered in the same lipid
nanoparticles (LNPs). Also tested biodistribution/metabolism of Pfizer’s two novel lipids (ALC -0315 and ALC-
0159):
IM injection in mice:Biodistribution

Biodistribution
Moderna- SPIKEVAX
High levels in:
-Draining lymph nodes
-Spleen
-Eye
-Liver
•Low levels detected in many tissues including:
-Heart, lung, testis, brain
•In brain, ~2– 4% of plasma levels (so trace crossing of the blood– brain barrier).FDA Summary Basis for
Regulatory Action (SBRA)
States no biodistribution study was performed with mRNA -1273; instead, FDA reviewed a biodistribution
study of a different mRNA vaccine made with the same SM -102 LNP, considered those results supportive for
Spikevax.

Biodistribution
Vaccine
mRNA in humansSitePersistence After
Vaccination Reference(s)
Axillary lymph node Up to 30 days Krauson et al. NPJ Vaccines (2023)
Heart
(myocardium/cardiac ventricles)Up to 30 days1.Yonker et al., Circulation (2023)
2.Boros et al, Pharmacol Res Perspect
(2024)
3.Krauson et al. NPJ Vaccines (2023)
Blood ~15 days to 23 months1.Patterson et al, Hum Vaccin
Immunother (2025)
2.Ogata et al, Clin Infect Dis (2022)
3.Fertig et al, Biomedicines (2022)
4.Bhattacharjee et al. medRxiv (2025)
5.Brogna et al. Proteomics Clin Appl
(2023)
CNS
(skull/meninges/ Cerebral arteriesUp to ~17 months1.Ota et al. J Clin Neurosci (2025)
2.Luis et al Brain Behav Immun Health
(2021)
Breast milk 45 hours Hanna et al. JAMA Pediatr (2022)

Biodistribution Summary
•Neither Moderna or Pfizer biodistribution studies used
commercial product for testing.
•Neither Moderna or Pfizer biodistribution data showed confinement to site of injection. Distribution included draining
lymph nodes, liver, spleen, heart, brain, lungs, and blood. It was noted that it could cross the BBB.
•Covid vaccine mRNA has been detected in multiple tissues in humans including lymph nodes, heart, CNS, blood, and
others.
•Covid vaccine mRNA has been reported to persist for up to 706 days.Covid vaccine safety issues

Frameshifting
Off-target protein production
1) Mulroney, T. E.. Nature 625, 189- 194 (2024).
2) Boros, L. G. et al. . Pharmacol Res Perspect (2024). •Therapeutic/in vitro- transcribed (IVT) mRNAs often contain
modified nucleotides (ribonucleotides), such as N¹-
methylpseudouridine to help reduce innate immune activation
and increase stability.
•Nucleoside- modified mRNA is synthetic and not a natural
mRNA.
•This modification instructs cells to produce off -target proteins
due to ribosomal slipping 1,2.
Covid vaccine safety issues
•There is evidence that these unintended/off -target proteins
generate an immune (T cell) response in humans 1
•Immunogenic or toxic properties of the non- spike proteins is
unknown.
•The health consequences of prolonged and persistent non-
spike protein production have not been studied Frameshifting
1) Mulroney, T. E.. Nature 625, 189- 194 (2024).

Impurities
Sources during manufacturing
1. Incomplete Digestion (DNAse )
2. Separation Challenges
1.Speicher, D. J., et al .(2025).
2.McKernan, K. (2023).
3.Raoult, D. (2024).
4.Kaiser, S., et al (2025).
5.Kämmerer , et al (2024).
6.Buckhaults , P. (2023).
7.König, B. (2024).
8.Wang et al (2024). DNA impurities in vaccines have
been reported in the following:
SV40 promoter -
enhancer ‐oriUnexpected impurities
Pfizer
Moderna
Differences between Pfizer vs Moderna
Pfizer/Comirnaty Moderna/Spikevax
Vector used for generating the
DNA templateBacterial plasmid that contains
mammalian -cell expression
elements, including SV40
promoter/enhancer sequences.Bacterial plasmid
Foreign DNA material of
concernSV40 promoter/enhancer -oriFull nucleotide sequences have not
been published
DNA fragment sizes &
quantityMean ~214 bp, maximum ~3.5 kb
~ 371-1,548 ng per dose* Similar fragmented distribution,
but maximum size smaller, consistent with smaller plasmid
backbone.
~ 1,130 -6,280 ng per
dose*
Clinical trial vs marketed
productClinical trials used a clean PCR
product template. Commercial product uses plasmid. No clinical trial was conducted on
marketed product . Same product on market as clinical
trial
*FDA limit of
10 ng set for naked DNA, not DNA in presence of LNP that carries DNA into cells and their nuclei.
Covid vaccine safety issues
•Pfizer vaccine: Exceeds limits1by ~36- 153-fold and SV40
promoter/enhancer sequences detected2.
•Moderna: Exceeds limits1by ~112- 627-fold and small sizes could
enable more integration events2.
•No safety considerations or guidelines for LNP enveloped DNA
impurities have been established by regulatory agencies.
•Concerns due to known DNA integration and gene
activation/disruption by SV40 promoter/enhancer sequences.Impurities
1) Regulatory limit guidelines (WHO/FDA/ EMA)
2) Speicher, D. J. et al. Autoimmunity (2025)

•Cancers have been reported in mRNA vaccinated individuals in
temporal association to immunization including (38 case reports and
study of 96 cases of PDAC outcomes vs IgG4):
•High grade sarcoma at injection site (case report).
•Kaposi’s sarcoma (cutaneous and conjunctival reported; 2 cases).
•Non- Hodgkin’s Lymphoma (8 cases reported in one publication).
•Primary Cutaneous Lymphomas (14 cases).
•Marginal Zone B -cell Lymphoma (case report).
•Glioblastoma (2 case reports).
•Gastric and intestinal polyposis (2 case reports).
•IgG4 correlates with poor survival outcomes in PDAC (96 cases).
•Axillary Lymphangioma (case report).
•Multiple Keratoacanthomas (skin cancer; case report).
•Ph+ B -cell ALL (leukemia; case report).
•T-cell ALL (leukemia; case report).
•CMML (leukemia; case report).
•Multiple Myeloma relapse (case report).
•Cardiac Myxoma (2 case reports).COVID Vaccine Safety Issues: Impurities

COVID Vaccine Safety Issues: Impurities
Gaps in Knowledge
•Extent of DNA contamination in current
lots; plasmid biodistribution.
•Genomic integration in tissues or tumors
in vaccinated patients; mechanisms.
•Prevalence of adverse outcomes from
impurities versus extent of contamination.•Multiple vaccinations and Spike persistence.
•Cancer mechanisms.
•Variations in host susceptibilities to
adverse outcomes.
COVID- 19 vaccine safety concerns stem from unexpected
biological activities of mRNA gene therapy platforms, raising
questions about potential pathogenic mechanisms and HRP.
Proactive and modernized safety
surveillance programs including:
Blood- and tissue- based monitoring
Epidemiologic studies
AI-driven analyses using reliable,
standardized datasets
Expanded autopsy programs to clarify causality in serious outcomesPrograms that systematically evaluate COVID -19 vaccine safety
FDA approval policies calibrated to gene therapy –like risks; DNA limits
Stronger pharmaceutical accountability
CDC guidelines ensuring transparent risk disclosure, mitigation strategies, and robust informed consentCOVID Vaccine Summary & Recommendations

Summary: Wafik El-Deiry , MD, PhD, FACP Director, Legorreta Cancer Center Associate Dean, Oncologic SciencesWarren Alpert Medical School, BrownUniversity September 19, 2025 Workgroup Safety Uncertainties of mRNA  COVID Vaccines Charlotte Kuperwasser, PhD Director, Tufts Convergence Laboratory of  Biomedical, Physical, and Engineering SciencesProfessor Developmental, Molecular & Chemical Biology, Tufts University School of Medicine  TERMS OF REFERENCE # 6, 7 & 8 1.Immune Changes   2.Biodistribution…


07 carleton covid 508

Genomics of Vaccine -Induced Myocarditis
Bruce Carleton
Professor and Chair, Division of Translational Therapeutics, Department of Pediatrics,
Professor of Pediatrics, Medical Genetics, Pharmaceutical Sciences, Population and Public Health
University of British Columbia
Clinical Pharmacology Lead, MedSafe  Clinics, BC Children’s and  St Paul’s Hospitals
Senior Clinician Scientist, BC Children’s Hospital Research Institute
Vancouver, Canada
Dr.Carleton has received financial support forgenomics research from the
following government and non -profit sources:
Canadian Institutes ofHealth Research, Genome Canada, Genome British
Columbia, Genome Alberta, Génome  Québec, Ontario Genomics, Health Canada,
BCChildren’s Hospital Foundation, BCProvincial Health Services Authority ,
Michael Smith Foundation for Health Research, USCenters forDisease Control
andPrevention , and the Coalition for Epidemic Preparedness Innovations (CEPI) .
The work today was funded by a grant to the Global Vaccine Data Network (GVDN)
provided by the US Centers for Disease Control.
Heisapast consultant totheUnited Health Group , Dynacare Next Specialized
Diagnostics andNeopharm Labs regarding pharmacogenetic testing.
This work was
funded by a grant
to the Global
Vaccine Data
Network (GVDN)
Steve Black MD,  Helen Petousis -Harris PhD, Jim Buttery MD
Co-Directors

the GVDN:
A collaborative Network of  32 countries and growing
Argentina
Australia
Brazil
Canada
Chile
China
Denmark
EnglandEthiopia
Finland
France
Ghana
Hong Kong
India
IndonesiaJapan
Korea, Republic of
New Zealand
Scotland
Taiwan
USA
VAC4EUSouth Africa
 and the
Alive collaboration
countries: DRC Congo
Ethiopia, Ghana,
Kenya, Malawi,
Mali, Mozambique,
Nigeria , Rwanda
COVID -19 mRNA Vaccine -induced Myocarditis
Exome Sequencing Cohort
Clinical Elements for Brighton Collaboration Level 1 Myocarditis Cases ( N=50)
Age, [Mean (SD); range]
[Median; IQR]26.5 (13.5); 11 to 83 yr
21.5 yr; 18 to 31 yr
Biological sex, n (%) Male ( n=40, 80%), Female ( n=10, 20%)
Self-reported ancestry, nEuropean ( n=31); Australian ( n=7);
Unknown (not reported) ( n=7); Egyptian ( n=1);
Lebanese ( n=1); Admixed American ( n=1);
Indian ( n=1); South African ( n=1)
Vaccine manufacturer, n (%) Pfizer ( n=37, 74%); Moderna ( n=13, 26%)
Dose, n (%)1st does ( n=10, 20%); 2nd dose ( n=36, 72%);
3rd dose ( n=4, 8%)
Vaccination to onset of myocarditis
symptoms, [Median; IQR]*4 days; 3 to 26
*available for 30 patients only
Methods
•50 Brighton Collaboration Level 1 myocarditis cases were sequenced
•Exome -captured library preparation was sequenced with the Illumina
NovaSeq  6000 system, reaching an average depth of 100x
•Reads were aligned to the GRch38 human reference genome
•49 of 50 samples passed the quality control process
•Examine variant frequencies ≥ 50% in cases when global allele
frequency ( ClinVar ) is ≤ 15%
7 variants across four genes identified with
clear linkage to myocarditis development
No. Gene Function SNP IDMinor allele
frequency (n=49)Global allele frequency
(n=5,008)Fisher's exact
P-valueOdds ratio
(95% CI)
1 LRP8 Missense rs5174 0.398 0.144 (T) 9.58x10-10 3.92 (2.53 - 5.99)
2 VKORC1 Intron rs2884737 0.306 0.0914 (C) 2.44x10-9 4.38 (2.74 - 6.87)
3 AGTR1 3 Prime UTR rs5186 0.327 0.118 (C) 5.34x10-8 3.63 (2.29 - 5.64)
4 ACAN Missense rs3817428 0.316 0.114 (G) 9.56x10-8 3.59 (2.25 - 5.60)
5 SUMF1 Missense rs2819590 0.306 0.117 (T) 5.24x10-7 3.34 (2.09 - 5.23)
6 WDR62 Synonymous rs2301734 0.316 0.125 (A) 6.93x10-7 3.24 (2.04 - 5.05)
7 TTN Missense rs36051007 0.316 0.126 (T) 8.22x10-7 3.21 (2.02 - 5.00)
8 TTN Missense rs35833641 0.316 0.127 (G) 9.74x10-7 3.18 (2.00 - 4.96)
9 ANHX Missense rs36146434 0.316 0.129 (C) 1.40x10-6 3.12 (1.96 - 4.86)
10 ALPP Missense rs1048988 0.327 0.141 (C) 3.02x10-6 2.96 (1.87 - 4.60)
11 TTN Missense rs12463674 0.310 0.130 (G) 3.25x10-6 3.01 (1.89 - 4.68)
12 EDARADD 3 Prime UTR rs6428955 0.316 0.138 (T) 5.75x10-6 2.90 (1.82 - 4.51)
13 MCPH1 Intron rs1961222 0.330 0.150 (T) 7.24x10-6 2.80 (1.78 - 4.32)
14 MSH6 Missense rs1800935 0.306 0.135 (C) 1.12x10-5 2.82 (1.77 - 4.42)
15 CHRNA5 Missense rs16969968 0.316 0.150 (A) 4.47x10-5 2.63 (1.65 - 4.10)
16 SUGP1 Stop Gained rs11555053 0.306 0.149 (A) 8.74x10-5 2.52 (1.57 - 3.94)
17 VPS53 Missense rs11558129 0.296 0.145 (A) 0.000138 2.47 (1.54 - 3.88)
18 TTN Missense rs12464787 0.296 0.147 (A) 0.000152 2.45 (1.53 - 3.84)
An increase in the number of homozygous risk
variants shortens the time to onset of myocarditis

LRP8 (LDL Receptor Related Protein 8)
•Expressed in the heart, endothelium, vascular smooth muscle, and
platelets
•R952Q variant (rs5174) is linked to cardiovascular inflammation and
immune response, particularly in coronary artery disease (CAD) and
myocardial infarction (MI) (OR: 1.31 –1.42, P<0.05)
•Among 49 Brighton Level 1 myocarditis cases, 10 are homozygous for
the risk allele (TT) and 19 are heterozygous (CT) for rs5174.
AGTR1 (Angiotensin II Type 1 Receptor)
•Patients with AGTR1 rs5186 risk CC genotype display both increased
LDL and triglycerides
•AC and CC genotypes are associated with ≥90% left anterior
descending artery stenosis [OR: 1.94 (1.059 -3.552, P=0.032)].
•The C allele is associated with MI susceptibility [OR:1.12 (1.01 -1.25);
P=0.03] and essential arterial hypertension severity ( P=0.033).
•Among 49 Brighton Level 1 myocarditis cases, 4 are homozygous for
the risk allele (CC) and 24 are heterozygous (AC) for rs5186.
LRP8 & AGTR1 in Renin -Angiotensin System (RAS)
AGTR1
rs5186
Angiotensin II
Hypertension;
Vasoconstriction;
Cardiac hypertrophy
Ref: Curr Treat Options Oncol. 2024;25(11):1406 -1427ApoELRP8
rs5174
p38 MARK pathway
activation
Cardiovascular
inflammationApoE
VKORC1
(Vitamin K Epoxide Reductase Complex Subunit 1)
•Highly expressed in the heart
•Key element of vitamin K signaling and warfarin dosage
•The rs2884737 C allele is associated with increased sensitivity to
warfarin dose compared to the wild -type A allele
•VKORC1 haplotypes are associated with arterial vascular diseases
(e.g., stroke, coronary heart disease, and aortic dissection)
•Among 49 Brighton Level 1 myocarditis cases, 3 are homozygous for
the risk allele (CC) and 24 are heterozygous (AC) for rs2884737
VKORC1
Ref: Pharmacol  Rev. 2013;65(3):987 -1009VKORC1
risk haplotypes
Prevent vascular calcification
Prevent atherosclerosis
TTN (Titin)
•TTN variants are the most frequent cause of dilated cardiomyopathy
and account for 25% of familial and 18% of idiopathic cases
•TTN is associated with acute myocarditis, with a higher variant
prevalence in cases (6%) than in controls (1% -2.9%) ( P=0.019).
•Among 49 Brighton Level 1 myocarditis cases, 3 are homozygous for
all four variants, 2 are homozygous for three variants, and 21 are
heterozygous for all four variants.
Consequences of TTN variants
TTN variants
Ref: Nat Rev Cardiol . 2018;15(4):241 -252.
Planned Next Steps
•Before the GVDN grant was cancelled
oGoal: 275 cases per each adverse event
and 2,750  controls per vaccine
platform (a total of 5,500  controls for
both mRNA and adenoviral vector -
based platforms)
•Further analysis and verification of the exome sequencing data
•Genome -wide analysis for the full cohort of myocarditis (+/ - pericarditis and
myopericarditis) will be conducted once the target enrollment is reached
•Exome analysis of vaccine -induced immune thrombotic thrombocytopenia (VITT) will be
conducted in a subset of patients with the highest certainty of being vaccine -induced
•Genome -wide analysis for the full cohort of VITT will be conducted once the target
enrollment is reached. Adverse event Expected # Enrolled #
Myocarditis 422 207 (195 mRNA)
Pericarditis 301 47 (39 mRNA)
Myopericarditis 273 36 (32 mRNA)
VITT 235 81 (51 AVV)
GBS 154 37  (27 AVV)
Control 4,9601,967 (1,005 mRNA & 804
AVV)
A final word about vaccine genomics
•Genomics studies of drugs have revolutionized drug
therapy allowing for personalized approaches to
treatment.  More than 500 FDA -approved drugs have
genetic information annotated in their labels.
•Identifying genetic markers of risk for vaccine adverse
events would serve two purposes:
•Facilitating a better understanding of the
pathophysiology of events
•Allow for personalized vaccine schedules that
reduce the risk of AEFIs.
GVDN  |  A coordinated program of vaccine safety activities

Summary: Genomics of Vaccine -Induced Myocarditis Bruce Carleton Professor and Chair, Division of Translational Therapeutics, Department of Pediatrics,  Professor of Pediatrics, Medical Genetics, Pharmaceutical Sciences, Population and Public Health  University of British Columbia Clinical Pharmacology Lead, MedSafe  Clinics, BC Children’s and  St Paul’s Hospitals Senior Clinician Scientist, BC Children’s Hospital Research Institute  Vancouver, Canada Dr.Carleton has received financial support…