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Preliminary Analysis of Guillain-Barré Syndrome
(GBS) following RSV Vaccination among adults 65 years and older
Dr. Patricia Lloyd, ScM PhD
Health Statistician
Office of Biostatistics and Pharmacovigilance
Center for Biologics Evaluation and Research
U. S. Food & Drug Administration
MEETING OF THE ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP)
Respiratory Syncytial Virus (RSV) Vaccines, Adults
February 29, 2024
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Outline
•Study Methods
•Statistical Analysis
•Study Results
•Limitations
•Conclusion
•Appendix
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Study Methods
Study ObjectiveTo evaluate preliminary rates of Guillain- Barré Syndrome (GBS) following one dose of either
RSVPreF3+AS01 (AREXVY) or RSVPreF (ABRYSVO) vaccine and to compare the observed
rates of GBS to the historical control (expected) rates
Study Design Retrospective cohort analysis with a historical comparator group
Data SourcesCenters for Medicare & Medicaid Services (CMS) administrative claims and enrollment
information derived from CMS Medicare Shared Systems Data (SSD) (Medicare Parts A, B, and D)
Study PopulationCMS Medicare Beneficiaries ages 65 years and older, enrolled in Medicare Fee- for-Service
(FFS) (Parts A and B) and Medicare Part D on the date of the first observed RSV vaccination
Study Period•RSVPreF : May 31, 2023 – Dec 2, 2023
•RSVPreF3+AS01: May 3, 2023 – Dec 2, 2023
ExposuresOne dose of either RSVPreF or RSVPreF3+AS01 that occurred after RSV vaccine
authorization and prior to the data through date, i.e., Dec 2, 2023
Health Outcome GBS (Risk Window: 1- 42 days; Care Setting: Inpatient – primary position only)
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•The expected number of outcomes are standardized by age and sex
•The analyses are adjusted for observational delay based on estimates from
historical data
•Incidence Rate Ratios (IRRs) are calculated by dividing observed rates by expected rates; corresponding 95% confidence intervals (CIs) are provided
•Estimation of GBS positive -predictive value (PPV) -adjusted rates is based on
multiple imputed datasets
•Chart review, PPV for GBS: 71% (95% CI: 63%, 79%)*Statistical Analyses
*Arya,D.P ., et al. Surveillance for Guillain -Barré syndrome after 2015- 2016 and 2016- 2017 influenza vaccination of Medicare
beneficiaries. Vaccine, 2019. 37(43): p. 6543- 6549.
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020,00040,00060,00080,000100,000120,000140,000160,000Number of RSV Vaccinations
Calendar WeekRSVPreF RSVPreF3+AS01RSV Vaccinations by Calendar Week and Vaccine Brand
Claims delay
Data through date 02DEC2023.
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Results
Incidence Rate Ratio (IRR) and 95% Confidence Interval (CI) of GBS Following an RSV
vaccination, stratified by age group and sex
Red font indicates statistically significant elevation in GBS risk. Summary
•A total of 2,061,602 RSV vaccine doses were
observed
•RSVPreF : 682,267 doses
•RSVPreF3+AS01 : 1,379,335 doses
•GBS was observed for both vaccines post- RSV
vaccination
•RSVPreF : 13 cases
•RSVPreF3+AS01: <11 cases
•An elevated IRR was observed for GBS
following RSV vaccination
•RSVPreF : 6.9 (95% CI: 3.7, 11.9)
•RSVPreF3+AS01: 2.8 (95% CI: 1.3, 5.1)
•Also observed was elevated risk by age groups and sex, but the number of cases were small by
subgroups (<5)RSV Vaccine
ExposureAge
Group
(years)SexEligible
VaccinesObserved
EventsIncidence Rate
Ratio
(IRR)IRR
95% Confidence
Interval (CI)
RSVPreF Overall Overall 682,267 13 6.9 (3.7, 11.9)
RSVPreF 65-74 Male 141,269 <11 5.8 (1.2, 17.0)
RSVPreF 75-84 Male 121,913 <11 8.5 (2.3, 21.8)
RSVPreF 85+ Male 28,091 <11 13.3 (0.3, 74.2)
RSVPreF 65-74 Female 191,409 <11 4.9 (0.6, 17.8)
RSVPreF 75-84 Female 154,152 <11 8.5 (1.8, 24.7)
RSVPreF 85+ Female 45,433 <11 - --
RSVPreF3+AS01 Overall Overall 1,379,335 <11 2.8 (1.3, 5.1)
RSVPreF3+AS01 65-74 Male 287,780 <11 2.0 (0.2, 7.2)
RSVPreF3+AS01 75-84 Male 246,852 <11 3.3 (0.7, 9.6)
RSVPreF3+AS01 85+ Male 55,292 <11 - --
RSVPreF3+AS01 65-74 Female 394,413 <11 3.8 (0.8, 11.0)
RSVPreF3+AS01 75-84 Female 310,546 <11 2.9 (0.4, 10.6)
RSVPreF3+AS01 85+ Female 84,452 <11 - --
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Results – PPV-adjusted Analyses
Adjusted IRR and 95% CI of GBS Following an RSV vaccination
Red font indicates statistically significant elevation in GBS risk.
*Adjusted estimate based on multiple imputation.**Accounts for claims delay and 1- 42 day risk window for GBS. The GBS rate per 1 million doses assuming a 1- 21 risk window:
RSVPreF 12.5 (95% CI 3.4, 21.7); RSVPreF3+AS01, 5.0 (95% CI 0.8, 9.2).Summary
•An elevated IRR was observed for GBS following
RSVPreF vaccination
•6.9 (95% CI: 1.9, 12.0)
•A non- statistically significant elevated IRR was
observed for GBS following RSVPreF3+AS01 vaccination
•2.8 (95% CI: 0.5, 5.0)RSV Vaccine ExposureEligible
Vaccines IRRIRR*
95% Confidence
Interval (CI)GBS Rate**
per 1 million
doses95% CI**
RSVPreF 682,267 6.9 (1.9, 12.0) 25.1 (6.7, 43.4)
RSVPreF3+AS01 1,379,335 2.8 (0.5, 5.0) 10.0 (1.7, 18.3)
•Adjusted GBS rates per 1 million doses:
•RSVPreF : 25.1 ( 95% CI: 6.7, 43.4)
•RSVPreF3+AS01: 10.0 ( 95% CI: 1.7, 18.3)
•Multiple imputation was not successful in estimating IRR for age and sex subgroups due to the small
number of cases
•Medical charts for observed cases have been
requested and will be reviewed
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•The observed vs. expected analysis utilizes aggregate historical rates rather
than individual historical persons as comparators, increasing the potential for
confounding and bias
•Health outcomes are identified by International Classification of Disease – 10th
Revision – Clinical Modification (ICD- 10-CM) diagnosis codes in administrative
claims databases, hence are subject to outcome misclassification
•GBS is a rare outcome, the number of cases are small, the uncertainty is high, therefore it poses a challenge for verification of a potential signalLimitations
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•An elevated risk of GBS was observed
following both RSV vaccines
•RSVPreF (n=13 cases) and
RSVPreF3+AS01 (n<11 cases)
•Results did not remain statistically significant for RSVPreF3+AS01 when adjusting for the PPV
•Safety monitoring following RSV vaccination using a self -controlled case
series design is planned and will provide more conclusive evidence of the potential risks following RSV vaccinationConclusions
https://bestinitiative.org/wp -content/uploads/2023/12/BEST_RSV_Safety_Older_Adults_2023- 2024.pdf
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Acknowledgments
•Steven Anderson
•Richard Forshee
•Henry Zhang
•Joann Gruber
•Carla Zelaya
•Tainya Clarke
•FDA BEST Partners:
–Acumen, CMS
www.bestinitiative.org
Questions?
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