Document text
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Evaluation of Guillain -Barré Syndrome (GBS)
following Respiratory Syncytial Virus (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) Vaccine, Adults
October 23 -24, 2024
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Outline
•Introduction
•Presentation of End -of-Season SCCS Analysis Results and
Comparison to Early -Season Results
•Discussion
•Conclusions
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Introduction
•Three RSV vaccines were approved for use in the U.S. in adults 60 years and
older
▪RSVPreF3+AS01 (GSK – AREXVY®) – May 3, 2023
▪RSVPreF (Pfizer – ABRYSVO®) – May 31, 2023
▪mRNA -1345 (Moderna – mRESVIA®) – May 31, 2024*
•Pre-licensure clinical trials identified a small number of GBS cases in
RSVPreF3+AS01 and RSVPreF vaccines
•Reports submitted to Vaccine Adverse Events Reporting System (VAERS)
identified higher GBS rates post -RSVPreF3+AS01 and RSVPreF vaccination than
expected background rates
* The analyses described in this presentation included vaccinations through Jan 2024, which was prior to the approval of mRNA -1345 vaccine
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RSV Vaccine Post -Market Analyses
AnalysesIncludes Vaccines
Administered
ThroughData
Through
DateNumber of DosesNumber
GBS
Cases RSV PreF3+AS01 RSVPreF
Early -Season SCCS October 22, 2023 April 6, 2024 872,068 456,107 28
End-of-Season SCCS January 28, 2024 July 13, 2024 2,202,247 1,024,442 95•Post-market analyses* to assess the safety of RSV vaccines among Medicare
Fee-for-Service (FFS) beneficiaries ages 65 and older
* The analyses described in this presentation included vaccinations through Jan 2024, which was prior to the approval of mRNA -1345 vaccine.
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Self-Controlled Case Series (SCCS) Design
Days 43 -90 Days 1 -42
365 Days Prior
Study Start Date
May 2023End-of-Season
Study End Date
July 2024
RSV Vaccination (Day 0)
* The clean window is relative to the outcome date; risk and control intervals are relative to the vaccination date
Ɨ Incident GBS identified in inpatient – primary position only; ICD -10-CM DGN G61.0= Risk Interval
= Control Interval
= GBS Outcome Ɨ= Clean Window (365 days)*
GBS Outcomes
Observed Through
Apr 2024Vaccinations
through
Jan 2024
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SCCS Analysis: Study Methods
Study Design Self-Controlled Case Series (SCCS)
Data Sources
/Study
Population•Medicare Fee -for-Service (FFS) (Parts A, B and D) beneficiaries aged 65 years and older
•Enrolled on date of first observed RSV vaccination and during 1 -year prior to vaccination
•Incident GBS case during the observation period (i.e., no GBS event in the clean window)
•Vaccinated with either RSVPreF3+AS01 or RSVPreF prior to Jan 28, 2024
Study Period May 2023 – Jul 2024
GBS Outcome
Definition•Risk Interval: 1 - 42 days
•Control Interval: 43 - 90 days
•Care Setting: inpatient – primary position only; ICD -10-CM DGN G61.0
Statistical
Analyses•Incidence Rate Ratios (IRR)
•Absolute Risk: Attributable Risk (AR) per 100,000 doses and 100,000 person -years (PY)
•Adjustment for outcome -dependent observation time (Farrington), seasonality, PPV
•Chart -confirmed analysis with Farrington and seasonality adjustments
•Secondary analyses: IRR, AR stratified by same day concomitant vaccination with 2023 -2024
COVID -19, 2023 -2024 influenza, pneumococcal, and shingles vaccines
Study end date for End of Season SCCS analysis was July 13, 2024
Note: RSV vaccinations observed prior to Jan 28, 2024 were needed for 90% complete observation in 90 days post vaccination
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End-of-Season SCCS Analysis
Weekly Uptake Trends in for RSVPreF3+AS01 and RSVPreF Vaccines
020,00040,00060,00080,000100,000120,000140,000160,000
Jul-23 Aug-23 Sep-23 Oct-23 Nov-23 Dec-23 Jan-24 Feb-24 Mar-24 Apr-24 May-24 Jun-24Number of RSV Vaccinations
Calendar WeekRSVPreF3+AS01
RSVPreFEnd-of-Season
Vaccination
Cutoff Date 01/28/2024
End of 90 -day
observation
period from
cutoff dateAdditional
11 weeks
for 90%
complete
claimsEarly -Season
Vaccination
Cutoff Date 10/22/2023
Data Through Date: July 13, 2024
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SCCS Analysis: Descriptive Results
Case Counts for GBS following RSV vaccination by Vaccine Type
*n = Medicare beneficiaries that received one RSV vaccination and eligible for early - and end -of-season SCCS analysis are presen ted. Product -specific and total dose counts
may not equal due to rounding
Ɨ Cell suppressed to protect patient confidentialityCase Population Eligibility
CriteriaEarly -Season SCCS Analysis End-of-Season SCCS Analysis
RSV Vaccinations
(n = 1.3 M doses)*RSV Vaccinations
(n = 3.2 M doses)*
RSVPreF3+AS01
(n = ~872k doses)*RSVPreF
(n = ~456k doses)*RSVPreF3+AS01
(n = 2.2 M doses)*RSVPreF
(n = 1.0 M doses)*
Total GBS cases [total number of
days in study period]160 [339 days] 92 [311 days] 236 [437 days] 130 [409 days]
GBS cases during 90 -day
observation period 105 74 119 89
Incident GBS cases after applying
clean window restriction55 36 <70 <50
GBS cases qualifying for SCCS
analyses11 17 56 39
Early -Season Data Through Date: April 6, 2024
End-of-Season Data Through Date: July 13, 2024
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GBS Medical Record Review (MRR) Results
GBS MRR Overall
Total GBS Cases and Records Requested 95
Records Received and Adjudicated 75
Chart -Confirmed GBS Cases* (Level 1, Level 2, Level 3) 51
Insufficient Evidence or Not a Case* (Level 4, Level 5) 24
Records Not Returned 20
Category PPV** with 95% Confidence Interval (CI)
Overall 68.0% (56.8%, 77.5%)
Risk Interval 62.3% (48.8%, 74.1%)
Control Interval 81.8% (61.5%, 92.7%)
** PPV calculations include all GBS case records assigned a case classification based on the MRR in the denominatorCase Classification of GBS Medical Records
Positive Predictive Value (PPV) of GBS* Medical records were adjudicated per the Brighton Collaboration clinical case definition for GBS
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SCCS analyses including most adjustments are highlighted in red
Farrington -Adjusted Analysis = Outcome -Dependent Observation Time Adjustment A statistically significant elevation in GBS risk was observed with
seasonality, Farrington, PPV adjusted analysis that included chart -confirmed and non -returned cases:
RSVPreF3+AS01
2.46 (95% CI: 1.19, 5.08)
Comparison of Early vs. End of Season Results
GBS and RSVPreF3+AS01
Incidence Rate Ratio (IRR) with 95% Confidence Intervals (95% CI)
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SCCS analyses including most adjustments are highlighted in red
Farrington -Adjusted Analysis = Outcome -Dependent Observation Time Adjustment An elevated but non -statistically significant IRR was observed for GBS
with seasonality, Farrington, PPV adjusted analysis that included chart -confirmed and non -returned cases:
RSVPreF
2.02 (95% CI: 0.93, 4.40)
Comparison of Early vs. End of Season Results
GBS and RSVPreF
IRR with 95% CI
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Seasonality, Farrington Analysis, and PPV -Based Multiple Imputation – Chart Confirmed + Not Returned
Cases
Inferential Analysis Results RSVPreF3+AS01 RSVPreF
Eligible Vaccines 2,202,247 1,024,442
*Cases in the Risk Interval 24 18
*Cases in the Control Interval 11 <11
IRR (95% CI) 2.46 (1.19, 5.08) 2.02 (0.93, 4.40)
AR per 100,000 Doses (95% CI) 0.65 (0.18, 1.12) 0.90 ( -0.02, 1.81)
AR Per 100,000 PY (95% CI) 5.71 (1.61, 9.80) 7.82 ( -0.17, 15.81)
PY = Person -YearsEnd-of-Season SCCS Results: GBS and RSV Vaccination
IRR and Attributable Risk (AR)
*Cases in risk and control intervals are the average number of true cases in the multiple imputation process
Small cell sizes <11; suppressed to protect patient confidentiality
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RSVPreF3+AS01 RSVPreF
Eligible Vaccines 2,202,247 1,024,442
Total GBS Cases 56 39
Number (%) with any concomitant
vaccination20 (35.7%) 19 (48.7%)End-of-Season Descriptive Results:
Concomitant Vaccination among GBS Cases
Concomitant vaccination is defined as vaccination on the same day as RSV vaccination with at least one of
2023 -2024 COVID -19, 2023 -2024 influenza, pneumococcal, and shingles vaccines.
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Seasonality and Farrington Adjusted Analysis, All CasesSecondary End -of-Season SCCS Results:
GBS risk by vaccine type and concomitant vaccination
IRR and 95% CI
There was no evidence of difference in GBS risk among persons with and without same day concomitant
vaccination with RSV vaccines
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Seasonality and Farrington Adjusted Analysis
Inferential Analysis ResultsWith Concomitant
VaccinationWithout Concomitant
Vaccination
Eligible Vaccines 833,067 1,369,180
Cases in the Risk Interval <15 <30
Cases in the Control Interval <11 <11
IRR (95% CI) 2.19 (0.87, 5.49) 3.47 (1.61, 7.46)
AR per 100,000 Doses (95% CI) 0.85 ( -0.09, 1.79) 1.40 (0.72, 2.09)
AR Per 100,000 PY* (95% CI) 7.40 ( -0.79, 15.59) 12.27 (6.26, 18.28)
*PY = Person -YearsSecondary End -of-Season SCCS Results:
Concomitant Vaccination among GBS cases vaccinated
with RSVPreF3+AS01 – IRR and AR
Small cell sizes <11; suppressed to protect patient confidentiality
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Seasonality and Farrington Adjusted Analysis
Inferential Analysis ResultsWith Concomitant
VaccinationWithout Concomitant
Vaccination
Eligible Vaccines 420,764 603,678
Cases in the Risk Interval <15 <20
Cases in the Control Interval <11 <11
IRR (95% CI) 2.26 (0.89, 5.73) 4.48 (1.50, 13.42)
AR per 100,000 Doses (95% CI) 1.59 ( -0.18, 3.35) 2.06 (0.99, 3.12)
AR Per 100,000 PY* (95% CI) 13.85 ( -1.55, 29.25) 18.01 (8.70, 27.31)Secondary End -of-Season SCCS Results:
Concomitant Vaccination among GBS cases vaccinated
with RSVPreF – IRR and AR
*PY = Person -YearsSmall cell sizes <11; suppressed to protect patient confidentiality
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SCCS Design: Strengths and Limitations
Strengths Limitations
•SCCS study design provides robust
adjustment for potential time -
invariant confounding
•Large database facilitates more
precise evaluation of GBS
•Study findings are generalizable to
U.S. population 65 years and older
•Medical Record Review improved
classification of GBS•Potential misclassification of GBS in
administrative claims data
•The study is not intended to compare
GBS risk between the two vaccine
products
•IRR estimates may be sensitive to the
number of records returned and
adjudicated through MRR
•Potential misspecification of post -RSV
vaccination risk and control intervals for
GBS
•Potential for residual confounding
•Attributable risk based on small number
of cases may be difficult to interpret
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Discussion
•Observed vs. Expected Analysis
▪An elevated risk of GBS was observed following both RSV vaccines
▪Results were not statistically significant for RSVPreF3+AS01 when adjusting for PPV
•Early -Season SCCS
▪Statistically significant elevation in GBS risk was observed following RSVPreF vaccine
▪Results did not remain statistically significant for RSVPreF vaccine when adjusting for PPV -
based multiple imputations
•End-of-Season SCCS
▪A statistically significant elevated IRR was observed for GBS following vaccination with
RSVPreF3+AS01; GBS risk was elevated yet not statistically significant following RSVPreF
vaccination
▪Results remained the same when restricting to confirmed GBS cases through MRR
▪There was no evidence of difference in GBS risk among persons with and without same day
concomitant vaccination with RSV vaccines
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Conclusions
•Our findings suggest an increased GBS risk following RSVPreF 3+AS01 and
RSVPreF among adults aged 65 years and older
•These results are consistent with pre -licensure clinical trials and surveillance
systems such as VAERS
•End-of-season SCCS analyses results are largely chart -confirmed from MRR
and include approximately three times more vaccine doses and GBS cases
compared to the early season SCCS results
•GBS risk following vaccination with RSVPreF3+AS01 and RSVPreF is rare, with
less than 10 cases per 1 million vaccinations
•There is no difference in GBS risk among persons with and without same
day concomitant vaccination with RSV vaccines
References
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Advisory Committee Meeting. FDA Briefing Document. March 1, 2023. https://www.fda.gov/media/165625/download
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7. Farrington, C. P., Anaya -Izquierdo, K., Whitaker, H. J., Hocine , M. N., Douglas, I., & Smeeth, L. (2011). Self -Controlled Case
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https://doi.org/10.1198/jasa.2011.ap10108
8. Arya, D.P., et al. Surveillance for Guillain -Barré syndrome after 2015 -2016 and 2016 -2017 influenza vaccination of Medicare
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Acknowledgements
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U.S. Food and Drug Administration
Steven A. Anderson
Richard A. Forshee
Henry T. Zhang
Narayan Nair
Krista Fekecs
Acumen
Purva Shah
Nimesh Shah
Zhiruo Wan
Mao Hu
Meng Chen
Centers for Medicare & Medicaid ServicesJing Wang
Yue Wu
Yoganand Chillarige
Acumen’s Physician TeamJoann F. Gruber
Tainya C. Clarke