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RSVpreF Vaccine Safety
Surveillance in Pregnancy from
The Vaccine Safety Datalink
Malini DeSilva, MD, MPH
ACIP meeting
September 22, 20231
Vaccine Safety Datalink (VSD), 2023
•Collaborative project between
CDC and integrated healthcare
organizations
•Monitors safety of vaccines
used in the U.S., primarily
through real -world data of
rare and serious events
following vaccination
•Includes data on ~15.5 million
individuals across all sites
annually
•~ 115,000 annual live births
•Data is organized using a
common data model with
standardized coding systems
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Vaccine Safety Datalink (VSD) data structure
•Distributed data model –each VSD site creates standardized data files
•Define cohort
•Vaccines
•Diagnoses & procedures from inpatient/outpatient/emergency
•Birth and death files
•Dynamic pregnancy episode file –validated algorithms for identifying
ongoing & completed pregnancies, updated weekly
•Pregnancy start, last menstrual period (LMP)
•Gestational age
•Pregnancy outcome (when available)
•Mom -baby linkage
•Ancillary drug or lab files available ad -hoc for specific studies
•Automated data files supplemented with chart review, as needed
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Prenatal RSVpreF
Vaccine Background
•RSVpreF (Pfizer) effective against
severe RSV -associated LRTI in infants
•RSVpreF clinical trial data on safety in
pregnant persons
•Injection site pain most common
reactogenicity event
•Imbalance in preterm births in
vaccinated group
•Most late preterm (34 –<37
weeks)
•Most occurred >30 days after
vaccination
•Most prominent in a single
country
•GSK RSV prenatal vaccine clinical trial
halted due to imbalance in preterm
birth in vaccinated5
Goal & Challenges
Prenatal RSVpreF Vaccine Surveillance
•Goal : To evaluate the safety of RSVpreF vaccine administered
during pregnancy in the VSD’s large, real -world population
•Challenges :
•Vaccine uptake
•Healthy vaccinee bias
•Uncertain recommendations for RSVpreF use & administration
•Coadministration of COVID -19, influenza, Tdap
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Pregnancy Outcomes
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1sttrimester 2ndtrimester 3rdtrimester
LMP
LMP = Last menstrual periodPregnancy
Pregnancy Outcomes
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1sttrimester 2ndtrimester 3rdtrimester
LMP 20 weeks 26 weeksNon -viablePeriviable
PretermTerm
37 weeksLive Birth
LMP = Last menstrual periodPregnancy
Pregnancy Outcomes
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1sttrimester 2ndtrimester 3rdtrimester
LMP 20 weeks 26 weeksNon -viablePeriviable
PretermTerm
37 weeksSpontaneous Abortion Stillbirth
IUFD
Live Birth
IUFD = Intrauterine Fetal DemiseLMP = Last menstrual periodPregnancy
Pregnancy Outcomes
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1sttrimester 2ndtrimester 3rdtrimester
LMP 20 weeks 26 weeksNon -viablePeriviable
PretermTerm
37 weeksSpontaneous Abortion Stillbirth
IUFD
Live Birth
IUFD = Intrauterine Fetal DemiseLMP = Last menstrual periodPregnancy
RSVpreF
32 weeks
Pregnancy Outcomes
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1sttrimester 2ndtrimester 3rdtrimester
LMP 20 weeks 26 weeksNon -viablePeriviable
PretermTerm
37 weeksSpontaneous Abortion Stillbirth
IUFD
Live Birth
IUFD = Intrauterine Fetal DemiseLMP = Last menstrual periodPregnancy
RSVpreF
32 weeks
Prenatal RSVpreF Surveillance
•Bimonthly surveillance
•Use validated algorithms applied to electronic health data in
VSD to identify pregnant persons 16 –49 years at ≥20 weeks’
gestation
•Exclude pregnancies: ending in therapeutic abortion, multiple
gestation, and with insufficient information to date pregnancy
•Exposure: RSVpreF vaccination ≥28 weeks gestation
•Match 1:1, vaccinated: unvaccinated
•VSD Site & gestational age
•Create propensity scores to account for confounding using readily
available variables (e.g., age, pregnancy start date, race, ethnicity,
medical comorbidities)
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•Acute outcomes
•Use algorithm developed for other VSD safety surveillance and
modified for pregnant population
•Diagnoses associated with outpatient, emergency department,
and hospital encounters
•Chart confirmation for selected outcomes
•Pregnancy related and birth outcomes
•Preeclampsia/eclampsia –ICD-10 codes
•Preterm birth –gestational age at birth
•Stillbirth –ICD-10 codes with chart review confirmation
13Adverse outcomes evaluated
Acute Outcomes
Outcome Risk window(s)
(days)VSD Background
rate/10,000*
Anaphylaxis 0–1 n/a
Fever 1–7 3.3
Malaise / fatigue 1–7 11.4
Skin and soft tissue or local allergic reactions 1–7 7.0
Acute disseminated encephalomyelitis 1–21, 1–42 0
Acute myocardial infarction 1–21, 1–42 0.3
Appendicitis 1–21, 1–42 0.6
Bell's Palsy 1–21, 1–42 0.8
Cerebral venous sinus thrombosis (CVST) 1–21, 1–42 0.1
Disseminated intravascular coagulation (DIC) 1–21, 1–42 0.3
Guillain -Barré syndrome 1–21, 1–42 0
Immune thrombocytopenic purpura (ITP) 1–21, 1–42 7.6
Lymphadenopathy / lymphadenitis 1–21, 1–42 4.6
14*Identified from unvaccinated pregnant persons, COVID -19 medically attended acute outcomes 1 –7 or 1 –21 day evaluation
Acute Outcomes, continued
15Outcome Risk window (d) Background
rate/10,000*
Myocarditis / pericarditis 1–21, 1–42 0
Pulmonary embolism (PE) 1–21, 1–42 0.1
Seizure 1–21, 1–42 0.8
Stevens -Johnson syndrome or toxic epidermal necrolysis 1–21, 1–42 n/a
Stroke, hemorrhagic 1–21, 1–42 0.4
Stroke, ischemic 1–21, 1–42 0.4
Thrombosis with thrombocytopenia syndrome (TTS) 1–21, 1–42 n/a
Thrombotic thrombocytopenic purpura (TTP) 1–21, 1–42 n/a
Transverse myelitis 1–21, 1–42 n/a
Trigeminal neuralgia and related disorders 1–21, 1–42 0.1
Venous thromboembolism (VTE) 1–21, 1–42 0.4
*Identified from unvaccinated pregnant persons, COVID -19 medically attended acute outcomes 1 -21 day evaluation
Pregnancy related and birth outcomes
16Outcome Risk window Pfizer phase 3
RSVpreF trial, n (%)¥
Preeclampsia and eclampsia 1-21, 1 -42 68/3682 (1.8)¥
Preterm birth (<37 w) Up to 37 weeks 126/2494 (5.1)∆
Stillbirth 1-21, 1 -42 10/3682 (0.3)¥
¥ RSVPreF Phase 3 clinical trial: Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants | NEJM
∆Preterm birth rate in high -income countries (Slide 23 Evidence to Recommendations Framework: (cdc.gov) )
Prenatal RSVpreF Surveillance Analysis
•Risk ratios with corresponding 95% CI using Poisson distribution
with robust variance using generalized estimating equation
(GEE)
•Censoring within risk windows when no longer at risk, due to
pregnancy outcome, or if an unvaccinated match is vaccinated
•Adjustments for known confounders
•If preterm births signal detected, exploration into etiology
•Sensitivity Analysis: alternative matching strategies
•Exploratory: Coadministration of Tdap and RSVpreF
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Example timeline
18Vaccines start 2 months 1stdata pull2-month data lag
10/1/2023 11/30/2023 1/22/202442-day follow -up
3/22/2024
Repeat analyses every 60 days/2 months
Our Team
HealthPartners
•Malini DeSilva
•Elyse Kharbanda
•Jacob Haapala
•Gabriela Vazquez -Benitez
•Leslie Kuckler
•Robyn Kaiser
•Jingyi Zhu
•Sunita Thapa
•Sheryl Kane
•Nicole Trower
19Weill Cornell Medicine
•Heather Lipkind
Kaiser Northwest
•Kimberly Vesco
CDC
•Eric Weintraub
•Elizabeth QuincerOther VSD sites
•Acumen
•Denver Health
•Harvard Pilgrim
•Indiana University
•Kaiser Permanente Northwest
•Kaiser Permanente Colorado
•Kaiser Permanente Southern
California
•Kaiser Permanente Northern
California
•Kaiser Permanente Washington
•Kaiser Permanente Mid -Atlantic
States
•Marshfield Clinic
•OCHIN