Document text
Safety of quadrivalent recombinant influenza
vaccine in pregnant women and their infants
Nicky Klein, MD, PhD
Director, Kaiser Permanente Vaccine Study Center
Kaiser Permanente Northern California
Advisory Committee on Immunization Practices Meeting
October 25, 2023
Disclosures
•Sanofi provide related research support for 'Flublok v.
Standard Dose Vaccine Effectiveness Among Kaiser Permanente Northern California Adults 18- 64 Years'
(NCT03694392).
•Sanofi provided all the recombinant influenza vaccine for this study (1.2 million doses).
•Unrelated research support from Pfizer, Merck, GSK and Seqirus.
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Background
•Since 2004, the US Advisory Committee on Immunization
Practices (ACIP) has recommended that all pregnant women receive an inactivated influenza vaccine during any trimester of pregnancy.
̶includes recombinant influenza vaccine (RIV), which has been
available since 2013
•There has been limited data regarding the safety of RIV during
pregnancy.
•We conducted a post -licensure observational study to assess the
safety of RIV4 during pregnancy.
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Study Setting:
Kaiser Permanente Northern California (KPNC)
•Integrated Healthcare Delivery System
•Annual membership of >4 million (~65% aged 18– 64 years).
•Members receive nearly all their care at KPNC facilities (259
medical clinics, 21 hospitals).
•KPNC has an electronic medical record (EMR) that captures all healthcare encounters, diagnoses, lab tests,
vaccines, and medications.
•Within KPNC, routine influenza PCR testing begins in early fall. Flu PCR tests are ordered at physician’s discretion.
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Study Objective
•Primary objective: Evaluate the safety of quadrivalent
recombinant influenza vaccine compared with
quadrivalent inactivated influenza vaccines in pregnant
women and their offspring
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Preliminary data
Study Design
•Study included all routinely influenza- vaccinated pregnant women
and their live born infants at Kaiser Permanente Northern
California (KPNC) during the 2018- 2019 and 2019- 2020 influenza
seasons.
•All vaccinated pregnant women were a subset of a separate, cluster randomized effectiveness trial which compared the relative vaccine effectiveness (rVE) of RIV4 vs. SD -IIV4 against influenza
and influenza- related outcome.
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Preliminary data
•Cluster randomized observational study of all KPNC adults vaccinated
with either RIV4 or SD -IIV4 during 2018- 2021 influenza seasons.
•KPNC aimed to administer 400,000 RIV4 doses and 400,000 SD -IIV4
doses to adults 18– 64 years during each of the 3 seasons.
•To minimize geographic and socioeconomic imbalances between facilities and achieve balance in covariates, we cluster -randomized facilities within
each of 7 service areas to receive RIV4 or SD -IIV4 on an alternating
weekly basis.
̶Randomization accounted for facility size, facilities within each service areas
̶Goal was to achieve balance in covariate distribution between those who received
RIV4 vs. SD -IIV4 (e.g., similar proportion of RIV4 vs. SD -IIV4 who were female)
7Larger Relative Vaccine Effectiveness Study
Context
Preliminary data
866 KPNC
facilities across
7 geographic
regionsRandomized within
geographic regions to
Block A or Block BBlock A
Block BWeek 1 Week 2 Week 3 Week 4
Facility 1 RIV4 SD-IIV4 RIV4 SD-IIV4
Facility 2 SD-IIV4 RIV4 SD-IIV4 RIV4
Facility 3 SD-IIV4 RIV4 SD-IIV4 RIV4
Facility 4 RIV4 SD-IIV4 RIV4 SD-IIV4
Facility 5 SD-IIV4 RIV4 SD-IIV4 RIV4
Facility 6 RIV4 SD-IIV4 RIV4 SD-IIV4Block A randomized
assigned (coin toss) to
use RIV4 for Week 1Design of RIV4 and SD-IIV4 Relative Vaccine
Effectiveness Study
•Overall RIV4 vs SD- IIV4 rVE study included ~1.6 million influenza- vaccinated
adults 18- 64 yrs
•Study ultimately only included 2 seasons (2018- 2020) due to the COVID -19 pandemic
•Current study focused on the subset of vaccinated pregnant women and their
offspring from this overall rVE study
Preliminary data
Study Outcomes
9Pregnancy •Spontaneous abortion
•Preterm labor
•Stillbirth/fetal death
•Congenital/fetal anomalies detected during pregnancy
•Eclampsia
•Placental abruption
Birth •Preterm birth
•Low birthweight
•Small for gestational age
Neonatal/Infant
(through 365 days)•Infant death
•Congenital anomalies
•Failure to thrive
Preliminary data
Statistical Analysis
Pregnancy outcomes:
•Compared the odds of a pregnancy outcome among RIV4 vaccinated
pregnant women with SD- IIV4 vaccinated pregnant women.
̶Conditional logistic regression ( conditioned on gestational age)
̶Adjusted for maternal race, ethnicity, age group, BMI, presence of any chronic
condition (asthma, CHD, COPD, diabetes), and trimester of influenza vaccination
Birth and neonatal/infant outcomes:
•Compared the odds of birth and neonatal outcomes among RIV4
vaccinated pregnant women with SD -IIV4 vaccinated pregnant women.
̶Logistic regression
̶Adjusted for infant sex, race, ethnicity, maternal age group, and maternal trimester
of influenza vaccination
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Preliminary data
Final Population: Flu Vaccinated Pregnant Women and their Infants
11Pregnant women vaccinated at KPNC
2018-2019 & 2019-2020 influenza seasons
N=54,360
RIV4 vaccinated
n=16,609SD-IIV4 vaccinated
n=37,751
Excluded*
n=1,628
RIV4 -vaccinated
Pregnant Women
n=14,981SD-IIV4-vaccinated
Pregnant Women
n=33,800
RIV4: Quadrivalent recombinant influenza vaccine ( Flublok Quadrivalent)
SD-IIV4: Quadrivalent standard- dose inactivated influenza vaccine (Fluarix Quadrivalent or Flulaval Quadrivalent)
*Excludes individuals who received ≥1 influenza vaccination in the same day and in the same season; data discrepancies such as missing sex, males identified as pregnant, date of death occurring
before date of birth, etc.; not a KPNC member at time of vaccination; vaccinated in inpatient setting; or did not have a prenatal visit during pregnancyRIV4 Infant Cohort
n=14,538SD-IIV4 Infant Cohort
n=32,856Excluded*
n= 3,951
Preliminary data
Demographics: Pregnant Women
12RIV4
N=14,981 (%)SD-IIV4
N=33,800 (%)
Maternal age* 17-24 years 1,544 (10.3) 3711 (11.0)
24-35 years 9,586 (64.0) 21,297 (63.0)
35-44 years 3,812 (25.4) 8680 (25.7)
≥45 years 39 (0.3) 112 (0.3)
Trimester of
vaccination28 days prior to conception 750 (5.0) 1,367 (4.0)
1sttrimester 5,092 (34.0) 10,787 (31.9)
2ndtrimester 4,851 (32.4) 11,470 (33.9)
3rdtrimester 4,288 (28.6) 10,176 (30.1)
Race Asian 4,620 (30.8) 9,916 (29.3)
Black 620 (4.1) 1,589 (4.7)
Multiracial 744 (5.0) 1,678 (5.0)
Native American 46 (0.3) 102 (0.3)
Pacific Islander 153 (1.0) 287 (0.3)
White 5,506 (36.8) 11,666 (34.5)
Unknown 3,292 (22.0) 8,562 (25.3)
Hispanic Hispanic 3,450 (23.0) 8,898 (26.3)
Non-Hispanic 11,531 (77.0) 24,902 (73.7)
Comorbidity † Asthma, CHD, COPD, or diabetes 2,036 (13.6) 4,779 (14.1)
*All subjects were 18 years of age at the time of immunization; †Asthma, CHD, COPD, or diabetes assessed during the 3 years p rior to vaccinationPreliminary data
13Outcome RIV4
N=14,981
n (%)SD-IIV4
N=33,800
n (%)Adjusted OR
(95% CI)*P-
value
Spontaneous abortion 470 (3.1) 1,013 (3.0) 0.95 (0.85, 1.05) 0.31
Preterm labor 546 (3.6) 1,170 (3.5) 1.06 (0.99, 1.14) 0.09
Stillbirth/fetal death 63 (0.4) 153 (0.5) 0.84 (0.68, 1.04) 0.12
Congenital/fetal anomalies
detected during pregnancy356 (2.4) 798 (2.4) 1.00 (0.91, 1.09) 0.96
Eclampsia/pre- eclampsia 1,235 (8.4) 2,793 (8.4) 1.01 (0.96, 1.06) 0.64
Placental abruption 115 (0.8) 237 (0.7) 1.12 (0.96, 1.31) 0.15
*SD-IIV4 was the reference group for all analyses. Conditional logistic regressions adjusted for maternal race, ethnicity,
maternal age group, trimester of influenza vaccine receive, chronic conditions, and BMIResults: Pregnancy Outcomes
Preliminary data
Infant Demographics
14RIV4
N=14,538 (%)SD-IIV4
N=32,856 (%)
Sex Male 7,437 (51.2) 16,940 (51.6)
Female 7,101 (48.8) 15,916 (48.4)
Race Asian 3,863 (26.6) 8,300 (25.3)
Black 496 (3.4) 1,257 (3.8)
Multiracial 949 (6.5) 1,949 (5.9)
Native American 20 (0.1) 66 (0.2)
Pacific Islander 128 (0.9) 298 (0.9)
White 4,690 (32.3) 9,880 (30.1)
Unknown 4,392 (30.2) 11,106 (33.8)
Hispanic Hispanic 3,059 (21.0) 7,857 (23.5)
Non- Hispanic 11,479 (79.0) 24,999 (76.1)
Gestational Age Preterm (<37 weeks) 1,061 (7.3) 2,450 (7.5)
Preliminary data
Results: Birth/Infant Outcomes
15*SD-IIV4 was the reference group for all analyses. Logistic regressions adjusted for infant sex, infant race, infant
ethnicity, maternal age group, and maternal trimester of influenza vaccine receiptOutcomeRIV4
N=14,538
n (%)SD-IIV4
N=32,856
n (%)Adjusted OR
(95% CI)*P-value
Birth
Preterm birth 1,061 (7.3) 2,450 (7.5) 0.98 (0.91, 1.05) 0.54
Low birth weight 852 (5.9) 1,918 (5.8) 1.00 (0.92, 1.09) 0.92
Small for gestational age 1,277 (8.8) 2,846 (8.7) 1.01 (0.94, 1.09) 0.72
Infant (up to 365 days)Infant death 27 (0.2) 59 (0.2) 1.05 (0.66, 1.65) 0.85
Congenital anomalies 6,259 (43.1) 14,018 (42.7) 1.01 (0.97, 1.05) 0.53
Major congenital anomalies 1,113 (7.7) 2,531 (7.7) N/A N/A
Minor congenital anomalies 5,698 (39.2) 12,762 (38.8) N/A N/A
Failure to thrive 150 (1.0) 372 (1.1) 0.90 (0.75, 1.09) 0.29
Preliminary data
Study Strengths
16•All pregnant women in this study were a subset of a large
modified cluster- randomized rVEstudy of RIV4 vs. SD -IIV4 (~1.6
million adults).
̶RIV4 recipients were very similar to SD -IIV4 recipients with respect to
risk factors for adverse outcomes.
̶Fewer sources of bias than in most observational studies.
Preliminary data
Study Limitations
17•There were slight imbalances in the timing of vaccination that may
have been related to provider preferences.
̶The proportion of pregnant women who received RIV4 during preconception or first
trimester was relatively higher than in the SD -IIV4 group.
̶Historically, the KPNC OB/GYN clinics have been accustomed to using SD -IIV4 in
pregnant woman.
̶It is possible that providers preferred to administer SD -IIV4 once they knew an individual
was pregnant.
•However, since demographic and covariate factors were similar
between the two groups, such slight imbalances were unlikely to have
affected the analyses.
Preliminary data
Summary
18•Within a large population of influenza- vaccinated pregnant women,
comparing RIV4 with SD -IIV4 there were no differences in pregnancy,
birth and neonatal/infant outcomes.
•No safety concerns were identified after RIV4 use in pregnancy.
•The proportion of pregnancies or live births with outcomes was lower
than published US rates from most other studies.
•This study provides reassuring safety evidence regarding the continued use of influenza vaccines in pregnant women.
Preliminary data
Acknowledgments
19Amber Hsiao
Arnold YeeBruce FiremanJohn HansenNed Lewis
Nicola KleinSonja Banga
Alexandre Selmani
Oxana TalanovaAjinkya Inamdar
*
Lynn SchultzBarbara CourssarisKimberly HarpPenny PostHeidi KablerMaria Martin
‡
Ruvim Izikson
*BioNTech -Cambridge, Massachusetts (United States)
‡Moderna -Cambridge, Massachusetts (United States)