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)

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Larger Relative Vaccine Effectiveness Study 

Context

Preliminary data
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66 KPNC 

facilities across 

7 geographic 

regions

Randomized within 

geographic regions to 

Block A or Block B

Block A

Block B

Week 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-IIV4

Block A randomized 

assigned (coin toss) to 

use RIV4 for Week 1

Design 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

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Pregnancy • 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

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Pregnant women vaccinated at KPNC

2018-2019 & 2019-2020 influenza seasons

N=54,360

RIV4 vaccinated

n=16,609

SD-IIV4 vaccinated

n=37,751

Excluded*

n=1,628

RIV4-vaccinated

Pregnant Women

n=14,981

SD-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 pregnancy

RIV4 Infant Cohort

n=14,538

SD-IIV4 Infant Cohort

n=32,856

Excluded*

n= 3,951

Preliminary data
Demographics: Pregnant Women

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RIV4

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 

vaccination

28 days prior to conception 750 (5.0) 1,367 (4.0)

1st trimester 5,092 (34.0) 10,787 (31.9)

2nd trimester 4,851 (32.4) 11,470 (33.9)

3rd trimester 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 prior to vaccination

Preliminary data
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Outcome RIV4

N=14,981 

n (%)

SD-IIV4

N=33,800 

n (%)

Adjusted OR 

(95% CI)*

Pvalue

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 pregnancy 356 (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 BMI

Results: Pregnancy Outcomes

Preliminary data
Infant Demographics

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RIV4

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

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*

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 receipt

Outcome

RIV4

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

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• All pregnant women in this study were a subset of a large 

modified cluster-randomized rVE study 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

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• 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

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• 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

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Amber Hsiao

Arnold Yee

Bruce Fireman

John Hansen

Ned Lewis

Nicola Klein

Sonja Banga

Alexandre Selmani

Oxana Talanova

Ajinkya Inamdar*

Lynn Schultz

Barbara Courssaris

Kimberly Harp

Penny Post

Heidi Kabler

Maria Martin‡

Ruvim Izikson

*

BioNTech - Cambridge, Massachusetts (United States)

‡Moderna - Cambridge, Massachusetts (United States)