Effectiveness of a third BNT162b2 mRNA COVID-19 vaccination during pregnancy: a national observational study in Israel

Pregnant women are at increased risk of severe COVID-19 illness, mechanical ventilation, and death compared with non-pregnant women, and infection during pregnancy is associated with adverse obstetric outcomes such as preterm birth and stillbirth. Despite this elevated risk, pregnant women were excluded from initial COVID-19 vaccine trials, creating evidence gaps regarding vaccine effectiveness and safety in pregnancy. Observational data later supported safety and effectiveness of two doses of BNT162b2 mRNA vaccine in pregnancy, but waning immunity and the emergence of immune-evasive variants raised concerns about sustained protection. Israel implemented a nationwide booster campaign beginning August 2021, recommending a third BNT162b2 dose at least 5 months after the second, including for pregnant women. This study evaluates the effectiveness of the third (booster) dose versus the second dose in preventing COVID-19-related hospitalization and severe outcomes among pregnant women during two variant-dominant periods: Delta (Aug–Dec 2021) and Omicron BA.1 (Dec 2021–Mar 2022).

Prior systematic reviews and cohort studies have established that pregnancy increases risk for severe COVID-19 and adverse perinatal outcomes. Early real-world studies in pregnant populations demonstrated that two doses of BNT162b2 were effective against infection and did not increase prenatal or early neonatal morbidity; however, effectiveness against significant or severe disease was less clear. As waning immunity and new variants (notably Delta and Omicron) emerged, booster doses were recommended, including during pregnancy, despite limited pregnancy-specific evidence. Additional immunologic studies indicated that a third dose markedly increases maternal and cord-blood antibody levels and is important for neutralizing Omicron, suggesting potential for enhanced clinical protection in pregnancy.

Design: National, population-based, historical cohort study using Israel Ministry of Health (MOH) linked databases capturing all SARS-CoV-2 PCR and institutionally administered antigen tests, COVID-19 hospitalizations, disease severity, outcomes, and all births. Population: Women with documented delivery between 1 Aug 2021 and 22 Mar 2022. Exclusions included prior confirmed SARS-CoV-2 infection before follow-up and receipt of only one dose or a fourth dose. Three time-varying exposure groups were defined per study period: (1) Third dose group: eligible pregnant women who received a third (booster) BNT162b2 dose prior to or during the period; (2) Second dose group: eligible women for a booster who had received only two doses; (3) Unvaccinated group. Study periods: Delta-dominant period: 1 Aug–1 Dec 2021; Omicron BA.1-dominant period: 15 Dec 2021–22 Mar 2022. Follow-up began at period start; women contributed person-time to groups according to current vaccination status, and were followed until delivery or occurrence of an outcome. Outcomes: (a) Hospitalization with a diagnosis of SARS-CoV-2 infection (any hospitalization with positive test, including incidental); (b) Hospitalization with significant COVID-19 disease (MOH-defined moderate disease or worse; e.g., COVID-19 pneumonia warranting hospitalization); (c) Hospitalization with severe COVID-19 disease (MOH-defined severe or worse: respiratory rate >30/min, SpO2 <94% on room air, PaO2/FiO2 <300, critical disease, need for mechanical ventilation, or severe organ failure). Covariates: Maternal age and parity; additional descriptive data included multifetal delivery and testing frequency. Statistical analysis: Given time-varying vaccination status, univariate Kaplan–Meier analyses with log-rank tests and multivariable time-dependent Cox proportional hazards models were fitted separately for each period. Models compared third vs second dose (primary) and each vaccinated group vs unvaccinated (secondary), adjusting for age and parity. Vaccine effectiveness (VE) was calculated as 100×(1−HR) with 95% CIs. To conservatively handle sparse events, single-case imputations were used when total cases were ≥5, with 1000 simulations in the Omicron period. Significance threshold p≤0.05. Analyses used Python 3.7.3 for time-dependent models and IBM SPSS v24 for other analyses.

- Cohorts: 82,689 pregnant women during the Delta wave and 33,303 during the Omicron BA.1 wave were included. - Primary comparative effectiveness (third vs second dose): - Delta period: Third dose was highly effective in preventing hospitalization with SARS-CoV-2 infection vs second dose, VE 92% (95% CI 83–96%). - Omicron period: Third dose enhanced protection against significant disease vs second dose, VE 92% (95% CI 26–99%), and provided 48% (95% CI 37–57%) effectiveness against hospitalization with SARS-CoV-2 infection overall. - Second dose effectiveness waned notably: During Omicron, the second dose was not effective in protecting against the study outcomes, whereas during Delta it offered protection shortly after vaccination but reduced over time. - Severe outcomes: During Omicron, the booster effectively protected against hospitalization with significant disease (~97%) and severe disease (~94%) in pregnancy (discussion estimates), whereas the second dose showed no effectiveness against these outcomes in Omicron. - Timing between second and third doses: Stratification by 30-day intervals during Omicron suggested minimal effect of time elapsed since the second dose on hospitalization risk once booster-eligible; estimated hospitalization risks over successive 30-day intervals following eligibility were approximately 1.46%, 1.55%, and 1.78%, indicating limited gradient by interval length.

The third (booster) BNT162b2 dose given at least 5 months after the second dose provided substantial additional protection for pregnant women against COVID-19-related hospitalization and against significant and severe disease. These findings align with immunologic evidence of boosted humoral responses, including enhanced neutralization against Omicron, and with data in non-pregnant populations showing waning effectiveness after two doses. Variant context was critical: while the second dose conferred protection against severe outcomes during Delta, it did not during Omicron, reflecting immune escape and waning immunity. The booster mitigated these challenges, restoring robust protection against clinically meaningful outcomes in pregnancy. Focusing on hospitalization-based endpoints minimized biases related to differential community testing behaviors. The observed minimal influence of the interval since second dose (among booster-eligible women) on hospitalization risk suggests that receiving the booster, rather than the precise waiting time beyond eligibility, is the key determinant of protection during Omicron.

A third dose of the BNT162b2 mRNA COVID-19 vaccine administered during pregnancy, at least 5 months after the second dose, significantly improves protection against hospitalization with SARS-CoV-2 infection and markedly reduces the risk of significant and severe COVID-19 disease, including during the Omicron BA.1 wave. These results support public health recommendations to provide booster vaccination to pregnant women. Future research should evaluate durability of booster-induced protection across subsequent variants, optimal timing within gestation, maternal-fetal immunologic correlates of protection, and impacts on perinatal outcomes.

- Observational cohort design is subject to residual confounding despite adjustment (e.g., health-seeking behaviors, comorbidities not detailed). - Differential testing behavior across vaccination groups could bias infection detection; although analyses focused on hospitalization outcomes and routine testing upon admission mitigated this, not all hospitals uniformly implemented screening. - Period definitions by dominant variant may allow some overlap of circulating strains. - Sparse events for some severe outcomes required conservative imputations, potentially widening uncertainty. - Generalizability may be limited to settings with similar healthcare access, vaccination policies, and variant circulation. - Some author-affiliation details and certain sample descriptors in the provided extract were incomplete, but do not affect the main effectiveness estimates derived from national data.