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

The COVID-19 pandemic posed significant risks to pregnant women, who experienced increased rates of severe illness, ventilation, and death compared to non-pregnant women. Initial COVID-19 vaccine trials excluded pregnant individuals, creating knowledge gaps. While two doses of the BNT162b2 vaccine showed protection against infection, their effectiveness against severe disease was unclear, prompting recommendations for a third dose. This study aimed to evaluate the effectiveness of a third BNT162b2 dose in preventing COVID-19-related hospitalizations during pregnancy across two distinct COVID-19 waves dominated by the Delta and Omicron variants in Israel. This was critical for informing public health policy and vaccination strategies for pregnant women, a particularly vulnerable population during the pandemic.

Existing literature highlighted the increased risk of severe COVID-19 outcomes in pregnant women compared to their non-pregnant counterparts. The exclusion of pregnant women from initial vaccine trials created a need for real-world data on vaccine safety and efficacy in this population. Early studies suggested that two doses of the BNT162b2 vaccine provided protection against infection, however, data on the effectiveness against severe disease were limited, leading to recommendations for booster doses. The waning of vaccine-induced immune protection over time and the emergence of new variants like Delta and Omicron further underscored the need to evaluate the effectiveness of a third dose during pregnancy.

This national, population-based, historical cohort study included pregnant women in Israel who delivered between August 1, 2021, and March 22, 2022. The study compared three groups: those who received a third dose, those who only received two doses but were eligible for a third, and unvaccinated women. Data were drawn from the Israeli Ministry of Health’s database, encompassing information on SARS-CoV-2 tests, hospitalizations, disease severity, and delivery outcomes. The study periods were divided into the Delta wave (August 1, 2021 – December 1, 2021) and the Omicron BA.1 wave (December 15, 2021 – March 22, 2022). Time-dependent Cox proportional-hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for COVID-19-related hospitalizations, with vaccine dose and effectiveness calculated as 1-HR. The study outcomes included hospitalization with a SARS-CoV-2 diagnosis; hospitalization with significant COVID-19 illness (moderate or worse); and hospitalization with severe COVID-19 illness (critical or death). Significant disease was defined as hospitalization with moderate COVID-19-related illness or worse, while severe disease was defined as a respiratory rate >30 breaths per minute, oxygen saturation <94% on room air, or need for mechanical ventilation and clinical severe organ failure. The study controlled for maternal age and parity. Ethical approval was obtained, and the study received exemption from informed consent due to anonymity.

The study included 82,689 pregnant women during the Delta wave and 33,303 during the Omicron wave. Compared to the second dose, the third dose demonstrated high effectiveness against overall SARS-CoV-2-related hospitalizations: 92% (95% CI 83–96%) during the Delta wave and 48% (95% CI 37–57%) during the Omicron wave. Effectiveness against significant disease was 92% (95% CI 26–99%) during the Omicron wave, and against severe disease was 96% (95% CI 86-99%) during the Delta wave and 94% during the Omicron wave. The time elapsed between the second and third doses showed minimal effect on hospitalization risk during the Omicron period. The second dose alone showed reduced effectiveness against all outcomes in the Omicron period, highlighting the importance of the booster. Notably, during the Delta wave, the second dose was highly effective against significant (97%) and severe (96%) disease, but this protection waned during the Omicron period.

The findings confirm the substantial added protection afforded by a third BNT162b2 mRNA COVID-19 vaccine dose during pregnancy against hospitalization for SARS-CoV-2 infection and severe disease. The reduced effectiveness of the second dose alone during the Omicron wave underscores the importance of booster doses, especially with the emergence of new variants. The high effectiveness observed in preventing severe disease is a crucial finding and could encourage vaccine uptake among pregnant women. The study's large sample size and national scope enhance its generalizability. The results align with findings in non-pregnant populations showing waning immunity after two doses and the need for boosters. The increased antibody levels observed after a third dose, both maternal and in cord blood, likely contributed to this protection.

This study provides robust evidence supporting the administration of a third BNT162b2 mRNA COVID-19 vaccine dose to pregnant women at least 5 months after the second dose. The significant increase in protection against severe COVID-19-related outcomes reinforces current vaccination guidelines and emphasizes the importance of booster shots, especially in light of emerging variants. Further research could explore the long-term effects of vaccination on both mother and child and explore the effectiveness of different vaccine types or schedules.

The observational nature of the study means causality cannot be definitively established. The study focused primarily on hospitalizations, and data on milder cases may be underrepresented due to differences in testing rates across groups. The study was conducted in Israel, and results might not be directly generalizable to populations with different demographic profiles or healthcare systems. Variations in the adherence to testing protocols could also affect the accurate representation of infection rates among the unvaccinated.