Our study showed that a third dose of the BNT162b2 mRNA COVID-19 vaccine, given at least 5 months after the second vaccine dose, provides additional protection during pregnancy against hospitalizations with a diagnosis of SARS-CoV-2 infection, and against significant and severe disease.
The mRNA vaccines currently available were designed to prevent infection and disease from the wild type SARS-CoV-2 strains. Data from non-pregnant populations demonstrate that the effectiveness of the second vaccine dose declines over time as the humoral immunity wanes and new variants emerge16–19. Our data concur with these reports. Previous studies reported 98% effectiveness of the second dose against hospitalization, shortly after vaccination1,20. We detected reduced effectiveness more than five months after the second vaccine dose (61% during the Delta period and none in the Omicron period), findings that might support waning of immunity. In this context, the third dose provided substantial additional protection during the Delta and Omicron periods (97% and 43% protection, respectively) when compared to unvaccinated patients, emphasizing the benefit of vaccine boosting.
We previously showed that a third dose of BNT162b2 mRNA vaccine significantly increased anti-SARS-CoV-2 antibody titers in maternal and cord blood21. In addition, a recent study found that a third booster dose was essential in building neutralizing antibody capacity against the Omicron variant among mothers and neonates22. These boosted antibody titers may have provided additional protection from the Delta variant and allowed protection from the Omicron variant.
When focusing on substantial COVID-19 illness, 5 months after the second dose, the second dose effectively protected against hospitalization complicated by significant disease (97%) and severe disease (96%) during the Delta period, but not during the Omicron period. The impact of the third boosting dose was significant during the Omicron period, effectively protecting against hospitalization complicated by significant disease (97%) and severe disease (94%). To the best of our knowledge, our results are the first to show data regarding significant vaccine effectiveness against severe COVID-19 disease during pregnancy. The fact that vaccines during pregnancy nearly abolish the risk for significant disease has been shown to play a role in patient decision-making regarding vaccination23. Hence, our study might contribute to promoting vaccination uptake among pregnant women.
In the present study, we focused on the impact of COVID-19 vaccine strategy on hospitalization with a diagnosis of SARS-CoV-2 infection, rather than population infection rates. Recorded infection rates may be significantly biased by differential rates of testing in various population subgroups, most notably among unvaccinated patients. Indeed, our data show that unvaccinated pregnant women were significantly less likely to be tested (Table 1). However, while not uniformly executed in all maternity units, routine SARS-CoV-2 testing during maternity admissions was mandatory in most hospitals in Israel. Given the unbiased approach to testing, a finding of positive SARS-CoV-2 during hospitalization represents a better sensor for infection burden, and we therefore assessed and analyzed the data accordingly.
Most previous reports analyzed pregnancy data from a single COVID-19 wave, narrowing observations. We analyzed data from two discrete periods, when two variants having different characteristics were dominant. We focused the time margins on the periods dominated by the Delta and Omicron variants, to present a more comprehensive understanding of vaccine and boosting effectiveness on different viral variants. Indeed, we found significant differences between the two time periods, which might reflect differences in virulence, ability to evade vaccine-mediated immune protection, and waning of protective titers over time.
Our findings provide insight into the impact of COVID-19 vaccines during pregnancy, providing clinicians and policymakers with essential evidence to inform consultation and decision-making.
We lack data on variant sequencing of the diagnostic tests used in this study. However, the Delta and Omicron variants were ascertained to be dominant during each of the study periods defined here, prior to and separate from our analyses. The inclusion of two distinct variants with differing transmissibility and virulence profiles, and comparison of vaccine regimens vs. no vaccine under these dynamic conditions, strengthen our findings. Our results highlight the advantage conferred by the third, boosting dose in pregnancy against serious illness, and serve to reinforce recommendations to vaccinate and boost this population.
Initial, preliminary reports of the long-term effects of maternal COVID-19 infection during pregnancy on child health, and worrying adverse neurodevelopmental sequelae24–26 have appeared. These cases highlight the potential adverse consequences of maternal COVID-19 disease and the urgent need for data on measures to limit maternal infection.
Our study has several limitations. Since the study is based on real-world collected data, no randomization was possible. Individuals opting to decline boosting doses or to refuse vaccination or evade testing may differ in demographic or obstetric characteristics from those opting in. This is a possible source of bias. We adjusted for known confounders to overcome these potential biases, but recognize that other, unaccounted-for individual and group differences in risk factors for severe illness or the likelihood of exposure to the virus, may have impacted our results. Our findings were limited to the BNT162b2 vaccine. We cannot infer whether our observations are relevant to preventing reinfection in convalescent COVID-19 pregnant women, or populations administering other vaccines. The decision to vaccinate during pregnancy is a balance between benefit and effectiveness vs. safety. We did not evaluate COVID-19 vaccine safety, however several other large studies have done so1,27, and demonstrated a favorable safety profile.
In conclusion, when compared to eligible non-boosted or unvaccinated pregnant women, women who received a third dose of BNT162b2 had a lower incidence of hospitalization with SARS-CoV-2 infection during the Delta period and significantly lower incidence of COVID-19 related outcomes during the Omicron period. Our data and analyses provide the necessary evidence to support current recommendations to vaccinate pregnant women with the third boosting dose of COVID-19 vaccine.