Maternal third dose of BNT162b2 mRNA vaccine and risk of infant COVID-19 hospitalization

In this study, we provide evidence to support the role of maternal booster vaccination to support infant SARS-CoV-2 immunity in the prevention of early infant COVID-19 morbidity. We report a lower incidence rate and shorter duration of early infant COVID-19 hospitalizations among infants of mothers who received a third vaccine dose compared to infants of mothers who received the second dose only, at least 5 months before delivery. We found an association between the timing of the third dose and the timing of infant COVID-19 hospitalization, which supports an advantage of vaccination in the later stages of pregnancy. The protective effect of the third vaccine dose declined over time after delivery. Infants of mothers who were in the second-dose group (at least 5 months from the second dose) were not protected from serious disease, emphasizing the importance of maternal booster vaccination. Together, these findings show how waning of maternal SARS-CoV-2 immunity influences infant health.

To date, most of the data regarding the possible benefits of maternal vaccination on early infant infections come from studies that show efficient transport of protective anti SARS-CoV-2 IgG from the mother to the umbilical cord blood at birth13,14,16,22,23,24,25. Vertical SARS-CoV-2 immunity may explain the observations of reduced risk for COVID-19 in infants during early life in mothers who had third-dose vaccination. These findings corroborate previous reports from the Norwegian population that found an association between maternal vaccination and reduced risk for positive SARS-CoV-2 test during the first 4 months of life19 and data from the United States reporting the associations of maternal vaccination with two doses and reduced risk of infant hospitalizations12. Our data provide additional evidence for the role of the third vaccine dose in protecting against COVID-19-related hospitalizations during early infancy. Unlike these previous studies12,19 that included women at any time after administration of the second dose, we included only vaccinated mothers when 5 months had elapsed from the second dose. This allowed us to isolate the effect of the waning of maternal vaccine protection on the immunity extended to infants. As many women have waning immunity after the second dose, we show that a third-dose booster provides additional protection for their children. We further show an association between the timing of maternal vaccination with the third dose and the timing of infant COVID-19-related hospitalizations, suggesting that a booster dose given in later pregnancy would increase infant protection. Nevertheless, determining the appropriate timing for boosting is challenging, as the benefits of maximizing infant protection must be balanced against maternal risks of delaying vaccination, considering the risk of severe maternal COVID-19 during pregnancy.

This study focused on the indirect benefits of vaccine boosting in pregnant mothers for their unvaccinated infants. Our results extend previous data showing how parental vaccination confers protection on children residing in the same household26,27, further highlighting the broad impact of parental vaccination on their children’s health. In the case of vaccination during pregnancy, infant vaccine effects are mediated by two main mechanisms: (1) by passage of antibodies across the placenta during pregnancy and through breast milk for breastfed infants and (2) by direct decrease in the chance of exposure to infective agents resulting from a better-protected mother (reduced vector susceptibility and infectiousness)26,28,29,30. Although we acknowledge the importance of a thorough understanding of the relative contribution of each of these protective components, these data were not available for this study and, therefore, require further investigation in future studies.

We found differences between the COVID-19 periods dominated by the Delta and Omicron variants when comparing the impact of maternal vaccination with a third dose on the rates of infant hospitalization. These findings are in agreement with previous reports in the general population of reduced effectiveness of the current mRNA vaccines against COVID-19 mediated by the Omicron variant31,32. As the Omicron variant is genetically divergent from the wild-type SARS-CoV-2 strain, for which the BNT162b2 vaccine was tailored, it seems to escape vaccine-mediated protection. These findings emphasize the potency and broad effects of maternal vaccination while highlighting the need to tailor vaccines for novel variants. In this context, future studies should evaluate the association of maternal bivalent boosters with infant hospitalizations, as these vaccines are better tailored against the Omicron variant.

The CDC, the American College of Obstetricians and Gynecologists and other health organizations currently recommend booster doses for pregnant women as soon as they are eligible, to minimize the risk of severe disease15,33,34. These recommendations are based on information showing that COVID-19 vaccination in pregnancy safely protects against severe COVID-19 (refs. 35,36,37,38). Nevertheless, vaccine uptake among pregnant populations has been slow in many societies37,39,40. Our results, showing that vaccines during pregnancy reduce the risk for infant COVID-19-related hospitalizations, in addition to the reduction in previously reported maternal risks, may support women’s decisions to be vaccinated and, thereby, improve vaccination uptake rates among pregnant women41. Moreover, as the circulation of SARS-CoV-2 persists, we anticipate that future guidelines will adopt recommendations for routine COVID-19 booster vaccination during the third trimester16, aiming to reduce early infant morbidity, similar to recommendations for pertussis and influenza prevention42,43,44.

Our study’s strengths include the use of registry data covering the whole Israeli population, with high data completeness. In addition, the high compliance with COVID-19 vaccination campaigns among the pregnant population in Israel provides a large cohort for analysis. Mandatory reporting to the Israeli national registries (Methods) limited potential selection bias and provided detailed data on clinical and sociodemographic variables. In addition, we estimated vaccine effectiveness for different subpopulations and found similar effectiveness, further strengthening the relevance of the findings to infants of diverse backgrounds.

This study has several limitations. It is a real-world observational study; therefore, participants were not randomly selected for vaccination. Patients who declined a boosting dose may vary in demographic or obstetric characteristics from other eligible individuals. Sociodemographic variables were unavailable for this study; therefore, we could not control for those potential confounders. Moreover, groups who received booster vaccination could behave in a more cautious way that may reduce their risk of infection. Although women with previous documentation of a positive SARS-CoV-2 test were excluded from the study, natural and hybrid immunity acquired during the pandemic, which may not have been captured by testing in the community, might have affected the results. These possible sources of bias are challenges in a retrospective study design. To overcome these potential biases, we adjusted data for known confounders, but we acknowledge that other, unaccounted-for group and individual risk factors for severe illness or exposure to the virus could have affected our results. We did not adjust our results for maternal morbidities or COVID-19 severity of the infants during hospitalization (for example, COVID-19 degree of severity); therefore, our results must be interpreted with caution. Also, women were included in the third-dose group from the day they received the booster. It is possible that the level of protective antibodies in the first days after booster vaccination was suboptimal. This may have impacted the results overall (that is, lessened the degree of estimated effectiveness). Nonetheless, the level of protection was found to be higher in the third-dose group compared to the second-dose group (among whom at least 5 months had elapsed from the second dose). Furthermore, the data did not include disease symptoms and allowed only limited assessment of disease severity. Finally, data regarding breastfeeding were not available in this study; therefore, we cannot evaluate the role of breastfeeding in mediating protection.

In conclusion, in this national cohort study, a third boosting dose of the BNT162b2 mRNA COVID-19 vaccine during pregnancy was associated with a reduced risk, and a shorter duration, of infant hospitalization for COVID-19 during the first 4 months of life compared to mothers who did not receive a booster. Our data provide evidence to support infant protection against serious COVID-19 disease after maternal vaccination with the third dose during pregnancy.

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