Maternal hybrid immunity and risk of infant COVID-19 hospitalizations: national case-control study in Israel – Nature.com

In this study, we found that maternal hybrid immunity provides heightened protection against infant COVID-19 hospitalization during the first six months of life, as compared to natural immunity. Our analyses show that hybrid immunity effectiveness reached 84% (95% CI, 7590%) throughout the study period, whereas natural immunity effectiveness was 56% (95% CI, 3968%). These results emphasize the significance of immunizing women who have recovered from COVID-19 infection during pregnancy to confer robust protection against early infant COVID-19 illness. Infant hospitalizations for COVID-19 were in general brief in all maternal immunity subgroups, and admission to the pediatric ICU was rare. We studied the effect of maternal hybrid immunity on infant COVID-19 hospitalizations, rather than infant SARS-CoV2 infections. Recorded infection rates may be biased by varying testing frequencies among different population groups, particularly among unvaccinated individuals. In Israel, while not consistently implemented across all healthcare facilities, routine SARS-CoV-2 testing of infants presenting with upper respiratory infection symptoms was widely established as a standard procedure in most hospitals during the study period. Given the unbiased approach to testing, and the fact that COVID-19 hospitalization better reflects significant disease burden, we analyzed the data accordingly.

This study concentrated on the indirect benefits of maternal hybrid immunity for unvaccinated newborns. Our findings augment the growing body of evidence underscoring the considerable protective effects of maternal vaccination during pregnancy on early infant COVID-19 disease. Prior research has primarily focused on vaccinating pregnant women who have not been previously exposed to the virus. A Norwegian study published in 2022 linked maternal vaccination with a reduced risk of infant infection during the first four months of life18, while a U.S. study associated pregnancy vaccination with a decreased risk of infant hospitalizations and critical disease up to six months of age12. Our 2023 study, summarizing data from Israel, demonstrated the significant impact of maternal third booster dose in limiting infant COVID-19 hospitalization11. However, clinical data on the durability and benefits of maternal hybrid immunization remain limited. Information on this type of protection stems from studies investigating maternal and newborn protective antibody levels, which indicate high levels of SARS-CoV-2-specific immunoglobulins in maternal blood, cord blood, and milk after vaccinating recovered pregnant women, compared to recovered non-vaccinated pregnant women13,19,20. Our study further expands current knowledge with substantial clinical data, illustrating how maternal hybrid immunity translates to early infant protection. Importantly, we demonstrate that hybrid immunization offers greater protection than all other maternal immunization status groups.

Despite significant differences in infant hospitalization rates based on maternal immunity, we observed similar hospitalization durations across all groups, regardless of maternal immunization status. We postulate that the uniformity in stay length may be due to a shared clinical presentation, primarily fever in infants, which necessitates brief hospital stays. However, it is important to note that we lack data regarding the prevalence of fever.

Two studies from 2021 demonstrated that administering the SARS-CoV-2 vaccine during the late second or early third trimester of pregnancy results in increased antibody levels in umbilical cord blood21,22, and a reduced risk of infant COVID-19 morbidity, compared to earlier gestation vaccination4,12. Our previous research supports these findings, revealing that vaccination during the third trimester leads to elevated anti-COVID-19 antibodies in cord blood compared to the first trimester13. Our findings align with this observation, indicating that when immune stimulation occurs after 20 weeks of gestation, the level of protection appears to be higher compared to stimulation during the first 20 weeks. However, the difference in protection was somewhat reduced compared to previous reports on vaccination alone4,12. It is worth noting that the number of infants born to mothers who were last stimulated before pregnancy was limited in our data, which restricts our ability to accurately predict the true protective effect for infants in that particular group.

Intriguingly, protection resulting from immune stimulation before pregnancy was more robust than that conferred during the first 20 weeks of gestation. This suggests that the durability of immunity acquired through early pregnancy immunization may differ from that obtained pre-pregnancy. Further investigations should focus on these disparities, striving to better understand their origins.

Hybrid-mediated immunity resulted in robust infant protection regardless of the sequence of stimulations (i.e., vaccination before infection or vice-versa). Additionally, our findings suggest that the effectiveness of hybrid-mediated immunity acquired from one vaccine dose is lower than that obtained after two or more doses. Overall these new data provide novel insights into daily clinical questions relevant for patients and families, obstetricians, and healthcare policy. As COVID-19 spread continues, we predict that future guidelines will adopt recommendations for routine SARS-CoV-2 booster vaccination before pregnancy, or during the third trimester23, aiming to reduce early infant morbidity, similar to recommendations for pertussis and influenza prevention24,25,26.

In our analysis, we focus on two key waves of SARS-CoV-2 variants: Delta and Omicron. While Omicron variants have become more prevalent, examining the Delta wave is crucial to understanding the evolving dynamics of the pandemic. This comparison highlights differences between the waves which can be crucial for understanding the importance of updating vaccines to match the currently circulating strains and boosting immunity to overcome waning. However, hybrid immunization enhances protection for both waves.

Our national data reveals a 2.8-fold increase in hospitalization rates among infants aged less than six months during the peak week of Omicron predominance compared to the period of Delta predominance. These results are consistent with CDC reports, which documented a five-fold increase in hospitalization rates when comparing these periods3. The observed differences could be due to higher infant infection rates, decreased protection from vaccines and natural immunity, or increased virulence of variants in infants. Our study did not examine the causes underlying these differences: further research is needed to understand these key factors.

Our study has several strengths. We used population-based databases covering the entire Israeli population with high data completeness. In Israel, a substantial proportion of the convalescent pregnant population received the COVID-19 vaccine during pregnancy, providing a large cohort for analysis. The mandatory reporting of information to the Israeli national registries, as described in the Methods section, limited the potential for selection bias and provided detailed data on clinical and sociodemographic factors. However, data did not include disease symptoms, constraining any evaluation of severity.

Our investigation presents certain limitations. As a real-world observational study, participants opted for vaccination at different times, making it difficult to account for potential disparities in asymptomatic (and unrecorded) infections, household exposures, health-seeking, behaviors, or risk aversion among individuals.

While we made efforts to adjust for multiple potential confounding factors, the absence of data on critical variables such as breastfeeding practices, enrollment in daycare centers, and other family or behavioral variables could have influenced the observed outcomes. Additionally, during the study period, changes in testing eligibility occurred, and data on home rapid antigen test results were unavailable. These limitations underscore the complexities of real-world observational research, emphasizing the need for future investigations that incorporate a more comprehensive dataset and account for these variables.

Maternal vaccination during pregnancy offers infant protection through two primary mechanisms: (a) the transfer of protective antibodies via the placenta and breast milk, and (b) a reduction in the infants exposure to infectious agents due to a better-protected mother (resulting in decreased vector susceptibility and infectiousness)27,28,29. While it is crucial to comprehensively understand the relative contribution of each protective factor, the necessary data for such determination was not available in this study, highlighting the need for further investigation in future research.

In summary, this real-world assessment revealed that maternal hybrid immunization was associated with a reduced risk of infant hospitalization due to COVID-19 compared to natural immunity via infection alone. Our results show that effectiveness of hybrid immunity remains robust regardless of the timing of stimulation during pregnancy. Our findings supply crucial evidence to reinforce current recommendations advocating for COVID-19 vaccination of previously infected individuals during pregnancy to mitigate substantial illness in early infancy.

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Maternal hybrid immunity and risk of infant COVID-19 hospitalizations: national case-control study in Israel - Nature.com