Maternal Hybrid Immunity and Risk of Infant COVID-19 Hospitalizations: National Case-Control Study in Israel

Infants with COVID-19, especially the Omicron variant, are at increased risk of acute respiratory failure and hospitalization. Pfizer and Moderna mRNA vaccines significantly reduce this risk but are not approved for infants under 6 months. Previous studies have shown that children of mothers with 2 to 3 vaccine doses before birth are less likely to be hospitalized for COVID-19 during the first 6 months of life. Studies have also demonstrated that hybrid immunity—immunity from both previous infection and vaccination—increases the concentration of anti–SARS-CoV-2 antibodies in the umbilical cord during birth. However, the clinical significance of this result remains unclear. This study aims to elucidate the association between hybrid immunity of mothers and the incidence of hospitalization due to COVID-19 in their infants within 6 months postpartum. In this nationwide, case-control study using Israel’s Ministry of Health database between August 24, 2021 and March 15, 2022, 661 case infants and 59,460 age-matched controls were identified. Case infants were those aged 6 months or younger who were hospitalized due to COVID-19 complications. Exclusions included infants born before 23 weeks of gestation, with low birthweight, or hospitalized for unrelated reasons. About 90 nonhospitalized controls were matched to each case based on birthdate. Cases were grouped based on the presence and type of COVID-19 immunity in the infants’ mothers: naïve (no documentation of infection or vaccination, reference group) natural immunity (documented positive SARS-CoV-2 test without vaccination), hybrid immunity (natural immunity and vaccination), partial vaccination (1–2 doses and no infection), and full vaccination (3–4 doses). The primary outcome was a hazards ratio assessing the infants’ protection against COVID-19 hospitalization. Covariates including maternal age, gestational age, birthweight, dominant SARS-CoV-2 variant, and timing of immunity-conferring events were identified and results were adjusted accordingly. There was a significant difference in protection against infant hospitalization with hybrid immunity, natural immunity, full vaccination, and partial vaccination resulted in a protection ratio against hospitalization of 84% (95% confidence interval [CI], 75–90), 56% (95% CI, 39–68), 66% (95% CI, 56–64), and 29% (95% CI, 15–41), respectively. Protection ratios were higher for the Delta variant than the Omicron variant. No infant hospitalizations occurred for children of mothers with hybrid immunity and full vaccination during Delta predominance, and the protective impact of natural immunity and partial vaccination during this time were 75% and 49%, respectively. During Omicron predominance, the protection ratios of maternal hybrid immunity, natural immunity, and full vaccination were found to be 81%, 48%, and 64%, respectively, whereas partial vaccination protection was not significantly different than naïve patients. Maternal hybrid immunity provided greater protection against infant hospitalization than maternal natural immunity, regardless of timing or order of immune events. Protection ratios increased with number of vaccination doses, with ratios of 56%, 78%, and 92% for 0, 1, and 2+ doses, respectively. These results show that maternal hybrid immunity confers greater protection against infant hospitalization for COVID-19 than natural immunity, emphasizing the importance of vaccinating women during pregnancy for COVID-19, even those who have been previously infected to protect their children. This study highlights the clinical significance of the increased anti–SARS-CoV-2 antibody concentration in the umbilical cord of women with hybrid immunity and suggests that the Omicron variant resulted in higher infant hospitalization rates than the Delta variant. Study limitations included differences in healthcare-seeking behavior and variations in exposure to COVID-19. Further research is needed to understand the factors influencing this difference.