Timing of Maternal Vaccination Against COVID-19 for Effective Protection of Neonates: A Cohort Study from South Korea

Background: Controversy remains regarding the safety of COVID-19 vaccination during pregnancy. Here, we investigated the impact of vaccination and SARS-CoV-2 infection on maternal-neonate immune response in a cohort study involving pregnant individuals, and defined the importance of maternal COVID-19 vaccination timing for its effectiveness.Methods: We divided 141 pregnant study participants into groups according to the time of vaccination and SARS CoV-2 infection. Maternal blood samples were collected during pregnancy and at the time of delivery. Newborn blood samples were collected from cord blood taken after delivery. Blood sera were used for PRNT assays against Wuhan-Hu-1 and Omicron BA.5 strains, and 50% neutralizing doses (ND50) were calculated. Maternal and neonatal serum-neutralizing activities were calculated according to the previous infection and vaccination status of pregnant individuals. We calculated the neutralizing antibody transfer ratio [log10(neonate ND50)/log10(maternal ND50)] for each coupled sample and performed a comparative analysis of ND50 values in all 141 dyads. Next, we plotted ND50 values for maternal serum collected during pregnancy and delivery to examine changes in neutralizing activity over pregnancy. Finally, we assessed differences between neutralizing activity against Wuhan and Omicron strains by analyzing their ND50 values in each participant.Findings: Neutralizing antibody (nAb) activities in the breakthrough infection (infection after vaccination) mothers and their offspring were significantly higher than those in the vaccination-only or naïve infection (infection only) groups. The median ND50 value against the Wuhan strain in the breakthrough infection mothers (3819, [1476–10330]) was 6–fold and 32–fold higher than those in the vaccination-only (658·4, [152·1–2068]) and naïve infection (119·3, [58·7–324·1]) groups, respectively, while that against the Omicron strain was 3–fold and 8–fold higher, respectively (breakthrough infection 1072, [424·5–1804]; vaccination-only 361·3, [95·1–1542]; naïve infection 137·2, [71·4–862·5]). The same proportions were found among the corresponding neonatal groups. Vaccination timing did not have a detectible effect on the nAb levels in the infected cohort. However, vaccination-only before pregnancy (VBP) increased the level of nAb activity against both strains in maternal and infant sera. The median ND50 values against Wuhan-Hu-1 for mothers and neonates of the VBP group (mothers 865·1, [195·4–3746]; babies 769·9, [175·5–1425]) were 2·6–fold and 2·3–fold higher, respectively, than those in the vaccination-only during pregnancy (VDP) group (mothers 337·5, [146·1–1509]; babies 338, [139·6–1259]). The ND50 median values for the VBP group against Omicron BA.5 (mothers 1051, [132·1–1716]; babies 586·9, [53·6–1424]) were 6·5–fold (mothers 161·1, [89·9–649·2]) and 3·6–fold (babies 162·2, [84·5–774·9]) higher, respectively. The nAb transfer ratio was approximately 1 for all groups, indicating that maternal vaccination supported transplacental transmission of antibodies regardless of immunization timing. A lower nAb transfer ratio was seen in the naïve infection cohort, where the medians were 0·95 [0·89–1·04] and 0·96 [0·82–1·06] for the Wuhan Hu-1 and Omicron BA.5 strains, respectively. The lack of a prominent decrease in neutralizing activity during pregnancy among vaccinated mothers indicated that immunization exerted a positive effect on maternal protection during pregnancy by maintaining or enhancing the neutralizing potency until delivery. The vast majority of maternal-neonate samples showed much less neutralization activity against the Omicron BA.5 variant, indicating the presence of immune evasion.Interpretation: Vertically transferred maternal hybrid immunity provides significantly better antiviral protection for a neonate than either maternal post-infection or post-vaccination immunity alone. The neutralization potency is higher among mothers immunized before pregnancy and their newborns, highlighting the critical impact of vaccination timing on its effectiveness during pregnancy. Additionally, comparison of neutralizing antibody titers calculated for each dyad suggests that infection and pre-/during-pregnancy vaccination all support transplacental transfer, providing the offspring with strong passive immunity against SARS-CoV2.Funding: This work was supported by the Research Program funded by the Korea Disease Control and Prevention Agency (fund code 2021ER230700), the Ministry of Food and Drug Safety(22183MFDS443), and the Korean Health Technology R&D Project (No. HV23C0074 and HV22C0263).Declaration of Interest: All authors declare no competing interests.Ethical Approval: The institutional review board of Seoul National University Hospital approved this study (No 2112-109-1284). Qualified participants were at least 18 years old and provided their informed consent to participate 18 in the research