Results
Between June 6, 2022 and September 20, 2022, there were 89 women admitted to the NCKUH Maternal Unit for delivery. Of these, 46 were either previously diagnosed with SARS-CoV-2 infection during pregnancy or had a positive nasopharyngeal RT-PCR test result upon admission. Of the 46 women with SARS-CoV-2 infection, 42 had paired maternal and cord blood samples available for the analysis. Four women without SARS-CoV-2 vaccination had negative maternal plasma anti-S antibody levels; therefore, they were not eligible for further analysis of transplacental antibody transfer and were excluded from the SARS-CoV-2 infection group. Of the 89 women, 43 had no history of SARS-CoV-2 infection and had negative nasopharyngeal RT-PCR test results upon admission with paired maternal and cord blood samples. Six women were excluded from the SARS-CoV-2 negative group due to reactive anti-N antibody levels, which indicated a possible previous asymptomatic SARS-CoV-2 infection without documentation. Ultimately, 75 maternal-cord pairs were enrolled for analysis, including 38 pairs from the SARS-CoV-2 infection group and 37 pairs from the SARS-CoV-2 negative group (Fig. S1).
Demographic, obstetric, and clinical characteristics of the participants are summarized in Table 1. The median ages of the participants in the SARS-CoV-2 and SARS-CoV-2 negative group were 32.5 (IQR, 29.75–38) and 34 (IQR, 30–37), respectively. Both groups had similar profiles in terms of body mass index (BMI), gravidity, and gestational age at birth. Cesarean section rate was higher in the SARS-CoV-2 negative group (49% vs. 21%, p=0.012).
Both groups had similar vaccination profiles, and all the participants included in the analysis received a vaccine. Approximately 60% of the patients from both groups (58% in the SARS-CoV-2 group and 60% in the non-SARS-CoV-2 group) were fully vaccinated with a primary series plus one booster dose. Most of the patients (58% in the SARS-CoV-2 group and 62% in the non-SARS-CoV-2 group) received various types of vaccines, including mRNA (NT162b2, Pfizer/BioNTech, or mRNA-1273, Moderna), viral vector (ChAdOx1 nCoV-19, Oxford-AstraZeneca), and protein subunit (MVC-COV1901, Medigen) vaccines. The difference in median intervals from the last vaccination to delivery was not significant with median intervals of 125 days in the SARS-CoV-2 group and 105 days in the non-SARS-CoV-2 group (p=0.824). (Table 1)
The participants were categorized based on the timing of their last vaccination: during the T3, T2, and before/during the T1 (Fig. 1). The highest concentration of maternal and cord plasma anti-S antibodies was observed in the T3 group among all the participants (median 10627.5 U/mL, IQR 6102.75–18021.5 U/mL in maternal plasma; median 16082.5, IQR 10805.5–19823.75 U/mL in cord plasma; p<0.001 and <0.001, respectively) (Fig. 1A). For the SARS-CoV-2 negative pregnant women, the anti-S titer was significantly higher in the T3 group (median 10442 U/mL, IQR 9535–13033 U/mL for maternal plasma; median 14999 U/mL, IQR 12085–19042 U/mL for cord plasma; p<0.001 and <0.001, respectively) than in the T1 (median 578.5 U/mL, IQR 160.25–6425 U/mL for maternal plasma; median 576.1 U/mL, IQR 184–3757 U/mL for cord plasma) and T2 (median 4565 U/mL, IQR 1749–10213.25 U/mL for maternal plasma; median 6017 U/mL, IQR 3838.75–11717.25 U/mL for cord plasma) groups (p<0.001 for maternal plasma and <0.001 for cord plasma) (Fig. 1B). However, the significance of vaccine timing on both maternal and cord plasma anti-S titer was diminished when comparing the SARS-CoV-2 positive T1, T2, and T3 groups (Fig. 1C), which emphases the effect of recent infection on the anti-S titer. (Table S1)
The nAbs response at different times after the last vaccination were similar to those of anti-S antibodies. Maximum neutralizing responses against both the Wuhan wild-type strain and Omicron variant were found in the maternal and cord sera of the T3 group (Fig. 1D, 1G). The neutralizing responses of the SARS-CoV-2 vaccine against the Omicron variant were more pronounced in the SARS-CoV-2 negative participants, and the neutralizing responses increased significantly across the T1, T2, and T3 groups (T3 group of cord sera with median 98.15%, IQR 98.04–98.22% for the Wuhan strain; median 88.94, IQR 79.36–91.98% for the Omicron strain; p <0.001) (Fig. 1E, 1H). However, the nAb response rates in both maternal and cord sera were not significant for participants with SARS-CoV-2 infection across the T1, T2, and T3 groups (Fig. 1F, 1I). (Table S2)
The levels of maternal and cord serum anti-S antibody concentrations increased significantly seven days after SARS-CoV-2 infection (Fig. S2) (Table S3) and peaked around 50 days from the day of the last vaccination (Fig 2A) or SARS-CoV-2 infection (Fig. 2B). Delayed peaks and declines were observed in the cord sera of both groups. The anti-S antibodies were measurable in maternal and cord sera up to one year after the last vaccination (Fig. 2A). A delayed appearance of anti-N antibody in cord sera was also found following SARS-CoV-2 diagnosis. While the anti-N antibodies were detected in 5 out of the total 46 maternal serum samples within 7 days from diagnosis, a delayed response was observed in cord serum, with a rise in anti-N antibodies not observed until 18 days after SARS-CoV-2 diagnosis. (Figure S3)
The transplacental transfer ratio (TR), which was calculated as the cord serum antibody concentration divided by the maternal serum antibody concentration measured the transplacental transfer of antibodies. Time variable was presented as the time interval from delivery to the last antigen exposure, either the last vaccination or infection, which ever occurred last. The TRs of anti-S from the post-infection and non-infection groups and anti-N from the post-infection group showed a similar linear correlation with the time variable before 100 days (Fig. 3). The TRs peaked at approximately 100 days, reaching as high as 3–4, then plateaued at approximately 1–2 after 150 days.