Neutralizing antibody activity against SARS-CoV-2 variants in gestational age-matched mother-infant dyads after infection or vaccination

Abstract

Pregnancy confers unique immune responses to infection and vaccination across gestation. To date, there are limited data comparing vaccine- and infection-induced neutralizing Abs (nAbs) against COVID-19 variants in mothers during pregnancy. We analyzed paired maternal and cord plasma samples from 60 pregnant individuals. Thirty women vaccinated with mRNA vaccines (from December 2020 through August 2021) were matched with 30 naturally infected women (from March 2020 through January 2021) by gestational age of exposure. Neutralization activity against the 5 SARS-CoV-2 spike sequences was measured by a SARS-CoV-2-pseudotyped spike virion assay. Effective nAbs against SARS-CoV-2 were present in maternal and cord plasma after both infection and vaccination. Compared with WT spike protein, these nAbs were less effective against the Delta and Mu spike variants. Vaccination during the third trimester induced higher cord-nAb levels at delivery than did infection during the third trimester. In contrast, vaccine-induced nAb levels were lower at the time of delivery compared with infection during the first trimester. The transfer ratio (cord nAb level divided by maternal nAb level) was greatest in mothers vaccinated in the second trimester. SARS-CoV-2 vaccination or infection in pregnancy elicits effective nAbs with differing neutralization kinetics that are influenced by gestational time of exposure.

Keywords: Adaptive immunity; COVID-19; Immunoglobulins; Infectious disease.

Figure 1. Neutralizing activity of maternal and cord plasma samples from the vaccination cohort and infection cohort.

(A) Comparison of the mean NT₅₀ titers against all examined strains between the vaccinated (n = 30) and infected (n = 26) groups. The dot plots show mean NT₅₀ values against variants of each patient in maternal plasma and cord plasma. Black bars represent the median of mean NT₅₀ values. (B and C) Mean NT₅₀ values of the maternal and cord blood were compared by 3 trimesters separately. The dot plots show mean NT₅₀ values against all variants of each patient. Black bars represent the median of mean NT₅₀ values. (D and E) Comparison of the NT₅₀ values by trimester and by 5 strains in the maternal blood (D) and cord blood (E). The dot plots show NT₅₀ values against each variant (vaccinated group: n = 30 for the WT strain and the Alpha, Kappa, Delta, and Mu variants; infected group: n = 30 for the WT strain and the Alpha and Kappa variants, n = 27 for the Delta variant, and n = 26 for the Mu variant). Black bars represent the median of NT₅₀ values. The dotted lines indicate the cutoff threshold of this assay. Trimester of exposure is indicated by color (red, first trimester; blue, second trimester; yellow, third trimester). *P < 0.05; **P < 0.01; *** P < 0.001; ****P < 0.0001 by Mann-Whitney U test or Friedman’s test with Dunn’s multiple comparisons.

Figure 2. SARS-CoV-2 nAb activity in plasma from vaccinated and infected pregnant women and infant cord blood dyads.

Among a vaccinated cohort and an infected cohort, we matched the timing of the first vaccination to the timing of the infection. Neutralization assays were performed by exposing Calu-6-ACE2 cells with pseudotyped virions displaying the WT SARS-CoV-2 spike, or Alpha, Kappa, Delta, or Mu variants to serial dilutions of plasma. NT₅₀ values of the plasma samples were defined as the sample dilution at which a 50% reduction (in RLUs) was observed relative to the average of the virus control wells. Triplicates were performed for each tested serum dilution. The dot plots represent NT₅₀ values against each variant. Black bars represent the median NT₅₀ values. Trimester of exposure is indicated by color (red, first trimester; blue, second trimester; yellow, third trimester). Type of exposure is indicated by different shapes (circle, BNT162b2; triangle, mRNA-1273; rectangle, infection). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by Friedman’s test with Dunn’s multiple comparisons.

Figure 3. Variance in neutralizing activity in maternal and cord plasma from vaccination cohort and infection cohort.

Paired maternal and cord blood NT₅₀ titers against each SARS-CoV-2 strain of each vaccinated patient and each infected patient were matched and displayed as a single row, ordered by increasing gestational age (GA), grouped by trimester. Variability of NT₅₀ was compared using the Brown-Forsythe test. Patient characteristics are indicated by color (trimester of exposure: red, first trimester; blue, second trimester; yellow, third trimester. Vaccine type is indicated by color (green, mRNA-1273; orange, BNT162b2). Fetal sex is indicated by pink for female fetus; blue for male fetus). N/A, samples were not sufficient.

Figure 4. Placental transfer of SARS-CoV-2 Abs.

(A) The effect of trimester on Ab transfer. The dot plots show NT₅₀ titers for a cohort of vaccinated maternal–cord blood pairs. Three separate analyses were performed on the trimester at time of first exposure (red, first trimester; blue, second trimester; yellow, third trimester). Lines connect the maternal–cord blood dyads. Significance was determined by the Wilcoxon signed-rank test. (B) Maternal–cord blood TRs of nAbs were calculated by cord NT₅₀ divided by maternal NT₅₀ to assess efficiency of nAb transfer. nAb TRs are shown by timing of the first vaccine dose or the first positive PCR result. The dot plots represent mean TR of nAbs against variants. Correlations between the cord to maternal nAb ratio and days from events were analyzed using nonlinear regression analysis. (C) Maternal and cord blood NT₅₀ values are shown by timing of the first vaccine dose or the first positive PCR result in the vaccinated or infected group. (D) Patient-based nAb TRs for each SARS-CoV-2 strain in both vaccinated and infected patients, showing the variance in nAb TR on an individual level. All patients were ordered according to increasing gestational age within their groups. *P < 0.05; ***P < 0.001; ****P < 0.0001 by Wilcoxon signed-rank test. C, cord blood; M, maternal blood; N/A, samples were not sufficient.