Boosting maternal and neonatal humoral immunity following SARS-CoV-2 infection using a single messenger RNA vaccine dose

Abstract

Background: Post-COVID-19 vaccine boosting is a potent tool in the ongoing pandemic. Relevant data regarding this approach during pregnancy are lacking, which affects vaccination policy guidance, public acceptance, and vaccine uptake during pregnancy. We aimed to investigate the dynamics of anti-SARS-CoV-2 antibody levels following SARS-CoV-2 infection during pregnancy and to characterize the effect of a single postinfection vaccine booster dose on the anti-SARS-CoV-2 antibody levels in parturients in comparison with the levels in naïve vaccinated and convalescent, nonboosted parturients.

Study design: Serum samples prospectively collected from parturients and umbilical cords at delivery at our university-affiliated urban medical center in Jerusalem, Israel, from May to October 2021, were selected and analyzed in a case-control manner. Study groups comprised the following participants: a consecutive sample of parturients with a polymerase chain reaction-confirmed history of COVID-19 during any stage of pregnancy; and comparison groups selected according to time of exposure comprising (1) convalescent, nonboosted parturients with polymerase chain reaction-confirmed COVID-19; (2) convalescent parturients with polymerase chain reaction-confirmed COVID-19 who received a single booster dose of the BNT162b2 messenger RNA vaccine; and (3) infection-naïve, fully vaccinated parturients who received 2 doses of the BNT162b2 messenger RNA vaccine. Outcomes that were determined included maternal and umbilical cord blood anti-SARS-CoV-2 antibody levels detected at delivery, the reported side effects, and pregnancy outcomes.

Results: A total of 228 parturients aged 18 to 45 years were included. Of those, samples from 64 were studied to characterize the titer dynamics following COVID-19 at all stages of pregnancy. The boosting effect was determined by comparing (1) convalescent (n=54), (2) boosted convalescent (n=60), and (3) naïve, fully vaccinated (n=114) parturients. Anti-SARS-CoV-2 antibody levels detected on delivery showed a gradual and significant decline over time from infection to delivery (r=0.4371; P=.0003). Of the gravidae infected during the first trimester, 34.6% (9/26) tested negative at delivery, compared with 9.1% (3/33) of those infected during the second trimester (P=.023). Significantly higher anti-SARS-CoV-2 antibody levels were observed among boosted convalescent than among nonboosted convalescent (17.6-fold; P<.001) and naïve vaccinated parturients (3.2-fold; P<.001). Similar patterns were observed in umbilical cord blood. Side effects in convalescent gravidae resembled those in previous reports of mild symptoms following COVID-19 vaccination during pregnancy.

Conclusion: Postinfection maternal humoral immunity wanes during pregnancy, leading to low or undetectable protective titers for a marked proportion of patients. A single boosting dose of the BNT162b2 messenger RNA vaccine induced a robust increase in protective titers for both the mother and newborn with moderate reported side effects.

Keywords: COVID-19; anti SARS-CoV-2 antibody; boosting vaccine dose; case-control study; postinfection vaccine; pregnancy; single dose; vaccine during.

Figure 1

Patient selection flowchart (created with BioRender.com) Nevo et al. Single messenger RNA vaccine dose post-infection boosts maternal and neonatal immunity. Am J Obstet Gynecol 2022.

Figure 2

Maternal anti–SARS-CoV-2 antibody titer decay across gestation A, Maternal SARS-CoV-2 anti-RBD–specific immunoglobulin G (IgG) antibody concentrations at the time of delivery are plotted (y-axis) against the time of exposure (ie, positive RT-PCR, x-axis). Anti–SARS-CoV-2 RBD-specific IgG concentrations in maternal sera at delivery were positively correlated with the time from exposure (r=0.4371; P=.0003). B, Comparison of serologic data at delivery between women infected during the first (I), second (II), and third (III) trimesters. Differences among the groups were analyzed using a Kruskal-Wallis 1-way ANOVA test, followed by a Dunn multiple comparisons test. An asterisk indicates P<.05. For the box and whiskers plot, the middle line indicates the median, the box indicates the interquartile range, and the whiskers represent the minimum and maximum. Nevo et al. Single messenger RNA vaccine dose post-infection boosts maternal and neonatal immunity. Am J Obstet Gynecol 2022.

Figure 3

Maternal anti-SARS-CoV-2 antibody titers for study groups and non pregnant participants Boosting convalescent patients with a single dose of the BNT162b2 messenger RNA vaccine, administered during pregnancy, elicited a robust surge in anti–SARS-CoV-2 antibody titers detected at delivery. SARS-CoV-2 anti-RBD–specific immunoglobulin (IgG) antibody titers for gravidae (right panel) and nongravid patients (left panel). The pink box represents convalescent participants, the blue box represents boosted convalescent participants, and the gray box represents naïve, fully vaccinated participants. The horizontal dotted line indicates a titer below 50 (negative result). Differences among the groups were analyzed using Kruskal-Wallis 1-way ANOVA tests, followed by a Dunn multiple comparisons test. Quadruple asterisks indicate a significance of P<.0001; single asterisk indicates a significance of P<.05. ns, nonsignificant. Nevo et al. Single messenger RNA vaccine dose post-infection boosts maternal and neonatal immunity. Am J Obstet Gynecol 2022.

Figure 4

Maternal protective anti–COVID-19 antibodies efficiently transfer to the fetus A, The connected dot plots show SARS-CoV-2 anti-RBD–specific immunoglobulin G (IgG) antibody titers at delivery for maternal (M) and umbilical cord blood (C) pairs. Pink dots indicate the results for convalescent participants. Blue dots represent the results for boosted convalescent participants. Gray dots represent the results for naïve, fully vaccinated participants. Notably, 1 dyad of the boosted convalescent pairs showed a lower titer for the neonate than for the mother. This patient delivered 2 weeks following boosting. We speculate that the time elapsed from the boosting dose to delivery was insufficient for optimal vertical transmission. Significant differences between maternal and umbilical cord blood antibody levels within the same group was determined by a Wilcoxon matched-pairs signed-rank test. Triple asterisks indicate a significance of P<.001. Quadruple asterisks indicate a significance of P<.0001. Significant differences between maternal vs maternal (hashtag indicates P<.0001) and cord blood vs cord blood (double dollars indicate P<.0001) groups were found only when comparing titers with convalescent titers (Kruskal-Wallis 1-way ANOVA test, followed by a Dunn all-pairwise comparisons test). B, Maternal (M) and umbilical cord blood (C) sera neutralizing activity, reflected by NT50 values (provided in the Materials and Methods section), presented as maternal-cord pairs. Significant differences between the maternal and umbilical cord blood neutralizing activity within the same group was determined by a Wilcoxon matched-pairs signed-rank test and an unpaired t test for comparisons between groups. Double asterisks indicate a significance of P<.01. Single asterisk indicates a significance of P<.05. Nevo et al. Single messenger RNA vaccine dose post-infection boosts maternal and neonatal immunity. Am J Obstet Gynecol 2022.

Figure 5

Anti–SARS-CoV-2 antibody titers following delivery and postpartum boosting A, The connected dot plots show SARS-CoV-2 anti-RBD–specific immunoglobulin G (IgG) antibody titers at delivery and in the postpartum period for individual participants, presented as paired time points. Pink dots represent the results for convalescent participants, blue dots represent the results for boosted convalescent participants, and gray dots represent the results for naïve, fully vaccinated participants. Significance was determined using Wilcoxon signed-matched pairs test. Triple asterisks indicate significance of P<.001. B, The dot plots show SARS-CoV-2 anti-RBD–specific IgG antibody titers at delivery and in the postpartum period for individual participants, presented as paired time points. Convalescent participants (left) and convalescent participants who received a single postpartum boosting dose of the BNT162b2 messenger RNA vaccine (right). Nevo et al. Single messenger RNA vaccine dose post-infection boosts maternal and neonatal immunity. Am J Obstet Gynecol 2022.

Figure 6

Comparison of side effects reported by participants following boosting and second mRNA vaccine Most frequent local and systemic reactions reported after a single boosting dose of the BNT162b2 messenger RNA (mRNA) vaccine during pregnancy when compared with the second vaccine dose among naïve vaccinated parturients. Data are reported as the proportion of frequently reported side effects among convalescent parturients following vaccine boosting (blue) and following the second BNT162b2 mRNA vaccine (gray). Data were collected before or after labor using a detailed standard questionnaire. Differences between groups were analyzed using a Pearson chi-squared analysis. Single asterisk indicates significance of P<.05. Nevo et al. Single messenger RNA vaccine dose post-infection boosts maternal and neonatal immunity. Am J Obstet Gynecol 2022.

Supplemental Figure

Timing of study exposures A, Gestational age (GA) at exposure for all study groups (pink: positive RT-PCR test; gray: booster dose or second vaccine dose). The middle line in each violin plot indicates the median. The broken lines indicate the 25th and 75th percentiles. The red broken line indicates the timing of last menses. B,Box and whiskers plot showing the duration of time from confirmed RT-PCR test to boosting vaccine dose among boosted convalescent participants. The middle line indicates the median, the box indicates the interquartile range, and the whiskers represent the minimum and maximum. RT-PCR, reverse transcription polymerase chain reaction. Nevo et al. Single messenger RNA vaccine dose post-infection boosts maternal and neonatal immunity. Am J Obstet Gynecol 2022.