Maternal-fetal cytokine profiles in acute SARS-CoV-2 "breakthrough" infection after COVID-19 vaccination

Abstract

Objective: Vaccination is protective against severe COVID-19 disease, yet whether vaccination reduces COVID-19-associated inflammation in pregnancy has not been established. The objective of this study is to characterize maternal and cord cytokine profiles of acute SARS-CoV-2 "breakthrough" infection (BTI) after vaccination, compared with unvaccinated infection and uninfected controls.

Study design: 66 pregnant individuals enrolled in the MGH COVID-19 biorepository (March 2020-April 2022) were included. Maternal sera were collected from 26 unvaccinated and 21 vaccinated individuals with acute SARS-CoV-2 infection. Cord sera were collected at delivery. Maternal and cord sera from 19 term dyads without current or prior SARS-CoV-2 infection were analyzed as controls. Cytokines were quantified using the Human Inflammation 20-Plex ProcartaPlex assay.

Results: There was a significantly higher incidence of severe/critical maternal illness in unvaccinated pregnant individuals with SARS-CoV-2 compared to vaccinated (10/26 (38%) vs. 0/21 (0%), p<0.01). Significantly higher maternal levels of TNFα and CD62P were observed in vaccinated individuals with SARS-CoV-2 BTI compared with unvaccinated individuals with infection (p<0.05). Network correlation analyses revealed a distinct maternal cytokine response to SARS-CoV-2 in vaccinated vs unvaccinated individuals. Neither unvaccinated nor vaccinated SARS-CoV-2 infection resulted in elevated cord cytokines compared to controls. Multivariate analyses demonstrate distinct maternal and cord cytokine profiles in the setting of maternal SARS-CoV-2 at delivery.

Conclusion: Vaccination was associated with higher maternal cytokine levels during acute SARS-CoV-2 infection compared to unvaccinated infection, which may reflect vaccine-mediated priming of the immune system. A fetal inflammatory response specific to maternal SARS-CoV-2 infection was not observed.

Keywords: COVID-19; COVID-19 vaccines; SARS-CoV-2; breakthrough infection; cytokines; pregnancy.

Figure 1

Cytokine levels in maternal sera from vaccinated and unvaccinated participants with maternal SARS-CoV-2 infection, and negative controls. COVID-19 severity as defined by NIH criteria indicated by shape. Unvax = unvaccinated; vax = received primary COVID-19 vaccine series prior to infection. (A) Analyte levels of maternal sera collected from unvaccinated (blue, N=26) and vaccinated (orange, N=21) participants during acute SARS-CoV-2 infection, and negative controls at delivery (purple, N=19). Concentrations reported as pg/mL. Boxplots indicate median and interquartile range. Group differences assessed by Kruskal-Wallis test (group P-value shown). Significant differences between groups on Dunn’s posthoc testing indicated by *P<0.05. (B) Correlation analysis of maternal serum analytes from unvaccinated participants (N=26) and (C) vaccinated participants (N=21). Left panel: dot plot of significant Spearman correlations (padj<0.05). Dot size and color indicate strength of correlation, with blue indicating positive and red indicating negative correlations. Right panel: network correlation plot with each analyte depicted as a node and positively-correlated analytes (padj<0.05) indicated by weighted gray lines.

Figure 2

Correlation of cytokine analytes in the maternal and cord sera at delivery in acute SARS-CoV-2 infection and in SARS-CoV-2 negative controls. N=41 dyads: 23 maternal:cord pairs with acute maternal SARS-CoV-2 infection at delivery (purple, N=11 vaccinated, 12 unvaccinated),18 SARS-CoV-2 negative controls (pink). Maternal (M) analyte levels depicted on y-axis and cord blood (CB) levels on x-axis, with Spearman correlation and p-value indicated on plots. Open circles = vaccinated “breakthrough” infection.

Figure 3

Principal component analysis (PCA) of maternal and cord analyte levels during acute maternal SARS-CoV-2 infection. (A) PCA plot of samples obtained during acute maternal SARS-CoV-2 infection. Cord samples were obtained following delivery occurring during acute maternal SARS-CoV-2 infection; no newborns tested positive for SARS-CoV-2 after birth. M, maternal blood (N=47, light blue). CB, cord blood (N=23, dark blue). Ellipses show 95% CI of sample distribution. (B) Contribution of analytes to PC1 vs PC2 (top) and PC2 vs PC3 (bottom). (C) Analytes with highest contributions to PC1, PC2 and PC3.