Seasonal Betacoronavirus Antibodies' Expansion Post-BNT161b2 Vaccination Associates with Reduced SARS-CoV-2 VoC Neutralization

Abstract

SARS-CoV-2 vaccination is known to induce antibodies that recognize also variants of concerns (VoCs) of the virus. However, epidemiological and laboratory evidences indicate that these antibodies have a reduced neutralization ability against VoCs. We studied binding and neutralizing antibodies against the Spike protein domains and subunits of the Wuhan-Hu-1 virus and its alpha, beta, delta VoCs and of seasonal betacoronaviruses (HKU1 and OC43) in a cohort of 31 health care workers prospectively followed post-vaccination with BNT162b2-Comirnaty. The study of sequential samples collected up to 64 days post-vaccination showed that serological assays measuring IgG against Wuhan-Hu-1 antigens were a poor proxy for VoC neutralization. In addition, in subjects who had asymptomatic or mild COVID-19 prior to vaccination, the loss of nAbs following disease could be rapid and accompanied by post-vaccination antibody levels similar to those of naïve vaccinees. Interestingly, in health care workers naïve for SARS-CoV-2 infection, vaccination induced a rapid and transient reactivation of pre-existing seasonal coronaviruses IgG responses that was associated with a subsequent reduced ability to neutralize alpha and beta VoCs.

Trial registration: ClinicalTrials.gov NCT04318366.

Keywords: Antibodies; COVID-19; Neutralizing antibodies; Vaccine.

Fig. 1

Antibody responses to Spike antigens of SARS-CoV-2 variants post-BNT162b2 vaccination show significant differences in nAbs titer but not in IgG binding to the RBD of VoCs. Line plots of ID50 titer (A) and RBD IgG arbitrary units (AU) (B) against SARS-CoV-2 Wuhan-Hu-1 and VoCs in sequential samples after vaccination. Vaccinees are presented in left to right panels stratified as follows: (left panel) subjects naïve for SARS-CoV-2 infection (n = 13), (middle panel) with prior confirmed COVID-19 presenting at vaccination either without Wuhan-Hu-1 nAbs and RBD IgGs (n = 6), and (right panel) with prior COVID-19 and SARS-CoV-2 antibodies at baseline (n = 12). Filled circles and bars represent the median ± inter quartile range at each time-point, and empty circles show each individual measurement. The horizontal dashed lines stand for the threshold for positivity. The asterisks indicate statistically significant differences in mean titers of nAbs or RBD IgGs levels across VoCs at the corresponding time-points (two-way repeated measures ANOVA, *p adjusted < 0.05, **p adjusted < 0.01, ***p adjusted < 0.001)

Fig. 2

Post-BNT162b2 vaccination, antibody levels to spike antigens of SARS-CoV-2 and its variants are correlated to previous disease severity. The line plots show the moving average of antibody levels against the indicated SARS-CoV-2 variants after fitting of a LOESS polynomial regression. Subjects are stratified according to symptoms after SARS-CoV-2 infection. Antibody responses to Spike antigens of SARS-CoV-2 VoCs post-BNT162b2 vaccination show differences in nAbs titer (A) but not in IgG binding to the RBD (B)

Fig. 3

BNT162b2-Comirnaty vaccination can induce a large, early boost of antibodies against seasonal betacoronaviruses in COVID-19-naïve subjects. Line plots of ID50 nAbs and RBD IgG arbitrary units (AU) to SARS-CoV-2 Wuhan-Hu-1 and S2 spike proteins of SARS-CoV-2, OC43, and HKU1 betacoronaviruses at sequential time-points after vaccination. Vaccinees are stratified as follows: (A) subjects naïve for SARS-CoV-2 infection (n = 13), (B) subjects with prior confirmed COVID-19 presenting at vaccination either without Wuhan-Hu-1 nAbs and RBD IgGs (n = 6), and (C) with prior COVID-19 and SARS-CoV-2 antibodies at baseline (n = 12). The vertical dashed line indicates the 2nd vaccine jab

Fig. 4

An early boost of HKU1 IgGs post-vaccination is associated with a rapidly decreasing Ab response against SARS-CoV-2 in COVID-19-naïve subjects. Line plots of Wuhan-Hu-1 and indicated VoCs ID50 nAbs (A) and RBD IgG arbitrary units (AU) (B). Subjects naïve for COVID-19 were stratified as above or below the median of HKU1 S2 IgGs at day 10 post-vaccination. Filled circles and bars represent the median ± inter quartile range at each time-point, and empty circles show each individual measurement. The horizontal dashed lines stand for the threshold for positivity. The asterisks indicate statistically significant differences in mean ID50 nAbs or RBD IgG AU at the corresponding time-points between subjects with or without an early boost of seasonal coronaviruses responses after vaccination (two-way repeated measures ANOVA, *p < 0.05, **p < 0.01)