Pre-existing anti-HCoV-OC43 immunity influences the durability and cross-reactivity of humoral response to SARS-CoV-2 vaccination

Abstract

Purpose: This study was conducted in order to properly understand whether prior seasonal human coronavirus (HCoV) immunity could impact the potential cross-reactivity of humoral responses induced by SARS-CoV-2 vaccine, thereby devising universal coronavirus vaccines for future outbreaks.

Methods: We performed enzyme-linked immunosorbent assay (ELISA) to quantify the immunoglobulin G (IgG) antibody levels to spike (S) protein and S1 subunit of HCoVs (HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E), and ELISA [anti-RBD and anti-nucleoprotein (N)], chemiluminescence immunoassay assays (anti-RBD), pseudovirus neutralization test, and authentic viral neutralization test to detect the binding and neutralizing antibodies to SARS-CoV-2 in the vaccinees.

Results: We found that the antibody of seasonal HCoVs did exist before vaccination and could be boosted by SARS-CoV-2 vaccine. A further analysis demonstrated that the prior S and S1 IgG antibodies of HCoV-OC43 were positively correlated with anti-RBD and neutralization antibodies to SARS-CoV-2 at 12 and 24 weeks after the second vaccination, and the correlation is more statistically significant at 24 weeks. The persistent antibody levels of SARS-CoV-2 were observed in vaccinees with higher pre-existing HCoV-OC43 antibodies.

Conclusion: Our data indicate that inactivated SARS-CoV-2 vaccination may confer cross-protection against seasonal coronaviruses in most individuals, and more importantly, the pre-existing HCoV-OC43 antibody was associated with protective immunity to SARS-CoV-2, supporting the development of a pan-coronavirus vaccine.

Keywords: SARS-CoV-2; antibody; cross-reactivity; protective immunity; seasonal human coronavirus.

Figure 1

Sequence homology and conservation between SARS-CoV-2 and seasonal HCoVs. (A) The conservation and the antigenic epitopes of RBD are shown as a yellow bar chart and a red rectangle. The amino acid conservation scores were classified into 10 levels (1, most variable; +, most conserved). (B) Sequence homology and conservation of spike protein and nucleoprotein between SARS-CoV-2 and seasonal HCoVs. The identity and the similarity (%) of these two proteins were aligned and analyzed by the BLOSUM50 method of MatGAT (version 2.0) (James and Campanella*, 2003).

Figure 2

The SARS-CoV-2 vaccine boosts antibodies that are reactive to seasonal HCoVs. We quantified the serum IgG antibodies to the S and S1 proteins against HCoVs (HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E). The IgG geometric mean titers (GMT) against seasonal HCoVs spike and S1 are shown in the boxplot. Two-tailed, nonparametric Dunn’s Kruskal–Wallis test was used for multiple comparisons. The middle bars indicate the GMT values, the box indicates interquartile range, and the lines indicate minimum and maximum. Statistically significant values are marked in the figure.

Figure 3

Pearson correlation matrices of antibody levels to SARS-CoV-2 and seasonal HCoVs. Heat map of the Pearson correlation matrices of pre-existing spike and S1 subunits’ IgG antibody levels to seasonal HCoVs (HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E) and S-RBD/N antibody and nAbs to SARS-CoV-2 at 4, 12, and 24 weeks after vaccination. Statistically significant correlations are indicated with an asterisk (*) in the first two columns of every heat map. *P < 0.05, **P < 0.005.

Figure 4

Linear correlation of antibody levels between SARS-CoV-2 and HCoV-OC43. The linear correlation between prior S/S1-IgG antibody levels to HCoV-OC43 and S-RBD/N/neutralizing antibodies to SARS-CoV-2 at 12 and 24 weeks after vaccination is shown in the figure. A scatter point represents a record. R ² represents the degree of linear deviation obtained by fitting the experimental data. The p-value tests whether the regression equation is significant. The larger the R ² value, the smaller the p-value. When the p-value is less than 0.05, this linear model can be considered valuable.

Figure 5

Prior antibody to seasonal HCoVs in the groups with and without antibodies to SARS-CoV-2 at 24 weeks after vaccination. The anti-RBD antibody levels were detected by chemiluminescent microparticle immunoassay (A). The nAb levels were detected by pseudovirus neutralization test (B), and neutralizing antibodies against authentic SARS-CoV-2 variants (C). Two-tailed, nonparametric Mann–Whitney test was used for comparisons. The bars display the mean and SD. Part of the results between groups is shown in the figure. *p < 0.05.