Abstract
The origins of preexisting SARS-CoV-2 cross-reactive antibodies and their potential impacts on vaccine efficacy have not been fully clarified. In this study, we demonstrated that S2 was the prevailing target of the preexisting S protein cross-reactive antibodies in both healthy human and SPF mice. A dominant antibody epitope was identified on the connector domain of S2 (1147-SFKEELDKYFKNHT-1160, P144), which could be recognized by preexisting antibodies in both human and mouse. Through metagenomic sequencing and fecal bacteria transplant, we demonstrated that the generation of S2 cross-reactive antibodies was associated with commensal gut bacteria. Furthermore, six P144 reactive monoclonal antibodies were isolated from naïve SPF mice and were proven to cross-react with commensal gut bacteria collected from both human and mouse. A variety of cross-reactive microbial proteins were identified using LC-MS, of which E. coli derived HSP60 and HSP70 proteins were confirmed to be able to bind to one of the isolated monoclonal antibodies. Mice with high levels of preexisting S2 cross-reactive antibodies mounted higher S protein specific binding antibodies, especially against S2, after being immunized with a SARS-CoV-2 S DNA vaccine. Similarly, we found that levels of preexisting S2 and P144-specific antibodies correlated positively with RBD binding antibody titers after two doses of inactivated SARS-CoV-2 vaccination in human. Collectively, our study revealed an alternative origin of preexisting S2-targeted antibodies and disclosed a previously neglected aspect of the impact of gut microbiota on host anti-SARS-CoV-2 immunity.
Keywords: Cross-reactive antibody; SARS-CoV-2; commensal gut bacteria; spike protein; vaccine immunogenicity.
【저자키워드】 SARS-CoV-2, Spike protein, vaccine immunogenicity, cross-reactive antibody, commensal gut bacteria, 【초록키워드】 antibodies, Efficacy, Vaccine, Immunity, S protein, antibody, monoclonal antibody, monoclonal antibodies, anti-SARS-CoV-2, Protein, mice, Impact, Antibody titer, Bacteria, gut microbiota, epitope, metagenomic sequencing, DNA vaccine, SARS-CoV-2 vaccination, inactivated, LC-MS, binding, dose, fecal, Gut, microbial, Hsp60, vaccine immunogenicity, cross-reactive, E. coli, domain, naïve, RBD binding, SARS-CoV-2 S, gut bacteria, Hsp70, dominant, Host, immunized, reactive, collected, healthy, variety, demonstrated, correlated, cross-react, SPF, mounted, P144, 【제목키워드】 COVID-19 vaccine, Immunity, antibody, gut bacteria, SARS-CoV-2 S2, cross-react,