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Pre-existing antibodies targeting a linear epitope on SARS-CoV-2 S2 cross-reacted with commensal gut bacteria and shaped vaccine induced immunity

By Liqiu Jia, Shufeng Weng, Jing Wu, Xiangxiang Tian, Yifan Zhang, Xuyang Wang, Jing Wang, Dongmei Yan, Wanhai Wang, Fang Fang, Zhaoqin Zhu, Chao Qiu, Wenhong Zhang, Ying Xu, Yanmin Wan

Posted 15 Jul 2021
medRxiv DOI: 10.1101/2021.07.13.21260404

The origins of pre-existing 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 pre-existing 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 pre-existing antibodies in both human and mouse. Through metagenomic sequencing and fecal bacteria transplant, we proved that the generation of S2 cross-reactive antibodies was associated with commensal gut bacteria. Furthermore, six P144 specific monoclonal antibodies were isolated from naive SPF mice and proved to cross-react with commensal gut bacteria collected from both human and mouse. Mice with high levels of pre-existing 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 pre-existing S2 and P144 reactive antibodies correlated positively with RBD specific binding antibody titers after two doses of inactivated SARS-CoV-2 vaccination in human. Finally, we provided data demonstrating that immunization of a SARS-CoV-2 S DNA vaccine could alter the gut microbiota compositions of mice.

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