Preexisting antibodies targeting SARS-CoV-2 S2 cross-react with commensal gut bacteria and impact COVID-19 vaccine induced immunity
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
Affiliations
Liqiu Jia
Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
Shufeng Weng
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, China
Jing Wu
Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
Xiangxiang Tian
Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Yifan Zhang
Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Xuyang Wang
Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
Jing Wang
Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Dongmei Yan
Department of Immunology, School of Basic Medical, Jiamusi University, Jiamusi, China
Wanhai Wang
Clinical Laboratory, the First Affiliated Hospital of Zhengzhou University, Key Laboratory of Laboratory Medicine of Henan Province, Zhengzhou, China
Fang Fang
Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Zhaoqin Zhu
Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Chao Qiu
Institutes of Biomedical Sciences & Shanghai Key Laboratory of Medical Epigenetics, Fudan University, Shanghai, China
Wenhong Zhang
Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
Ying Xu
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, China
Yanmin Wan
Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
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.
