Yeast-produced RBD-based recombinant protein vaccines elicit broadly neutralizing antibodies and durable protective immunity against SARS-CoV-2 infection

Jinkai Zang; Yuanfei Zhu; Yu Zhou; Chenjian Gu; Yufang Yi; Shuxia Wang; Shiqi Xu; Gaowei Hu; Shujuan Du; Yannan Yin; Yalei Wang; Yong Yang; Xueyang Zhang; Haikun Wang; Feifei Yin; Chao Zhang; Qiang Deng; Youhua Xie; Zhong Huang

doi:10.1038/s41421-021-00315-9

Yeast-produced RBD-based recombinant protein vaccines elicit broadly neutralizing antibodies and durable protective immunity against SARS-CoV-2 infection

Cell Discov. 2021 Aug 18;7(1):71. doi: 10.1038/s41421-021-00315-9.

Authors

Jinkai Zang^#¹, Yuanfei Zhu^#², Yu Zhou^#¹, Chenjian Gu^#², Yufang Yi^#^{3

4}, Shuxia Wang¹, Shiqi Xu¹, Gaowei Hu⁵, Shujuan Du², Yannan Yin¹, Yalei Wang¹, Yong Yang¹, Xueyang Zhang¹, Haikun Wang¹, Feifei Yin^{3

4}, Chao Zhang⁶, Qiang Deng⁷, Youhua Xie^{8

9}, Zhong Huang¹⁰

Affiliations

¹ CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
² Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China.
³ Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, Hainan, China.
⁴ Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, Hainan, China.
⁵ BSL-3 Laboratory of Fudan University, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
⁶ CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. chaozhang@ips.ac.cn.
⁷ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China. qdeng@fudan.edu.cn.
⁸ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China. yhxie@fudan.edu.cn.
⁹ Children's Hospital, Shanghai Medical College, Fudan University, Shanghai, China. yhxie@fudan.edu.cn.
¹⁰ CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. huangzhong@ips.ac.cn.

^# Contributed equally.

Abstract

Massive production of efficacious SARS-CoV-2 vaccines is essential for controlling the ongoing COVID-19 pandemic. We report here the preclinical development of yeast-produced receptor-binding domain (RBD)-based recombinant protein SARS-CoV-2 vaccines. We found that monomeric RBD of SARS-CoV-2 could be efficiently produced as a secreted protein from transformed Pichia pastoris (P. pastoris) yeast. Yeast-derived RBD-monomer possessed functional conformation and was able to elicit protective level of neutralizing antibodies in mice. We further designed and expressed a genetically linked dimeric RBD protein in yeast. The engineered dimeric RBD was more potent than the monomeric RBD in inducing long-lasting neutralizing antibodies. Mice immunized with either monomeric RBD or dimeric RBD were effectively protected from live SARS-CoV-2 virus challenge even at 18 weeks after the last vaccine dose. Importantly, we found that the antisera raised against the RBD of a single SARS-CoV-2 prototype strain could effectively neutralize the two predominant circulating variants B.1.1.7 and B.1.351, implying broad-spectrum protective potential of the RBD-based vaccines. Our data demonstrate that yeast-derived RBD-based recombinant SARS-CoV-2 vaccines are feasible and efficacious, opening up a new avenue for rapid and cost-effective production of SARS-CoV-2 vaccines to achieve global immunization.