The E484K Substitution in a SARS-CoV-2 Spike Protein Subunit Vaccine Resulted in Limited Cross-Reactive Neutralizing Antibody Responses in Mice
Longbo Hu,
Yuhua Xu,
Liping Wu,
Jin Feng,
Lu Zhang,
Yongjie Tang,
Xiang Zhao,
Runming Mai,
Liyun Chen,
Lingling Mei,
Yuanzhen Tan,
Yingying Du,
Yanping Zhen,
Wenhan Su,
Tao Peng
Affiliations
Longbo Hu
State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
Yuhua Xu
Guangdong South China Vaccine Co., Ltd., Guangzhou 510663, China
Liping Wu
State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
Jin Feng
State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
Lu Zhang
Guangzhou Customs District Technology Center, Guangzhou 510665, China
Yongjie Tang
State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
Xiang Zhao
State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
Runming Mai
Guangdong South China Vaccine Co., Ltd., Guangzhou 510663, China
Liyun Chen
Guangdong South China Vaccine Co., Ltd., Guangzhou 510663, China
Lingling Mei
State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
Yuanzhen Tan
Guangdong South China Vaccine Co., Ltd., Guangzhou 510663, China
Yingying Du
Guangdong South China Vaccine Co., Ltd., Guangzhou 510663, China
Yanping Zhen
Guangdong South China Vaccine Co., Ltd., Guangzhou 510663, China
Wenhan Su
Guangdong South China Vaccine Co., Ltd., Guangzhou 510663, China
Tao Peng
State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially emerging variants, poses an increased threat to global public health. The significant reduction in neutralization activity against the variants such as B.1.351 in the serum of convalescent patients and vaccinated people calls for the design of new potent vaccines targeting the emerging variant. However, since most vaccines approved and in clinical trials are based on the sequence of the original SARS-CoV-2 strain, the immunogenicity and protective efficacy of vaccines based on the B.1.351 variant remain largely unknown. In this study, we evaluated the immunogenicity, induced neutralization activity, and protective efficacy of wild-type spike protein nanoparticle (S-2P) and mutant spike protein nanoparticle (S-4M-2P) carrying characteristic mutations of B.1.351 variant in mice. Although there was no significant difference in the induction of spike-specific IgG responses in S-2P- and S-4M-2P-immunized mice, neutralizing antibodies elicited by S-4M-2P exhibited noteworthy, narrower breadth of reactivity with SARS-CoV-2 variants compared with neutralizing antibodies elicited by S-2P. Furthermore, the decrease of induced neutralizing antibody breadth at least partly resulted from the amino acid substitution at position 484. Moreover, S-4M-2P vaccination conferred insufficient protection against live SARS-CoV-2 virus infection, while S-2P vaccination gave definite protection against SARS-CoV-2 challenge in mice. Together, our study provides direct evidence that the E484K substitution in a SARS-CoV-2 subunit protein vaccine limited the cross-reactive neutralizing antibody breadth in mice and, more importantly, draws attention to the unfavorable impact of this mutation in spike protein of SARS-CoV-2 variants on the induction of potent neutralizing antibody responses.
