Potent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants

Tingting Li,Yanan Zhang,Zherui Zhang,Yang Wu,Xiaojian Han,Luo Li,Bo Zhang,Hangtian Guo,Feiyang Luo,Zhenghong Yuan,Shenglong Li,Chao Hu,Feng Gao ,Wei Wang,Jie Hu,Jingjing Huang,Guiji Zhang,Xiaoyun Ji,Yan Gao,Hongqing Zhang,Xiujun Cai ,Meiying Shen,Youhua Xie,Chaojun He ,Aiping Huang ,Fengjiang Liu,Yanan Hao,Qi Gao ,Song Mu,Ni Tang,Wei Xü ,Haitao Yang,Kai Wang,Huajun Zhang,Yingyi Long,Shunhua Long,Di Qu,Qian Chen,Cheng Gu ,Ying‐Ming Wang ,Jianwei Wang,Wang Wang,Na Li,Shuyi Song,Ruixue Wu ,Aishun Jin

doi:10.1038/s41467-021-26539-7

Abstract

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470–495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450–458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

Highlights

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions
By our recently established rapid neutralizing Abs screening system[23], we have successfully obtained 20 neutralizing Abs with high affinities to receptor binding domain (RBD) from COVID-19 convalescent individuals, and their neutralizing potency was confirmed by the half inhibition concentrations (IC50s) against authentic SARS-CoV-2 virus quantified via qRT-PCR (Fig. 1a, c and Supplementary Fig. 1)
3 RBD specific monoclonal antibodies (mAbs) demonstrated potent neutralizing efficacy against authentic SARS-CoV-2 and B.1.351 viruses, suggesting that our neutralizing Abs might be applied for the current COVID-19 pandemic

Summary

Introduction

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Transmissible SARS-CoV-2 variants, such as B.1.351 emerged in South Africa, harbor multiple immune escape mutations, and have raised global concerns for the efficacy of available interventions and for reinfection[2,3,4,5,6,7,8,9,11] As these challenges presented, the protective efficacy of current antibody-based countermeasures needs to be thoroughly assessed against the current mutational variants. A small group of SARSCoV-2 RBD specific neutralizing Abs demonstrated undisturbed in vitro potency against B.1.3512–7,9 Evaluating their therapeutic efficacy against the circulating strains is necessary for the reformulation of protective interventions and vaccines against the evolving pandemic. Our study has characterized a pair of neutralizing Abs with potential effective therapeutic value in clinical applications, which may provide updated information for RBD specific mAbs against the prolonged COVID-19 pandemic

Methods

Results

Conclusion