Design of a mutation-integrated trimeric RBD with broad protection against SARS-CoV-2

Yu Liang,Run Yu Yuan,Ru Qin Gao,Ji Guo Su,Zi Bo Han,Si Yu Ren,Ya Nan Hou,Jin Juan Wu,Fu Jie Shen,Chang Wen Ke,Mei Yu Wang,Gui Zhen Wu,Ze Hua Lei,Shuai Shao,Xue Feng Zhang,Zhao Ming Liu,Qi Ming Li,Li Fang Du,Fan Zheng,Peng He,Wei Zhen,Ke Xu,Hao Zhang,Hai‐Jing Zhong ,Jun Hou ,Xiang Zheng,Jing Zhang,Shi Chen,Ning Liu,Shuo Liu,Zhi Jing ,Weijin Huang ,Fang Tang,Jing Yu ,Wei Zhou

doi:10.1038/s41421-022-00383-5

Abstract

The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen. When compared with a homo-tri-RBD vaccine candidate in the stage of phase II trial, of which all three RBDs are derived from the SARS-CoV-2 prototype strain, mutI-tri-RBD induced significantly higher neutralizing antibody titers against the Delta and Beta variants, and maintained a similar immune response against the prototype strain. Pseudo-virus neutralization assay demonstrated that mutI-tri-RBD also induced broadly strong neutralizing activities against all tested 23 SARS-CoV-2 variants. The in vivo protective capability of mutI-tri-RBD was further validated in hACE2-transgenic mice challenged by the live virus, and the results showed that mutI-tri-RBD provided potent protection not only against the SARS-CoV-2 prototype strain but also against the Delta and Beta variants.

Highlights

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has spread rapidly around the world since the end of 2019 and resulted in a pandemic of this new coronavirus infections[1,2], which has imposed a big threat to public health and a heavy burden on the global economy
CoV-2 to host cells, which is immunodominant in eliciting neutralizing antibody responses
As of October 2021, at least 23 receptor-binding domain (RBD)-based vaccine candidates are under clinical trials, among which a dimeric RBD-based protein subunit vaccine, ZF2001, has been authorized for emergency use[38]

Summary

Introduction

(SARS-CoV-2) has spread rapidly around the world since the end of 2019 and resulted in a pandemic of this new coronavirus infections[1,2], which has imposed a big threat to public health and a heavy burden on the global economy. New variants are continuously emerging due to the fast evolution of the virus. SARS-CoV-2 strains, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2), are classified as variants of concern by WHO. More lines of evidence have demonstrated the increased transmissibility and virulence of these viriants[6,7,8]. The Beta and Gamma variants have been proved to be able to evade the neutralizing antibodies elicited by natural infections and vaccinations[10].

Methods

Results

Conclusion