Molecular Aspects Concerning the Use of the SARS-CoV-2 Receptor Binding Domain as a Target for Preventive Vaccines.

Lila Castellanos-Serra,Darielys Santana-Mederos,Daniel G. Rivera,Laura Rodríguez,Raine Garrido,Yanet Climent,Sonsire Fernandez,Guang-Wu Chen,Vicente Verez-Bencomo,Françoise Paquet,Fabrizio Chiodo,Kalet Leon,Belinda Sanchez Ramirez,Yury Valdes-Balbin,Tays Hernandez,Dagmar Garcia-Rivera

doi:10.1021/acscentsci.1c00216

Abstract

The development of recombinant COVID-19 vaccines has resulted from scientific progress made at an unprecedented speed during 2020. The recombinant spike glycoprotein monomer, its trimer, and its recombinant receptor-binding domain (RBD) induce a potent anti-RBD neutralizing antibody response in animals. In COVID-19 convalescent sera, there is a good correlation between the antibody response and potent neutralization. In this review, we summarize with a critical view the molecular aspects associated with the interaction of SARS-CoV-2 RBD with its receptor in human cells, the angiotensin-converting enzyme 2 (ACE2), the epitopes involved in the neutralizing activity, and the impact of virus mutations thereof. Recent trends in RBD-based vaccines are analyzed, providing detailed insights into the role of antigen display and multivalence in the immune response of vaccines under development.

Highlights

Viral infections are initiated with the binding of viral particles to the host’s surface cellular receptors, a process that defines the virus’s cellular and tissue tropism
The cryoelectron microscopy (CEM) of SARS-CoV-2 S-glycoprotein reveals a predominance of the “down” conformation,[36] which is ineffective for binding the receptor
The receptor-binding domain (RBD)−angiotensinconverting enzyme 2 (ACE2) interaction is essential for SARS-CoV-2 infectivity

Summary

INTRODUCTION

Viral infections are initiated with the binding of viral particles to the host’s surface cellular receptors, a process that defines the virus’s cellular and tissue tropism. In SARS-CoV-2, this process is mediated by the viral spike (S) glycoprotein trimer on the virion surface through its receptor-binding domain (RBD). SARS-CoV-2 uses the same host-cell entry receptor as SARS-CoV, ACE2,3 which is expressed, among others, in specific subsets of human respiratory epithelial cells in nasal passages, airways, and alveoli.[4] S-Glycoprotein trimers have most of the time all RBDs in a hidden conformation, the “down” conformation, which seeks to evade immune recognition but, at the same time, cannot interact with ACE2. Recombinant protein subunit vaccines in clinical development include recombinant SARS-CoV-2 proteins as active components: (i) S-glycoprotein monomer,[6] (ii) S-glycoprotein trimer,[7,8] and (iii) RBD-based immunogens with several forms of antigen display (monomeric, dimeric, or multivalent, vide infra). Attention is paid to how these aspects relate to vaccine development, as well as to the different types of RBD displays in vaccine candidates

STRUCTURE OF SARS-CoV-2 RBD AND ITS INTERACTION WITH THE hACE2 RECEPTOR

SARS-CoV-2 RBD AS A TARGET FOR NEUTRALIZING ANTIBODIES

ANTIGEN ORIENTATION AND MULTIVALENT DISPLAY IN RBD-BASED VACCINES

CONCLUSIONS

METHODS

Findings

■ REFERENCES