A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS

Cell. 2020 Aug 6;182(3):722-733.e11. doi: 10.1016/j.cell.2020.06.035. Epub 2020 Jun 28.

Abstract

Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously emerging MERS/SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs. Structure-guided design further yielded a stable version of RBD-dimer as a tandem repeat single-chain (RBD-sc-dimer) which retained the vaccine potency. We generalized this strategy to design vaccines against COVID-19 and SARS, achieving 10- to 100-fold enhancement of NAb titers. RBD-sc-dimers in pilot scale production yielded high yields, supporting their scalability for further clinical development. The framework of immunogen design can be universally applied to other beta-CoV vaccines to counter emerging threats.

Keywords: COVID-19; MERS; MERS-CoV; SARS; SARS-CoV; SARS-CoV-2; betacoronavirus; coronavirus; receptor-binding domain (RBD); vaccine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • Betacoronavirus / chemistry
  • Betacoronavirus / immunology*
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Coronavirus Infections / prevention & control*
  • Coronavirus Infections / virology
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Middle East Respiratory Syndrome Coronavirus / chemistry
  • Middle East Respiratory Syndrome Coronavirus / immunology*
  • Pandemics / prevention & control*
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / prevention & control*
  • Pneumonia, Viral / virology
  • Protein Binding
  • Protein Interaction Domains and Motifs / immunology
  • Receptors, Virus / metabolism
  • SARS Virus / chemistry
  • SARS Virus / immunology*
  • Sf9 Cells
  • Specific Pathogen-Free Organisms
  • Spodoptera
  • Transfection
  • Universal Design*
  • Vaccination / methods
  • Vero Cells
  • Viral Vaccines

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19 vaccine
  • Receptors, Virus
  • Viral Vaccines
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2

Supplementary concepts

  • COVID-19
  • severe acute respiratory syndrome coronavirus 2