BNT162b vaccines protect rhesus macaques from SARS-CoV-2

Nature. 2021 Apr;592(7853):283-289. doi: 10.1038/s41586-021-03275-y. Epub 2021 Feb 1.

Abstract

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD-foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD-foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD 'down', one-RBD 'up' state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Prime-boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2-18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1-3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).

MeSH terms

  • Aging / immunology
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • Antigens, Viral / chemistry
  • Antigens, Viral / genetics
  • Antigens, Viral / immunology
  • COVID-19 / blood
  • COVID-19 / immunology*
  • COVID-19 / prevention & control*
  • COVID-19 / therapy
  • COVID-19 / virology
  • COVID-19 Vaccines / administration & dosage
  • COVID-19 Vaccines / chemistry
  • COVID-19 Vaccines / genetics
  • COVID-19 Vaccines / immunology*
  • Cell Line
  • Clinical Trials as Topic
  • Disease Models, Animal*
  • Female
  • Humans
  • Immunization, Passive
  • Internationality
  • Macaca mulatta / immunology
  • Macaca mulatta / virology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Protein Multimerization
  • RNA, Viral / analysis
  • Respiratory System / immunology
  • Respiratory System / virology
  • SARS-CoV-2 / chemistry
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / immunology*
  • Solubility
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology
  • T-Lymphocytes / immunology
  • Vaccination
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / chemistry
  • Vaccines, Synthetic / genetics
  • Vaccines, Synthetic / immunology

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antigens, Viral
  • COVID-19 Vaccines
  • RNA, Viral
  • Spike Glycoprotein, Coronavirus
  • Vaccines, Synthetic
  • mRNA Vaccine
  • spike protein, SARS-CoV-2
  • BNT162 vaccine

Supplementary concepts

  • COVID-19 serotherapy

Associated data

  • ClinicalTrials.gov/NCT04368728
  • ClinicalTrials.gov/NCT04380701