A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates

Abstract

To contain the coronavirus disease 2019 (COVID-19) pandemic, a safe and effective vaccine against the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is urgently needed in quantities sufficient to immunise large populations. In this study, we report the design, preclinical development, immunogenicity and anti-viral protective effect in rhesus macaques of the BNT162b2 vaccine candidate. BNT162b2 contains an LNP-formulated nucleoside-modified mRNA that encodes the spike glycoprotein captured in its prefusion conformation. After expression of the BNT162b2 coding sequence in cells, approximately 20% of the spike molecules are in the one-RBD ‘up’, two-RBD ‘down’ state. Immunisation of mice with a single dose of BNT162b2 induced dose level-dependent increases in pseudovirus neutralisation titers. Prime-boost vaccination of rhesus macaques elicited authentic SARS-CoV-2 neutralising geometric mean titers 10.2 to 18.0 times that of a SARS-CoV-2 convalescent human serum panel. BNT162b2 generated strong TH1 type CD4+ and IFNγ+ CD8+ T-cell responses in mice and rhesus macaques. The BNT162b2 vaccine candidate fully protected the lungs of immunised rhesus macaques from infectious SARS-CoV-2 challenge. BNT162b2 is currently being evaluated in a global, pivotal Phase 2/3 trial (NCT04368728).

BANCOVID, the first D614G variant mRNA-based vaccine candidate against SARS-CoV-2 elicits neutralizing antibody and balanced cellular immune response

“…32 The pH (7.2) of our formulation buffer for mRNA-LNP is also lower than the other relevant references (7.4~8.0). 2,7,8,9 Lower pH helps quick release of the cargo from endosomal compartment and protects mRNA from acid hydrolysis and lysosomal digestion in intracellular milieu. 33 Together, numbers of minute changes in the design context likely playing in concert and produced quick, balanced, stable Th1-IgG2-biased antibody response.…”

“…6 Several other leading vaccines under development against SARS-CoV-2 are also mRNA-based. 2,7,8,9 Lipid nanoparticle technology has been developed for effective delivery of single-stranded therapeutics like siRNA, antisense oligo, mRNA etc. The first RNA-LNP therapeutic was approved in 2018 and has set the example for clinical safety of LNP-formulated RNA.…”

A materials-science perspective on tackling COVID-19

“…Although there is no mRNA vaccine yet approved for any disease, several clinical trials are under way. For example, Pfizer Inc., in a collaboration with BioNTech AG, is working on the phase II/III clinical trial of BNT162 mRNA vaccines for COVID-19 (NCT04368728) 90 and has just announced data from preclinical studies 91 . Moderna, Inc. is currently conducting phase II clinical trials (NCT04232280) with an mRNA vaccine encoding a monoclonal antibody against cytomegalovirus 92 .…”

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“…Th1 biased T cell responses were detected in recall assays performed 12 and 28 days after vaccination. As compared to control mice that received no antigen, mice that received 5μg dose of BNT162b2 had an increased frequency of plasma cells, class switched B cells, and overall germinal center activity at 12 days post-vaccination [ 253 ].…”

“…There was no detectable viral RNA in BAL fluid at any time point sampled after challenge and no detectable viral RNA in nasal swabs three days and at subsequent time points after challenge. Thus, the vaccine protected animals from SARS-CoV-2 infection [ 253 ].…”