SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness
Authors:K.S. Corbett et al.
Link to paper: https://www.biorxiv.org/content/10.1101/2020.06.11.145920v1
Key Words: Vaccine
Immunising mice with the mRNA-1273 nano-particle based vaccine (0.01µg, 0.1µg and 1µg) in a prime-boost (3wk) regimen elicits strong dose-dependent pseudovirus-neutralising antibody responses, with higher doses inducing preferential Th1 humoral and T cell responses.
A single 10µg dose of the mRNA-1273 was able to induce high pseudovirus-neutralising Ab responses 4 weeks post-vaccination and Spike peptide-reactive CD4 and CD8 T cells producing IFNy, IL2 and TNF.
Balb/c mice immunised with two doses of 1µg mRNA-1273 were protected against challenge with a mouse-adapted strain of SARS-CoV-2: there was no detectable viral load in lungs (7/7 mice) and nasal turbinates (6/7 mice) after 5- and 13-weeks post boost. Similarly, a single 10µg dose of mRNA-1273 was fully protective at 7 weeks post immunisation.
Immunisation of three mouse strains (BALB/cJ, C57BL/6J, and B6C3F1/J) with lipid nanoparticles carrying mRNA-1273, encoding a Spike protein stabilised in its prefusion conformational state, elicits dose-dependent Spike-specific antibody responses that neutralise Spike pseudotyped lentivirus. A booster vaccine three weeks after the prime considerably improved levels of neutralising antibodies. Two doses of 1µg mRNA-1273 in B6C3F1/J mice led to a balanced Th1/Th2 humoral response after 2 weeks, although with lower vaccine doses the Th2 IgG isotype IgG1 was more prevalent. Splenocytes re-stimulated with Spike peptide pools at 7 weeks post boost showed CD4 T cells producing IFNy , IL2 and TNF, IL4 and IL5 at lower vaccine doses, and absence of IL4 and IL5 at the 1µg dose in both CD4 and CD8 splenocytes, indicating induction of a Th1 response with the higher vaccine dose. The same immunisation approach protects BALB/cJ mice from viral replication in lungs (7/7 mice) and nasal turbinates (6/7 mice) after challenge with mouse-adapted SARS-CoV-2 at 5- and 13-weeks post boost. Immunisation with lower doses of mRNA-1273 (0.01µg and 0.1µg) did not prime mice for enhanced immunopathology following challenge. A single 10µg dose also induced protective immunity in BALB/cJ mice.
Impact for SARS-CoV2/COVID19 research efforts
Develop a vaccine for SARS-CoV2/COVID19
In vivo study; BALB/cJ, C57BL/6J, B6C3F1/J
In vitro study; HEK293T/17, Vero E6, Huh7.5, hACE-2-expressing 293T cell lines
Strengths and limitations of the paper
Novelty: First in vivo study in mice with the GMP produced mRNA-1273 vaccine that is currently in clinical trials.
Standing in the field: The authors illustrate the rapid development of a vaccine based on mRNA in contrast to protein subunit vaccines. However, it should be noted that no RNA-based vaccine has yet been licensed.
This is not the first RNA/lipid nanoparticle-based vaccine developed to combat COVID19 and it is difficult to compare it to other RNA-based COVID-19 vaccines in development as they are different formulations, comprising replicating or non-replicating RNA, and using different animal models to demonstrate immunogenicity and/or efficacy. In this model, a single high dose was sufficient to protect mice against a mouse-adapted strain of SARS-CoV-2.
Viral model used: SARS-CoV-2 Spike protein pseudotyped lentivirus & mouse-adapted SARS-CoV-2 (https://www.biorxiv.org/content/10.1101/2020.05.06.081497v1).
Translatability: Moderate to high (1) protective efficacy is shown here with a mouse-adapted strain of SARS-CoV-2. As this is a new and unvalidated challenge mouse model, the question of clinical relevancy remains, (2) it is already GMP produced, and (3) in Moderna’s press release (https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-interim-phase-1-data-its-mrna-vaccine) they mention unpublished Phase I clinical trial results that 25 human individuals developed SARS-CoV-2 recognizing antibody responses to levels similar to or higher than those in blood of convalescent COVID19 patients. mRNA-1273 vaccine is currently in Phase II clinical Trials.
In parallel, Sinovac Biotech’s inactivated virus vaccine is in Phase II and the Oxford-AstraZeneca viral vectored vaccine is in Phase II/III. Other RNA/DNA vaccines are currently being developed by Biontech, Curevac, Inovio and Imperial College London.
Main limitations: Immunogenicity only demonstrated in mice, not in non-human primates.
Inconsistent use of prime-boost interval (2 wk and 3 wk).
Although a promising vaccination technology, messenger RNA vaccines have not yet been approved for use in humans. As a result, little is known about the vaccine stability and long-term immunity.