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Authors:K.S. Corbett et al.  

Journal/ Pre-Print:bioRxiv 

Key Words: Vaccine 

Research Highlights

  1. 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. 

  1. 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 IFNyIL2 and TNF. 

  1. 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.   

Summary 

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 TNFIL4 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  

Study Type  

In vivo study; BALB/cJ, C57BL/6J, B6C3F1/J 

In vitro studyHEK293T/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 fieldThe authors illustrate the rapid development of 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.  

Appropriate statistics:Adequate 

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) iModerna’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/IIIOther RNA/DNA vaccines are currently being developed by BiontechCurevacInovio 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.