Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models

Kirill Kalnin ,Sheila M Cummings,Natalie G Anosova,Michael Kishko,Anusha Dias,Josh Dinapoli,Peter Piepenhagen,Kimberly Gillis,Victoria Landolfi,Frank Derosa,Deanne Vincent,Po Wei Huang ,Katherine L Fries ,James W Huleatt ,Tong Fu ,Tim Tibbitts,Jorel Vargas,Monic Shah,Gregory Ulinski,Shrirang Karve,Timothy Plitnik,Adrien Beauvais,Travis Jeannotte,Minnie Zacharia,Jonathan Abysalh,Sudha Chivukula,Khang Tran,Hardip Gopani,Jinrong Zhang,Donghui Zhang,Lianne Boeglin,Dinesh S Bangari,Rebecca Goldman,Angela Beaulieu,Xiaobo Gu,Susan Ryan,Ron Swearingen,Danilo R Casimiro

doi:10.1038/s41541-021-00324-5

Kirill Kalnin , Sheila M Cummings + Show 36 more

Open Access

https://doi.org/10.1038/s41541-021-00324-5

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Abstract

Emergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycoprotein of SARS-CoV-2. Several mRNA constructs of S-protein, including wild type, a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), as well as others, were tested in animal models for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques, and for efficacy in a Syrian golden hamster model. The selected 2P/GSAS vaccine formulation, designated MRT5500, elicited potent nAbs as measured in neutralization assays in all three preclinical models and more importantly, protected against SARS-CoV-2-induced weight loss and lung pathology in hamsters. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate (NHP), thus alleviating a hypothetical concern of potential vaccine-associated enhanced respiratory diseases known associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for entering clinical development.

Highlights

severe acute respiratory syndrome (SARS)-CoV-2, previously known as the 2019-novel coronavirus (2019-nCoV)[1], is a β-coronavirus with a yet-to-be defined zoonotic origin
45% of the total S protein monomers presented within intact SARS-CoV-2 virions have been reported as cleaved at the furin cleavage site;[32] it is not clear which form is favored by the virus to facilitate the fusion process[28,37,38,39]
We demonstrated that the peak PsV titers (D35) in mice were significantly higher than those observed in a panel of 93 convalescent sera from COVID-19 patients (Supplementary Fig. 13)

Summary

Introduction

SARS-CoV-2, previously known as the 2019-novel coronavirus (2019-nCoV)[1], is a β-coronavirus with a yet-to-be defined zoonotic origin. Consistent with the observations in the mouse study, all GSAS constructs with the exception of 6P/GSAS induced higher neutralizing titers after the second dose, with GMTs (95% CI) at D35 recorded as 425 (48; 3769) for GSAS, 772 (116; 5121) for 2P/ GSAS, 280 (11; 6970) for 2 P/GSAS/ALAYT, as compared to those of comprising just the 2P mutation vaccine group.

Results

Conclusion