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

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.

Development of an mRNA-LNP Vaccine against SARS-CoV-2: Evaluation of Immune Response in Mouse and Rhesus Macaque

“…Although there are disputed opinions in the literature about the effect of LNP size on its entrapping capability as well as cell entry, our LNPs demonstrated interesting encapsulation and transfection efficiencies (even in the KG-1 cell line with a low transfection rate) as well. The observed cell surface localization was in agreement to what was formerly reported when either a wild-type or 2P mutant spike encoding mRNA was used [25]. The stability and accelerated shelf-life of mRNA-LNP vaccines were examined after one month of being refrigerated.…”

An Update on mRNA-Based Viral Vaccines

“…Moderna mRNA-1273 vaccine expresses prefusion S protein via two consecutive proline substitutions (2P; K986P and V987P) and retains an intact S1–S2 cleavage site [ 7 , 30 ]. TranslateBio mRNA S prefusion vaccine (MRT55500) was stabilized by dual mutations of 2P and the cleavage site (GSAS from RRAR polybasic residues), which was selected from comparison of wild type S and multiple S mutants including 2P, GSAS, 2P/GSAS, 6P, and 6P/GSAS in mice and non-human primates [ 109 ]. Novavax SARS-CoV-2 S nanoparticle protein vaccine candidate (NVX-CoV2373) is a full-length spike with similar double mutant 2P–3Q (QQAQ from RRAR cleavage site) [ 110 ].…”

Counting on COVID-19 Vaccine: Insights into the Current Strategies, Progress and Future Challenges

“…However, due to inadequate immune response as observed in phase I clinical trial (NCT04679909), further development of AdCOVID was suspended [ 260 ]. MRT5500, a double mutant RNA vaccine candidate expressing S protein (2P/GSAS S mRNA) of SARS-CoV-2 developed under collaboration between Sanofi Pasteur and Translate Bio, which exhibited potential immunogenic response by activating neutralizing antibodies and Th1-mediated immune response in preclinical studies [ 261 ]. Owing to preclinical success, the developer initiated Phase I/II clinical trial (NCT04798027) of MRT5500 [ 262 ].…”