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 expe...

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Main Authors: Kirill V. Kalnin, Timothy Plitnik, Michael Kishko, Jinrong Zhang, Donghui Zhang, Adrien Beauvais, Natalie G. Anosova, Tim Tibbitts, Josh DiNapoli, Gregory Ulinski, Peter Piepenhagen, Sheila M. Cummings, Dinesh S. Bangari, Susan Ryan, Po-Wei D. Huang, James Huleatt, Deanne Vincent, Katherine Fries, Shrirang Karve, Rebecca Goldman, Hardip Gopani, Anusha Dias, Khang Tran, Minnie Zacharia, Xiaobo Gu, Lianne Boeglin, Jonathan Abysalh, Jorel Vargas, Angela Beaulieu, Monic Shah, Travis Jeannotte, Kimberly Gillis, Sudha Chivukula, Ron Swearingen, Victoria Landolfi, Tong-Ming Fu, Frank DeRosa, Danilo Casimiro
Format: Article
Language:English
Published: Nature Portfolio 2021-04-01
Series:npj Vaccines
Online Access:https://doi.org/10.1038/s41541-021-00324-5
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author Kirill V. Kalnin
Timothy Plitnik
Michael Kishko
Jinrong Zhang
Donghui Zhang
Adrien Beauvais
Natalie G. Anosova
Tim Tibbitts
Josh DiNapoli
Gregory Ulinski
Peter Piepenhagen
Sheila M. Cummings
Dinesh S. Bangari
Susan Ryan
Po-Wei D. Huang
James Huleatt
Deanne Vincent
Katherine Fries
Shrirang Karve
Rebecca Goldman
Hardip Gopani
Anusha Dias
Khang Tran
Minnie Zacharia
Xiaobo Gu
Lianne Boeglin
Jonathan Abysalh
Jorel Vargas
Angela Beaulieu
Monic Shah
Travis Jeannotte
Kimberly Gillis
Sudha Chivukula
Ron Swearingen
Victoria Landolfi
Tong-Ming Fu
Frank DeRosa
Danilo Casimiro
author_facet Kirill V. Kalnin
Timothy Plitnik
Michael Kishko
Jinrong Zhang
Donghui Zhang
Adrien Beauvais
Natalie G. Anosova
Tim Tibbitts
Josh DiNapoli
Gregory Ulinski
Peter Piepenhagen
Sheila M. Cummings
Dinesh S. Bangari
Susan Ryan
Po-Wei D. Huang
James Huleatt
Deanne Vincent
Katherine Fries
Shrirang Karve
Rebecca Goldman
Hardip Gopani
Anusha Dias
Khang Tran
Minnie Zacharia
Xiaobo Gu
Lianne Boeglin
Jonathan Abysalh
Jorel Vargas
Angela Beaulieu
Monic Shah
Travis Jeannotte
Kimberly Gillis
Sudha Chivukula
Ron Swearingen
Victoria Landolfi
Tong-Ming Fu
Frank DeRosa
Danilo Casimiro
author_sort Kirill V. Kalnin
collection DOAJ
description 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.
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spelling doaj.art-9fae835e0be047258ae7c50814033e8c2023-11-02T00:40:41ZengNature Portfolionpj Vaccines2059-01052021-04-016111210.1038/s41541-021-00324-5Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal modelsKirill V. Kalnin0Timothy Plitnik1Michael Kishko2Jinrong Zhang3Donghui Zhang4Adrien Beauvais5Natalie G. Anosova6Tim Tibbitts7Josh DiNapoli8Gregory Ulinski9Peter Piepenhagen10Sheila M. Cummings11Dinesh S. Bangari12Susan Ryan13Po-Wei D. Huang14James Huleatt15Deanne Vincent16Katherine Fries17Shrirang Karve18Rebecca Goldman19Hardip Gopani20Anusha Dias21Khang Tran22Minnie Zacharia23Xiaobo Gu24Lianne Boeglin25Jonathan Abysalh26Jorel Vargas27Angela Beaulieu28Monic Shah29Travis Jeannotte30Kimberly Gillis31Sudha Chivukula32Ron Swearingen33Victoria Landolfi34Tong-Ming Fu35Frank DeRosa36Danilo Casimiro37Sanofi PasteurYoh Services LLCSanofi PasteurSanofi PasteurSanofi PasteurSanofi PasteurSanofi PasteurSanofi PasteurSanofi PasteurGlobal Discovery Pathology, SanofiGlobal Discovery Pathology, SanofiGlobal Discovery Pathology, SanofiGlobal Discovery Pathology, SanofiGlobal Discovery Pathology, SanofiSanofi PasteurSanofi PasteurSanofi PasteurSanofi PasteurTranslate BioTranslate BioTranslate BioTranslate BioTranslate BioTranslate BioTranslate BioTranslate BioTranslate BioTranslate BioTranslate BioTranslate BioTranslate BioTranslate BioSanofi PasteurTranslate BioSanofi PasteurSanofi PasteurTranslate BioSanofi PasteurAbstract 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.https://doi.org/10.1038/s41541-021-00324-5
spellingShingle Kirill V. Kalnin
Timothy Plitnik
Michael Kishko
Jinrong Zhang
Donghui Zhang
Adrien Beauvais
Natalie G. Anosova
Tim Tibbitts
Josh DiNapoli
Gregory Ulinski
Peter Piepenhagen
Sheila M. Cummings
Dinesh S. Bangari
Susan Ryan
Po-Wei D. Huang
James Huleatt
Deanne Vincent
Katherine Fries
Shrirang Karve
Rebecca Goldman
Hardip Gopani
Anusha Dias
Khang Tran
Minnie Zacharia
Xiaobo Gu
Lianne Boeglin
Jonathan Abysalh
Jorel Vargas
Angela Beaulieu
Monic Shah
Travis Jeannotte
Kimberly Gillis
Sudha Chivukula
Ron Swearingen
Victoria Landolfi
Tong-Ming Fu
Frank DeRosa
Danilo Casimiro
Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models
npj Vaccines
title Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models
title_full Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models
title_fullStr Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models
title_full_unstemmed Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models
title_short Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models
title_sort immunogenicity and efficacy of mrna covid 19 vaccine mrt5500 in preclinical animal models
url https://doi.org/10.1038/s41541-021-00324-5
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