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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Nature Portfolio
2021
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oai:doaj.org-article:9fae835e0be047258ae7c50814033e8c2021-12-02T18:27:46ZImmunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models10.1038/s41541-021-00324-52059-0105https://doaj.org/article/9fae835e0be047258ae7c50814033e8c2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41541-021-00324-5https://doaj.org/toc/2059-0105Abstract 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.Kirill V. KalninTimothy PlitnikMichael KishkoJinrong ZhangDonghui ZhangAdrien BeauvaisNatalie G. AnosovaTim TibbittsJosh DiNapoliGregory UlinskiPeter PiepenhagenSheila M. CummingsDinesh S. BangariSusan RyanPo-Wei D. HuangJames HuleattDeanne VincentKatherine FriesShrirang KarveRebecca GoldmanHardip GopaniAnusha DiasKhang TranMinnie ZachariaXiaobo GuLianne BoeglinJonathan AbysalhJorel VargasAngela BeaulieuMonic ShahTravis JeannotteKimberly GillisSudha ChivukulaRon SwearingenVictoria LandolfiTong-Ming FuFrank DeRosaDanilo CasimiroNature PortfolioarticleImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Vaccines, Vol 6, Iss 1, Pp 1-12 (2021) |
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DOAJ |
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DOAJ |
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EN |
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Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
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Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 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 |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
immunogenicity and efficacy of mrna covid-19 vaccine mrt5500 in preclinical animal models |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/9fae835e0be047258ae7c50814033e8c |
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