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Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice

Nucleoside-modified, lipid nanoparticle-encapsulated mRNAs have recently emerged as suitable vaccines for influenza viruses and other pathogens in part because the platform allows delivery of multiple antigens in a single immunization. mRNA vaccines allow for easy antigen modification, enabling rapi...

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Autores principales: Freyn, Alec W., Pine, Matthew, Rosado, Victoria C., Benz, Marcel, Muramatsu, Hiromi, Beattie, Mitchell, Tam, Ying K., Krammer, Florian, Palese, Peter, Nachbagauer, Raffael, McMahon, Meagan, Pardi, Norbert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390451/
https://www.ncbi.nlm.nih.gov/pubmed/34485597
http://dx.doi.org/10.1016/j.omtm.2021.06.003
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author Freyn, Alec W.
Pine, Matthew
Rosado, Victoria C.
Benz, Marcel
Muramatsu, Hiromi
Beattie, Mitchell
Tam, Ying K.
Krammer, Florian
Palese, Peter
Nachbagauer, Raffael
McMahon, Meagan
Pardi, Norbert
author_facet Freyn, Alec W.
Pine, Matthew
Rosado, Victoria C.
Benz, Marcel
Muramatsu, Hiromi
Beattie, Mitchell
Tam, Ying K.
Krammer, Florian
Palese, Peter
Nachbagauer, Raffael
McMahon, Meagan
Pardi, Norbert
author_sort Freyn, Alec W.
collection PubMed
description Nucleoside-modified, lipid nanoparticle-encapsulated mRNAs have recently emerged as suitable vaccines for influenza viruses and other pathogens in part because the platform allows delivery of multiple antigens in a single immunization. mRNA vaccines allow for easy antigen modification, enabling rapid iterative design. We studied protein modifications such as mutating functional sites, changing secretion potential, and altering protein conformation, which could improve the safety and/or potency of mRNA-based influenza virus vaccines. Mice were vaccinated intradermally with wild-type or mutant constructs of influenza virus hemagglutinin (HA), neuraminidase (NA), matrix protein 2 (M2), nucleoprotein (NP), or matrix protein 1 (M1). Membrane-bound HA constructs elicited more potent and protective antibody responses than secreted forms. Altering the catalytic site of NA to reduce enzymatic activity decreased reactogenicity while protective immunity was maintained. Disruption of M2 ion channel activity improved immunogenicity and protective efficacy. A comparison of internal proteins NP and M1 revealed the superiority of NP in conferring protection from influenza virus challenge. These findings support the use of the nucleoside-modified mRNA platform for guided antigen design for influenza virus with extension to other pathogens.
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spelling pubmed-83904512021-09-03 Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice Freyn, Alec W. Pine, Matthew Rosado, Victoria C. Benz, Marcel Muramatsu, Hiromi Beattie, Mitchell Tam, Ying K. Krammer, Florian Palese, Peter Nachbagauer, Raffael McMahon, Meagan Pardi, Norbert Mol Ther Methods Clin Dev Original Article Nucleoside-modified, lipid nanoparticle-encapsulated mRNAs have recently emerged as suitable vaccines for influenza viruses and other pathogens in part because the platform allows delivery of multiple antigens in a single immunization. mRNA vaccines allow for easy antigen modification, enabling rapid iterative design. We studied protein modifications such as mutating functional sites, changing secretion potential, and altering protein conformation, which could improve the safety and/or potency of mRNA-based influenza virus vaccines. Mice were vaccinated intradermally with wild-type or mutant constructs of influenza virus hemagglutinin (HA), neuraminidase (NA), matrix protein 2 (M2), nucleoprotein (NP), or matrix protein 1 (M1). Membrane-bound HA constructs elicited more potent and protective antibody responses than secreted forms. Altering the catalytic site of NA to reduce enzymatic activity decreased reactogenicity while protective immunity was maintained. Disruption of M2 ion channel activity improved immunogenicity and protective efficacy. A comparison of internal proteins NP and M1 revealed the superiority of NP in conferring protection from influenza virus challenge. These findings support the use of the nucleoside-modified mRNA platform for guided antigen design for influenza virus with extension to other pathogens. American Society of Gene & Cell Therapy 2021-06-12 /pmc/articles/PMC8390451/ /pubmed/34485597 http://dx.doi.org/10.1016/j.omtm.2021.06.003 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Freyn, Alec W.
Pine, Matthew
Rosado, Victoria C.
Benz, Marcel
Muramatsu, Hiromi
Beattie, Mitchell
Tam, Ying K.
Krammer, Florian
Palese, Peter
Nachbagauer, Raffael
McMahon, Meagan
Pardi, Norbert
Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice
title Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice
title_full Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice
title_fullStr Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice
title_full_unstemmed Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice
title_short Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice
title_sort antigen modifications improve nucleoside-modified mrna-based influenza virus vaccines in mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390451/
https://www.ncbi.nlm.nih.gov/pubmed/34485597
http://dx.doi.org/10.1016/j.omtm.2021.06.003
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