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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| Format: | Article |
| Language: | English |
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Elsevier
2021-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050121001054 |
| _version_ | 1818671590520389632 |
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| author | Alec W. Freyn Matthew Pine Victoria C. Rosado Marcel Benz Hiromi Muramatsu Mitchell Beattie Ying K. Tam Florian Krammer Peter Palese Raffael Nachbagauer Meagan McMahon Norbert Pardi |
| author_facet | Alec W. Freyn Matthew Pine Victoria C. Rosado Marcel Benz Hiromi Muramatsu Mitchell Beattie Ying K. Tam Florian Krammer Peter Palese Raffael Nachbagauer Meagan McMahon Norbert Pardi |
| author_sort | Alec W. Freyn |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-17T07:26:25Z |
| format | Article |
| id | doaj.art-170090d7563642ec8a6592c47132c75d |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-17T07:26:25Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-170090d7563642ec8a6592c47132c75d2022-12-21T21:58:37ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012021-09-01228495Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in miceAlec W. Freyn0Matthew Pine1Victoria C. Rosado2Marcel Benz3Hiromi Muramatsu4Mitchell Beattie5Ying K. Tam6Florian Krammer7Peter Palese8Raffael Nachbagauer9Meagan McMahon10Norbert Pardi11Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAAcuitas Therapeutics, Vancouver, BC V6T 1Z3, CanadaAcuitas Therapeutics, Vancouver, BC V6T 1Z3, CanadaDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author: Norbert Pardi, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.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.http://www.sciencedirect.com/science/article/pii/S2329050121001054mRNAnucleoside-modifiedvaccineinfluenzauniversalantigen |
| spellingShingle | Alec W. Freyn Matthew Pine Victoria C. Rosado Marcel Benz Hiromi Muramatsu Mitchell Beattie Ying K. Tam Florian Krammer Peter Palese Raffael Nachbagauer Meagan McMahon Norbert Pardi Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice Molecular Therapy: Methods & Clinical Development mRNA nucleoside-modified vaccine influenza universal antigen |
| 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 | mRNA nucleoside-modified vaccine influenza universal antigen |
| url | http://www.sciencedirect.com/science/article/pii/S2329050121001054 |
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