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

Autor:	Freyn AW; Department 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, USA., Pine M; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Rosado VC; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Benz M; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Muramatsu H; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Beattie M; Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada., Tam YK; Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada., Krammer F; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Palese P; Department 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, USA., Nachbagauer R; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., McMahon M; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Pardi N; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2021 Jun 12; Vol. 22, pp. 84-95. Date of Electronic Publication: 2021 Jun 12 (Print Publication: 2021).
DOI:	10.1016/j.omtm.2021.06.003
Abstrakt:	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. Competing Interests: The Icahn School of Medicine has filed patents on influenza virus vaccines, naming R.N., F.K., and P.P. as inventors. In accordance with the University of Pennsylvania policies and procedures and our ethical obligations as researchers, we report that N.P. and Y.K.T. are named on a patent describing the use of nucleoside-modified mRNA in lipid nanoparticles as a vaccine platform. N.P., R.N., P.P., F.K., and A.W.F. are named on a patent filed on universal influenza vaccines using nucleoside-modified mRNA. We have disclosed those interests fully to the University of Pennsylvania and The Icahn School of Medicine at Mount Sinai, and we have in place an approved plan for managing any potential conflicts arising from licensing of our patents. M. Beattie and Y.K.T. are employees of Acuitas Therapeutics, a company focused on the development of LNP nucleic acid delivery systems for therapeutic applications. (© 2021 The Authors.)
Databáze:	MEDLINE
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