A Multivalent Nucleoside-modified MRNA Vaccine Against All Known Influenza Virus Subtypes

Overview

Journal Science

Specialty Science

Date 2022 Nov 24

PMID 36423275

Authors

Claudia P Arevalo

Marcus J Bolton

Valerie Le Sage

Naiqing Ye

Colleen Furey

Hiromi Muramatsu

Mohamad-Gabriel Alameh

Norbert Pardi

Elizabeth M Drapeau

Kaela Parkhouse

Tyler Garretson

Jeffrey S Morris

Louise H Moncla

Ying K Tam

Steven H Y Fan

Seema S Lakdawala

Drew Weissman

Scott E Hensley

Affiliations

Soon will be listed here.

Abstract

Seasonal influenza vaccines offer little protection against pandemic influenza virus strains. It is difficult to create effective prepandemic vaccines because it is uncertain which influenza virus subtype will cause the next pandemic. In this work, we developed a nucleoside-modified messenger RNA (mRNA)-lipid nanoparticle vaccine encoding hemagglutinin antigens from all 20 known influenza A virus subtypes and influenza B virus lineages. This multivalent vaccine elicited high levels of cross-reactive and subtype-specific antibodies in mice and ferrets that reacted to all 20 encoded antigens. Vaccination protected mice and ferrets challenged with matched and mismatched viral strains, and this protection was at least partially dependent on antibodies. Our studies indicate that mRNA vaccines can provide protection against antigenically variable viruses by simultaneously inducing antibodies against multiple antigens.

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References

Harrington W, Kackos C, Webby R . The evolution and future of influenza pandemic preparedness. Exp Mol Med. 2021; 53(5):737-749. PMC: 8099712. DOI: 10.1038/s12276-021-00603-0. View

Corbett K, Moin S, Yassine H, Cagigi A, Kanekiyo M, Boyoglu-Barnum S . Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages. mBio. 2019; 10(1). PMC: 6391921. DOI: 10.1128/mBio.02810-18. View

Pardi N, Parkhouse K, Kirkpatrick E, McMahon M, Zost S, Mui B . Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat Commun. 2018; 9(1):3361. PMC: 6105651. DOI: 10.1038/s41467-018-05482-0. View

Krammer F, Smith G, Fouchier R, Peiris M, Kedzierska K, Doherty P . Influenza. Nat Rev Dis Primers. 2018; 4(1):3. PMC: 7097467. DOI: 10.1038/s41572-018-0002-y. View

Lederer K, Bettini E, Parvathaneni K, Painter M, Agarwal D, Lundgreen K . Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals. Cell. 2022; 185(6):1008-1024.e15. PMC: 8808747. DOI: 10.1016/j.cell.2022.01.027. View

Pardi N, Hogan M, Porter F, Weissman D . mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 2018; 17(4):261-279. PMC: 5906799. DOI: 10.1038/nrd.2017.243. View

Nelson M, Lloyd-Smith J, Simonsen L, Rambaut A, Holmes E, Chowell G . Fogarty International Center collaborative networks in infectious disease modeling: Lessons learnt in research and capacity building. Epidemics. 2018; 26:116-127. PMC: 7105018. DOI: 10.1016/j.epidem.2018.10.004. View

McLean G, Kamil J, Lee B, Moore P, Schulz T, Muik A . The Impact of Evolving SARS-CoV-2 Mutations and Variants on COVID-19 Vaccines. mBio. 2022; 13(2):e0297921. PMC: 9040821. DOI: 10.1128/mbio.02979-21. View

Willis E, Pardi N, Parkhouse K, Mui B, Tam Y, Weissman D . Nucleoside-modified mRNA vaccination partially overcomes maternal antibody inhibition of de novo immune responses in mice. Sci Transl Med. 2020; 12(525). PMC: 7339908. DOI: 10.1126/scitranslmed.aav5701. View

10.

Sheikh A, McMenamin J, Taylor B, Robertson C . SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet. 2021; 397(10293):2461-2462. PMC: 8201647. DOI: 10.1016/S0140-6736(21)01358-1. View

11.

Erbelding E, Post D, Stemmy E, Roberts P, Augustine A, Ferguson S . A Universal Influenza Vaccine: The Strategic Plan for the National Institute of Allergy and Infectious Diseases. J Infect Dis. 2018; 218(3):347-354. PMC: 6279170. DOI: 10.1093/infdis/jiy103. View

12.

Nachbagauer R, Feser J, Naficy A, Bernstein D, Guptill J, Walter E . A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial. Nat Med. 2020; 27(1):106-114. DOI: 10.1038/s41591-020-1118-7. View

13.

Schwartzman L, Cathcart A, Pujanauski L, Qi L, Kash J, Taubenberger J . An Intranasal Virus-Like Particle Vaccine Broadly Protects Mice from Multiple Subtypes of Influenza A Virus. mBio. 2015; 6(4):e01044. PMC: 4513078. DOI: 10.1128/mBio.01044-15. View

14.

DiLillo D, Tan G, Palese P, Ravetch J . Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo. Nat Med. 2014; 20(2):143-51. PMC: 3966466. DOI: 10.1038/nm.3443. View

15.

He W, Tan G, Mullarkey C, Lee A, Lam M, Krammer F . Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus. Proc Natl Acad Sci U S A. 2016; 113(42):11931-11936. PMC: 5081650. DOI: 10.1073/pnas.1609316113. View

16.

Leon P, He W, Mullarkey C, Bailey M, Miller M, Krammer F . Optimal activation of Fc-mediated effector functions by influenza virus hemagglutinin antibodies requires two points of contact. Proc Natl Acad Sci U S A. 2016; 113(40):E5944-E5951. PMC: 5056099. DOI: 10.1073/pnas.1613225113. View

17.

Yassine H, Boyington J, McTamney P, Wei C, Kanekiyo M, Kong W . Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat Med. 2015; 21(9):1065-70. DOI: 10.1038/nm.3927. View

18.

Pardi N, Hogan M, Naradikian M, Parkhouse K, Cain D, Jones L . Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med. 2018; 215(6):1571-1588. PMC: 5987916. DOI: 10.1084/jem.20171450. View

19.

Freyn A, Silva J, Rosado V, Bliss C, Pine M, Mui B . A Multi-Targeting, Nucleoside-Modified mRNA Influenza Virus Vaccine Provides Broad Protection in Mice. Mol Ther. 2020; 28(7):1569-1584. PMC: 7335735. DOI: 10.1016/j.ymthe.2020.04.018. View

20.

Pardi N, Hogan M, Weissman D . Recent advances in mRNA vaccine technology. Curr Opin Immunol. 2020; 65:14-20. DOI: 10.1016/j.coi.2020.01.008. View