Nucleoside-modified MRNA Immunization Elicits Influenza Virus Hemagglutinin Stalk-specific Antibodies

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Aug 24

PMID 30135514

Citations 145

Authors

Norbert Pardi

Kaela Parkhouse

Ericka Kirkpatrick

Meagan McMahon

Seth J Zost

Barbara L Mui

Ying K Tam

Katalin Kariko

Christopher J Barbosa

Thomas D Madden

Michael J Hope

Florian Krammer

Scott E Hensley

Drew Weissman

Affiliations

Soon will be listed here.

Abstract

Currently available influenza virus vaccines have inadequate effectiveness and are reformulated annually due to viral antigenic drift. Thus, development of a vaccine that confers long-term protective immunity against antigenically distant influenza virus strains is urgently needed. The highly conserved influenza virus hemagglutinin (HA) stalk represents one of the potential targets of broadly protective/universal influenza virus vaccines. Here, we evaluate a potent broadly protective influenza virus vaccine candidate that uses nucleoside-modified and purified mRNA encoding full-length influenza virus HA formulated in lipid nanoparticles (LNPs). We demonstrate that immunization with HA mRNA-LNPs induces antibody responses against the HA stalk domain of influenza virus in mice, rabbits, and ferrets. The HA stalk-specific antibody response is associated with protection from homologous, heterologous, and heterosubtypic influenza virus infection in mice.

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References

Terajima M, Cruz J, Co M, Lee J, Kaur K, Wrammert J . Complement-dependent lysis of influenza a virus-infected cells by broadly cross-reactive human monoclonal antibodies. J Virol. 2011; 85(24):13463-7. PMC: 3233150. DOI: 10.1128/JVI.05193-11. View

Swain S, Agrewala J, Brown D, Jelley-Gibbs D, Golech S, Huston G . CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza. Immunol Rev. 2006; 211:8-22. PMC: 2266984. DOI: 10.1111/j.0105-2896.2006.00388.x. View

Scorza F, Pardi N . New Kids on the Block: RNA-Based Influenza Virus Vaccines. Vaccines (Basel). 2018; 6(2). PMC: 6027361. DOI: 10.3390/vaccines6020020. View

Valkenburg S, Mallajosyula V, Li O, Chin A, Carnell G, Temperton N . Stalking influenza by vaccination with pre-fusion headless HA mini-stem. Sci Rep. 2016; 6:22666. PMC: 4780079. DOI: 10.1038/srep22666. View

Nachbagauer R, Choi A, Hirsh A, Margine I, Iida S, Barrera A . Defining the antibody cross-reactome directed against the influenza virus surface glycoproteins. Nat Immunol. 2017; 18(4):464-473. PMC: 5360498. DOI: 10.1038/ni.3684. View

Krammer F, Palese P . Influenza virus hemagglutinin stalk-based antibodies and vaccines. Curr Opin Virol. 2013; 3(5):521-30. PMC: 3804342. DOI: 10.1016/j.coviro.2013.07.007. View

Corti D, Suguitan Jr A, Pinna D, Silacci C, Fernandez-Rodriguez B, Vanzetta F . Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J Clin Invest. 2010; 120(5):1663-73. PMC: 2860935. DOI: 10.1172/JCI41902. View

Pardi N, Weissman D . Nucleoside Modified mRNA Vaccines for Infectious Diseases. Methods Mol Biol. 2016; 1499:109-121. DOI: 10.1007/978-1-4939-6481-9_6. View

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

10.

Xu R, Ekiert D, Krause J, Hai R, Crowe Jr J, Wilson I . Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science. 2010; 328(5976):357-60. PMC: 2897825. DOI: 10.1126/science.1186430. View

11.

Bahl K, Senn J, Yuzhakov O, Bulychev A, Brito L, Hassett K . Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses. Mol Ther. 2017; 25(6):1316-1327. PMC: 5475249. DOI: 10.1016/j.ymthe.2017.03.035. View

12.

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

13.

Chahal J, Khan O, Cooper C, McPartlan J, Tsosie J, Tilley L . Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Proc Natl Acad Sci U S A. 2016; 113(29):E4133-42. PMC: 4961123. DOI: 10.1073/pnas.1600299113. View

14.

Andrews S, Graham B, Mascola J, McDermott A . Is It Possible to Develop a "Universal" Influenza Virus Vaccine? Immunogenetic Considerations Underlying B-Cell Biology in the Development of a Pan-Subtype Influenza A Vaccine Targeting the Hemagglutinin Stem. Cold Spring Harb Perspect Biol. 2017; 10(7). PMC: 6028068. DOI: 10.1101/cshperspect.a029413. View

15.

Lutz J, Lazzaro S, Habbeddine M, Schmidt K, Baumhof P, Mui B . Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. NPJ Vaccines. 2017; 2:29. PMC: 5648897. DOI: 10.1038/s41541-017-0032-6. View

16.

Wu N, Zost S, Thompson A, Oyen D, Nycholat C, McBride R . A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine. PLoS Pathog. 2017; 13(10):e1006682. PMC: 5667890. DOI: 10.1371/journal.ppat.1006682. View

17.

Pardi N, Tuyishime S, Muramatsu H, Kariko K, Mui B, Tam Y . Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J Control Release. 2015; 217:345-51. PMC: 4624045. DOI: 10.1016/j.jconrel.2015.08.007. View

18.

Li Y, Myers J, Bostick D, Sullivan C, Madara J, Linderman S . Immune history shapes specificity of pandemic H1N1 influenza antibody responses. J Exp Med. 2013; 210(8):1493-500. PMC: 3727314. DOI: 10.1084/jem.20130212. View

19.

Kariko K, Muramatsu H, Welsh F, Ludwig J, Kato H, Akira S . Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. 2008; 16(11):1833-40. PMC: 2775451. DOI: 10.1038/mt.2008.200. View

20.

Krammer F, Margine I, Tan G, Pica N, Krause J, Palese P . A carboxy-terminal trimerization domain stabilizes conformational epitopes on the stalk domain of soluble recombinant hemagglutinin substrates. PLoS One. 2012; 7(8):e43603. PMC: 3426533. DOI: 10.1371/journal.pone.0043603. View