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Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection

Abstract

Despite substantial improvements, influenza vaccine production—and availability—remain suboptimal. Influenza vaccines based on mRNA may offer a solution as sequence-matched, clinical-grade material could be produced reliably and rapidly in a scalable process, allowing quick response to the emergence of pandemic strains. Here we show that mRNA vaccines induce balanced, long-lived and protective immunity to influenza A virus infections in even very young and very old mice and that the vaccine remains protective upon thermal stress. This vaccine format elicits B and T cell–dependent protection and targets multiple antigens, including the highly conserved viral nucleoprotein, indicating its usefulness as a cross-protective vaccine. In ferrets and pigs, mRNA vaccines induce immunological correlates of protection and protective effects similar to those of a licensed influenza vaccine in pigs. Thus, mRNA vaccines could address substantial medical need in the area of influenza prophylaxis and the broader realm of anti-infective vaccinology.

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Figure 1: mRNA vaccination induces antigen-specific B- and T-cell immune responses in BALB/c mice.
Figure 2: Protective efficacy of mRNA vaccine against lethal virus challenge in BALB/c mice.
Figure 3: mRNA vaccine is immunogenic in newborn and aged mice and elicits durable protection.
Figure 4: Selected mRNA vaccines induce protection after single administration and protect against challenge with heterologous virus.
Figure 5: Immunogenicity of mRNA vaccine in ferrets and pigs and protective efficacy in pigs.

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Acknowledgements

We thank A. Carnitz, A. Möbes, K. Neumann, M. Queiser, N. Schneck, H. Schneider and E. Zirdum for excellent technical assistance and T. Ketterer, T. Mutzke, A. Schmid and their team for production of mRNA vaccines. We thank the following colleagues for graciously providing virus strains: M. Büttner (A/mallard/Bavaria/1/2006 (H5N1)), J. McCauley (A/Vietnam/1194/2004 (H5N1)), S. Becker (A/Regensburg/D6/2009 (H1N1v); received from M. Beer and T. Mettenleiter), O. Haller and G. Kochs (A/HongKong/1/1968 (H3N2)). We thank R. Zinkernagel and B. Schönfisch for critically reading the manuscript. This work was supported by grants from the Federal Ministry for Education and Research (BMBF), Germany (KMU-innovativ, grant no. 0315802 to T.K.) and by the Federal Ministry of Food, Agriculture and Consumer Protection (BMELV), Germany (FSI, project no. 2-43 to L.S.).

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B.P., M.S., A.B.V., E.L., D.V., K.-J.K., L.S. and T.K. conceived the project and designed experiments; B.P., M.S., A.B.V., E.L., B.H., A.T., T.S., D.V. and L.S. performed experiments; B.P., M.S., A.B.V., E.L., B.H., A.T., T.S. and D.V. did data analysis; B.P., M.S., K.-J.K., L.S. and T.K. wrote the paper.

Corresponding authors

Correspondence to Karl-Josef Kallen or Lothar Stitz.

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Competing interests

B.P., M.S., D.V., A.T., T.S., K.-J.K. and T.K. are employees of CureVac GmbH, a private company developing RNA-based vaccines and immunotherapeutics. B.P., M.S., K.-J.K., L.S. and T.K. are inventors on two patent applications claiming technical aspects of this work.

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Petsch, B., Schnee, M., Vogel, A. et al. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol 30, 1210–1216 (2012). https://doi.org/10.1038/nbt.2436

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