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Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies

Nature volume 499, pages 102–106 (2013)Cite this article

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Abstract

Influenza viruses pose a significant threat to the public and are a burden on global health systems1,2. Each year, influenza vaccines must be rapidly produced to match circulating viruses, a process constrained by dated technology and vulnerable to unexpected strains emerging from humans and animal reservoirs. Here we use knowledge of protein structure to design self-assembling nanoparticles that elicit broader and more potent immunity than traditional influenza vaccines. The viral haemagglutinin was genetically fused to ferritin, a protein that naturally forms nanoparticles composed of 24 identical polypeptides3. Haemagglutinin was inserted at the interface of adjacent subunits so that it spontaneously assembled and generated eight trimeric viral spikes on its surface. Immunization with this influenza nanoparticle vaccine elicited haemagglutination inhibition antibody titres more than tenfold higher than those from the licensed inactivated vaccine. Furthermore, it elicited neutralizing antibodies to two highly conserved vulnerable haemagglutinin structures that are targets of universal vaccines: the stem4,5 and the receptor binding site on the head6,7. Antibodies elicited by a 1999 haemagglutinin–nanoparticle vaccine neutralized H1N1 viruses from 1934 to 2007 and protected ferrets from an unmatched 2007 H1N1 virus challenge. This structure-based, self-assembling synthetic nanoparticle vaccine improves the potency and breadth of influenza virus immunity, and it provides a foundation for building broader vaccine protection against emerging influenza viruses and other pathogens.

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Figure 1: Molecular design and characterization of ferritin nanoparticles displaying influenza virus HA.
Figure 2: Immune responses in HA-nanoparticle-immunized mice.
Figure 3: Protective immunity induced in ferrets immunized with the HA-nanoparticles.
Figure 4: Improved neutralization breadth and detection of stem- and RBS-directed antibodies.

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Acknowledgements

We thank H. Andersen, A. Taylor, A. Zajac and C. Chiedi for help with the animal studies; U. Baxa, K. Nagashima and A. Harned for electron microscopy studies; X. Chen for technical support; A. Panet, B. Graham, R. Schwartz and members of the Nabel lab for discussions; S. Sun and M. Rossmann for technical and conceptual advice; A. Tislerics, B. Hartman and J. Farrar for manuscript preparation. The MF59 adjuvant was kindly provided by Novartis. This work was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health.

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Author notes

  1. Patrick M. McTamney & Gary J. Nabel

    Present address: Present addresses: MedImmune, 1 MedImmune Way, Gaithersburg, Maryland 20878, USA (P.M.M.); Sanofi, 640 Memorial Drive, Cambridge, Massachusetts 02139, USA (G.J.N.).,

Authors and Affiliations

  1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Masaru Kanekiyo, Chih-Jen Wei, Hadi M. Yassine, Patrick M. McTamney, Jeffrey C. Boyington, James R. R. Whittle, Srinivas S. Rao, Wing-Pui Kong, Lingshu Wang & Gary J. Nabel

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Contributions

M.K., J.C.B. and G.J.N. developed the concept of HA–ferritin nanoparticles; M.K., C.-J.W. and G.J.N. designed the research studies; M.K., C.-J.W., H.M.Y., P.M.M., J.C.B., J.R.R.W., W.-P.K., L.W. and G.J.N. performed the research and analysed data; M.K., C.-J.W., H.M.Y., P.M.M., J.C.B., J.R.R.W. and G.J.N. discussed the results and implications; S.S.R. assisted in animal studies and sample collection; M.K., C.-J.W., J.C.B. and G.J.N. wrote the paper and all authors participated in manuscript revisions.

Corresponding author

Correspondence to Gary J. Nabel.

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Competing interests

G.J.N. is currently an employee of Sanofi, which produces commercial influenza vaccines. P.M.M. is currently an employee of MedImmune which also makes commercial influenza vaccines.

Additional information

The authors declare that an intellectual property application has been filed by NIH based on data presented in this paper.

Supplementary information

Supplementary Figures

This fie contains Supplementary Figures 1-7, which show a phylogenetic tree analysis and protein surface conservation between H. pylori and ferritins from other species; biochemical characterization of HA-nanoparticles; antigenic characterization of HA-nanoparticles; the effect of preexisting anti-ferritin immunity on subsequent immunization using HA-nanoparticles; iron incorporation by H. pylori ferritin and HA-nanoparticles; development of a trivalent vaccine comprising three independent HA-nanoparticles (H1, H3 and influenza B); and biochemical characterization of ΔRBS HA proteins. (PDF 775 kb)

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Kanekiyo, M., Wei, CJ., Yassine, H. et al. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature 499, 102–106 (2013). https://doi.org/10.1038/nature12202

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