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A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection

Nature Medicine volume 16, pages 334–338 (2010)Cite this article

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Abstract

Chikungunya virus (CHIKV) has infected millions of people in Africa, Europe and Asia1,2 since this alphavirus reemerged from Kenya in 2004. The severity of the disease and the spread of this epidemic virus present a serious public health threat in the absence of vaccines or antiviral therapies. Here, we describe a new vaccine that protects against CHIKV infection of nonhuman primates. We show that selective expression of viral structural proteins gives rise to virus-like particles (VLPs) in vitro that resemble replication-competent alphaviruses. Immunization with these VLPs elicited neutralizing antibodies against envelope proteins from alternative CHIKV strains. Monkeys immunized with VLPs produced high-titer neutralizing antibodies that protected against viremia after high-dose challenge. We transferred these antibodies into immunodeficient mice, where they protected against subsequent lethal CHIKV challenge, indicating a humoral mechanism of protection. Immunization with alphavirus VLP vaccines represents a strategy to contain the spread of CHIKV and related pathogenic viruses in humans.

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Figure 1: Characterization of CHIKV E–pseudotyped lentiviral vectors.
Figure 2: Characterization of CHIKV VLPs.
Figure 3: Neutralization of CHIKV strains 37997 and LR2006 OPY-1 after DNA or VLP vaccination in mice and monkeys.
Figure 4: Protection against CHIKV LR2006 OPY-1 challenge in monkeys immunized with VLPs and in a CHIKV mouse model after passive transfer of purified IgG.

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Acknowledgements

We thank K. Nagashima for help with electron microscopy and J.D. Yoder for initiating cryoelectron microscopy reconstruction. We also thank A. Tislerics and J. Stein for help with manuscript preparation, B. Hartman for graphic arts and members of the Nabel lab for helpful discussions. We thank R. Seder and D.D. Pinschewer (Department of Pathology and Immunology, University of Geneva) for their kind gift of Ifnar1−/− mice, A. Ault, J.-P. Todd, A. Zajac, C. Chiedi (Vaccine Research Center) and D. Gordon (Bioqual) for plaque assay and processed animal blood samples, J. Greenhouse for RT-PCR assay, B.W. Finneyfrock, T. Jenkins and A. Dodson for animal sampling and care, K. Foulds, M. Donaldson and M. Roederer for monkey sample procedures and J. Lee for preparing 293F cells for VLP production. This research was supported by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

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Authors and Affiliations

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

    Wataru Akahata, Zhi-Yong Yang, Wing-Pui Kong, Srinivas Rao & Gary J Nabel

  2. Bioqual, Inc., Rockville, Maryland, USA

    Hanne Andersen & Mark G Lewis

  3. Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA

    Siyang Sun, Heather A Holdaway & Michael G Rossmann

  4. Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA

    Stephen Higgs

Authors
  1. Wataru Akahata
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  2. Zhi-Yong Yang
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  11. Gary J Nabel
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Contributions

W.A., Z.-Y.Y., S.H., S.R. and G.J.N. designed the research studies; W.A., Z.-Y.Y., H.A., S.S., H.A.H., W.-P.K., M.G.L. and S.R. performed the research; W.A. and Z.-Y.Y. contributed to development and generation of vectors; and W.A., Z.-Y.Y., H.A., S.S., H.A.H., W.-P.K., M.G.L., S.H., M.G.R., S.R. and G.J.N. analyzed data; and W.A., Z.-Y.Y., S.H., M.G.R., S.R. and G.J.N. wrote the paper.

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Correspondence to Gary J Nabel.

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Akahata, W., Yang, ZY., Andersen, H. et al. A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection. Nat Med 16, 334–338 (2010). https://doi.org/10.1038/nm.2105

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