Single-dose attenuated Vesiculovax vaccines protect primates against Ebola Makona virus

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Abstract

The family Filoviridae contains three genera, Ebolavirus (EBOV), Marburg virus, and Cuevavirus1. Some members of the EBOV genus, including Zaire ebolavirus (ZEBOV), can cause lethal haemorrhagic fever in humans. During 2014 an unprecedented ZEBOV outbreak occurred in West Africa and is still ongoing, resulting in over 10,000 deaths, and causing global concern of uncontrolled disease. To meet this challenge a rapid-acting vaccine is needed. Many vaccine approaches have shown promise in being able to protect nonhuman primates against ZEBOV2. In response to the current ZEBOV outbreak several of these vaccines have been fast tracked for human use. However, it is not known whether any of these vaccines can provide protection against the new outbreak Makona strain of ZEBOV. One of these approaches is a first-generation recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing the ZEBOV glycoprotein (GP) (rVSV/ZEBOV). To address safety concerns associated with this vector, we developed two candidate, further-attenuated rVSV/ZEBOV vaccines. Both attenuated vaccines produced an approximately tenfold lower vaccine-associated viraemia compared to the first-generation vaccine and both provided complete, single-dose protection of macaques from lethal challenge with the Makona outbreak strain of ZEBOV.

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Figure 1: rVSV/ZEBOV vector design, growth kinetics and vaccine study strategy.
Figure 2: N1 and N4 vaccination results in circulating anti-ZEBOV GP IgG and protection in cynomolgus macaques.
Figure 3: Comparison of ZEBOV antigen in tissues of cynomolgus macaques either vaccinated or unvaccinated.

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Acknowledgements

We thank V. Borisevich and D. Deer for assistance with clinical pathology assays performed in the GNL BSL-4 laboratory, and the staff of the UTMB Animal Resources Center for animal care. This study was supported by the funds from the Department of Microbiology and Immunology at UTMB to T.W.G. and in part by the Department of Health and Human Services, National Institutes of Health grant R01AI09881701 to J.H.E. and T.W.G.

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D.K.C., D.M., and T.E.L. designed the vaccine vectors and did preparative work. J.H.E., M.A.E., A.O.-S., and R.X. designed, conducted, and analysed the in vitro vaccine characterization studies. C.E.M., J.H.E., and T.W.G. conceived and designed the NHP study. C.E.M., J.B.G., and T.W.G. performed the NHP vaccination and challenge experiments, and conducted clinical observations of the animals. J.B.G. and K.N.A. performed the clinical pathology assays. J.B.G. performed the ZEBOV infectivity assays. C.E.M., D.M., J.B.G., K.N.A., M.A.E., K.A.F., D.K.C, J.H.E, and T.W.G. analysed the data. K.A.F. performed histologic and immunohistochemical analysis of the data. C.E.M., D.M., D.K.C., and T.W.G. wrote the paper. All authors had access to all of the data and approved the final version of the manuscript.

Corresponding author

Correspondence to Thomas W. Geisbert.

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Competing interests

The N1 and N4 rVSV vectors described in this manuscript are the subject of patents licensed to Profectus BioSciences, Inc. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the University of Texas Medical Branch.

Extended data figures and tables

Extended Data Figure 1 Relative immunogenicity of rVSV/ZEBOV vectors in cynomolgus macaques.

At study day −28, cynomolgus macaques were immunized IM with 2 × 107 PFU of either N4 or N1 vectors. Ten days after a single immunization, PBMCs were prepared and ZEBOV GP-specific T-cell responses were quantitated by IFN-γ ELISpot assay. a, ZEBOV GP-specific IFN-γ ELISpot responses in individual macaques. b, Average ZEBOV GP-specific IFN-γ ELISpot responses with standard error of the means indicated.

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Mire, C., Matassov, D., Geisbert, J. et al. Single-dose attenuated Vesiculovax vaccines protect primates against Ebola Makona virus. Nature 520, 688–691 (2015). https://doi.org/10.1038/nature14428

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