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CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates

Nature Medicine volume 17, pages 1128–1131 (2011)Cite this article

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Abstract

Vaccine-induced immunity to Ebola virus infection in nonhuman primates (NHPs) is marked by potent antigen-specific cellular and humoral immune responses1,2; however, the immune mechanism of protection remains unknown. Here we define the immune basis of protection conferred by a highly protective recombinant adenovirus virus serotype 5 (rAd5) encoding Ebola virus glycoprotein (GP)1,3 in NHPs. Passive transfer of high-titer polyclonal antibodies from vaccinated Ebola virus–immune cynomolgus macaques to naive macaques failed to confer protection against disease, suggesting a limited role of humoral immunity. In contrast, depletion of CD3+ T cells in vivo after vaccination and immediately before challenge eliminated immunity in two vaccinated macaques, indicating a crucial requirement for T cells in this setting. The protective effect was mediated largely by CD8+ cells, as depletion of CD8+ cells in vivo using the cM-T807 monoclonal antibody (mAb), which does not affect CD4+ T cell or humoral immune responses, abrogated protection in four out of five subjects. These findings indicate that CD8+ cells have a major role in rAd5-GP–induced immune protection against Ebola virus infection in NHPs. Understanding the immunologic mechanism of Ebola virus protection will facilitate the development of vaccines for Ebola and related hemorrhagic fever viruses in humans.

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Figure 1: The effect of CD3+ T cell depletion on infectious Ebola virus challenge of vaccinated cynomolgus macaques.
Figure 2: Vaccine-induced immune responses present before immunodepletion.
Figure 3: CD8+ cell depletion effects on Ebola virus GP vaccine–induced protective immunity.

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Acknowledgements

We thank D. Jeffers, T. Suhana, A. Tislerics and B. Hartman for help with manuscript preparation; M. Cichanowski for graphics; D. Braun, K. Daddario and C. Rice for technical and animal care assistance; S. Norris and M. Nason for assistance with statistical considerations; and K. Kenyon for editorial support. We thank D. Neville (US National Institute of Mental Health) for the generous gift of FN18-CRM9 immunotoxin. Reagent support was provided by the Nonhuman Primate Reagent Resource (grant number R24RR016001 from the National Center for Research Resource, US National Institutes of Health). Support for this work was provided by the Intramural Research Program of the US National Institutes of Health. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the US Army or the Department of Defense.

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Author notes

  1. Thomas W Geisbert, Michael Bailey & Joan B Geisbert

    Present address: Present addresses: University of Texas Medical Branch, Galveston, Texas, USA (T.W.G. and J.B.G.) and Transformational Medical Technologies, Joint Program Executive Office, US Department of the Army, Fort Belvoir, Virginia, USA (M.B.).,

Authors and Affiliations

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

    Nancy J Sullivan, Clement Asiedu, Daphne Stanley, Michael Bailey, Saran Bao, Srinivas Rao, Mario Roederer, Richard A Koup & Gary J Nabel

  2. United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA

    Lisa Hensley, Thomas W Geisbert, Joshua Johnson, Anna Honko, Gene Olinger & Joan B Geisbert

  3. Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    Keith A Reimann

  4. Integrated Research Facility, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Peter B Jahrling

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Contributions

N.J.S. and G.J.N. conceived of the studies and wrote the manuscript. T.W.G., J.B.G., L.H., J.J., G.O. and A.H. contributed to animal study design, conducted infectious Ebola virus challenge, post-challenge assays and passive antibody administration. N.J.S., M.B., C.A. and D.S. performed vaccine preparation, animal immunization, characterization of vaccine-induced immune responses and immunodepleting antibody administration. K.A.R. provided depleting antibodies and contributed to experimental design. S.B. and S.R. performed immunohistochemistry. M.R., P.B.J. and R.A.K. contributed to experimental design or provided reagents.

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Correspondence to Nancy J Sullivan.

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Competing interests

N.J.S., G.J.N., T.W.G. and P.B.J. have intellectual property on gene-based vaccines for Ebola.

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Sullivan, N., Hensley, L., Asiedu, C. et al. CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates. Nat Med 17, 1128–1131 (2011). https://doi.org/10.1038/nm.2447

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