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Development of a preventive vaccine for Ebola virus infection in primates

Abstract

Outbreaks of haemorrhagic fever caused by the Ebola virus are associated with high mortality rates that are a distinguishing feature of this human pathogen. The highest lethality is associated with the Zaire subtype, one of four strains identified to date1,2. Its rapid progression allows little opportunity to develop natural immunity, and there is currently no effective anti-viral therapy. Therefore, vaccination offers a promising intervention to prevent infection and limit spread. Here we describe a highly effective vaccine strategy for Ebola virus infection in non-human primates. A combination of DNA immunization and boosting with adenoviral vectors that encode viral proteins generated cellular and humoral immunity in cynomolgus macaques. Challenge with a lethal dose of the highly pathogenic, wild-type, 1976 Mayinga strain of Ebola Zaire virus resulted in uniform infection in controls, who progressed to a moribund state and death in less than one week. In contrast, all vaccinated animals were asymptomatic for more than six months, with no detectable virus after the initial challenge. These findings demonstrate that it is possible to develop a preventive vaccine against Ebola virus infection in primates.

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Figure 1: Ebola-specific antibody responses generated by different DNA/adenovirus prime-boost combinations.
Figure 2: DNA-adenovirus immunization of cynomolgus macaques.
Figure 3: Protection of cynomolgus macaques against lethal challenge with Ebola virus after DNA-adenovirus immunization.

References

  1. Feldmann, H., Nichol, S. T., Klenk, H. D., Peters, C. J. & Sanchez, A. Characterization of filoviruses based on differences in structure and antigenicity of the virion glycoprotein. Virology 199, 469–473 (1994).

    Article  CAS  Google Scholar 

  2. Sanchez, A., Trappier, S. G., Mahy, B. W. J., Peters, C. J. & Nichol, S. T. The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing. Proc. Natl Acad. Sci. USA 93, 3602–3607 (1996).

    Article  ADS  CAS  Google Scholar 

  3. Tang, D. C., DeVit, M. & Johnston, S. A. Genetic immunization is a simple method for eliciting an immune response. Nature 356, 152–154 (1992).

    Article  ADS  CAS  Google Scholar 

  4. Ulmer, J. B. et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259, 1745–1749 (1993).

    Article  ADS  CAS  Google Scholar 

  5. Wang, B. et al. Gene inoculation generates immune responses against human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA 90, 4156–4160 (1993).

    Article  ADS  CAS  Google Scholar 

  6. Sedegah, M., Hedstrom, R., Hobart, P. & Hoffman, S. L. Protection against malaria by immunization with plasmid DNA encoding circumsporozoite protein. Proc. Natl Acad. Sci. USA 91, 9866–9870 (1994).

    Article  ADS  CAS  Google Scholar 

  7. Krieg, A. M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546–549 (1995).

    Article  ADS  CAS  Google Scholar 

  8. Sato, Y. et al. Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273, 352–354 (1996).

    Article  ADS  CAS  Google Scholar 

  9. Xu, L. et al. Immunization for Ebola virus infection. Nature Med. 4, 37–42 (1998).

    Article  CAS  Google Scholar 

  10. Vanderzanden, L. et al. DNA vaccines expressing either the GP or NP genes of Ebola virus protect mice from lethal challenge. Virology 246, 134–144 (1998).

    Article  CAS  Google Scholar 

  11. Connolly, B. M. et al. Pathogenesis of experimental Ebola virus infection in guinea pigs. J. Infect. Dis. 179, S203–S217 (1999).

    Article  Google Scholar 

  12. Bray, M., Davis, K., Geisbert, T., Schmaljohn, C. & Huggins, J. A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. J. Infect. Dis. 178, 651–661 (1998).

    Article  CAS  Google Scholar 

  13. Baize, S. et al. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nature Med. 5, 423–426 (1999).

    Article  CAS  Google Scholar 

  14. Maruyama, T. et al. Ebola virus can be effectively neutralized by antibody produced in natural human infection. J. Virol. 73, 6024–6030 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Sedegah, M. et al. Boosting with recombinant vaccinia increases immunogenicity and protective efficacy of malaria DNA vaccine. Proc. Natl Acad. Sci. USA 95, 7648–7653 (1998).

    Article  ADS  CAS  Google Scholar 

  16. Hanke, T. et al. Enhancement of MHC class I-restricted peptide-specific T cell induction by a DNA prime/MVA boost vaccination regime. Vaccine 16, 439–445 (1998).

    Article  ADS  CAS  Google Scholar 

  17. Robinson, H. L. et al. Neutralizing antibody-independent containment of immunodeficiency virus challenges by DNA priming and recombinant pox virus booster immunizations. Nature Med. 5, 526–534 (1999).

    Article  CAS  Google Scholar 

  18. Schneider, J. et al. Enhanced immunogenicity for CD8+ T cell induction and complete protective efficacy of malaria DNA vaccination by boosting with modified vaccinia virus Ankara. Nature Med. 4, 397–402 (1998).

    Article  CAS  Google Scholar 

  19. Davis, A. R. et al. Expression of hepatitis B surface antigen with a recombinant adenovirus. Proc. Natl Acad. Sci. USA 82, 7560–7564 (1985).

    Article  ADS  CAS  Google Scholar 

  20. Natuk, R. J. et al. Adenovirus-human immunodeficiency virus (HIV) envelope recombinant vaccines elicit high-titered HIV-neutralizing antibodies in the dog model. Proc. Natl Acad. Sci. USA 89, 7777–7781 (1992).

    Article  ADS  CAS  Google Scholar 

  21. Xiang, Z. Q., Yang, Y., Wilson, J. M. & Ertl, H. C. A replication-defective human adenovirus recombinant serves as a highly efficacious vaccine carrier. Virology 219, 220–227 (1996).

    Article  CAS  Google Scholar 

  22. Xiang, Z. Q., Pasquini, S. & Ertl, H. C. Induction of genital immunity by DNA priming and intranasal booster immunization with a replication-defective adenoviral recombinant. J. Immunol. 162, 6716–6723 (1999).

    CAS  PubMed  Google Scholar 

  23. Letvin, N. L. et al. Potent, protective anti-HIV immune responses generated by bimodal HIV envelope DNA plus protein vaccination. Proc. Natl Acad. Sci. USA 94, 9378–9383 (1997).

    Article  ADS  CAS  Google Scholar 

  24. Fisher-Hoch, S. P. et al. Pathophysiology of shock and hemorrhage in a fulminating viral infection (Ebola). J. Infect. Dis. 152, 887–894 (1985).

    Article  CAS  Google Scholar 

  25. Wilson, J. et al. Epitopes involved in antibody-mediated protection from Ebola virus. Science 287, 1664–1666 (2000).

    Article  ADS  CAS  Google Scholar 

  26. Ohno, T. et al. Gene therapy for vascular smooth muscle cell proliferation after arterial injury. Science 265, 781–784 (1994).

    Article  ADS  CAS  Google Scholar 

  27. Aoki, K., Barker, C., Danthinne, X., Imperiale, M. J. & Nabel, G. J. Efficient generation of recombinant adenoviral vectors by Cre-lox recombination in vitro. Mol. Med. 5, 224–231 (1999).

    Article  CAS  Google Scholar 

  28. Ksiazek, T. G. et al. Enzyme immunosorbent assay for Ebola virus antigens in tissues of infected primates. J. Clin. Microbiol. 30, 947–950 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kiley, M. P., Regnery, R. L. & Johnson, K. M. Ebola virus: identification of virion structural proteins. J. Gen. Virol. 49, 333–341 (1980).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. DeCoster and R. Grecoe for technical assistance with primates and G. Reynolds for the animal handling in the Biosafety Laboratory-4, K. Reiman and J. Stein for advice, assistance and comments, and N. Barrett, C. Davis and A. Tislerics for help in preparing the manuscript.

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Correspondence to Gary J. Nabel.

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Sullivan, N., Sanchez, A., Rollin, P. et al. Development of a preventive vaccine for Ebola virus infection in primates. Nature 408, 605–609 (2000). https://doi.org/10.1038/35046108

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