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Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp

Nature volume 514, pages 47–53 (2014)Cite this article

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Abstract

Without an approved vaccine or treatments, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. Here we show that a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viraemia and abnormalities in blood count and blood chemistry were evident in many animals before ZMapp intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal haemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola. ZMapp exceeds the efficacy of any other therapeutics described so far, and results warrant further development of this cocktail for clinical use.

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Figure 1: Post-exposure protection of EBOV-infected nonhuman primates with ZMapp1 and ZMapp2.
Figure 2: Post-exposure protection of EBOV-infected nonhuman primates with ZMapp.
Figure 3: Amino acid alignment of the Kikwit and Guinea variants of EBOV, and in vitro antibody assays of mAbs c13C6, c2G4 and c4G7 with EBOV-G or EBOV-K virions.

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References

  1. Bausch, D. G., Sprecher, A. G., Jeffs, B. & Boumandouki, P. Treatment of Marburg and Ebola hemorrhagic fevers: a strategy for testing new drugs and vaccines under outbreak conditions. Antiviral Res. 78, 150–161 (2008)

    Article  CAS  Google Scholar 

  2. Baize, S. et al. Emergence of Zaire Ebola virus disease in Guinea — preliminary report. N. Engl. J. Med. http://dx.doi.org/10.1056/NEJMoa1404505 (2014)

  3. WHO. Ebola virus disease (EVD) http://www.who.int/csr/don/archive/disease/ebola/en/ (accessed, 15 August 2014)

  4. CDC. Chronology of Ebola Hemorrhagic Fever Outbreaks, http://www.cdc.gov/vhf/ebola/resources/outbreak-table.html (accessed, 15 August 2014)

  5. Reliefweb. W. African Ebola epidemic ‘likely to last months': UN http://reliefweb.int/report/guinea/w-african-ebola-epidemic-likely-last-months-un (7 March 2014)

  6. Clark, D. V., Jahrling, P. B. & Lawler, J. V. Clinical management of filovirus-infected patients. Viruses 4, 1668–1686 (2012)

    Article  Google Scholar 

  7. Guimard, Y. et al. Organization of patient care during the Ebola hemorrhagic fever epidemic in Kikwit, Democratic Republic of the Congo, 1995. J. Infect. Dis. 179 (Suppl. 1). S268–S273 (1999)

    Article  Google Scholar 

  8. Hensley, L. E. et al. Recombinant human activated protein C for the postexposure treatment of Ebola hemorrhagic fever. J. Infect. Dis. 196 (Suppl 2). S390–S399 (2007)

    Article  CAS  Google Scholar 

  9. Geisbert, T. W. et al. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 362, 1953–1958 (2003)

    Article  CAS  Google Scholar 

  10. Geisbert, T. W. et al. Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet 375, 1896–1905 (2010)

    Article  CAS  Google Scholar 

  11. Warren, T. K. et al. Advanced antisense therapies for postexposure protection against lethal filovirus infections. Nature Med. 16, 991–994 (2010)

    Article  CAS  Google Scholar 

  12. Feldmann, H. et al. Effective post-exposure treatment of Ebola infection. PLoS Pathog. 3, e2 (2007)

    Article  Google Scholar 

  13. Olinger, G. G., Jr et al. Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Proc. Natl Acad. Sci. USA 109, 18030–18035 (2012)

    Article  CAS  ADS  Google Scholar 

  14. Qiu, X. et al. Successful treatment of ebola virus-infected cynomolgus macaques with monoclonal antibodies. Sci. Transl. Med. 4, 138ra181 (2012)

    Article  Google Scholar 

  15. Pettitt, J. et al. Therapeutic intervention of Ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail. Sci. Transl. Med. 5, 199ra113 (2013)

    Article  Google Scholar 

  16. Qiu, X. et al. mAbs and Ad-vectored IFN-α therapy rescue Ebola-infected nonhuman primates when administered after the detection of viremia and symptoms. Sci. Transl. Med. 5, 207ra143 (2013)

    Article  Google Scholar 

  17. Giritch, A. et al. Rapid high-yield expression of full-size IgG antibodies in plants coinfected with noncompeting viral vectors. Proc. Natl Acad. Sci. USA 103, 14701–14706 (2006)

    Article  CAS  ADS  Google Scholar 

  18. Jahrling, P. B. et al. Evaluation of immune globulin and recombinant interferon-alpha2b for treatment of experimental Ebola virus infections. J. Infect. Dis. 179 (Suppl 1). S224–S234 (1999)

    Article  CAS  Google Scholar 

  19. Qiu, X. et al. Ebola GP-specific monoclonal antibodies protect mice and guinea pigs from lethal Ebola virus infection. PLoS Negl. Trop. Dis. 6, e1575 (2012)

    Article  CAS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

  21. Qiu, X. et al. Characterization of Zaire ebolavirus glycoprotein-specific monoclonal antibodies. Clin. Immunol. 141, 218–227 (2011)

    Article  CAS  Google Scholar 

  22. Dye, J. M. et al. Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease. Proc. Natl Acad. Sci. USA 109, 5034–5039 (2012)

    Article  CAS  ADS  Google Scholar 

  23. Wong, G. et al. Immune parameters correlate with protection against ebola virus infection in rodents and nonhuman primates. Sci. Transl. Med. 4, 158ra146 (2012)

    Article  ADS  Google Scholar 

  24. Marzi, A. et al. Antibodies are necessary for rVSV/ZEBOV-GP-mediated protection against lethal Ebola virus challenge in nonhuman primates. Proc. Natl Acad. Sci. USA 110, 1893–1898 (2013)

    Article  CAS  ADS  Google Scholar 

  25. ProMEDmail.org. Ebola virus disease - West Africa (117): WHO, Nigeria, Liberia, drug, more. http://www.promedmail.org/direct.php?id=2666073 (6 August 2014)

  26. NC3RS. Practical blood sample volumes for laboratory animals, domestic species and non-human primates. http://www.nc3rs.org.uk/bloodsamplingmicrosite/page.asp?id=426 (accessed, 3 August 2014)

  27. Qiu, X. et al. Sustained protection against Ebola virus infection following treatment of infected nonhuman primates with ZMAb. Sci. Rep. 3, 3365 (2013)

    Article  Google Scholar 

  28. Wong, G. et al. Immunization with vesicular stomatitis virus vaccine expressing the Ebola glycoprotein provides sustained long-term protection in rodents. Vaccine http://dx.doi.org/10.1016/j.vaccine.2014.08.028 (in the press)

  29. Mupapa, K. et al. Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. International Scientific and Technical Committee. J. Infect. Dis. 179 (Suppl. 1). S18–S23 (1999)

    Article  Google Scholar 

  30. UPMChealthsecurity.org. Next-Generation Monoclonal Antibodies: Challenges and Opportunitieshttp://www.upmchealthsecurity.org/our-work/pubs_archive/pubs-pdfs/2013/2013-02-04-next-gen-monoclonal-antibodies.pdf (UPMC Center for Biosecurity, 2013)

  31. Zeitlin, L. et al. Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant. Proc. Natl Acad. Sci. USA 108, 20690–20694 (2011)

    Article  CAS  ADS  Google Scholar 

  32. Connolly, B. M. et al. Pathogenesis of experimental Ebola virus infection in guinea pigs. J. Infect. Dis. 179 (Suppl. 1). S203–S217 (1999)

    Article  Google Scholar 

  33. Reed, L. J. & Muench, H. A simple method of estimating fifty per cent endpoints. Am. J. Hyg. 27, 493–497 (1938)

    Google Scholar 

Download references

Acknowledgements

The authors thank K. Tierney, A. Grolla, S. Jones, J. Dong and D. Kobasa for their technical assistance, V. Klimyuk and Y. Gleba for access to the magnICON expression system, and H. Steinkellner for access to transgenic N. benthamiana. This work was supported by the Defense Threat Reduction Agency (DTRA contract HDTRA1-13-C-0018), the National Institutes of Health (U19AI109762), the Public Health Agency of Canada (PHAC), and a Canadian Safety and Security Program (CSSP) grant to G.P.K. and X.Q. G.W. is the recipient of a Doctoral Research Award from the Canadian Institute for Health Research (CIHR).

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Author notes

  1. James Pettitt & Gene G. Olinger

    Present address: Present address: Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland 21702, USA.,

Authors and Affiliations

  1. National Laboratory for Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada,

    Xiangguo Qiu, Gary Wong, Jonathan Audet, Alexander Bello, Lisa Fernando, Judie B. Alimonti, Hugues Fausther-Bovendo, Haiyan Wei, Jenna Aviles, James E. Strong & Gary P. Kobinger

  2. Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada,

    Gary Wong, Jonathan Audet, Alexander Bello, Hugues Fausther-Bovendo, James E. Strong & Gary P. Kobinger

  3. Institute of Infectious Disease, Henan Centre for Disease Control and Prevention, Zhengzhou, 450012 Henan, China,

    Haiyan Wei & Bianli Xu

  4. Kentucky BioProcessing, Owensboro, 42301, Kentucky, USA

    Ernie Hiatt, Ashley Johnson, Josh Morton & Kelsi Swope

  5. Mapp Biopharmaceutical Inc., San Diego, 92121, California, USA

    Ognian Bohorov, Natasha Bohorova, Charles Goodman, Do Kim, Michael H. Pauly, Jesus Velasco, Kevin Whaley & Larry Zeitlin

  6. United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Frederick, 21702, Maryland, USA

    James Pettitt & Gene G. Olinger

  7. Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba R3A 1S1, Canada,

    James E. Strong

  8. Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada,

    Gary P. Kobinger

  9. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Gary P. Kobinger

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  1. Xiangguo Qiu
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Contributions

X.Q., G.P.K. and L.Z. designed the experiments. X.Q., G.W., J.A., A.B., L.F., J.B.A., H.F., H.W., J.A., J. P., G.G.O. and G.P.K. performed the experiments. X.Q., G.W., J.A., K.W., B.X., J.E.S., L.Z. and G.P.K. wrote the manuscript. E.H., A.J., J.M., K.S., O.B., N.B., C.G., D.K., M.H.P., J.V., K.W. and L.Z. contributed reagents for this study.

Corresponding authors

Correspondence to Larry Zeitlin or Gary P. Kobinger.

Ethics declarations

Competing interests

Her Majesty the Queen in right of Canada holds a patent on mAbs 2G4, and 4G7, PCT/CA2009/000070, “Monoclonal antibodies for Ebola and Marburg viruses.” K.W. and L.Z. are the owners of Mapp Biopharmaceutical Inc. The authors declare no other competing interests.

Extended data figures and tables

Extended Data Figure 1 Clinical scores for each ZMapp-treated group.

Arrows indicate treatment days. Dashed line represents humane endpoint threshold. Faded symbols/lines are the other two treatment groups, for comparison. Control group (Group G) is shown in black on all three panels. a, Clinical score of Group D (blue); b, clinical score of Group E (orange); c, clinical score of Group F (green).

Extended Data Figure 2 Viraemia for each ZMapp-treated group.

Arrows indicate treatment days. Faded symbols/lines are the other two treatment groups, for comparison. Control group (Group G) is shown in black on all three panels. a, TCID50 of Group D (blue); b, TCID50 of Group E (orange); c, TCID50 of Group F (green). d, Viraemia by RT–qPCR of Group D (blue); e, viraemia by RT–qPCR of Group E (orange); f, viraemia by RT–qPCR of Group F (green).

Extended Data Table 1 Blood viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs
Full size table
Extended Data Table 2 Oral swab viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs
Full size table
Extended Data Table 3 Nasal swab viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs
Full size table
Extended Data Table 4 Rectal swab viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs
Full size table
Extended Data Table 5 Blood viraemia measured by RT–qPCR for the ZMapp-treated NHPs
Full size table

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Qiu, X., Wong, G., Audet, J. et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 514, 47–53 (2014). https://doi.org/10.1038/nature13777

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