Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp

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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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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Authors

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.

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

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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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