Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp

Journal name:
Nature
Year published:
DOI:
doi:10.1038/nature13777
Received
Accepted
Published online

Abstract

Without an approved vaccine or treatment, 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.

At a glance

Figures

  1. Post-exposure protection of EBOV-infected nonhuman primates with ZMapp1 and ZMapp2.
    Figure 1: Post-exposure protection of EBOV-infected nonhuman primates with ZMapp1 and ZMapp2.

    Rhesus macaques were challenged with EBOV-K, and 50 mg kg−1 of ZMapp1 (Group A) or ZMapp2 (Group B) were administered on days 3, 6, and 9 (n = 6 per treatment group, n = 2 for controls). Non-specific IgG mAb or PBS was administered as a control (Group C). a, Kaplan–Meier survival curves (log-rank tests: Group A vs Group C P = 0.0039; Group B vs Group C P = 0.0039). b, Clinical score. c, Rectal temperature. d, EBOV viraemia by TCID50. Blood parameters: e, white blood cell count; f, lymphocyte count; g, lymphocyte percentage; h, platelet count; i, neutrophil count; j, neutrophil percentage; k, alanine aminotransferase; l, alkaline phosphatase; m, blood urea nitrogen; n, creatinine; o, glucose.

  2. Post-exposure protection of EBOV-infected nonhuman primates with ZMapp.
    Figure 2: Post-exposure protection of EBOV-infected nonhuman primates with ZMapp.

    af, Rhesus macaques (n = 6 per ZMapp treatment group, n = 3 for controls) were challenged with EBOV-K, and 50 mg kg−1 of ZMapp were administered beginning at 3 (Group A), 4 (Group B) or 5 (Group C) days after challenge. Non-specific IgG mAb or PBS was administered as a control (Group D). a, Timeline of infection, treatment and sample days. b, Kaplan–Meier survival curves (log-rank test: overall comparison P = 3.58 × 10−5). c, Clinical scores; the dashed line indicates the minimum score requiring mandatory euthanasia. d, Rectal temperature. e, Percentage body weight change. f, EBOV viraemia by TCID50. gl, Selected clinical parameters of Group A to D animals. g, Alanine aminotransferase; h, alkaline phosphatase; i, total bilirubin. jl, Counts for lymphocytes (j), neutrophils (k) and platelets (l) over the course of the experiment.

  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.
    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.

    a, Sequence alignment of the EBOV glycoprotein from the Kikwit (EBOV-K) and Guinea (EBOV-G) variants, with the binding epitopes of ZMapp pointed with an arrow. b, ELISA, not that for each antibody, the median effective concentrations (EC50) are different (P < 0.05, regression analysis) between the two antigens. c, Neutralizing antibody assay showing the activity of the individual mAbs composing ZMapp against EBOV-K (black) and EBOV-G (purple), the samples were run in triplicate.

  4. Clinical scores for each ZMapp-treated group.
    Extended Data Fig. 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).

  5. Viraemia for each ZMapp-treated group.
    Extended Data Fig. 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).

Tables

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

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Author information

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, Kentucky 42301, USA

    • Ernie Hiatt,
    • Ashley Johnson,
    • Josh Morton &
    • Kelsi Swope
  5. Mapp Biopharmaceutical Inc., San Diego, California 92121, 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, Maryland 21702, 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, Pennsylvania 19104, USA

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

    • James Pettitt &
    • Gene G. Olinger

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.

Competing financial 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.

Corresponding authors

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Author details

Extended data figures and tables

Extended Data Figures

  1. Extended Data Figure 1: Clinical scores for each ZMapp-treated group. (432 KB)

    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).

  2. Extended Data Figure 2: Viraemia for each ZMapp-treated group. (374 KB)

    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 Tables

  1. Extended Data Table 1: Blood viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs (63 KB)
  2. Extended Data Table 2: Oral swab viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs (46 KB)
  3. Extended Data Table 3: Nasal swab viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs (48 KB)
  4. Extended Data Table 4: Rectal swab viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs (48 KB)
  5. Extended Data Table 5: Blood viraemia measured by RT–qPCR for the ZMapp-treated NHPs (81 KB)

Additional data