[Source: Proceedings of the National Academy of Sciences of the United States of America, full text: (LINK). Abstract, edited.]
Antibodies are necessary for rVSV/ZEBOV-GP–mediated protection against lethal Ebola virus challenge in nonhuman primates
Andrea Marzia,1, Flora Engelmannb,1, Friederike Feldmannc, Kristen Haberthurd, W. Lesley Shuperta, Douglas Brininge, Dana P. Scotte, Thomas W. Geisbertf,g, Yoshihiro Kawaokah,i,j, Michael G. Katzek,l, Heinz Feldmanna,2, and Ilhem Messaoudib,d,m,2
Author Affiliations: aLaboratory of Virology, cOffice of Operations Management, and eRocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; bVaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; dDepartment of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239; fDepartment of Microbiology and Immunology, and gGalveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550; hDivision of Virology, Department of Microbiology and Immunology, and iInternational Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; jExploratory Research for Advanced Technology Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan; kDepartment of Microbiology, and lWashington National Primate Research Center, University of Washington, Seattle, WA 98195; and mDivision of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR 97006
Edited by Tilahun D. Yilma, University of California, Davis, CA, and approved December 12, 2012 (received for review June 5, 2012)
Ebola viruses cause hemorrhagic disease in humans and nonhuman primates with high fatality rates. These viruses pose a significant health concern worldwide due to the lack of approved therapeutics and vaccines as well as their potential misuse as bioterrorism agents. Although not licensed for human use, recombinant vesicular stomatitis virus (rVSV) expressing the filovirus glycoprotein (GP) has been shown to protect macaques from Ebola virus and Marburg virus infections, both prophylactically and postexposure in a homologous challenge setting. However, the immune mechanisms of protection conferred by this vaccine platform remain poorly understood. In this study, we set out to investigate the role of humoral versus cellular immunity in rVSV vaccine-mediated protection against lethal Zaire ebolavirus (ZEBOV) challenge. Groups of cynomolgus macaques were depleted of CD4+ T, CD8+ T, or CD20+ B cells before and during vaccination with rVSV/ZEBOV-GP. Unfortunately, CD20-depleted animals generated a robust IgG response. Therefore, an additional group of vaccinated animals were depleted of CD4+ T cells during challenge. All animals were subsequently challenged with a lethal dose of ZEBOV. Animals depleted of CD8+ T cells survived, suggesting a minimal role for CD8+ T cells in vaccine-mediated protection. Depletion of CD4+ T cells during vaccination caused a complete loss of glycoprotein-specific antibodies and abrogated vaccine protection. In contrast, depletion of CD4+ T cells during challenge resulted in survival of the animals, indicating a minimal role for CD4+ T-cell immunity in rVSV-mediated protection. Our results suggest that antibodies play a critical role in rVSV-mediated protection against ZEBOV.
1A.M. and F.E. contributed equally to this work.
Author contributions: A.M., Y.K., M.G.K., H.F., and I.M. designed research; A.M., F.E., F.F., K.H., W.L.S., D.B., D.P.S., and H.F. performed research; A.M., H.F., and I.M. analyzed data; and A.M., T.W.G., H.F., and I.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1209591110/-/DCSupplemental.