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PLoS - Ebola - Immune Protection of Nonhuman Primates

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  • PLoS - Ebola - Immune Protection of Nonhuman Primates

    Immune Protection of Nonhuman Primates against Ebola Virus with Single Low-Dose Adenovirus Vectors Encoding Modified GPs

    <!-- end title area --> <!-- start authors --> Nancy J. Sullivan<sup>1</sup><sup></sup>, Thomas W. Geisbert<sup>2</sup><sup></sup>, Joan B. Geisbert<sup>2</sup>, Devon J. Shedlock<sup>1</sup>, Ling Xu<sup>1</sup>, Laurie Lamoreaux<sup>1</sup>, Jerome H. H. V. Custers<sup>3</sup>, Paul M. Popernack<sup>1</sup>, Zhi-Yong Yang<sup>1</sup>, Maria G. Pau<sup>3</sup>, Mario Roederer<sup>1</sup>, Richard A. Koup<sup>1</sup>, Jaap Goudsmit<sup>3</sup>, Peter B. Jahrling<sup>4</sup>, Gary J. Nabel<sup>1</sup><sup>*</sup>
    <!-- end authors --> <!-- start affiliations --> 1 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America, 2 United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America, 3 Crucell Holland B.V., Leiden, Netherlands, 4 Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
    <!-- end affiliations --><!-- start: abstract --> Background
    Ebola virus causes a hemorrhagic fever syndrome that is associated with high mortality in humans. In the absence of effective therapies for Ebola virus infection, the development of a vaccine becomes an important strategy to contain outbreaks. Immunization with DNA and/or replication-defective adenoviral vectors (rAd) encoding the Ebola glycoprotein (GP) and nucleoprotein (NP) has been previously shown to confer specific protective immunity in nonhuman primates. GP can exert cytopathic effects on transfected cells in vitro, and multiple GP forms have been identified in nature, raising the question of which would be optimal for a human vaccine.
    Methods and Findings
    To address this question, we have explored the efficacy of mutant GPs from multiple Ebola virus strains with reduced in vitro cytopathicity and analyzed their protective effects in the primate challenge model, with or without NP. Deletion of the GP transmembrane domain eliminated in vitro cytopathicity but reduced its protective efficacy by at least one order of magnitude. In contrast, a point mutation was identified that abolished this cytopathicity but retained immunogenicity and conferred immune protection in the absence of NP. The minimal effective rAd dose was established at 10<sup>10</sup> particles, two logs lower than that used previously.
    Conclusions
    Expression of specific GPs alone vectored by rAd are sufficient to confer protection against lethal challenge in a relevant nonhuman primate model. Elimination of NP from the vaccine and dose reductions to 10<sup>10</sup> rAd particles do not diminish protection and simplify the vaccine, providing the basis for selection of a human vaccine candidate.

    <!-- end abstract --> <!-- start footnote section -->Funding: This research was supported in part by the Intramural Research Program of the National Institutes of Health, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and in part by the Medical Chemical/Biological Defense Research Program, U.S. Army Medical Research and Material Command (project 03–4–7J-020).
    Competing Interests: GJN: Intellectual property on gene-based vaccines for Ebola. NJS: Intellectual property on gene-based vaccines for Ebola. ZYY: Intellectual property on gene-based vaccines for Ebola. The company Crucell is developing an Ebola vaccine.
    Academic Editor: Peter Palese, Mount Sinai School of Medicine, United States of America
    Citation: Sullivan NJ, Geisbert TW, Geisbert JB, Shedlock DJ, Xu L, et al. (2006) Immune Protection of Nonhuman Primates against Ebola Virus with Single Low-Dose Adenovirus Vectors Encoding Modified GPs. PLoS Med 3(6): e177 doi:10.1371/journal.pmed.0030177
    Received: September 1, 2005; Accepted: February 14, 2006; Published: May 16, 2006
    This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
    Abbreviations: aa, amino acid; Ad5, adenovirus type 5; GP, glycoprotein; NP, nucleoprotein; pfu, plaque-forming unit; rAd, replication-defective adenoviral (vector); SEBOV, Sudan ebolavirus; TNF, tumor necrosis factor; ZEBOV, Zaire ebolavirus
    * To whom correspondence should be addressed. E-mail: gnabel@nih.gov


    http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0030177

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