Neurovirulence and Immunogenicity of Attenuated Recombinant Vesicular Stomatitis Viruses in Nonhuman Primates
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Le résumé fourni par la source
UNLABELLED: In previous work, a prototypic recombinant vesicular stomatitis virus Indiana serotype (rVSIV) vector expressing simian immunodeficiency virus (SIV) gag and human immunodeficiency virus type 1 (HIV-1) env antigens protected nonhuman primates (NHPs) from disease following challenge with an HIV-1/SIV recombinant (SHIV). However, when tested in a stringent NHP neurovirulence (NV) model, this vector was not adequately attenuated for clinical evaluation. For the work described here, the prototypic rVSIV vector was attenuated by combining specific G protein truncations with either N gene translocations or mutations (M33A and M51A) that ablate expression of subgenic M polypeptides, by incorporation of temperature-sensitive mutations in the N and L genes, and by deletion of the VSIV G gene to generate a replicon that is dependent on trans expression of G protein for in vitro propagation. When evaluated in a series of NHP NV studies, these attenuated rVSIV variants caused no clinical disease and demonstrated a very significant reduction in neuropathology compared to wild-type VSIV and the prototypic rVSIV vaccine vector. In spite of greatly increased in vivo attenuation, some of the rVSIV vectors elicited cell-mediated immune responses that were similar in magnitude to those induced by the much more virulent prototypic vector. These data demonstrate novel approaches to the rational attenuation of VSIV NV while retaining vector immunogenicity and have led to identification of an rVSIV N4CT1gag1 vaccine vector that has now successfully completed phase I clinical evaluation. IMPORTANCE: The work described in this article demonstrates a rational approach to the attenuation of vesicular stomatitis virus neurovirulence. The major attenuation strategy described here will be most likely applicable to other members of the Rhabdoviridae and possibly other families of nonsegmented negative-strand RNA viruses. These studies have also enabled the identification of an attenuated, replication-competent rVSIV vector that has successfully undergone its first clinical evaluation in humans. Therefore, these studies represent a major milestone in the development of attenuated rVSIV, and likely other vesiculoviruses, as a new vaccine platform(s) for use in humans.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Neurovirulence and Immunogenicity of Attenuated Recombinant Vesicular Stomatitis Viruses in Nonhuman Primates
- Date Crossref
- 15/06/2014
- Éditeur
- American Society for Microbiology
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Profectus Biosciences (United States) pays non établi dans la noticeEntreprise
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The University of Texas Medical Branch at Galveston pays non établi dans la noticeUniversité ou école supérieure
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Pfizer (United States) pays non établi dans la noticeEntreprise
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International AIDS Vaccine Initiative pays non établi dans la noticeOrganisme public
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Tulane University Tulane National Primate Research Center pays non établi dans la noticeUniversité ou école supérieure
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Research Triangle Park Foundation pays non établi dans la noticeOrganisation à but non lucratif
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Triangle pays non établi dans la noticeOrganisation à but non lucratif
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Centers for Disease Control and Prevention pays non établi dans la noticeOrganisme public
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National Center for HIV/AIDS Viral Hepatitis STD and TB Prevention pays non établi dans la noticeStructure de recherche
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University of Texas. Medical Branch pays non établi dans la noticeUniversité ou école supérieure
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Pfizer Pharmaceuticals pays non établi dans la noticeInstitution
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AIDS Vaccine Design and Development Laboratory The International AIDS Vaccine Initiative pays non établi dans la noticeStructure de recherche
Profectus Biosciences (United States), The University of Texas Medical Branch at Galveston et Pfizer (United States), avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.