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Antibodies are necessary for rVSV/ZEBOV-GP-mediated protection against lethal Ebola virus challenge in nonhuman primates

机译:抗体对于rVSV / ZEBOV-GP介导的针对非人类灵长类动物的致命埃博拉病毒攻击的保护是必需的

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摘要

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.
机译:埃博拉病毒在人类和非人类灵长类动物中导致高死亡率的出血性疾病。由于缺乏批准的治疗剂和疫苗以及它们可能被滥用为生物恐怖药,这些病毒在全世界引起了人们对健康的极大关注。尽管未获得人类使用许可,但已证明表达线状病毒糖蛋白(GP)的重组水泡性口腔炎病毒(rVSV)可以预防猕猴受到埃博拉病毒和马尔堡病毒感染,无论是预防还是接触后在同源攻击环境中均如此。但是,该疫苗平台赋予的保护性免疫机制仍然知之甚少。在这项研究中,我们着手研究体液免疫与细胞免疫在rVSV疫苗介导的对致命扎伊尔埃博拉病毒(ZEBOV)攻击的保护中的作用。在用rVSV / ZEBOV-GP疫苗接种之前和期间,猕猴猕猴组的CD4 + T,CD8 + T或CD20 + B细胞被清除。不幸的是,耗竭CD20的动物产生了强大的IgG反应。因此,另一组接种的动物在攻击过程中耗尽了CD4 + T细胞。随后用致死剂量的ZEBOV攻击所有动物。耗尽CD8 + T细胞的动物存活下来,这表明CD8 + T细胞在疫苗介导的保护中起着最小的作用。疫苗接种过程中CD4 + T细胞的耗尽导致糖蛋白特异性抗体完全丧失,并取消了疫苗保护。相反,攻击过程中CD4 + T细胞的耗尽导致动物存活,这表明CD4 + T细胞免疫在rVSV介导的保护中起着最小的作用。我们的结果表明,抗体在rVSV介导的针对ZEBOV的保护中起关键作用。

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    Laboratory of Virology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;

    Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006;

    Office of Operations Management, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;

    Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239;

    Laboratory of Virology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;

    Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;

    Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;

    Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77550,Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77550;

    Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan,International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan,Exploratory Research for Advanced Technology Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan;

    Department of Microbiology, University of Washington, Seattle, WA 98195,Washington National Primate Research Center, University of Washington, Seattle, WA 98195;

    Laboratory of Virology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;

    Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006,Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239,Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton, OR 97006;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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  • 入库时间 2022-08-18 00:39:55

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