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Proof of principle for epitope-focused vaccine design

机译：针对抗原决定簇的疫苗设计的原理证明

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摘要

Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.%William Schief及同事采用计算蛋白设计方法来生成人"呼吸道合胞体病毒"（RSV)疫苗的新rn颖候选药物。模仿一个RSV抗原决定基的结构的人造蛋白支架，被发现能在恒河猴身上诱导产生中和RSV的抗体。
机译：疫苗在很大程度上通过诱导针对脆弱表位的保护性中和抗体来预防传染病。几种主要的病原体已经抵制了传统的疫苗开发，尽管已经针对几种此类情况鉴定了以中和抗体为靶标的易受攻击的抗原决定簇。因此，需要诱导表位特异性中和抗体的新疫苗设计方法。在这里，我们显示了来自呼吸道合胞病毒的中和表位，计算蛋白设计可以生成小的，热和构象稳定的蛋白支架，可精确模拟病毒表位结构并诱导有效的中和抗体。这些支架代表了研究和开发保护婴儿，幼儿和老年人所需的人类呼吸道合胞病毒疫苗的有前途的线索。更普遍地，结果提供了针对抗原决定簇和基于支架的疫苗设计的原理性证据，并鼓励针对多种其他疫苗靶标，包括抗原性高度可变的病原体，例如人免疫缺陷病毒和流感，对这些策略进行评估和进一步开发。％William Schief和同事采用计算蛋白设计方法来生成人“呼吸道合胞体病毒”（RSV）疫苗的新rn颖注射药物。模仿一个RSV抗原决定基的结构的人造蛋白支架，被发现能在恒河猴身上诱导产生中和RSV的抗体。

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  • 来源
    《Nature》 |2014年第7491期|201-206A3|共7页
  • 作者

    Bruno E. Correia; John T. Bates; Rebecca J. Loomis; Gretchen Baneyx; Chris Carrico; Joseph G. Jardine; Peter Rupert; Colin Correnti; Oleksandr Kalyuzhniy; Vinayak Vittal; Mary J. Connell; Eric Stevens; Alexandria Schroeter; Man Chen; Skye MacPherson; Andreia M. Serra; Yumiko Adachi; Margaret A. Holmes; Yuxing Li; Rachel E. Klevit; Barney S. Graham; Richard T. Wyatt; David Baker; Roland K. Strong; James E. Crowe Jr; Philip R. Johnson; William R. Schief;

  • 作者单位

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA,PhD Program in Computational Biology, Instituto Gulbenkian Ciencia and Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa, Oeiras 27804 57, Portugal,Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA;

    The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville,Tennessee 37232, USA;

    The Children's Hospital of Philadelphia Research Institute, Philadelphia. Pennsylvania 19104, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA;

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA,Department of Immunology and MicrobialScience,The Scripps Research Institute, La Jolla, California 92037, USA,IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA,Centerfor HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA;

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA;

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA,IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA,Centerfor HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA;

    The Children's Hospital of Philadelphia Research Institute, Philadelphia. Pennsylvania 19104, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA,Department of Immunology and MicrobialScience,The Scripps Research Institute, La Jolla, California 92037, USA,IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA,Centerfor HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA,IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA,Centerfor HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA,IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA,Centerfor HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA;

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA;

    Department of Immunology and MicrobialScience,The Scripps Research Institute, La Jolla, California 92037, USA,IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA,Centerfor HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Department of Immunology and MicrobialScience,The Scripps Research Institute, La Jolla, California 92037, USA,IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA,Centerfor HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA;

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA;

    The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville,Tennessee 37232, USA,Department of Pathology.Microbiology and Immunology, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA,Department of Pediatrics, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA;

    The Children's Hospital of Philadelphia Research Institute, Philadelphia. Pennsylvania 19104, USA;

    Department of Biochemistry, University of Washington, Seattie, Washington 9S195, USA,Department of Immunology and Microbial Science,The Scripps Research Institute, La Jolla, California 92037, USA,IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA,Centerfor HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA;

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  • 入库时间 2022-08-18 02:52:56

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