EIAV Envelope Variation and Vaccine Efficacy

EIAV 包膜变异和疫苗功效

• 批准号: 7784447
• 负责人: Ronald C Montelaro
• 金额: $ 69.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7784447
• 关键词: AIDS Vaccines; AIDS vaccine development; Acquired Immunodeficiency Syndrome; Address; Adenovirus Vector; Affect; Africa; Animals; Antibodies; Antibody Formation; Antigens; Asia; Attenuated; Biological Assay; China; Consensus; Country; Developed Countries; Developing Countries; Development; Disease; Engineering; Epidemic; Equine Infectious Anemia Virus; Equus caballus; Evaluation; Evolution; Explosion; Face; Failure; Goals; Grant; HIV-1; Healthcare; Human; Immune; Immune response; Immune system; Immunity; Immunization; India; Infection; Infection Control; Interdisciplinary Study; Length; Life; Maps; Methods; Modality; Modeling; Nature; Patients; Pharmacotherapy; Procedures; Quality of life; Research; Resources; Role; Russia; SIV Vaccines; Seminal; Series; South Africa; Specificity; Subfamily lentivirinae; System; Testing; Time; Vaccine Research; Vaccines; Variant; Viral; Virus; Virus Diseases; Virus-like particle; base; design; env Gene Products; experience; immunogenicity; improved; insight; novel; prevent; programs; protective efficacy; public health relevance; research study; response; vaccine candidate; vaccine development; vaccine efficacy; virus antigenic variation; virus envelope

DESCRIPTION (provided by applicant): During the past 30 years we have developed a comprehensive multidisciplinary research program using the equine infectious anemia virus (EIAV) system to examine the fundamental mechanisms by which lentiviruses persist despite robust host immune responses and to evaluate experimental immunization strategies as models for HIV-1 infection and vaccine development. In the previous grant period, we demonstrated for the first time that Env variation is indeed a primary determinant of lentivirus vaccine efficacy that will need to be addressed in the effort to develop broadly protective vaccines. In the current competitive renewal application we propose to extend these studies to test our central hypothesis that EIAV Env is the primary determinant of vaccine efficacy and that effective vaccines must elicit appropriate broadly reactive immunity against diverse virus strains. Moreover, we suggest that Env antigen and its method of presentation need to be optimized to elicit enduring broadly protective immunity. Thus, the following complementary specific aims are proposed: (i) to define the Env determinants of vaccine protection and to characterize the specificity of vaccine immunity to these critical determinants, (ii) to characterize the maturation of immune responses to attenuated EIAV vaccines that is associated with the development of enduring protective vaccine immunity, and (iii) to develop and evaluate novel immunization procedures using multivalent and consensus Env immunogens for their ability to elicit broadly protective immunity to diverse EIAV strains. In the first specific aim, we will use selected chimeric Env viruses derived from two defined variant Env species that differ markedly in vaccine protection to map specific Env determinants of protection based on experimental challenge of ponies immunized with a reference attenuated EIAV vaccine. In the second specific aim, we will perform a complementary study to define the immune correlates of vaccine efficacy by characterizing the Env-specific antibody and cellular immune reponses that distinguish nonprotective and protective vaccine immunity. In the third specific aim, we will evaluate a series of vaccine modalities (attenuated virus, virus like particles, and adenovirus vectors) expressing either a mixture of variant Env species or a consensus Env for their ability to produce broadly reactive vaccine immunity and to protect against diverse Env strains of EIAV in experimentally immunized ponies. It is anticiapated that the results of these studies will provide novel insights into the fundamental mechanisms by which Env variation can circumvent protective vaccine immunity and determine the potential of alternative vaccine strategies to overcome the challenge of Env diversity in vaccine development. Thus, these EIAV studies address critical issues in AIDS vaccine research and can provide important information relevant to the design of candidate human AIDS vaccines. PUBLIC HEALTH RELEVANCE: Development of an effective and practical AIDS vaccine represents a critical need in the effort to control the worldwide AIDS epidemic. Recent advances in multiple drug therapy for HIV-1 infected patients have certainly improved the length and quality of life for patients in economically developed countries, but have had little impact on the predominant AIDS epidemic centered in developing countries in Africa and Asia with severely limited health care resources. In fact, the explosion of new HIV-1 infections being experienced in countries such as India, China, Russia, and South Africa and the failure to substantially reduce HIV-1 infections in targeted developing countries highlight the urgency of increasing AIDS vaccine efforts. We have developed a comprehensive multidisciplinary research program using the equine infectious anemia virus (EIAV) system to examine the fundamental mechanisms by which lentiviruses persist despite robust host immune responses and to evaluate experimental immunization strategies as models for HIV-1 infection and vaccine development. We recently demonstrated for the first time that Env variation is indeed a primary determinant of lentivirus vaccine efficacy that will need to be addressed in the effort to develop broadly protective vaccines. Thus, these EIAV studies address critical issues in AIDS vaccine research and can provide important information relevant to the design of candidate human AIDS vaccines.

描述（由申请人提供）：在过去的 30 年中，我们利用马传染性贫血病毒 (EIAV) 系统开发了一项综合性多学科研究计划，以研究慢病毒在宿主免疫反应强烈的情况下持续存在的基本机制，并评估作为 HIV-1 感染和疫苗开发模型的实验性免疫策略。在上一个资助期内，我们首次证明，包膜变异确实是慢病毒疫苗功效的主要决定因素，在开发广泛保护性疫苗的过程中需要解决这一问题。在当前的竞争性更新应用中，我们建议扩展这些研究，以测试我们的中心假设，即 EIAV Env 是疫苗功效的主要决定因素，有效的疫苗必须引发针对不同病毒株的适当的广泛反应性免疫。此外，我们建议需要优化 Env 抗原及其呈递方法，以引发持久的广泛保护性免疫。因此，提出以下补充性具体目标：(i) 定义疫苗保护的环境决定因素，并表征疫苗免疫对这些关键决定因素的特异性，(ii) 表征与持久保护性疫苗免疫力的发展相关的减毒 EIAV 疫苗免疫反应的成熟，以及 (iii) 使用多价和共识来开发和评估新型免疫程序 Env 免疫原能够引发针对不同 EIAV 毒株的广泛保护性免疫。在第一个具体目标中，我们将使用源自两种在疫苗保护方面显着不同的定义的变异 Env 物种的选定嵌合 Env 病毒，根据用参考减毒 EIAV 疫苗免疫的小马的实验攻击来绘制保护的特定 Env 决定因素。在第二个具体目标中，我们将进行一项补充研究，通过表征区分非保护性和保护性疫苗免疫的 Env 特异性抗体和细胞免疫反应来定义疫苗功效的免疫相关性。在第三个具体目标中，我们将评估一系列表达变体 Env 物种混合物或共有 Env 的疫苗模式（减毒病毒、病毒样颗粒和腺病毒载体），以评估它们产生广泛反应性疫苗免疫力并在实验免疫的小马中抵御 EIAV 多种 Env 病毒株的能力。预计这些研究的结果将为 Env 变异规避保护性疫苗免疫的基本机制提供新的见解，并确定替代疫苗策略克服疫苗开发中 Env 多样性挑战的潜力。因此，这些 EIAV 研究解决了艾滋病疫苗研究中的关键问题，并可以提供与候选人类艾滋病疫苗设计相关的重要信息。公共卫生相关性：开发有效且实用的艾滋病疫苗是控制全球艾滋病流行的迫切需要。针对 HIV-1 感染患者的多种药物治疗的最新进展无疑提高了经济发达国家患者的生活时间和质量，但对以非洲和亚洲发展中国家为中心的艾滋病流行影响甚微，这些国家的卫生保健资源严重有限。事实上，印度、中国、俄罗斯和南非等国新发 HIV-1 感染的激增，以及目标发展中国家未能大幅减少 HIV-1 感染的情况，凸显了加大艾滋病疫苗接种力度的紧迫性。我们利用马传染性贫血病毒 (EIAV) 系统开发了一项综合性多学科研究计划，以研究慢病毒在宿主免疫反应强劲的情况下持续存在的基本机制，并评估作为 HIV-1 感染和疫苗开发模型的实验性免疫策略。我们最近首次证明，包膜变异确实是慢病毒疫苗功效的主要决定因素，在开发广泛保护性疫苗的过程中需要解决这一问题。因此，这些 EIAV 研究解决了艾滋病疫苗研究中的关键问题，并可以提供与候选人类艾滋病疫苗设计相关的重要信息。