EIAV Envelope Variation and Vaccine Efficacy

EIAV 包膜变异和疫苗功效

• 批准号: 8241094
• 负责人: Ronald C Montelaro
• 金额: $ 68.1万
• 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/8241094
• 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; Failure; Goals; Grant; HIV-1; Health; 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; 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，我们已经开发了一个全面的多学科研究计划，使用马传染性贫血病毒（EIAV）系统来检查慢病毒在强大的宿主免疫应答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免疫策略。在上一个资助期，我们首次证明了Env变异确实是慢病毒疫苗效力的主要决定因素，需要在开发广泛保护性疫苗的努力中加以解决。在目前的竞争性更新申请中，我们建议扩展这些研究，以检验我们的中心假设，即EIAV Env是疫苗效力的主要决定因素，有效的疫苗必须引起针对不同病毒株的适当的广泛反应性免疫。此外，我们建议Env抗原及其呈递方法需要优化以引发持久的广泛保护性免疫。因此，提出了以下补充性具体目标：（i）定义疫苗保护的Env决定簇并表征疫苗免疫对这些关键决定簇的特异性，（ii）表征与持久保护性疫苗免疫的发展相关的对减毒EIAV疫苗的免疫应答的成熟，和（iii）开发和评价使用多价和共有Env免疫原的新型免疫程序，以评估它们引起对不同EIAV毒株的广泛保护性免疫的能力。在第一个具体的目标，我们将使用选定的嵌合Env病毒来自两个定义的变异Env物种，在疫苗保护显着不同映射特定的Env保护的决定因素的基础上，实验挑战的小马免疫参考减毒EIAV疫苗。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，确定疫苗有效性的免疫相关性。在第三个具体目标中，我们将评估一系列疫苗形式（减毒病毒、病毒样颗粒和腺病毒载体），这些疫苗形式表达变异Env物种的混合物或共有Env，以评估它们产生广泛反应性疫苗免疫的能力，并在实验免疫的小马中保护免受EIAV的不同Env毒株的侵害。预计这些研究的结果将为Env变异规避疫苗保护性免疫的基本机制提供新的见解，并确定替代疫苗策略的潜力，以克服疫苗开发中Env多样性的挑战。因此，这些EIAV研究解决了艾滋病疫苗研究中的关键问题，并可提供与候选人艾滋病疫苗设计相关的重要信息。公共卫生关系：开发有效和实用的艾滋病疫苗是控制全球艾滋病流行的关键。HIV-1感染患者的多种药物治疗的最新进展确实改善了经济发达国家患者的寿命和生活质量，但对以非洲和亚洲发展中国家为中心的主要艾滋病流行病几乎没有影响，这些国家的卫生保健资源严重有限。事实上，在印度、中国、俄罗斯和南非等国，新的HIV-1感染呈爆炸式增长，而在目标发展中国家，HIV-1感染未能大幅减少，这突出表明了加强艾滋病疫苗工作的紧迫性。我们已经开发了一个全面的多学科研究计划，使用马传染性贫血病毒（EIAV）系统，以检查慢病毒持续存在的基本机制，尽管强大的宿主免疫反应，并评估实验免疫策略作为HIV-1感染和疫苗开发的模型。我们最近首次证明，Env变异确实是慢病毒疫苗效力的主要决定因素，需要在开发广泛保护性疫苗的努力中加以解决。因此，这些EIAV研究解决了艾滋病疫苗研究中的关键问题，并可提供与候选人艾滋病疫苗设计相关的重要信息。