EIAV Envelope Variation and Vaccine Efficacy

描述（由申请人提供）：在过去的30年里，我们开发了一个综合的多学科研究项目，利用马传染性贫血病毒（EIAV）系统来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。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，在开发广泛保护性疫苗的努力中需要解决这一问题。在目前的竞争性更新申请中，我们建议扩展这些研究，以验证我们的中心假设，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，以引起持久的广泛保护性免疫。因此，提出了以下补充的具体目标：（一）确定疫苗保护的环境决定因素，并确定疫苗对这些关键决定因素免疫的特异性；（二）确定与持久保护性疫苗免疫发展相关的对EIAV减毒疫苗免疫反应的成熟；（iii）开发和评估使用多价和共识Env免疫原的新型免疫程序，因为它们能够对不同的EIAV毒株产生广泛的保护性免疫。在第一个特定目标中，我们将选择嵌合Env病毒，这些病毒来自两种定义的Env变体，它们在疫苗保护方面存在显著差异，根据接种了参考减毒EIAV疫苗的小马的实验挑战，绘制特定的Env保护决定因素。在第二个具体目标中，我们将进行一项补充性研究，通过表征env特异性抗体和区分非保护性和保护性疫苗免疫的细胞免疫反应来确定疫苗效力的免疫相关因素。在第三个具体目标中，我们将评估一系列疫苗模式（减毒病毒、病毒样颗粒和腺病毒载体），它们要么表达不同Env物种的混合物，要么表达一致的Env，因为它们能够产生广泛的反应性疫苗免疫，并保护实验免疫的小马免受不同Env菌株的EIAV。预计这些研究结果将为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，并可以为设计候选人类艾滋病疫苗提供重要信息。与公共卫生的关系：研制一种有效和实用的艾滋病疫苗是控制全世界艾滋病流行的一项迫切需要。艾滋病毒-1感染患者的多种药物治疗的最新进展无疑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、俄罗斯和南非等国家，新发HIV-1感染病例呈爆炸式增长，而在目标发展中国家，HIV-1感染病例未能大幅减少，这凸显了加大艾滋病疫苗工作的紧迫性。我们利用马传染性贫血病毒（EIAV）系统开展了一项全面的多学科研究计划，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，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，并可以为设计候选人类艾滋病疫苗提供重要信息。

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.