Using VSV Vectors to Display and Evolve Novel HIV Envelope Immunogens

描述（由申请方提供）：本项目的目的是基于关键病毒包膜（Env）蛋白设计和开发三类高度新颖的HIV-1疫苗免疫原，并随后测试这些候选疫苗，以确定其引发保护免受HIV感染所需的广泛中和抗体应答的能力。水泡性口炎病毒（VSV）载体在这些新候选疫苗的设计，开发和交付中发挥着战略作用。这三种新的免疫原平台被专门设计用于通过VSV载体作为跨膜蛋白表达，所述跨膜蛋白将在几种天然环境中向免疫系统呈递表位，所述天然环境包括：疫苗中载体颗粒的表面上、接种后感染细胞的膜中以及接种宿主中产生的子代病毒颗粒的表面上。将要开发的新型免疫原平台包括：i）针对VSV表达而优化的稳定Env三聚体; ii）来源于与VSV G载体分子或支架一起展示的近膜外部区（MPER）的Env表位;和iii）在近膜环境中与称为G-Stem的截短G蛋白平台一起呈递的MPER表位。 此外，将开发一种新的方法，利用VSV的先天和动态能力，通过突变的累积，在遗传上适应生物衍生的独特免疫原配置，这将表现出增强的特征，例如表达改善、病毒和细胞膜中丰度更高、稳定性增加或关键表位暴露和构象。在最佳候选疫苗进入兔免疫原性研究之前，将对实验疫苗进行测试、表征和“体外”排名，以评估新疫苗指导的体液免疫应答的特征。将在猕猴攻毒保护模型中评价在兔中引发广泛中和抗体应答的候选疫苗。将全面评价接种猕猴中的抗体应答，然后用致病性杂合猿猴/人免疫缺陷病毒（SHIV）攻毒动物，以评估疫苗有效性。 项目相关性：将专门开发三种新的实验疫苗，以刺激免疫系统产生针对HIV-1的抗体反应。这些疫苗将使用一种新的方法来开发，以生物学方式进化候选物，从而引发针对HIV包膜蛋白特定区域的强大免疫反应。有希望的候选疫苗将在动物模型中进行系统评估，以确定它们是否引起比早期实验疫苗更有效的抗体反应。

DESCRIPTION (provided by applicant): The objective of this Program is to design and develop three classes of highly novel HIV-1 vaccine immunogens based on the critical viral envelope (Env) protein, and subsequently test these vaccine candidates to determine their capacity to elicit broadly neutralizing antibody responses required to provide protection from HIV infection. Vesicular stomatitis virus (VSV) vectors take on strategic roles in design, development and delivery of these new vaccine candidates. The three new immunogen platforms are designed specifically for expression by VSV vectors as transmembrane proteins that will present epitopes to the immune system in several natural contexts including; on the surfaces of vector particles in the vaccine, in the membrane of infected cells following vaccination, and on the surface of progeny virus particles produced in the vaccinated host. The novel immunogen platforms that will be developed include: i) stable Env trimers optimized for expression by VSV; ii) Env epitopes derived from the membrane-proximal external region (MPER) displayed with a VSV G carrier molecule or scaffold; and iii) MPER epitopes presented in a membrane- proximal environment with a truncated G protein platform called G-Stem. Moreover, a novel process will be developed that makes use of the innate and dynamic ability of VSV to genetically adapt, through accrual of mutations, to biologically derived unique immunogen configurations, which will exhibit enhanced characteristics such as improved expression, greater abundance in viral and cellular membranes, increased stability, or critical epitope exposure and conformation. Experimental vaccines will be tested, characterized and ranked 'in vitro' before top candidates are advanced into rabbit immunogenicity studies to assess the character of the humoral immune response directed by the new vaccines. Candidate vaccines that elicit broadly neutralizing antibody responses in rabbits will be evaluated in a macaque challenge protection model. Antibody responses in vaccinated macaques will be evaluated thoroughly, and then animals will be challenged with a pathogenic hybrid simian/human immunodeficiency virus (SHIV) to assess vaccine efficacy. Project Relevance: Three new experimental vaccines will be developed specifically to stimulate the immune system to produce antibody responses against HIV-1. These vaccines will be developed using a novel methodology to biologically evolve candidates that elicit robust immune responses against specific regions of the HIV envelope protein. Promising vaccine candidates will be evaluated systematically in animal models to determine whether they elicit antibody responses that are more efficacious than those produced with earlier experimental vaccines.