Using VSV Vectors to Display and Evolve Novel HIV Envelope Immunogens

描述（由申请人提供）：本项目的目标是设计和开发三种基于关键病毒包膜（Env）蛋白的高度新颖的HIV-1疫苗免疫原，并随后测试这些候选疫苗以确定其引发广泛中和抗体反应的能力，以提供保护免受HIV感染。水疱性口炎病毒（VSV）载体在这些新的候选疫苗的设计、开发和交付中发挥着战略性作用。这三种新的免疫原平台是专门为VSV载体作为跨膜蛋白表达而设计的，这些蛋白将在几种自然环境下向免疫系统呈现抗原表位，包括；在疫苗载体颗粒的表面，在接种后感染细胞的膜上，以及在接种宿主产生的子代病毒颗粒的表面。将开发的新型免疫原平台包括：1)优化VSV表达的稳定Env三聚体；ii)来自膜近端外区（MPER）的Env表位与VSV G载体分子或支架一起显示；iii) MPER表位通过截断的G蛋白平台G- stem在膜近端环境中呈现。

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.