Using VSV Vectors to Display and Evolve Novel HIV Envelope Immunogens

使用 VSV 载体展示和进化新型 HIV 包膜免疫原

• 批准号: 8307876
• 负责人: Ivo C Lorenz
• 金额: $ 45.1万
• 依托单位: INTERNATIONAL AIDS VACCINE INITIATIVE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307876
• 关键词: Affect; Affinity; Amino Acid Sequence; Amino Acids; Animal Model; Animals; Antibodies; Antibody Formation; Antigens; Avidity; Binding; Biological; Biological Assay; CCR5 gene; Cell Line; Cell membrane; Cells; Cellular Membrane; Characteristics; Chimeric Proteins; Code; Cytoplasmic Tail; Development; Environment; Enzyme-Linked Immunosorbent Assay; Epitopes; Exhibits; GTP-Binding Proteins; Genes; Goals; HIV; HIV Infections; HIV envelope protein; HIV-1; Hybrids; Immune Sera; Immune response; Immune system; Immunization; In Vitro; Infection; Integral Membrane Protein; Intravenous; Length; Macaca; Macaca mulatta; Membrane; Membrane Glycoproteins; Methodology; Methods; Modeling; Modification; Molecular Conformation; Monoclonal Antibodies; Mutation; Oryctolagus cuniculus; Process; Production; Property; Protein Binding; Recombinants; Role; SIV; Serial Passage; Serum; Site; Surface; Testing; Vaccinated; Vaccination; Vaccines; Vesicular stomatitis Indiana virus; Viral; Viral Envelope Proteins; Virion; Virus; Virus-like particle; base; design; env Gene Products; extracellular; fitness; glycoprotein G; immunogenicity; improved; in vivo; mutant; neutralizing antibody; nonhuman primate; novel; novel vaccines; particle; polypeptide; pressure; programs; recombinant virus; response; scaffold; simian human immunodeficiency virus; stem; vaccine candidate; vaccine delivery; vaccine efficacy; vector; virus envelope

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.

描述（由申请人提供）：该计划的目标是设计和开发基于关键病毒包膜 (Env) 蛋白的三类高度新颖的 HIV-1 疫苗免疫原，并随后测试这些候选疫苗以确定其引发的能力广泛中和提供保护免受艾滋病毒感染所需的抗体反应。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。这三个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，这些跨膜蛋白将在多种自然环境中向免疫系统呈递表位，包括：疫苗中载体颗粒的表面、接种疫苗后受感染细胞的膜以及接种疫苗的宿主中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： i) 针对 VSV 表达进行优化的稳定 Env 三聚体； ii) 源自用 VSV G 载体分子或支架展示的近膜外部区域 (MPER) 的 Env 表位； iii) MPER表位存在于近膜环境中，具有称为G-Stem的截短G蛋白平台。 此外，将开发一种新的工艺，利用 VSV 的先天和动态能力，通过突变的积累，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性，例如表达改善、病毒和病毒的丰度更大。细胞膜、稳定性增加或关键表位暴露和构象。实验疫苗将在“体外”进行测试、表征和排名，然后将顶级候选疫苗推进兔子免疫原性研究，以评估新疫苗引导的体液免疫反应的特征。将在猕猴攻击保护模型中评估在兔子中引起广泛中和抗体反应的候选疫苗。将彻底评估接种疫苗的猕猴的抗体反应，然后用致病性混合猿猴/人类免疫缺陷病毒（SHIV）对动物进行攻击，以评估疫苗功效。 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疫苗，从而引发针对 HIV 包膜蛋白特定区域的强大免疫反应。有前景的候选疫苗将在动物模型中进行系统评估，以确定它们是否引发比早期实验疫苗产生的抗体反应更有效的抗体反应。