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）：该程序的目的是根据关键病毒包膜（INK）蛋白设计和开发三类高度新颖的HIV-1疫苗免疫原蛋白，并随后测试这些疫苗候选者，以确定其引起广泛中和抗体反应的能力，以提供抗HIV感染所需的保护所需的抗体反应。囊泡气孔病毒（VSV）载体在这些新疫苗候选物的设计，开发和传递中扮演战略作用。这三个新的免疫原平台专为VSV载体作为跨膜蛋白而专门设计，这些蛋白会在几种自然环境中向免疫系统展示，包括：在疫苗接种后感染细胞的膜上以及在接种宿主中产生的后代病毒颗粒的表面上，在感染细胞的膜上，在感染细胞的膜上。将要开发的新型免疫原平台包括：i）VSV为表达优化的稳定的ENV三聚体； ii）ENV表位源自带有VSV G载体分子或支架的膜外部区域（MPER）； iii）在膜 - 近端环境中提出的MPER表位，其截短的G蛋白平台称为G-STEM。 此外，将开发出一个新的过程，利用VSV的先天和动态能力，通过突变的应计对生物学衍生的独特的免疫原构型在遗传上适应，这将表现出增强的特征，例如改善的表达，病毒性和细胞膜上的丰度，更大的丰度，病毒性和关键的稳定性，或关键的稳定性，或关键的ePepsiper和Confepusepormation。在将顶级候选者推进兔子免疫原性研究之前，将测试，表征和排名“体外”实验疫苗，以评估新疫苗指导的体液免疫反应的特征。在猕猴的挑战保护模型中，将评估引起兔子中广泛中和抗体反应的候选疫苗。接种猕猴中的抗体反应将进行彻底评估，然后将通过致病性邻氨酸/人类免疫缺陷病毒（SHIV）来挑战动物，以评估疫苗的功效。 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。这些疫苗将采用一种新型方法来开发，从而在生物学上进化了候选物，从而引起针对HIV包膜蛋白特定区域的强大免疫反应。在动物模型中，将对有希望的疫苗候选物进行系统评估，以确定它们是否引起抗体反应，该抗体反应比早期实验疫苗产生的抗体反应更有效。