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: 7928917
• 负责人: Ivo C Lorenz
• 金额: $ 38.05万
• 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/7928917
• 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; HIV-1 vaccine; 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; 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)：本计划的目标是设计和开发三类基于关键病毒包膜(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，以确定它们诱导广泛中和抗体反应的能力，所需抗体反应提供预防艾滋病毒感染所需的能力。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。这三个新的免疫原平台是专门为VSV载体作为跨膜蛋白而设计的，这些跨膜蛋白将在几种自然环境中向免疫系统提供表位，包括疫苗中的载体颗粒表面、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。将开发的新型免疫原平台包括：i)VSV优化表达的稳定的Env三聚体；ii)来自VSV G载体分子或支架展示的膜-近端外区(MPER)的Env表位；以及iii)在膜-近端环境中呈现的MPER表位，称为G-Stem。 此外，将开发一种新的方法，利用VSV与生俱来的和动态的能力，通过突变的累积，从遗传上适应生物来源的独特免疫原配置，这些配置将显示出增强的特征，如更好的表达，更多的病毒和细胞膜，更高的稳定性，或关键的表位暴露和构象。在进入兔子免疫原性研究之前，将对实验疫苗进行测试、表征和‘体外’评级，以评估新疫苗指导的体液免疫反应的特征。在兔子中引起广泛中和抗体反应的候选疫苗将在猕猴挑战保护模型中进行评估。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)攻击动物，以评估疫苗效果。 项目相关性：将专门开发三种新的实验性疫苗，以刺激免疫系统产生对艾滋病毒-1的抗体反应。这些疫苗将使用一种新的方法来开发，以生物进化候选疫苗，从而针对艾滋病毒包膜蛋白的特定区域产生强大的免疫反应。有希望的候选疫苗将在动物模型中进行系统评估，以确定它们是否会引发比早期实验疫苗更有效的抗体反应。