Replicating Ad4-HIV vaccine development based on improved HIV Env and GBV-C E2

基于改进的 HIV Env 和 GBV-C E2 复制 Ad4-HIV 疫苗开发

• 批准号: 8487365
• 负责人: Jeffery Alexander
• 金额: $ 28.72万
• 依托单位: PAXVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487365
• 关键词: Acquired Immunodeficiency Syndrome; Adenoviruses; Animals; Antibodies; Antibody Avidity; Antibody Formation; Antigens; Binding; Binding Sites; Biomedical Engineering; Cell Surface Proteins; Cell surface; Clinical; Cytoplasmic Tail; Data; Development; Dosage Forms; Engineering; Evaluation; GB virus; GB virus C; Genes; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; Human; Immune response; Immunization; In Vitro; Injection of therapeutic agent; Length; Life; Measles Vaccine; Military Personnel; Modification; Molecular Conformation; Mucosal Immune Responses; Mucous Membrane; Oral; Oral cavity; Oryctolagus cuniculus; Poliomyelitis; Process; Production; Proteins; Recombinant Proteins; Recombinants; Regimen; Research; Risk; Route; Safety; Scheme; Serotyping; Site; Small Business Innovation Research Grant; System; T cell response; Technology; Transgenes; Vaccine Design; Vaccines; Viral; Viral Proteins; Virus; Virus Diseases; Western Blotting; Work; base; citrate carrier; cost; env Gene Products; env Glycoproteins; gp160; immunogenic; immunogenicity; improved; in vivo; neutralizing antibody; novel strategies; oral vaccine; prevent; programs; response; transgene expression; vaccine delivery; vaccine development; vaccine efficacy; vector; vector vaccine

DESCRIPTION (provided by applicant): Development of a vaccine to prevent, or reduce the rate of, HIV infections remains a high priority despite recent setbacks in the field. The lessons from failed and successful experimental programs indicate the need to apply new approaches to HIV vaccine design with the goal of inducing immune responses that are the appropriate type, quality, magnitude and active in the appropriate sites in the body. A promising approach is the use of the Adenovirus serotype 4 (Ad4) as a vaccine delivery vehicle. The Ad4 virus is a component in the US Military adenovirus vaccine which was formulated for administration in an oral dosage form. Oral delivery should be advantageous for HIV vaccines because this route of administration is more likely to induce mucosal immune responses than parenteral injection and would target the gut mucosal tissues in particular. The Ad4 vaccine vector is replication-competent in humans which should drive the induction and expansion of immune responses that are higher in quality, in terms of magnitude and effector functions, than those induced by non-replicating vectors. In Y1, multiple Ad4 vectors will be engineered to express unique antigens including: 1) HIV-1 Env clade C protein with the appropriate modifications for the purpose of inducing antibody responses broadly effective against a variety of HIV strains; and 2) GB virus type C E2 protein, which may induce synergistic antibody responses which would significantly broaden HIV-1 neutralization. In Y1-Y2, all vectors will be assessed for immunogenicity in small animals (rabbits). HIV-1 Env-specific antibody, both neutralizing and binding, will be determined. Completion of this SBIR program will provide sufficient data to determine the utility of this Ad4 vector system for inducing effective antibody and T cell responses and potentially could yield an experimental vaccine suitable for clinical development.

描述（由申请人提供）：尽管最近在该领域遇到挫折，但开发预防或降低艾滋病毒感染率的疫苗仍然是一个高度优先事项。从失败和成功的实验方案中吸取的教训表明，需要在艾滋病毒疫苗设计中应用新的方法，目的是诱导在体内适当部位具有适当类型、质量、强度和活性的免疫反应。一种有希望的方法是使用腺病毒血清型4 （Ad4）作为疫苗递送载体。Ad4病毒是美国军用腺病毒疫苗中的一种成分，该疫苗是为口服剂型而配制的。口服给药对于HIV疫苗是有利的，因为这种给药途径比肠外注射更有可能诱导粘膜免疫反应，特别是针对肠道粘膜组织。Ad4疫苗载体在人体内具有复制能力，与非复制载体诱导的免疫反应相比，在数量和效应功能方面，应能促进免疫反应的诱导和扩大。在Y1中，多个Ad4载体将被改造以表达独特的抗原，包括：1)HIV-1 Env clade C蛋白经过适当修饰，目的是诱导广泛有效地对抗各种HIV毒株的抗体反应；2) GB病毒C型E2蛋白，可诱导协同抗体反应，显著扩大HIV-1的中和作用。在Y1-Y2期，将评估所有载体在小动物（兔）中的免疫原性。HIV-1 env特异性抗体，中和和结合，将被确定。SBIR项目的完成将提供足够的数据来确定Ad4载体系统在诱导有效抗体和T细胞反应方面的效用，并可能产生适合临床开发的实验性疫苗。