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

基本信息

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
项目类别：
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

项目摘要

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）：尽管该领域最近遇到了挫折，但开发预防艾滋病毒感染或降低艾滋病毒感染率的疫苗仍然是重中之重。失败和成功的实验计划的教训表明，需要采用新的方法来设计艾滋病毒疫苗，目的是在体内适当的部位诱导适当类型、质量、强度和活性的免疫反应。一种有前途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的一个组成部分，该疫苗被配制为口服剂型。口服给药对于艾滋病毒疫苗应该是有利的，因为这种给药途径比肠胃外注射更有可能诱导粘膜免疫反应，并且特别针对肠道粘膜组织。 Ad4疫苗载体在人体中具有复制能力，应能驱动免疫反应的诱导和扩展，其质量、强度和效应功能均高于非复制载体诱导的免疫反应。在 Y1 中，多个 Ad4 载体将被设计为表达独特的抗原，包括：1）经过适当修饰的 HIV-1 Env clade C 蛋白，用于诱导广泛有效对抗多种 HIV 毒株的抗体反应； 2) GB 病毒 C 型 E2 蛋白，它可能诱导协同抗体反应，从而显着扩大 HIV-1 中和作用。在 Y1-Y2 中，将评估所有载体在小动物（兔子）中的免疫原性。将测定 HIV-1 Env 特异性抗体，包括中和抗体和结合抗体。该 SBIR 计划的完成将提供足够的数据来确定该 Ad4 载体系统在诱导有效抗体和 T 细胞反应方面的效用，并有可能产生适合临床开发的实验疫苗。