Phase I HIV vaccine trial with DNAALVAC-HIV gp120 delta V1 vaccines

DNAALVAC-HIV gp120 delta V1 疫苗的 I 期 HIV 疫苗试验

• 批准号: 10702823
• 负责人: Genoveffa Franchini
• 金额: $ 905.6万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702823
• 关键词: ALVAC; Adjuvant; Antibodies; Antigens; Binding; CD4 Positive T Lymphocytes; Communicable Diseases; DNA; DNA Vaccines; Development; Engineering; Epidemic; Epigenetic Process; Exposure to; Goals; Government; Grant; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; Human; Hydroxides; Immune response; Immune system; Immunity; Inflammatory; Intellectual Property; Invertebrates; Investigation; Lead; Legal patent; Licensing; Macaca; Malignant Neoplasms; Mediating; Memory; Modeling; Natural Immunity; Natural Killer Cells; Phase; Preparation; Private Sector; Production; Proteins; Recombinants; Risk; SIV; T cell response; Testing; Thailand; Training; Translating; Vaccination; Vaccines; Virus; aluminum sulfate; antibody-dependent cell cytotoxicity; base; design; efficacy trial; gp160; monocyte; nonhuman primate; novel; pathogen; programs; trait; vaccine efficacy; vaccine platform; vaccine trial

The project will exploit the DNA/ALVAC-HIV vaccine platform's ability to induce lasting trained monocyte memory in combination with a clade AE (A244 strain) V1-deleted HIV-gp160 prime and a novel V1-deleted HIV gp120/alum protein boost. The deletion of V1 from the gp120 envelope will be specially engineered to minimize antibody interference and elicit a high level of antibodies to V2, the primary correlate of risk in RV144. Alum hydroxide will be used as adjuvant for its ability to maximize the induction of trained immunity (through its ability to induce IL-1B) and CD4+ T-cell responses that constituted the secondary correlate of decreased risk of HIV acquisition in RV144. The overall objective of this proposal is to design and produce both a novel HIV V1-deleted A244 gp160 (A244 DeltaV1 gp160) DNA vaccine and a novel HIV V1-deleted A244 gp120 (A244 DeltaV1 gp120) in GMP conditions for testing in a phase I human HIV vaccine trial. These immunogens will first be tested in macaques to assess whether this approach also induces long-lasting, non-interfering antibodies, innate monocyte memory, and adaptive CD4+ T-cells with a low inflammatory profile in humans. The investigation of protective monocyte, or NK memory trained immunity, will prove beneficial in combatting additional infectious diseases and cancer. Evolutionary conserved from invertebrates, trained immunity is an ancient trait of the human immune system that is defined by durable epigenetic reprogramming of monocytes, providing the first line of defense against pathogens .This will lead not only to the production and testing of a novel HIV vaccine, but also to the thorough investigation of unexplored host protective immune responses in non-human primates (NHP) whose immune system mirrors that of humans.

该项目将利用DNA/ALVAC-HIV疫苗平台诱导持久免疫的能力， 训练的单核细胞记忆与进化枝AE（A244株）V1缺失的HIV-gp 160组合 初免和新的V1缺失的HIV gp 120/明矾蛋白加强。从gp 120中删除V1 包膜将被特别工程化以最小化抗体干扰并引起高的免疫应答。 V2抗体水平是RV 144风险的主要相关因素。将使用氢氧化铝 作为佐剂，因为其能够最大化诱导训练的免疫（通过其能力 诱导IL-1B）和CD 4 + T细胞应答，这构成了 RV 144中HIV感染的风险降低。本建议的总体目标是 设计并生产新型HIV V1-deleted A244 gp 160（A244 DeltaV 1 gp 160）DNA疫苗， 一种新的HIV V1-缺失的A244 gp 120（A244 DeltaV 1 gp 120），在GMP条件下进行检测， 第一阶段人类艾滋病疫苗试验。这些免疫原将首先在猕猴身上进行测试， 这种方法是否也能诱导持久的、非干扰性的抗体，先天性单核细胞， 记忆和适应性CD 4 + T细胞，在人类中具有低炎症特征。调查 保护性单核细胞，或NK记忆训练免疫，将证明有利于打击 其他传染病和癌症。从无脊椎动物进化而来， 免疫力是人类免疫系统的一个古老特征，由持久的表观遗传学定义。 单核细胞的重编程，提供了抵抗病原体的第一道防线。这将 不仅导致生产和测试一种新的艾滋病毒疫苗，而且还导致彻底的 非人灵长类动物（NHP）中未探索的宿主保护性免疫应答的研究， 免疫系统反映了人类的免疫系统。