Non-human Primate Immunogenicity Studies of HIV-1 immunogens

HIV-1 免疫原的非人灵长类动物免疫原性研究

• 批准号: 8745607
• 负责人: John Mascola
• 金额: $ 33.08万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 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/8745607
• 关键词: AIDS Vaccines; Adenoviruses; Adjuvant Study; Antibodies; Antibody Formation; Antigens; Characteristics; Combined Vaccines; DNA; Data; Development; Distant; Epitopes; Exhibits; Genetic Variation; HIV-1; Human; Immune response; Immunization; Macaca; Macaca mulatta; Monkeys; Proteins; Recombinant DNA; Recombinants; Regimen; Serotyping; Structure; Vaccinated; Vaccination; Vaccines; Virus; base; design; env Gene Products; env Glycoproteins; immunogenicity; neutralizing antibody; nonhuman primate; poxvirus vectors; response; vector

The genetic diversity of HIV-1 envelope glycoproteins (Env) remains a major obstacle to the development of an antibody-based AIDS vaccine. In prior studies, we examined the breadth and magnitude of neutralizing antibody (NAb) responses in rhesus monkeys after immunization with DNA prime-recombinant adenovirus (rAd) boost vaccines encoding either single or multiple genetically distant Env immunogens. Using a standardized multi-tier panel of reference Env pseudoviruses for NAb assessment, we showed that monkeys immunized with a mixture of Env immunogens (clades A, B, and C) exhibited a greater breadth of NAb activity against neutralization sensitive Tier 1 viruses following both vaccination and challenge compared to monkeys immunized with a single Env immunogen (clade B or C). However, all groups of Env-vaccinated monkeys demonstrated only limited neutralizing activity against Tier 2 pseudoviruses, which are more characteristic of the neutralization sensitivity of circulating HIV-1. Additional immunogenicity studies are evaluating vectors with new Env inserts and various forms of soluble Env proteins. New antigens, structure based design of known neutralizing epitopes, are being evaluated.

HIV-1包膜糖蛋白(Env)的遗传多样性仍然是开发基于抗体的艾滋病疫苗的主要障碍。在先前的研究中，我们检测了用编码单个或多个遗传距离的Env免疫原的DNA基元重组腺病毒(Rad)Boost疫苗免疫恒河猴后，猕猴中和抗体(NAB)反应的广度和幅度。使用标准的多层参考Env伪病毒小组进行NAB评估，我们发现，与用单一Env免疫原(分支B或C)免疫的猴子相比，用混合Env免疫原(分支A、B和C)免疫的猴子在接种疫苗和攻击后对中和敏感的Tier 1病毒表现出更大的NAB活性。然而，所有接种了Env疫苗的猴子对Tier 2伪病毒的中和活性都是有限的，而Tier 2伪病毒更具有循环中和HIV-1的敏感性。 其他免疫原性研究正在评估带有新的Env插入片段和各种形式的可溶性Env蛋白的载体。新的抗原，基于已知中和表位的结构设计，正在评估中。