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: 7964803
• 负责人: John Mascola
• 金额: $ 21.17万
• 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/7964803
• 关键词: AIDS Vaccines; Adenoviruses; Adjuvant Study; Antibodies; Antibody Formation; Antigens; Characteristics; DNA; Data; Development; Distant; Exhibits; Genetic Variation; HIV-1; Immune response; Immunization; Infection; Macaca; Macaca mulatta; Monkeys; Proteins; Recombinants; Serotyping; Vaccinated; Vaccination; Vaccines; Virus; base; env Gene Products; env Glycoproteins; immunogenicity; neutralizing antibody; nonhuman primate; response; AIDS Vaccines; Adenoviruses; Adjuvant Study; Antibodies; Antibody Formation; Antigens; Characteristics; DNA; Data; Development; Distant; Exhibits; Genetic Variation; HIV-1; Immune response; Immunization; Infection; Macaca; Macaca mulatta; Monkeys; Proteins; Recombinants; Serotyping; Vaccinated; Vaccination; Vaccines; Virus; base; env Gene Products; env Glycoproteins; immunogenicity; neutralizing antibody; nonhuman primate; response

The genetic diversity of HIV-1 envelope glycoproteins (Env) remains a major obstacle to the development of an antibody-based AIDS vaccine. The present studies examine 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. Notably, the development of a post-challenge NAb response against SHIV-89.6P was similar in monkeys receiving either clade B, clade C, or clade A+B+C Env immunogens, suggesting cross-clade priming of NAb responses. In addition, vaccines encoding Env immunogens heterologous to SHIV-89.6P primed for a rapid anamnestic NAb response following infection compared to vaccines lacking an Env component. These results show that DNA/rAd immunization with multiple diverse Env immunogens is a viable approach for enhancing the breadth of NAb responses against HIV-1, and suggest that Env immunogens can prime for anamnestic NAb responses against a heterologous challenge virus. Additional studies are evaluating various forms of soluble Env proteins for breadth and potency of neutralizing antibodies generated.

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。 本研究检验了用DNA素蛋白成熟腺病毒（RAD）免疫后恒河猴中和抗体反应的广度和大小，增强了编码单个或多个遗传远处ENV免疫原子的疫苗。 使用标准的NAB评估参考eNV假病毒的多层层面板，我们表明，与Env免疫原子混合物（进化枝A，B和C）免疫的猴子表现出与中和敏感的Tier 1病毒的更大广度，与与猴子接种后的疫苗接种和挑战相比，与单次免疫机（Clade ny eymun of Envene）（Clade clade b. clade c）。 然而，所有环境接种量的猴子仅表现出对第2层假病毒的中和活性有限，这是循环HIV-1的中和灵敏度的更具特征。 值得注意的是，在接受进化枝B，进化枝C或进化枝A+B+C ENV免疫剂的猴子中，对SHIV-89.6p的挑战后NAB反应的发展相似，这表明NAB反应的交叉启动。 此外，与缺少ENV成分的疫苗相比，感染后快速吞咽NAB反应的SHIV-89.6P的ENV免疫原疫苗异源。 这些结果表明，具有多种不同ENV免疫剂的DNA/RAD免疫是一种可行的方法，是增强对HIV-1的NAB反应的广度，并表明ENV免疫可以用于抗异源挑战病毒的厌食NAB反应的趋势。 其他研究正在评估各种形式的可溶性ENV蛋白，以实现中和抗体的宽度和效力。