Optimization Of HIV Specific Immune Responses In Vivo

HIV 体内特异性免疫反应的优化

• 批准号: 8745611
• 负责人: ROBERT A SEDER
• 金额: $ 418.66万
• 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/8745611
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Adenoviruses; Adjuvant; Affinity; Agonist; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Attenuated; B-Lymphocytes; CD8B1 gene; Cause of Death; Cellular Immunity; Cellular Immunology; Clinical; DNA Vaccines; Data; Dendritic Cells; Development; Disease; Drug Formulations; Emulsions; Gagging; Generations; HIV; HIV vaccine; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Adjuvants; Infection; Infection prevention; Life; Ligands; Maintenance; Malaria; Mediating; Mus; Natural Immunity; Oils; Pathway interactions; Play; Poly I-C; Primates; Proteins; Recombinants; Rodent; Role; SIV; Safety; Serotyping; Somatic Mutation; T cell response; T-Lymphocyte; Tuberculosis; Vaccination; Vaccine Adjuvant; Vaccines; Viral; Viral Vector; Water; Work; aluminum sulfate; base; comparative; cytokine; deep sequencing; env Gene Products; gag Gene Products; in vivo; nonhuman primate; pathogen; plasmid DNA; recombinant virus vaccine; response; vaccine development; vector-induced

Successful development of a vaccine against HIV will likely require the induction of both antibody and/or cellular immune responses sufficient to prevent infection or disease respectively following infectious challenge. While the induction of antibody responses for a variety of other infectious pathogens is readily achieved by a variety of vaccine formulations, live attenuated, recombinant viral vaccines or plasmid DNA vaccines only induce the induction of long-lived cellular immune responses, particularly CD8+ T cell responses. Moreover, since live attenuated HIV vaccines might be precluded from use due to safety concerns and DNA vaccines at present only induce modest CD8+ T cell responses in humans, there is an urgent need to develop ways to enhance the generation and maintenance of CD8+ T cell responses in humans in following immunization. This study focuses on how to optimize the magnitude and duration of CD8+ T cell responses following vaccination in rodents and primates using a variety of vaccine formulations. The data obtained over this past year have shown the following; 1. A comparative analysis of single or combination TLR ligands was done in NHP using SIV Gag protein and an oil/water emulsion. Amongst the adjuvants used, Poly IC and a TLR 7/8 agonist were the most potent for inducing SIV Gag specific CD4 and CD8+ T cell responses. 2. A comparative analysis of adjuvants and formulation was recently completed in NHP using HIV Env protein. This study focused on two clinically approved adjuvants ( alum and MF-59) with or without TLR 4 or TLR 7 ligands as additional immune stimulators. The data generated so far show that MF-59 induces more potent humoral and cellular immunity than alum when given with HIV Env protein. Combining alum with a TLR 7 ligand strongly enhanced immunity compared to alum alone. By contrast, adding TLR 4 or TLR 7 ligands to MF 59 did increase immunity compared to alum alone. In terms of T cell immunity, MF 59 induced a mixed Th1 and Th2 cytokine response. More recent analysis has been done to determine the extent of affinity maturation of the HIV Env B cell response using deep sequencing. 4. A comparative analysis of adenoviral or pox viral vectors encoding SIV Gag was initiated this year. The data show that the amount and duration of antigen has a dramatic influence on the strong CD8+ T cell immunity with rAd5 compared to other Ad serotypes. By contrast, there is minimal innate immunity induced by Ad5. The current work focuses on the mechanisms by which innate immune controls antigen expression in antigen presenting cells and determining how specific innate pathways enhance or inhibit the CD8+ T cell response.

成功开发抗 HIV 疫苗可能需要诱导抗体和/或细胞免疫反应，足以分别预防感染攻击后的感染或疾病。虽然通过多种疫苗配方很容易实现针对多种其他感染性病原体的抗体反应的诱导，但减毒活重组病毒疫苗或质粒DNA疫苗只能诱导长效细胞免疫反应，特别是CD8+T细胞反应。此外，由于出于安全考虑，HIV减毒活疫苗可能被禁止使用，而DNA疫苗目前只能在人类中诱导适度的CD8+T细胞反应，因此迫切需要开发增强CD8+T细胞反应的产生和维持的方法在人类免疫接种后。本研究的重点是如何优化啮齿动物和灵长类动物使用各种疫苗配方接种疫苗后 CD8+ T 细胞反应的程度和持续时间。 去年获得的数据表明： 1. 使用 SIV Gag 蛋白和油/水乳液在 NHP 中对单一或组合 TLR 配体进行比较分析。 在使用的佐剂中，Poly IC 和 TLR 7/8 激动剂对于诱导 SIV Gag 特异性 CD4 和 CD8+ T 细胞反应最有效。 2.最近在NHP中使用HIV包膜蛋白完成了佐剂和制剂的比较分析。本研究重点关注两种临床批准的佐剂（明矾和 MF-59），有或没有 TLR 4 或 TLR 7 配体作为额外的免疫刺激剂。迄今为止产生的数据表明，当与 HIV 包膜蛋白一起服用时，MF-59 比明矾诱导更有效的体液和细胞免疫。与单独使用明矾相比，将明矾与 TLR 7 配体结合可显着增强免疫力。相比之下，与单独的明矾相比，向 MF 59 添加 TLR 4 或 TLR 7 配体确实增加了免疫力。在 T 细胞免疫方面，MF 59 诱导混合 Th1 和 Th2 细胞因子反应。最近进行的分析是使用深度测序来确定 HIV 包膜 B 细胞反应的亲和力成熟程度。 4. 今年启动了编码 SIV Gag 的腺病毒或痘病毒载体的比较分析。数据显示，与其他 Ad 血清型相比，抗原的量和持续时间对 rAd5 的强 CD8+ T 细胞免疫有显着影响。相比之下，Ad5 诱导的先天免疫微乎其微。目前的工作重点是先天免疫控制抗原呈递细胞中抗原表达的机制，并确定特定先天途径如何增强或抑制 CD8+ T 细胞反应。