Optimization Of HIV Specific Immune Responses In Vivo

HIV 体内特异性免疫反应的优化

• 批准号: 8556092
• 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/8556092
• 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; 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.

成功开发针对HIV的疫苗可能需要诱导抗体和/或细胞免疫反应，足以防止感染挑战后分别预防感染或疾病。尽管多种疫苗制剂可以轻松地诱导各种其他感染性病原体的抗体反应，但仅诱导长期寿命的细胞免疫反应，尤其是CD8+ T细胞反应。此外，由于由于安全问题和DNA疫苗目前仅诱导人类中的适度CD8+ T细胞反应，因此可能无法使用活死的HIV疫苗，因此迫切需要开发方法来增强人类免疫后人类中CD8+ T细胞反应的产生和维持。这项研究的重点是如何使用多种疫苗配方在啮齿动物和灵长类动物接种后优化CD8+ T细胞反应的幅度和持续时间。 过去一年获得的数据显示了以下内容； 1。使用SIV GAG蛋白和油/水乳液在NHP中对单个或组合TLR配体进行了比较分析。 在使用的佐剂中，Poly IC和TLR 7/8激动剂是诱导SIV GAG特异性CD4和CD8+ T细胞反应的最有效的。 2。最近使用HIV Env蛋白在NHP中完成了佐剂和配方的比较分析。这项研究的重点是有或没有TLR 4或TLR 7配体的两个临床批准的辅助剂（Alum和MF-59）作为其他免疫刺激剂。迄今为止生成的数据表明，与HIV Env蛋白一起给出时，MF-59比明矾更有效的体液和细胞免疫。与单独的明矾相比，与TLR 7配体相比，明矾与TLR 7配体相比强烈增强了免疫力。相比之下，与单独的明矾相比，将TLR 4或TLR 7配体添加到MF 59确实会增加免疫力。在T细胞免疫方面，MF 59诱导了混合的Th1和Th2细胞因子反应。进行了更新的分析，以确定使用深层测序的HIV ENV B细胞反应的亲和力成熟程度。 4。对编码SIV GAG的腺病毒或痘病毒载体进行了比较分析。数据表明，与其他AD血清型相比，抗原的量和持续时间对具有RAD5的强CD8+ T细胞免疫具有巨大影响。相比之下，AD5诱导的先天免疫力最低。当前的工作着重于先天免疫控制抗原呈现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。