Durable HIV Vaccine Targeting Mucosal Epithelium

针对粘膜上皮的耐用 HIV 疫苗

• 批准号: 10675701
• 负责人: Marie-Claire Elisabeth Gauduin
• 金额: $ 93.9万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675701
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animals; Antibodies; Antigen Presentation; Antigens; Antiviral Response; Attenuated; Attenuated Vaccines; Biopsy; Cells; Clinical Trials; Cross-Priming; Curiosities; Cytomegalovirus; Data; Daughter; Development; Dose; Epithelial Cells; Epithelium; Female; Genome; HIV; HIV Infections; HIV vaccine; HIV/SIV vaccine; Histologic; Human; Immune Targeting; Immune response; Immune system; Immunization; ImmunoPET; Immunologic Stimulation; Infection; Infection Control; Lentivirus; Lentivirus Vector; Macaca; Macaca mulatta; Manuscripts; Measures; Modeling; Modification; Monkeys; Mucosal Immune Responses; Mucous Membrane; Pathogenicity; Penetration; Phase; Positron-Emission Tomography; Preparation; Production; Proliferating; Proteins; Rectum; Recurrence; Resolution; Risk; SIV; SIV Vaccines; Safety; Site; Solid; Source; Stimulus; Stratum Basale; System; T cell response; T-Lymphocyte; Testing; Time; Tissues; Transfection; Translating; Translations; Vaccinated; Vaccination; Vaccine Antigen; Vaccinee; Vaccines; Vagina; Viral; Viral Antigens; Viral Vector; Virus; Virus Replication; Visualization; chronic infection; clinical efficacy; draining lymph node; efficacy study; epidermal stem cell; epithelial stem cell; follow-up; immune clearance; improved; in vivo; infection risk; involucrin; keratinocyte differentiation; lymphoid organ; mucosal site; mutant; novel vaccines; offspring; pathogen; preclinical trial; prevent; promoter; rectal; reproductive; reproductive tract; response; time use; transmission process; vaccination strategy; vaccine delivery; vaccine platform; vaccine strategy; vector vaccine; viral transmission

Abstract The impressive amount of data generated by experimental HIV/SIV vaccines has led to the realization that protection will most likely requires 2 levels of barriers, the initial one at the mucosal port of entry and if breached, a second set of systemic defenses. The capacity of humoral and cellular immune responses in mucosal tissues to block or contain replication at the initial stage of virus transmission may have a profound impact on the ability of a vaccinated host to resist infection, even in the case when virus progresses beyond the port of entry, allowing the systemic response more time to control or eradicate the incoming pathogen. We hypothesized that there are two necessary features for a successful vaccine: 1) A prolonged if not life-long stimulation of the immune system with viral antigens to maintain “alert” immune responses; and 2) a targeted immune response at the site of primary replication of HIV. A vaccine approach that simultaneously addresses these two issues would have the potential to achieve solid, long-term active protection. To fulfill these requirements, we have developed an original strategy to successfully deliver a vaccine to mucosal sites that provide antigen stimuli at recurrent intervals and elicit protective mucosal immune responses. Our strategy leverages epithelial stem cells as permanent but non-expressing source of viral antigen while their differentiated offspring express and present antigen to the local immune system, along the reproductive cycle. Using a single cycle SIV (SIVsc) approach, which has been shown to be safe compared to traditional attenuated vaccines, we have cloned the SIVsc genome under the control of the involucrin promoter (pINV- SIVsc), a terminally differentiated keratinocyte specific promoter. When administered, the vaccine targets and transduces basal epithelial stem cells from vaginal tissues. These then proliferate and differentiate into mature epithelial cells, triggering SIV antigen expression via the promoter and leading to both direct and cross priming. For this project, we propose: 1) To confirm and further improve the efficacy and safety profile of the pINV-SIVsc vaccine in female macaques; 2) To visualize and optimize vaccine delivery, and investigate the mechanisms of action underlying protection; and, 3) Using our best optimized vaccine strategy, demonstrate protection from virus acquisition and/or viral replication in vivo and determine the correlates of protection or control against repeated low-dose vaginal challenges with heterologous SIV.

抽象的 实验性 HIV/SIV 疫苗产生的大量数据使人们认识到 这种保护很可能需要两层屏障，第一层是在粘膜入口处，如果 突破了第二套系统性防御。体液和细胞免疫反应的能力 在病毒传播的初始阶段，粘膜组织阻止或遏制复制可能具有深远的意义。 对接种疫苗的宿主抵抗感染的能力的影响，即使在病毒进展超过 进入口岸，使系统反应有更多时间来控制或根除传入的病原体。 我们假设成功的疫苗有两个必要特征：1）即使不成功，疫苗的持续时间也很长。 用病毒抗原终生刺激免疫系统，以维持“警觉”的免疫反应；和 2) 一个 HIV初级复制位点的靶向免疫反应。一种疫苗方法，同时 解决这两个问题将有可能实现坚实、长期的主动保护。履行 根据这些要求，我们制定了一项原创策略，以成功地将疫苗递送至粘膜部位 定期提供抗原刺激并引发保护性粘膜免疫反应。我们的 该策略利用上皮干细胞作为永久但非表达的病毒抗原来源，而它们的 分化的后代在​​生殖周期中表达并向局部免疫系统呈递抗原。 使用单周期 SIV (SIVsc) 方法，与传统方法相比，该方法已被证明是安全的 减毒疫苗中，我们克隆了 SIVsc 基因组，置于外皮启动子 (pINV- SIVsc)，一种终末分化的角质形成细胞特异性启动子。注射后，疫苗的目标是 从阴道组织转导基底上皮干细胞。然后它们增殖并分化成成熟的 上皮细胞，通过启动子触发 SIV 抗原表达，并导致直接和交叉引发。 对于该项目，我们建议：1）确认并进一步提高该药物的有效性和安全性。 雌性猕猴的 pINV-SIVsc 疫苗； 2) 可视化和优化疫苗交付，并调查 保护的行动机制； 3) 使用我们最优化的疫苗策略，证明 防止体内病毒获得和/或病毒复制，并确定保护或病毒的相关性 控制异源 SIV 反复低剂量阴道攻击。