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HIV/SIV疫苗产生的令人印象深刻的数据导致了实现 这种保护很可能需要2个障碍，这是粘膜入境口处的壁垒，如果 违反了第二组系统防御。体液和细胞免疫复杂的能力 在病毒传播的初始阶段阻塞或包含复制的粘膜组织可能具有深刻的 即使病毒进展超出 进入港口，允许全身反应更多地控制或消除传入的病原体。 我们假设成功的疫苗有两个必要的特征：1）延长的话 用病毒抗原对免疫系统的终身刺激，以维持“警觉”免疫回报；和2）a 艾滋病毒主要复制部位的靶向免疫反应。简单的疫苗方法 解决这两个问题将有可能实现坚实的长期积极保护。实现 这些要求，我们制定了一种原始策略，可以成功地向粘膜站点输送疫苗 以复发的间隔提供抗原刺激并引起受保护的粘膜免疫反应。我们的 策略利用上皮干细胞作为病毒抗原的永久但不表达的来源 分化后代表达并沿复制周期呈现局部免疫系统的抗原。 使用单个循环SIV（SIVSC）方法，与传统相比，该方法已被证明是安全的 减弱的疫苗，我们将SIVSC基因组克隆在易素蛋白启动子的控制下（PINV-- SIVSC），一种末端分化的角质形成特异性启动子。管理时，疫苗目标和 从阴道组织传递碱性上皮干细胞。然后这些扩散并分化为成熟 上皮细胞，通过启动子触发SIV抗原表达，并导致直接和交叉启动。 对于这个项目，我们建议：1）确认并进一步提高 雌性猕猴中的PINV-SIVSC疫苗； 2）可视化和优化疫苗输送，并研究 保护基础的作用机制； 3）使用我们最佳优化疫苗策略，证明 保护体内免受病毒获取和/或病毒复制的保护，并确定保护的相关性或 控制反复的低剂量阴道阴道挑战的控制。