SOSIP-NP/mRNA combination for novel preventive and therapeutic HIV-1 vaccine regimens

摘要 拟议研究的最终目标是为结束艾滋病毒/艾滋病流行作出贡献。已经 自艾滋病毒/艾滋病流行开始以来的四十年里， 难以捉摸2020年，估计有3760万人感染艾滋病毒。尽管有高效的抗逆转录病毒药物 尽管目前的治疗方法缺乏，但仍有数十万人死于与艾滋病有关的疾病， 继续出现。因此，找到结束这一流行病的方法仍然是一个全球优先事项。 创新艾滋病毒/艾滋病疫苗和治疗研究联合会（CIAVCR）的总体目标是 开发一种有效的联合免疫方案，用于预防和治疗HIV-1， 人类灵长类动物（NHP）模型，具有直接进入临床用于人类的路径。有两个FOCI 在CIAVCR中提出：在FOCUS 1中，我们的总体目标是证明以下因素的相关性和机制： 保护性疫苗的保护，以及疫苗诱导的免疫应答在选择和限制 潜在的水库使用新的mRNA构建体来递送免疫原的好处是， 将评价体液和细胞反应。在FOCUS 2中，我们的总体目标是确定 疫苗诱导的免疫反应：1）通过减少HIV-1的大小或消除HIV-1来控制HIV-1感染 储库，和/或2）延迟血浆病毒载量反弹。FOCUS 1中研究的保护性疫苗将 测试以确定疫苗诱导的B和T细胞应答在清除HIV-1储库中的机制。 此外，新的疗法将与疫苗结合，以增加HIV-1储库的清除。 在FOCUS 1和2中，突破和潜在储层Env层序的分析将为 设计新的疫苗加强一种改进的保护性疫苗方案，也可以限制反弹 病毒。 NHP-SHIV集中研究资源（CRR）将支持FOCUS 1中的NHP研究，并 2研究疫苗诱导的多功能反应和新型免疫疗法的有效性 清除HIV-1病毒库。这些研究将使用创新的条形码SHIV来确定 疫苗诱导的消除病毒宿主的反应，并评估疫苗的数量和质量。 治疗中断后被潜伏期逆转剂（LRA）重新激活的病毒。 管理和业务支助股将协调科学和 本CIAVCR计划的行政活动，以确保FOCI和NHP-SHIV CRR的功能 凝聚力。 在这笔赠款结束时，我们预计将设计一种预防和治疗相结合的方法， 有效保护免受感染和消除病毒携带者-有效影响艾滋病毒/艾滋病的战略 流行病

ABSTRACT The ultimate goal of the proposed studies is to contribute to ending the HIV/AIDS epidemic. It has been four decades since the start of the HIV/AIDS epidemic and a protective vaccine or functional cure has been elusive. In 2020, there was an estimated 37.6 million people living with HIV. Despite highly active anti-retroviral therapies, hundreds of thousands of people still die from AIDS-related diseases and millions of new infections continue to emerge. Thus, finding a way to end this pandemic remains a global priority. The overall goal of the Consortium for Innovative HIV/AIDS Vaccine and Cure Research (CIAVCR) is to develop an effective combined immunotherapeutic regimen for HIV-1 prevention and cure using the non- human primate (NHP) model that has a direct path to the clinic for use in humans. There are two FOCI proposed in the CIAVCR: In FOCUS 1, our overall goal is to demonstrate the correlates and mechanisms of protection for a protective vaccine, and the role of vaccine-induced immune responses in selecting and limiting the latent reservoir. The benefits of using novel mRNA constructs to deliver immunogens that can elicit both humoral and cellular responses will be evaluated. In FOCUS 2, our overall goal is to determine the role of vaccine-induced immune responses to 1) control HIV-1 infection by reducing the size or eliminating HIV-1 reservoirs, and/or 2) delay plasma virus load rebound. The protective vaccines studied in FOCUS 1 will be tested to define the mechanisms of vaccine-induced B and T cell responses in clearing HIV-1 reservoirs. Additionally, novel therapies will be combined with the vaccines to augment clearance of HIV-1 reservoirs. In both FOCUS 1 and 2, analysis of the breakthrough and latent reservoir Env sequences will inform the design of new vaccine boosts for an improved protective vaccine regimen that can also limit rebound viruses. The NHP-SHIV Centralized Research Resource (CRR) will support the NHP studies in FOCUS 1 and 2 to investigate the effectiveness of vaccine-induced polyfunctional responses and novel immunotherapies in clearing HIV-1 reservoirs. These studies will use innovative barcoded-SHIVs to determine the effect of vaccine-induced responses on eliminating the viral reservoirs, and to evaluate the quantity and quality of viruses that are reactivated by latency reversing agents (LRAs) following treatment interruption. The Management and Operations Support Unit (MOS) will coordinate the scientific and administrative activities of this CIAVCR Program to ensure that the FOCI and NHP-SHIV CRR function cohesively. By the end of this grant, we expect to have designed a combined preventive and therapeutic approach to effectively protect from infection and eliminate viral reservoirs—a strategy for effectively impacting the HIV/AIDS pandemic.