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

用于新型预防性和治疗性 HIV-1 疫苗方案的 SOSIP-NP/mRNA 组合

• 批准号: 10461584
• 负责人: Guido Ferrari
• 金额: $ 571.99万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-02 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461584
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Animals; Antibody Response; Antibody-mediated protection; Antigens; Autologous; B-Lymphocytes; Bar Codes; CD8-Positive T-Lymphocytes; COVID-19 pandemic; COVID-19 prevention; Characteristics; Clinic; Clinical Research; Clinical Treatment; Collaborations; Complex; Data; Development; Diagnosis; Disease; Ensure; Epidemic; Generations; Goals; Grant; HIV; HIV vaccine; HIV-1; Health Priorities; Highly Active Antiretroviral Therapy; Human; Immune response; Immunity; Immunoglobulin G; Immunology; Immunotherapeutic agent; Immunotherapy; Infection; Infusion procedures; Interruption; Licensing; Messenger RNA; Modeling; Monoclonal Antibodies; Natural Killer Cells; Outcome; Peptides; Persons; Plasma; Prevention; Prevention approach; Preventive; Process; RNA vaccine; Recombinants; Regimen; Research; Research Personnel; Resources; Role; Sampling; Seeds; Sequence Analysis; T cell response; T-Lymphocyte; Testing; Therapeutic; Universities; Vaccines; Variant; Viral load measurement; Viral reservoir; Virus; Virus Diseases; Virus Replication; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; cohesion; cytotoxic; design; efficacy evaluation; global health; improved; in vivo; innovation; insight; latent HIV reservoir; nanoparticle; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel; novel strategies; novel therapeutics; novel vaccines; operation; pandemic disease; pre-clinical; prevent; programs; response; simian human immunodeficiency virus; success; therapeutic vaccine; vaccination strategy; vaccine effectiveness; vaccine response; vaccine strategy; vaccine trial; viral rebound

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.

抽象的 拟议研究的最终目标是为结束艾滋病毒/艾滋病的流行做出贡献。它一直 自艾滋病毒/艾滋病流行以来四十年，保护性疫苗或功能性治疗方法已经问世 难以捉摸。 2020 年，估计有 3760 万人感染艾滋病毒。尽管具有高度活性的抗逆转录病毒药物 治疗，数十万人仍然死于艾滋病相关疾病和数百万新感染 不断涌现。因此，找到结束这一流行病的方法仍然是全球优先事项。 创新艾滋病毒/艾滋病疫苗和治疗研究联盟 (CIAVCR) 的总体目标是 使用非免疫疗法开发有效的联合免疫治疗方案来预防和治疗 HIV-1 人类灵长类动物 (NHP) 模型可直接进入临床用于人类。有两个FOCI CIAVCR 中提出：在焦点 1 中，我们的总体目标是展示 保护性疫苗的保护，以及疫苗诱导的免疫反应在选择和限制中的作用 潜在的水库。使用新型 mRNA 构建体传递免疫原的好处是可以引发这两种反应 将评估体液和细胞反应。在 FOCUS 2 中，我们的总体目标是确定 疫苗诱导的免疫反应 1) 通过减小 HIV-1 的大小或消除 HIV-1 来控制 HIV-1 感染 储存库，和/或 2) 延迟血浆病毒载量反弹。 FOCUS 1 研究的保护性疫苗将是 进行测试以确定疫苗诱导的 B 和 T 细胞反应清除 HIV-1 病毒库的机制。 此外，新疗法将与疫苗相结合，以增强对 HIV-1 病毒库的清除。 在焦点 1 和 2 中，对突破和潜在储层 Env 序列的分析将为 设计新的疫苗加强疫苗，以改进保护性疫苗方案，同时限制反弹 病毒。 NHP-SHIV 集中研究资源 (CRR) 将支持 FOCUS 1 和 FOCUS 1 中的 NHP 研究 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储存库的反应，并评估病毒的数量和质量 治疗中断后，病毒会被潜伏期逆转剂（LRAs）重新激活。 管理和运营支持部门（MOS）将协调科学和 本 CIAVCR 计划的行政活动，以确保 FOCI 和 NHP-SHIV CRR 发挥作用 凝聚力。 到这笔赠款结束时，我们希望设计出一种预防和治疗相结合的方法 有效防止感染并消除病毒库——有效影响艾滋病毒/艾滋病的策略 大流行。