Developing novel adjuvants for HIV vaccination

开发用于艾滋病毒疫苗接种的新型佐剂

• 批准号: 8518221
• 负责人: Si-Yi Chen
• 金额: $ 41.04万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-16 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518221
• 关键词: Activated B-Lymphocyte; Adjuvant; Agonist; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Autoantigens; B-Lymphocytes; Biological; Cells; Chimeric Proteins; Clinic; Complex; Cytokine Inducible SH2-Containing Protein; Dendritic Cell Vaccine; Dendritic Cells; Development; Enhancing Antibodies; Enzymes; Epitopes; Flagellin; Generations; HIV; HIV Antigens; HIV Infections; Human; Immune; Immune response; Immunization; In Vitro; Infection; Ligands; Maintenance; Memory; Mus; Mutate; Natural Immunity; Oryctolagus cuniculus; Play; Prevention; Protamines; Receptor Signaling; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Stimulus; T-Lymphocyte; TLR5 gene; Testing; Toll-like receptors; Tumor Necrosis Factor Receptor; Ubiquitin; Vaccination; Vaccine Adjuvant; Zinc Fingers; immunogenic; in vivo; inhibitor/antagonist; mutant; neutralizing antibody; novel; novel strategies; prevent; prophylactic; response; therapeutic vaccine

DESCRIPTION (provided by applicant): The immune responses induced by vaccination or natural infection fail to effectively prevent and control HIV infection. Thus, it is important to explore alternative immunization approaches and novel adjuvants to generate protective immune response that is superior to the natural immunity against HIV infection. Antigen-presenting cells (APCs) such as dendritic cells (DCs) play a critical role in the activation and maintenance of immune responses, and they are regulated by stimulatory as well as inhibitory signaling. Recently, we found that the negative regulators of proinflammatory signaling, such as the zinc-finger ubiquitin-modifying enzyme A20 and suppressor of cytokine signaling 1 (SOCS1), play critical roles in limiting the immunostimulatory potency of APCs and the autoreactive response against self-antigens. We demonstrated that silencing of A20 or SOCS1 drastically enhanced the stimulatory potency of TLR agonists and DC vaccines to induce both T cell and antibody responses. In this study we aim to develop novel and potent adjuvants by inhibiting key negative regulators of proinflammatory signaling to facilitate the development of prophylactic and therapeutic vaccines against HIV. The central hypothesis of this study is that a new type of vaccine adjuvants comprised of a TLR ligand and an inhibitor of the negative regulator of proinflammatory signaling for triggering and sustaining TLR signaling cascades in APCs can be created to enhance the magnitude and duration of cellular and humoral responses against HIV to higher levels that cannot be achieved by currently described vaccination approaches or natural infection and may be capable of overcoming HIV's immune evasion and suppression. The specific aims of this study are: 1). To test whether soluble flagellin (FliC)-protamine (P) fusion protein/siA20 complexes can potently stimulate APCs as novel adjuvants to induce stronger and broader HIV-specific CTL and Th responses in mice; 2). To investigate whether immunization of FliC-P/siA20 complexes and mutated HIV Env with enhanced exposure of naturally shielded, protective epitopes more efficiently induces neutralizing antibodies against HIV in mice and rabbits; and 3). To test whether FliC-P/sihA20 complexes are superior to TLR agonists in activating human DCs to stimulate HIV-specific T and B cells for potential clinic use. In summary, there is a compelling need for the development of the novel adjuvant comprised of TLR ligands and A20 inhibitors that have a unique stimulatory ability to enhance innate and adaptive cellular and humoral responses against HIV to higher levels that cannot be achieved by currently described adjuvants. In this proposed study, we aim to develop novel adjuvants for HIV vaccination to induce protective cellular and humoral immune responses. Specifically, we will generate and test the novel adjuvant comprised of TLR ligands and A20 inhibitors that have a unique stimulatory ability to enhance innate and adaptive cellular and humoral responses against HIV to higher levels that cannot be achieved by currently described adjuvants.

描述（申请人提供）：疫苗接种或自然感染引起的免疫反应不能有效预防和控制HIV感染。因此，探索替代免疫方法和新型佐剂以产生优于针对 HIV 感染的自然免疫的保护性免疫反应非常重要。树突状细胞 (DC) 等抗原呈递细胞 (APC) 在免疫反应的激活和维持中发挥着关键作用，它们受到刺激性和抑制性信号传导的调节。最近，我们发现促炎信号传导的负调节因子，例如锌指泛素修饰酶 A20 和细胞因子信号传导抑制因子 1 (SOCS1)，在限制 APC 的免疫刺激效力和针对自身免疫反应的自身反应中发挥着关键作用。抗原。我们证明，A20 或 SOCS1 的沉默极大增强了 TLR 激动剂和 DC 疫苗诱导 T 细胞和抗体反应的刺激效力。在这项研究中，我们的目标是通过抑制促炎信号传导的关键负调节因子来开发新型有效的佐剂，以促进艾滋病毒预防性和治疗性疫苗的开发。这项研究的中心假设是，可以创建一种由 TLR 配体和促炎信号负调节因子抑制剂组成的新型疫苗佐剂，用于触发和维持 APC 中的 TLR 信号级联反应，从而增强细胞和免疫反应的强度和持续时间。针对HIV的体液反应达到目前描述的疫苗接种方法或自然感染无法达到的更高水平，并且可能能够克服HIV的免疫逃避和抑制。本研究的具体目的是：1）．测试可溶性鞭毛蛋白 (FliC)-鱼精蛋白 (P) 融合蛋白/siA20 复合物是否可以作为新型佐剂有效刺激 APC，从而在小鼠体内诱导更强、更广泛的 HIV 特异性 CTL 和 Th 反应； 2）。调查 FliC-P/siA20 复合物和突变的 HIV Env 的免疫以及增强自然屏蔽的保护性表位的暴露是否可以更有效地在小鼠和兔子中诱导针对 HIV 的中和抗体；和3）。测试 FliC-P/sihA20 复合物在激活人类 DC 刺激 HIV 特异性 T 和 B 细胞方面是否优于 TLR 激动剂，以供潜在的临床使用。总之，迫切需要开发由 TLR 配体和 A20 抑制剂组成的新型佐剂，其具有独特的刺激能力，可将针对 HIV 的先天性和适应性细胞和体液反应增强至目前描述的佐剂无法达到的更高水平。在这项拟议的研究中，我们的目标是开发用于艾滋病毒疫苗接种的新型佐剂，以诱导保护性细胞和体液免疫反应。具体来说，我们将生成并测试由 TLR 配体和 A20 抑制剂组成的新型佐剂，该佐剂具有独特的刺激能力，可将针对 HIV 的先天性和适应性细胞和体液反应增强至目前描述的佐剂无法达到的更高水平。