Synthetic DNA-launched and adjuvanted Env immunogens for HIV

用于 HIV 的合成 DNA 启动和佐剂 Env 免疫原

• 批准号: 10589585
• 负责人: DAVID B. WEINER
• 金额: $ 449.79万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-08 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589585
• 关键词: Adjuvant; Adoptive Transfer; Advanced Development; Agreement; Animal Model; Antibodies; Antibody Repertoire; Antibody Response; Antigens; Apical; Asia; B-Lymphocytes; Binding Sites; CD8-Positive T-Lymphocytes; Cell Lineage; Cell physiology; Cellular Immunity; Clinic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Collaborations; Complex; Cyclic GMP; DNA; DNA Vaccines; DNA delivery; Development; Development Plans; Devices; Electroporation; Epitopes; Europe; Genetic; Goals; HIV; HIV Antigens; HIV Vaccine Trials Network; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunoglobulin G; Infection; Interleukin-12; International; Investigation; Knock-in Mouse; Macaca mulatta; Modeling; Molecular; Mucous Membrane; Mus; Needles; Nucleic Acids; Other Genetics; Peripheral; Pharmacologic Substance; Phase; Phenotype; Plasmids; Prevention strategy; Primates; Process; Production; Proteins; Reporting; Serum; Skin; Structure; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; Technology; Translations; Vaccine Design; Vaccines; Work; adenosine deaminase; cGMP production; candidate selection; clinical development; clinical translation; clinically relevant; cytokine; design; effector T cell; experience; global health; immunogenic; immunogenicity; in vivo; innovation; interleukin-21; lead candidate; manufacture; manufacturing facility; member; nanoparticle; neutralizing antibody; next generation; nonhuman primate; novel; novel strategies; novel vaccines; pandemic disease; phase 3 study; pre-clinical; programs; promoter; response; simian human immunodeficiency virus; synthetic construct; tool; vaccine delivery; vaccine development; vaccine trial; vaccine-induced immunity

Overall Summary A protective vaccine for HIV is arguably the most important prevention strategy to end the global HIV pandemic. The RV144 trial demonstrated a correlation between protection and envelope (Env) specific serum IgG antibodies. However, there was a notable lack of HIV-specific neutralizing antibodies (nAbs) and T cell responses. The DNA platform has several advantages, it is (1) simple to design, (2) can co-deliver molecular adjuvants, (3) can deliver complex structural antigens, and (4) is safe and well tolerated, even after numerous boosts. In our previous IPCAVD program we developed DNA-launched nanoparticle (DLNP) vaccines targeting Env which induced potent and neutralizing immunity in vivo. We have also developed DNA-launched native-like trimer (DL-NLT) immunogens including the clinically relevant BG505 MD39 trimer (Xu et al. Nat. Comm 2022). Protein nanoparticles are difficult to manufacture and poorly stimulate CD8+ T cells. We reported that in vivo assembled nanoparticles drive extremely rapid and strong B and T cell immunity. Functional antibody responses require help from germinal center (GC) follicular helper T cells (TFH). In previous clinical trials with HIV antigens, we observed increased B and T cell responses in the presence of plasmid-encoded IL-12 (pIL-12). Work from members of this team has demonstrated that co-delivery of adenosine deaminase (ADA-1) and plasmid-encoded IL-21 (pIL-21) can enhance antibody induction in mice in a GC-dependent fashion. Here, we combine the DLNP and DL-NLT platforms to generate DNLPs bearing stabilized NLTs focusing immune responses on apex and CD4bs B cell lineage-targeting Envs (DNLP-ACE). We will characterize humoral and cellular immunity to these constructs in the presence of molecular IL-12 with and without additional GC-targeting adjuvants, in mouse and non-human primate vaccination studies. The overarching hypothesis of this project is that DLNP-ACE immunogen technology combined with the co-delivery of genetic adjuvants is a novel approach for the development of HIV-1 vaccines that promotes robust, durable, broad, and neutralizing antibody responses, and supports effector T cell function in vivo A key innovation of this project will be to integrate the selected DNLP-ACE HIV vaccine constructs in a dual expressing plasmid construct with next generation noninvasive intradermal skin electroporation (EP) devices which promote functional CTL and humoral immune responses. The clinical development plan for this IPCAVD is directed by a leading HIV vaccine development organization, Inovio Pharmaceuticals (INO), which has expertise in development of synthetic DNA vaccines and in vivo electroporation delivery. Inovio will oversee clinical grade production of 2 plasmid constructs at a state- of-the-art cGMP plasmid manufacturing facility. Inovio’s processes have passed rigorous international regulatory reviews and have been used in dozens of human clinical trials in the U.S., Europe and Asia, including multiple Phase II and in Phase III studies.

总体摘要 可以说，艾滋病毒保护性疫苗是结束全球艾滋病毒大流行的最重要的预防战略。 RV144试验证明保护性和包膜(Env)特异性血清免疫球蛋白之间存在相关性。 抗体。然而，艾滋病毒特异性中和抗体(NAB)和T细胞明显缺乏 回应。DNA平台有几个优点，它(1)设计简单，(2)可以共同传递分子 佐剂，(3)可以递送复杂的结构抗原，以及(4)是安全和耐受性良好的，即使在 助推器。在我们之前的IPCAVD计划中，我们开发了针对以下目标的DNA发射纳米颗粒(DLNP)疫苗 Env能在体内诱导有效的中和免疫。我们还开发了DNA启动的类似本地的 三聚体(DL-NLT)免疫原，包括临床相关的BG505 MD39三聚体(Xu等人)。纳特。通信2022)。 蛋白质纳米颗粒很难制造，而且对CD8+T细胞的刺激作用很差。我们报道了在活体内 组装好的纳米颗粒可以极快地增强B细胞和T细胞的免疫功能。功能性抗体反应 需要生发中心(GC)毛囊辅助T细胞(TFH)的帮助。在之前的HIV抗原临床试验中， 我们观察到在质粒编码的IL-12(PIL-12)存在的情况下，B细胞和T细胞的反应增加。工作地点： 这个团队的成员已经证明了腺苷脱氨酶(ADA-1)和质粒编码的共同传递 白介素21(IL-21)能以GC依赖的方式增强小鼠的抗体诱导。在这里，我们结合了DLNP 和DL-NLT平台以产生承载稳定的NLT的DNLP，将免疫反应集中在顶端和 CD4b B细胞系靶向包膜蛋白(DNLP-ACE)。我们将描述对这些病毒的体液免疫和细胞免疫 在带有和不带有额外GC靶向佐剂的分子IL-12存在下，在小鼠和 非人灵长类疫苗接种研究。该项目的首要假设是DLNP-ACE 免疫基因技术结合基因佐剂的联合传递是一种新的治疗方法 开发可促进强健、持久、广泛和中和抗体的HIV-1疫苗 反应，并支持体内效应T细胞功能该项目的一个关键创新将是整合 所选的DNLP-ACE HIV疫苗与下一代构建成双表达载体 促进功能性CTL和体液免疫的无创真皮内皮肤电穿孔(EP)装置 回应。这种IPCAVD的临床开发计划是由领先的艾滋病毒疫苗开发指导的 Innovio PharmPharmticals(INO)，该组织在合成DNA疫苗和 体内电穿孔给药。Inovio将在一个状态下监督临床级别的两个质粒构建体的生产- 最先进的cGMP质粒生产设备。Inovio的流程已经通过了严格的国际监管 回顾并已在美国、欧洲和亚洲的数十项人体临床试验中使用，包括多项 第二阶段和第三阶段研究。