Synthetic DNA-launched and adjuvanted Env immunogens for HIV

总体汇总 艾滋病毒的保护性疫苗可以说是结束全球艾滋病毒大流行的最重要的预防战略。 RV 144试验证明了保护和包膜（Env）特异性血清IgG之间的相关性 抗体的然而，明显缺乏HIV特异性中和抗体（nAbs）和T细胞 应答DNA平台具有几个优点，它是（1）简单的设计，（2）可以共同提供分子 佐剂，（3）可以递送复杂的结构抗原，和（4）是安全的和良好的耐受性，即使在许多 增强在我们之前的IPCAVD计划中，我们开发了DNA发射的纳米颗粒（DLNP）疫苗， Env在体内诱导了有效的中和免疫。我们还开发了DNA启动的类天然 三聚体（DL-NLT）免疫原，包括临床相关的BG 505 MD 39三聚体（Xu et al. Nat. Comm 2022）。 蛋白质纳米颗粒难以制造，并且对CD 8 + T细胞的刺激作用很差。我们报道，在体内， 组装的纳米颗粒驱动极其快速和强烈的B和T细胞免疫。功能性抗体应答 需要生发中心（GC）滤泡辅助T细胞（TFH）的帮助。在以前的HIV抗原临床试验中， 我们观察到在质粒编码的IL-12（pIL-12）存在下增加的B和T细胞应答。工作从 这个小组的成员已经证明，腺苷脱氨酶（ADA-1）和质粒编码的 IL-21（pIL-21）可以以GC依赖性方式增强小鼠的抗体诱导。在这里，我们将联合收割机 和DL-NLT平台，以产生携带稳定的NLT的DNLP， CD 4 bs B细胞谱系靶向Envs（DNLP-ACE）。我们将描述体液和细胞免疫这些 在分子IL-12存在下，在有和没有另外的GC靶向佐剂的情况下， 非人类灵长类动物疫苗接种研究。该项目的首要假设是DLNP-ACE 免疫原技术与遗传佐剂的共递送相结合是一种用于免疫治疗的新方法。 开发HIV-1疫苗，促进强大，持久，广泛和中和抗体 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 选择的DNLP-ACE HIV疫苗构建体与下一代一起构建在双表达质粒构建体中 促进功能性CTL和体液免疫的非侵入性皮内皮肤电穿孔（EP）装置 应答该IPCAVD的临床开发计划由领先的HIV疫苗开发公司指导。 Inovio Pharmaceuticals（INO）是一家拥有合成DNA疫苗开发专业知识的组织， 体内电穿孔递送。Inovio将监督2种质粒构建体的临床级生产， 最先进的cGMP质粒生产设施Inovio的流程通过了严格的国际监管 已经在美国进行了数十项人体临床试验，欧洲和亚洲，包括多个 II期和III期研究。

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.