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

基本信息

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
项目类别：
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

项目摘要

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.

总体总结艾滋病毒保护性疫苗是结束全球艾滋病毒大流行最重要的预防策略，这一点颇具争议。 RV144 试验证明了保护和包膜 (Env) 特异性血清 IgG 之间的相关性然而，HIV特异性中和抗体（nAb）和T细胞明显缺乏。 DNA平台有几个优点，（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，（4）即使在经过多次注射后也是安全且耐受性良好的在我们之前的 IPCVD 项目中，我们开发了 DNA 发射的纳米颗粒 (DLNP) 疫苗靶向。 Env 可在体内诱导有效的中和免疫，我们还开发了 DNA 启动的类似天然的免疫。三聚体 (DL-NLT) 免疫原，包括临床相关的 BG505 MD39 三聚体 (Xu et al. Nat. Comm 2022)。我们报道称，蛋白质纳米颗粒难以制造，并且对体内 CD8+ T 细胞的刺激效果较差。组装的纳米颗粒可驱动极其快速和强烈的 B 和 T 细胞免疫功能性抗体反应。需要生发中心 (GC) 滤泡辅助 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) 存在下 B 细胞和 T 细胞反应增加。该团队的成员已经证明，腺苷脱氨酶 (ADA-1) 和质粒编码的共同传递 IL-21 (pIL-21) 可以以 GC 依赖性方式增强小鼠中的抗体诱导。在这里，我们结合了 DLNP。和 DL-NLT 平台，用于生成带有稳定 NLT 免疫聚焦反应的 DNLP CD4bs B 细胞谱系靶向 Envs (DNLP-ACE) 我们将表征针对这些的体液和细胞免疫。在分子 IL-12 存在下，在有或没有额外的 GC 靶向佐剂的情况下，在小鼠和该项目的总体假设是 DLNP-ACE。免疫原技术与基因佐剂共同递送相结合是一种新的方法开发可促进强效、持久、广泛和中和抗体的 HIV-1 疫苗响应，并支持体内效应 T 细胞功能该项目的一个关键创新是整合选定的 DNLP-ACE HIV 疫苗构建体与下一代双表达质粒构建体无创皮内皮肤电穿孔 (EP) 装置，可促进功能性 CTL 和体液免疫该 IPCVD 的临床开发计划由领先的 HIV 疫苗开发机构指导。 Inovio Pharmaceuticals (INO) 组织，该公司在开发合成 DNA 疫苗和 Inovio 将监督 2 种质粒构建体的临床级生产。最先进的 cGMP 质粒生产设施已通过严格的国际监管。审查并已用于美国、欧洲和亚洲的数十项人体临床试验，其中包括多项 II 期和 III 期研究。