Design and optimization of DL-NLTs and molecular adjuvants to increase potency and promote NAb formation in vivo

项目1摘要 多年来，已经进行了广泛的努力来设计一种艾滋病毒-1候选疫苗，该候选疫苗 诱导强大的免疫反应，支持广泛的中和和效应性T细胞反应。 最近，韦纳和库尔普实验室报告了新型DNA的开发--在 活体、自组装免疫原，包括DNA启动的天然类三聚体(DL-NLTS) 和DNA发射的纳米颗粒免疫原(DLNPs)。DNA都推出了NLT和NPs 组装并展示合适的表位，用于中和抗体，同时封闭表位 用于体内的非中和抗体。此外，它们还能促进强大的T细胞免疫力。这些 正在将候选疫苗转移到研究HVTN-304和HVTN-305的诊所。 SynDNA有助于快速设计免疫原，共同传递分子佐剂，支持 体内表达和组装复杂结构抗原，有安全的临床记录， 并保持助推能力。在我们之前IPCAVD进展的基础上，结合了这些 设计，我们将在项目2下与Kulp博士合作，制定含有NLT的DLNPs 显示顶端和CD4结合部位B细胞谱系靶向表位(DLNP-ACE)。 此外，我们还设计并表征了几种合成dna编码的分子佐剂。 支持增强体液免疫、细胞免疫和直接抗原特异性 对粘膜表面的反应。项目1的首要目标是将这些小说结合起来 具有DNA递送的遗传佐剂组合和/或异源佐剂的免疫原 方案，在与项目3开发的双表达质粒中支持疫苗诱导 它代表着艾滋病毒-1疫苗设计上的一大飞跃。

Project 1 Summary Extensive efforts have been carried out over the years to design a HIV-1 vaccine candidate which elicits robust immune responses supporting broad neutralization and effector T cell responses. Recently the Weiner and Kulp laboratories reported the development of novel DNA-launched, in vivo, self-assembling immunogens, including both DNA launched native like trimers (DL-NLTs) and DNA-launched nanoparticle immunogens (DLNPs). Both DNA launched NLTs and NPs assemble and display appropriate epitopes for neutralizing antibodies while occluding epitopes for non-neutralizing antibodies in vivo. Additionally, they drive robust T cell immunity. These vaccine candidates are being moved to the clinic under studies HVTN-304 and HVTN-305. synDNA facilitates rapid immunogen design, co-delivery of molecular adjuvants, supports expression and assembly of complex structural antigens in vivo, has a safe clinical track record, and maintains boost-ability. Building on progress from our previous IPCAVD, combining these designs, we will be working with Dr. Kulp under Project 2 to formulate DLNPs bearing NLTs displaying Apex and CD4 binding-site B cell lineage targeting Epitopes (DLNP-ACEs). Furthermore, we have designed and characterized several synDNA-encoded molecular adjuvants to support enhanced humoral immunity, cell-mediated immunity, and direct antigen-specific responses to mucosal surfaces. The overarching goal of Project 1 is to combine these novel immunogens with DNA-delivered genetic adjuvant combinations and/or heterologous adjuvant regimens, in dual expressing plasmids developed with Project 3 to support vaccine-induced immunity and represents a great leap forward in the design of HIV-1 vaccines.