Induction of protective antibodies for HIV vaccine development

这个艾滋病毒/艾滋病疫苗开发联合会（CHAVD）将采用最先进的技术， 免疫学工具，重点放在迭代，合理的疫苗设计，这将导致一个成功的最终疫苗设计。 前几年的大量工作导致了HIV-1疫苗开发的这一关键时刻， 保护性HIV-1疫苗的前景变得更加明朗。这笔赠款的理由是，前13年 艾滋病毒/艾滋病疫苗免疫学项目中心的负责人定义了阻止疫苗的障碍， 开发了第一代HIV-1免疫原，以诱导HIV-1保护性抗体，并建立了 加快HIV-1疫苗开发的转化管道。该补助金的总体目标是开发一个 全球使用的有效HIV-1疫苗。CHAVD中提出了两个重点：重点1， 诱导HIV-1广泛中和抗体（bnAb），焦点2，诱导保护性免疫应答的策略， HIV-1非中和抗体。在焦点1中，我们的总体目标是设计Env免疫原， bnAb的多重特异性。在这里，CHAVD团队将设计诱导bnAb的免疫原， 最佳的CD 4 T细胞有助于bnAb诱导，瞬时下调来自负调控的限制， 细胞和免疫耐受机制，并允许不利的bnAb B细胞谱系发展。聚焦 2，我们的总体目标是开发多价免疫原，诱导广泛和有效的保护性非免疫原。 中和HIV-1抗体（NNAb）。管理和业务股将监督该委员会 转化管道，我们的六个科学研究支持单位（SRSU）将提供关键 免疫原设计的要素或候选免疫原的临床前评价。一旦设计和 在bnAb基因敲入小鼠或猕猴中进行了测试，有希望通过我们的go-no-go标准的候选疫苗 将由CHAVD科学产品开发委员会和DAIDS审查，然后生产， 临床试验在我们的GMP生产单位在杜克和测试的第一阶段试验的艾滋病毒疫苗试验 网络我们的临床试验样品分析部门将确定达到的免疫原性， 为焦点1或焦点2以及我们的SRSU提供关于人体诱导的免疫应答的反馈， 改进免疫原。我们预计，在这笔赠款结束时，最终的候选疫苗将是 递送至NIAID，其在恒河猴中可再现地诱导持久水平的bnAb或保护性NNAb 猕猴（RM）或在人类的I期试验中，或在两者中。

This Consortium for HIV/AIDS Vaccine Development (CHAVD) will apply state-of-the-art technologies and immunologic tools to focus on iterative, rational vaccine design that will lead to a successful final vaccine design. Much work in previous years has led to this critical juncture in HIV-1 vaccine development where the route forward has become clearer to a protective HIV-1 vaccine. The rationale for this grant is that the first 13 years of the Center for HIV/AIDS Vaccine Immunology programs defined the roadblocks preventing a vaccine, developed first generation HIV-1 immunogens to induce HIV-1 protective antibodies and established a translational pipeline to accelerate HIV-1 vaccine development. The overall goal of this grant is to develop an effective HIV-1 vaccine for global use. There are two foci proposed in the CHAVD: Focus 1, strategies for induction of HIV-1 broadly neutralizing antibodies (bnAbs), and Focus 2, strategies for induction of protective HIV-1 non-neutralizing antibodies. In Focus 1, our overall goal is to design Env immunogens that will elicit multiple specificities of bnAbs. Here the CHAVD team will design immunogens that induce bnAbs, induce optimal CD4 T cell help for bnAb induction, transiently down-modulate constraints from negative regulatory cells and immune tolerance mechanisms, and allow for disfavored bnAb B cell lineages to develop. In Focus 2, our overall goal is to develop multivalent immunogens that induce broad and potent protective non- neutralizing HIV-1 antibodies (NNAbs). The Management and Operations Unit will oversee the CHAVD translational pipeline, and each of our six Science Research Support Units (SRSUs) will provide key elements of immunogen design or pre-clinical evaluation of candidate immunogens. Once designed and tested in bnAb knock-in mice or in macaques, promising vaccine candidates that pass our go-no go criteria will be vetted by the CHAVD Scientific Product Development Committee and DAIDS, then produced for clinical trials in our GMP Production Unit at Duke and tested in Phase I trials by the HIV Vaccine Trials Network. Our Clinical Trials Sample Analysis Unit will determine the immunogenicity achieved and provide feedback on immune responses induced in man to Focus 1 or Focus 2 and our SRSUs for iterative improvement of immunogens. We expect that by the end of this grant, a final vaccine candidate will be delivered to the NIAID that has reproducibly induced durable levels of either bnAbs or protective NNAbs in rhesus macaques (RMs) or in a Phase I trial in humans, or in both.