Induction of protective antibodies for HIV vaccine development

这个艾滋病毒/艾滋病疫苗开发联盟(CHAVD)将应用最先进的技术和 免疫学工具将重点放在迭代、合理的疫苗设计上，这将导致成功的最终疫苗设计。 前几年的大量工作导致了HIV-1疫苗开发的这个关键时刻，在那里路线 Forward对一种保护性的HIV-1疫苗变得更加明确。这笔赠款的基本原理是，最初的13年 艾滋病毒/艾滋病疫苗免疫项目中心的成员定义了阻止疫苗接种的障碍， 开发了第一代HIV-1免疫原来诱导HIV-1保护性抗体，并建立了 加快HIV-1疫苗开发的转译管道。这笔赠款的总体目标是开发一种 全球使用的有效HIV-1疫苗。CHAVD提出了两个重点：重点1，战略 诱导HIV-1广谱中和抗体(BNAbs)，焦点2，保护性诱导策略 HIV-1非中和抗体。在焦点1中，我们的总体目标是设计环境免疫原，以诱导 BNAbs的多重特异性。在这里，CHAVD团队将设计免疫原来诱导bNAbs，诱导 优化的CD4T细胞有助于bNab的诱导，暂时下调负调控的限制 细胞和免疫耐受机制，并允许不受欢迎的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，以诱导广泛而有效的保护性非 中和HIV-1抗体(NNAbs)。管理和业务股将监督CHAVD 翻译管道，我们的六个科学研究支持单位(SRSU)中的每一个都将提供关键 免疫原设计要素或候选免疫原的临床前评估。一旦设计并 在bNab转基因小鼠或猕猴身上进行了测试，有望通过我们的通过标准的候选疫苗 将由CHAVD科学产品开发委员会和DAIDS审查，然后为 在杜克大学的GMP生产部门进行的临床试验，以及艾滋病毒疫苗试验在第一阶段试验中进行的测试 网络。我们的临床试验样本分析单位将确定所实现的免疫原性和 针对Focus 1或Focus 2和我们的SRSU提供对MAN诱导的免疫反应的反馈，以进行迭代 免疫原水平的提高。我们预计，到这笔赠款结束时，最终的候选疫苗将是 传递给NIAID，该NIAID在恒河猴体内可重复诱导持久的bNAbs或保护性NNAbs水平 猕猴(RMS)或在人类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.