NHP Core for Development of an Integrase Defective Lentiviral Vector HIV Vaccine

一种有效的HIV-1疫苗可能需要激发广谱中和抗体来阻断病毒 粘膜表面的感染，以及强烈的T细胞反应，为抗体反应提供帮助 并在传播地点杀死受病毒感染的细胞。最强大的细胞免疫反应 到目前为止，已经使用活的重组疫苗载体产生了疫苗，但它们受到反式 病媒免疫并引发重大的安全问题。而关键的RV144试验令人鼓舞，有31.2% 保护，保护的体液相关性是不可持续的。整合酶缺陷型慢病毒载体 (IDLV)旨在增强抗原表达，安全地防止整合、重组、 复制或载体动员是开发有效的HIV-1疫苗的一种新方法，这种疫苗具有 通过单次免疫提供长期抗原暴露的明显优势。在初步研究中， 这种疫苗方法已经引起了持久的T细胞反应和持久的包膜特异性抗体 老鼠和非人灵长类动物(NHP)的反应。因此，我们现在的目标是确定 该疫苗方案提供的持久抗原表达可诱导高度体细胞突变抗体 可能导致广泛的中和能力和发展功能性CD4+和CD8+T细胞的反应 NHP中的细胞反应是有效的HIV-1疫苗候选所需的。IDLV设计为 表示Ch505传递的/方正信封和从 被发现与广谱中和抗体有关的个人将被顺序送往 有和没有蛋白质的NHP用相同的免疫原增强。这项计划项目赠款的核心是国家卫生计划， 将执行NHP免疫方案和SIV挑战，并向以下项目1和2提供样本 本项目旨在评估IDLV Env免疫原策略的安全性、免疫原性和有效性。这个 CORE还将对疫苗引发的、抗原特异的CD4+和CD8+T细胞进行深入分析。 这项工作将确定使用IDLV载体是否是艾滋病毒-1疫苗接种的可行和有效的策略 这应该被提交给临床试验。

An effective HIV-1 vaccine is likely to require elicitation of broadly neutralizing antibodies to block virus infection at mucosal surfaces, as well as strong T cell responses to provide help to for the antibody responses and to kill virus-infected cells at the site of transmission. The most robust cellular immune responses induced to date have been generated employing live, recombinant vaccine vectors however they are limited by anti- vector immunity and raise significant safety issues. While the pivotal RV144 trial was encouraging with 31.2% protection, the humoral correlates of protection were not sustained. Integrase-defective lentiviral vectors (IDLV) engineered to enhance antigen expression with safe guards against integration, recombination, replication or vector mobilization are a novel approach to developing an effective HIV-1 vaccine which has the distinct advantage of providing long term antigen exposure with a single immunization. In preliminary studies, this vaccine approach has elicited persistent T cell responses as well as durable Envelope-specific antibody responses in both mice and nonhuman primates (NHP). Thus, we now aim to determine the ability of the persistent antigen expression provided by this vaccine regimen to elicit highly somatically-mutated antibody responses that are likely to result in broad neutralization capacity and develop functional CD4+ and CD8+ T cell responses in NHP that are desirable in an efficacious HIV-1 vaccine candidate. IDLV engineered to express the CH505 transmitted/founder envelope and a series of subsequent variants derived from an individual that was found to be associated with broadly neutralizing antibodies will be sequentially delivered to NHP with and without protein boost with the same immunogen. The NHP core of this program project grant, will perform the NHP immunization protocols and SHIV challenge and provide samples to Projects 1 and 2 of this program to assess the safety, immunogenicity and efficacy of the IDLV Env immunogen strategy. The core will also perform in-depth analyses of the vaccine-elicited, antigen specific functional CD4+ and CD8+ T . This work will determine whether the use of IDLV vector is a viable and effective strategy for HIV-1 vaccination that should be forwarded to clinical trials.