Vaccination with self-launching RhCMV/SIV DNA vaccine vectors

使用自启动 RhCMV/SIV DNA 疫苗载体进行疫苗接种

• 批准号: 10037603
• 负责人: DENNIS J. HARTIGAN-O'CONNOR
• 金额: $ 23.34万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10037603
• 关键词: Address; Adult; Animals; Area; Attenuated Vaccines; Autopsy; Bacterial Artificial Chromosomes; Bacterial Genome; Blood; Clinical Trials; Cold Chains; Complex; Cytomegalovirus; DNA; DNA Vaccines; DNA delivery; Data; Development; Digestion; Disease; Dose; Effectiveness; Electroporation; Enterobacteria phage P1 Cre recombinase; Excision; Genetic; Genetic Recombination; Genome; Genomic DNA; Glycoproteins; Goals; HIV; HIV vaccine; Health; Human; Immune response; Immunity; In Vitro; Incidence; Infection; Intravenous; Laboratories; Macaca; Macaca mulatta; Malaria; Mediating; Methods; Modeling; Nature; Nucleic Acids; Outcome; Pathogenicity; Patients; Preparation; Replication Origin; Rhesus; SIV; SIV Vaccines; Saliva; Serial Passage; Signal Transduction; Site; Testing; Tissues; Transfection; Tuberculosis; Uncertainty; Vaccinated; Vaccination; Vaccines; Vertebral column; Viral; Viral Genome; Viral Vector; Virion; Virus; Work; base; cost effective; experimental study; global health; immunogenicity; in vivo; interest; mutant; nonhuman primate; novel; novel vaccines; particle; prophylactic; recombinase; response; restriction enzyme; terminase; tissue culture; vaccine delivery; vaccine development; vector; vector genome; vector vaccine; vector-based vaccine; virus envelope

PROJECT SUMMARY/ABSRACT A prophylactic HIV vaccine would be of tremendous benefit for global health by helping to reduce the number of infected people. Similarly, new vaccine approaches are needed with the potential to reduce incidence of tuberculosis and malaria. RhCMV-vectored SIV vaccines have demonstrated tremendous potential for eliciting immune responses that can control SIV infection, but the unstable CMV genome and the relatively large proportion of non-infectious virions in vaccine stocks present major practical challenges, which have already delayed tests of CMV-vectored vaccines in human patients. Additionally, the need for a cold chain that is likely infeasible in some HIV-endemic areas is problematic. Here we describe and propose to test a vaccine platform based on delivery of the CMV- based vaccine vector genome in nucleic-acid form. We have shown that the delivered genomes are capable of initiating self-sustaining replication in vivo, and that this vector replication engenders immune responses that appear at least equal if not superior to those stimulated by (conventional) vaccination with encapsidated vaccine-vector particles. Successful completion of this R21 project will thus accelerate CMV-based vaccine development for HIV and potentially other diseases as well. Indeed, we believe that an advance such as this is required before CMV-vectored vaccines can have the positive impact on human health that is so hoped for by the field. The goal of this work is to provide a practical, cost-effective platform for cytomegalovirus-based vaccine delivery in vivo. Our hypothesis is that RhCMVdIL10-SIVgag and -SIVenv vaccines delivered as replication-competent, self-excising BAC DNA can elicit immune responses that have the unique character associated with RhCMV-vectored vaccination and that are protective against SIV. This hypothesis will be addressed in two specific aims using the rhesus macaque non-human primate model. Aim 1 will determine the optimal in vivo delivery method for replication and dissemination of, as well as host immune responses to, a novel, self-launching RhCMVdIL10-SIV vaccine. Three different methods of in vivo BAC DNA delivery will be tested for immunogenicity. Cellular and humoral immune responses, including the development of Mamu-E-restricted responses, will be assessed in addition to replication and dissemination of the vector. Aim 2 will test if RhCMVdIL10-SIVgag and -SIVenv vaccines are protective against SIV disease when delivered as self-launching BACs. We will determine the extent of protection achieved against low-dose, pathogenic SIV challenge following vaccination of macaques using the optimal delivery method identified in Aim 1. The novel vaccine vectors that are described in this proposal will solve many of the hurdles that are limiting the development of current CMV-based viral vectors and have broad applicability for other diseases that impact human health.

项目概要/摘要 预防性艾滋病毒疫苗将有助于减少艾滋病毒感染， 感染人数。同样，需要新的疫苗方法， 减少肺结核和疟疾的发病率。RhCMV载体的SIV疫苗已经证明 巨大的潜力，引发免疫反应，可以控制SIV感染，但不稳定 CMV基因组和疫苗储备中相对较大比例的非感染性病毒体 主要的实际挑战，已经推迟了CMV载体疫苗在人类中的试验 患者此外，对冷链的需求在一些艾滋病毒流行地区可能是不可行的， 有问题在这里，我们描述并提出测试基于CMV-1的递送的疫苗平台。 基于核酸形式的疫苗载体基因组。我们已经证明，交付的基因组是 能够在体内启动自我维持复制，并且这种载体复制产生 与（常规）免疫刺激相比，至少表现出相等（如果不是上级的话）的免疫反应 用包被的疫苗载体颗粒接种。成功完成R21项目 因此，将加速基于CMV的艾滋病毒和其他潜在疾病疫苗的开发， 好.事实上，我们认为，在CMV载体疫苗能够 对人类健康产生积极影响，这是该领域所希望的。这项工作的目标是 为基于巨细胞病毒的疫苗体内递送提供了一个实用的、具有成本效益的平台。我们 假设RhCMVdIL 10-SIVgag和-SIVenv疫苗以复制能力递送， 自我切除的BAC DNA可以引发免疫反应，这种免疫反应具有与以下特征相关的独特特征： RhCMV载体疫苗接种，并对SIV具有保护作用。这一假设将得到解决 在两个特定的目标使用恒河猴非人类灵长类动物模型。目标1将决定 用于复制和传播以及宿主免疫的最佳体内递送方法 一种新型的自启动RhCMVdIL 10-SIV疫苗。三种不同的体内方法 将检测BAC DNA递送的免疫原性。细胞和体液免疫反应， 包括Mamu-E限制性反应的发展，除了复制外， 传播媒介。目标2将测试RhCMVdIL 10-SIVgag和-SIVenv疫苗是否 当作为自我启动的BAC提供时，可以预防SIV疾病。我们将确定 猕猴接种疫苗后， 使用目标1中确定的最佳交付方法。描述于以下文献中的新型疫苗载体： 这一建议将解决许多限制当前基于CMV的 病毒载体，并且对于影响人类健康的其它疾病具有广泛的适用性。