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率，从而为全球健康带来巨大益处。 感染人数。同样，需要新的疫苗方法，有可能 减少结核病和疟疾的发病率。 RhCMV 载体的 SIV 疫苗已被证明 引发控制 SIV 感染的免疫反应的巨大潜力，但不稳定 CMV 基因组和疫苗库存中相对较大比例的非感染性病毒粒子 重大的实际挑战，已经推迟了 CMV 载体疫苗的人体试验 患者。此外，对冷链的需求在某些艾滋病毒流行地区可能不可行 有问题的。在这里，我们描述并建议测试基于 CMV 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，并且该载体复制产生 免疫反应看起来至少等于（如果不优于）（传统）刺激的免疫反应 用封装的疫苗载体颗粒进行疫苗接种。 R21项目顺利完成 因此将加速针对艾滋病毒和其他潜在疾病的基于 CMV 的疫苗开发 出色地。事实上，我们相信，在 CMV 载体疫苗能够实现之前，需要取得这样的进展。 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 为体内基于巨细胞病毒的疫苗递送提供实用的、具有成本效益的平台。我们的 假设 RhCMVdIL10-SIVgag 和 -SIVenv 疫苗具有复制能力， 自我切除的 BAC DNA 可以引发免疫反应，该反应具有与 RhCMV 载体疫苗接种可预防 SIV。这个假设将得到解决 使用恒河猴非人类灵长类动物模型来实现两个特定目标。目标 1 将确定 用于复制和传播以及宿主免疫的最佳体内递送方法 对一种新型、自行启动的 RhCMVdIL10-SIV 疫苗的反应。三种不同的体内方法 BAC DNA 递送将进行免疫原性测试。细胞和体液免疫反应， 除了复制之外，还将评估 Mamu-E 限制性反应的发展 和载体的传播。目标 2 将测试 RhCMVdIL10-SIVgag 和 -SIVenv 疫苗是否有效 当作为自启动 BAC 提供时，可预防 SIV 疾病。我们将确定范围 猕猴接种疫苗后针对低剂量致病性 SIV 攻击所获得的保护 使用目标 1 中确定的最佳递送方法。 中描述的新型疫苗载体 该提案将解决限制当前基于 CMV 的发展的许多障碍 病毒载体，对影响人类健康的其他疾病具有广泛的适用性。