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.

项目摘要/弃权 预防性艾滋病毒疫苗将通过帮助减少来对全球卫生带来巨大的好处 受感染人数。同样，需要新的疫苗方法，有可能 减少结核病和疟疾的发生率。 RHCMV向量的SIV疫苗已证明 引起可以控制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的非感染病毒体的比例相对较大 主要的实践挑战已经延迟了人类CMV的疫苗测试 患者。此外，在某些HIV流行病地区可能不可行的冷链的需求是 有问题。在这里，我们描述并提议根据CMV的交付来测试疫苗平台 基于核酸形式的疫苗载体基因组。我们已经证明了传递的基因组是 能够在体内启动自我维持的复制，并且该矢量复制产生 免疫反应至少相等，即使不优于那些（常规）刺激的免疫反应 用封装的疫苗 - 载体颗粒疫苗接种。成功完成此R21项目 因此，将加速基于CMV的HIV和其他疾病的疫苗开发 出色地。确实，我们认为在CMV载体疫苗可以之前需要这样的进步 对人类健康对人类健康产生积极影响。这项工作的目的是 在体内提供基于巨细胞病毒的疫苗的实用，具有成本效益的平台。我们的 假设是rhcmvdil10-sivgag和-sivenV疫苗，以复制能力， 自审查的BAC DNA可以引起具有与之相关的独特特征的免疫反应 RHCMV向后的疫苗接种且对SIV具有保护作用。这个假设将被解决 在两个特定的目标中，使用恒河猕猴非人类灵长类动物模型。 AIM 1将确定 最佳的体内递送方法，用于复制和传播以及宿主免疫 对一种新颖的自发射Rhcmvdil10-Siv疫苗的反应。体内三种不同的方法 BAC DNA递送将测试免疫原性。细胞和体液免疫反应， 除了复制外，还将评估包括Mamu-E限制响应的发展 和向量的传播。 AIM 2将测试RHCMVDIL10 -SIVGAG和-SIVINV疫苗是 作为自我发射的BAC时，可以保护SIV疾病。我们将确定程度 猕猴疫苗接种后，针对低剂量的病原SIV挑战获得了保护 使用AIM 1中确定的最佳输送方法。 该建议将解决许多限制当前基于CMV的发展的障碍 病毒载体，并且对影响人类健康的其他疾病具有广泛的适用性。