Nucleic acid-based formulation of cytomegalovirus-vectored HIV vaccines

基于核酸的巨细胞病毒载体 HIV 疫苗配方

基本信息

批准号：
10011665
负责人：
DENNIS J. HARTIGAN-O'CONNOR
金额：
$ 30万
依托单位：
TENDEL THERAPIES INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-07 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10011665
关键词：
Adjuvant Antigens Antiviral Agents Attenuated Vaccines Bacterial Artificial Chromosomes Blood CD8-Positive T-Lymphocytes Capital Cations Cells Characteristics Cold Chains Cytomegalovirus Cytomegalovirus Vaccines DNA DNA Vaccines Development Distant Endotoxins Epidemic Escherichia coli Evaluation Event Excision Formulation Gene Expression Generations Genome Goals Government Grant HIV HIV vaccine Hand Harvest Heterogeneity Histology Human Human Resources IL10 gene Immune Immune response Immunize Infant Infection Inflammatory Injections Interleukin-10 Lead Left Licensing Light Lipid Bilayers Macaca Macaca mulatta Mammalian Cell Methods Mutation Nucleic Acids Peripheral Blood Mononuclear Cell Persons Phase Phenotype Polymers Production Property Rhesus SIV SIV Vaccines Site T cell response Technology Testing Time Tissues Transfection Vaccinated Vaccination Vaccine Antigen Vaccines Viral Viral Genes Virion Virus Work adaptive immune response base clinical development design experimental study fighting global health immunoregulation improved in vivo innovation interest particle recombinase response restriction enzyme tissue/cell culture tool transcriptomics vaccine candidate vaccine delivery vaccine development vector vector vaccine

项目摘要

This grant is for translational development of a scalable, nucleic acid-based formulation of cytomegalovirus-vectored vaccines that can be distributed without a cold chain. HIV candidate vaccines that use cytomegalovirus (CMV) as delivery vector and immunomodulatory adjuvant have shown extraordinary promise. In our preliminary work, for example, a rhesus cytomegalovirus-vectored SIV vaccine lacking the viral IL-10 gene (RhCMVdIL10-SIVgag) protected 4/6 infants from SIV infection. Tendel Therapies Inc. is licensing a portfolio of technology centered on these second-generation, CMV-vectored vaccines. Manufacturing and distribution of CMV-based vaccines present daunting challenges: (i) replication of CMV in culture is markedly slower than that of other vaccine vectors; (ii) CMV undergoes rapid genetic change when amplified in culture; (iii) the virus is enveloped and thus difficult to separate from cell- and virus-derived lipid bilayers of a similar size; (iv) methods for extreme concentration of the heterogenous particles are unknown; and (v) a cold chain is required for distribution. To eliminate these problems, Tendel is also licensing technology for vaccine delivery using purified CMV genomes propagated in E. coli. The technology permits efficient “rescue” of the genomes after introduction to mammalian cells. Similarly efficient rescue in vivo should lead to immune responses that are equivalent to those provoked by conventional vaccination with virions. We hypothesize that viral IL-10-deficient, CMV-vectored vaccine genomes (DNA) provoke immune responses that are indistinguishable from the protective responses stimulated by encapsidated live vaccine. Aim 1. Assess antigen expression and vaccine vector replication after delivery of vaccine genomes to macaques. CMV-vectored vaccines given as virions first replicate locally, leading to inflammatory cell influx, and then systemically, leading to viral gene expression in distant tissues. Our hypothesis predicts that successful rescue of vaccine genomes should lead to the same events. Aim 2. Test if innate and adaptive immune responses to vaccination with nucleic acid are comparable to protective anti-SIV responses observed previously. Previous studies have shown that protection against SIV is associated with specific immune responses, particularly Mamu-E-restricted CD8+ T cell responses. These innovative Phase I experiments will be sufficient to establish both the technical merit and—in light of the proven commercial interest in CMV-vectored vaccines—the commercial potential of Tendel's approach. Phase II experiments will build on this work to (i) demonstrate that macaques vaccinated with nucleic acid are protected against SIV challenge (ii) continue development of replication-defective HCMV-HIV Gag and Env vaccines.

这笔赠款用于可扩展的、基于核酸的制剂的转化开发无需冷链即可分发的巨细胞病毒载体疫苗。使用巨细胞病毒（CMV）作为递送载体和免疫调节佐剂的疫苗已被证明例如，在我们的初步工作中，恒河猴巨细胞病毒载体的 SIV 疫苗。缺乏病毒 IL-10 基因 (RhCMVdIL10-SIVgag) 可保护 4/6 的婴儿免受 Tendel 疗法感染。 Inc. 正在授权以这些第二代 CMV 载体疫苗为中心的技术组合。基于 CMV 的疫苗的制造和分销面临着严峻的挑战：(i) 在体内复制 CMV (ii) CMV 在以下情况下经历快速的遗传变化：在培养物中扩增；(iii) 病毒有包膜，因此难以与细胞和病毒来源的脂质分离 (iv) 异质颗粒极端浓缩的方法未知； (v) 配送需要冷链。为了消除这些问题，Tendel 还获得了使用纯化 CMV 进行疫苗接种的技术许可在大肠杆菌中繁殖的基因组。该技术允许在引入后有效地“拯救”基因组。类似地，有效的体内救援应该会产生相当于的免疫反应。那些由常规病毒颗粒疫苗接种引起的。我们致力于病毒 IL-10 缺陷、CMV 载体疫苗基因组 (DNA) 激发免疫反应这与由衣壳活疫苗刺激的保护性反应没有区别。目标 1. 将疫苗基因组递送至疫苗后评估抗原表达和疫苗载体复制以病毒粒子形式给予的巨细胞病毒载体疫苗首先在局部复制，导致炎症细胞涌入，然后系统地导致远处组织中的病毒基因表达。成功拯救疫苗基因组应该会导致同样的事件。目标 2. 测试对核酸疫苗接种的先天免疫反应和适应性免疫反应是否具有可比性先前观察到的保护性抗 SIV 反应已表明具有保护作用。抗 SIV 与特异性免疫反应相关，特别是 Mamu-E 限制性 CD8+ T 细胞回应。这些创新的第一阶段实验将足以确定技术优点，并且——鉴于 CMV 载体疫苗的商业利益已得到证实——Tendel 阶段方法的商业潜力。 II 实验将在此工作的基础上 (i) 证明含核酸的猕猴疫苗免受 SIV 挑战 (ii) 继续开发复制缺陷型 HCMV-HIV Gag 和 Env 疫苗。