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

• 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
• 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

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.

该赠款是用于转化开发的可扩展的，基于核酸的公式的 可以在没有冷链的情况下分布的巨细胞病毒载体疫苗。艾滋病毒候选人 使用巨细胞病毒（CMV）作为递送载体和免疫调节调整的疫苗已显示 非凡的承诺。例如，在我们的初步工作中 缺乏病毒IL-10基因（RHCMVDIL10-SIVGAG）保护4/6婴儿免受SIV感染。肌腱疗法 Inc.正在许可以这些第二代，CMV vect的疫苗为中心的技术组合。 基于CMV的疫苗的制造和分配带来了艰巨的挑战：（i）复制CMV 培养物比其他疫苗向量慢。 （ii）CMV在 在文化中放大； （iii）病毒被包裹，因此很难与细胞和病毒衍生的脂质分离 大小相似的双层； （iv）未知的异质颗粒的极端浓度的方法； （v）分配需要冷链。 为了消除这些问题，Tendel也是使用纯化CMV的疫苗传递技术许可技术 大肠杆菌中传播的基因组。该技术允许在引入后的基因组有效地“营救” 哺乳动物细胞。同样有效的体内营救应导致免疫反应，等效于 传统疫苗接种病毒引起的。 我们假设病毒IL-10缺陷，CMV载体疫苗基因组（DNA）引起免疫调查 与封装的活疫苗刺激的受保护反应没有区别。 AIM 1。评估疫苗基因组传递后的抗原表达和疫苗载体复制 猕猴。 CMV矢量为病毒的疫苗首先在局部复制，从而导致炎症细胞的影响， 然后是系统地，导致遥远组织中的病毒基因表达。我们的假设预测 成功营救疫苗基因组应导致相同的事件。 AIM 2。测试先天和适应性免疫调查是否可以与核酸疫苗接种 为了保护先前观察到的抗SIV反应。先前的研究表明保护 针对SIV与特定的免疫反应有关，尤其是Mamu-E限制的CD8+ T细胞 回答。 这些创新的I阶段实验将足以确定技术优点和 - 根据 对CMV载体的疫苗的经过验证的商业兴趣，这是Tendel方法的商业潜力。阶段 II实验将以这项工作为基础（i）证明了用核酸接种的猕猴是 免受SIV挑战（II）的保护继续发展复制缺陷的HCMV-HIV堵嘴和Env 疫苗。