Improved RhCMV/SIV vaccine efficacy via IL-10 pathway modulation

通过 IL-10 途径调节提高 RhCMV/SIV 疫苗功效

• 批准号: 10241329
• 负责人: DENNIS J. HARTIGAN-O'CONNOR
• 金额: $ 76.19万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241329
• 关键词: Adult; Affect; Animals; Antibodies; Antiviral Agents; Cytomegalovirus; Data; Epidemic; Gene Expression; Generations; Goals; HIV; HIV vaccine; IL10 gene; Immune response; Immunity; Immunologics; Infant; Infection; Interleukin-10; Lead; Macaca; Macaca mulatta; Mediating; Monkeys; Pathway interactions; Pattern; Pharmacology; Population; Proteins; Regimen; Rhesus; Role; SIV; SIV Vaccines; Sampling; Series; Signal Transduction; Testing; Vaccination; Vaccines; Viral; Virus; Work; base; experimental study; fighting; immunoregulation; improved; infant animal; insight; mature animal; neutralizing antibody; nonhuman primate; novel vaccines; protective efficacy; response; seropositive; tool; transcriptomics; vaccine candidate; vaccine efficacy; vaccine trial

The goal of this project is to test if rhesus cytomegalovirus-based SIV vaccines (RhCMV/SIV) can be improved via IL-10 pathway modulation to obtain significantly over 50% protective efficacy. We found that second-generation RhCMVdIL10/SIV vaccines lacking the viral IL-10 gene protect non-human primate infants, while first-generation (IL-10 intact) RhCMV/SIV vaccines do not. First-generation vaccines have been proven effective only in wild-type RhCMV-seropositive macaques having neutralizing antibodies to viral IL-10. The significance of this work is that if successful it will provide (i) new candidate HIV vaccines with greater efficacy in some or all segments of the population, (ii) a coherent, mechanistic explanation for previously obscure patterns of RhCMV/SIV vaccine protectiveness, (iii) new pharmacologic tools for control over IL-10 signaling, and (iv) immunologic insight into consequences of cellular and viral IL-10 pathway modulation. Our preliminary data show that rhesus macaques infected by wild-type rhesus cytomegalovirus (wtRhCMV) mount immune responses to viral interleukin-10 (vIL-10), which in most cases leads to generation of neutralizing antibodies. RhCMV/SIV vaccine stringently protects ~50% of such wtRhCMV+ but not wtRhCMV- seronegative monkeys against SIV challenge. A second-generation RhCMV/SIV vaccine lacking the viral IL-10 gene, however, can protect seronegative macaques. We hypothesize that RhCMV/SIV vaccination in the context of inhibited host IL-10 signaling will achieve superior efficacy (>50%) in infant and adult macaques. Our specific aims are: Aim 1. Define the transcriptomic and immunologic signatures of increased or decreased IL-10 signaling using previously collected samples. Here we determine the true transcriptomic signature of host IL-10 signaling using samples from animals receiving anti-IL-10 antibody or with forced IL-10 expression. We then evaluate host responses to RhCMV/SIV vaccination in the presence of varying levels of viral IL-10 neutralization to determine how such neutralization affects (i) host IL-10 signaling, (ii) likelihood of generating a transcriptomic signature associated with protection, and (iii) vaccine efficacy. Aim 2. Test if cellular IL-10 inhibition augments vaccine efficacy in infant (RhCMV-negative) macaques. Since viral IL-10 deletion presumably interferes with the host IL-10 response, we reason that further interference (via administration of neutralizing anti-IL-10 antibody) will further augment vaccine efficacy. In this aim we therefore administer RhCMVdIL10/SIVgag alone or in the presence of neutralizing anti-cIL-10 antibody. Aim 3. Test if cellular and/or viral IL-10 inhibition augment vaccine efficacy in adult (RhCMV-positive) macaques. Here we test if complete inhibition of viral and/or cellular IL-10 can substantially increase efficacy. Together these studies will provide clear understanding of the role of IL-10 signaling in RhCMV/SIV vaccine efficacy and may point the way to new vaccine regimens that are 85-100% effective.

本项目的目的是测试基于恒河猴巨细胞病毒的SIV疫苗（RhCMV/SIV）是否可以 通过IL-10途径调节而改善，以获得显著超过50%的保护功效。我们发现 缺乏病毒IL-10基因的第二代RhCMVdIL 10/SIV疫苗保护非人灵长类动物， 婴儿，而第一代（IL-10完整）RhCMV/SIV疫苗没有。第一代疫苗已经 仅在具有针对病毒IL-10的中和抗体的野生型RhCMV血清阳性猕猴中证明有效。 这项工作的意义在于，如果成功，它将提供（i）新的候选艾滋病毒疫苗， 在某些或所有人群中的疗效，（ii）对先前的 RhCMV/SIV疫苗保护性的模糊模式，（iii）控制IL-10的新药理学工具 信号传导，和（iv）对细胞和病毒IL-10通路调节的结果的免疫学洞察。 我们的初步数据表明，感染野生型恒河猴巨细胞病毒（wtRhCMV）的恒河猴， 对病毒性白细胞介素-10（vIL-10）产生免疫应答，在大多数情况下， 中和抗体RhCMV/SIV疫苗严格保护约50%的此类wtRhCMV+，但不保护wtRhCMV- 血清阴性猴对抗SIV攻击。缺乏病毒IL-10的第二代RhCMV/SIV疫苗 然而，基因可以保护血清阴性的猕猴。 我们假设在抑制宿主IL-10信号传导的情况下，RhCMV/SIV疫苗接种将实现 在婴儿和成年猕猴中具有上级疗效（>50%）。我们的具体目标是： 目标1.定义IL-10升高或降低的转录组学和免疫学特征 使用先前收集的样本进行信令。在这里，我们确定了宿主的真实转录组签名， 使用来自接受抗IL-10抗体或具有强制IL-10表达的动物的样品的IL-10信号传导。我们 然后在不同水平的病毒IL-10存在下评价宿主对RhCMV/SIV疫苗接种的应答 中和，以确定这种中和如何影响（i）宿主IL-10信号传导，（ii）产生免疫应答的可能性。 与保护相关的转录组签名，和（iii）疫苗效力。 目标2.测试细胞IL-10抑制是否增加婴儿（RhCMV阴性）猕猴中的疫苗效力。 由于病毒IL-10缺失可能干扰宿主IL-10应答，我们进一步推断， 干扰（通过施用中和抗IL-10抗体）将进一步增强疫苗效力。在这 因此，我们的目的是单独施用RhCMVdIL 10/SIVgag或在中和抗cIL-10抗体存在下施用。 目标3.测试细胞和/或病毒IL-10抑制是否增加成人（RhCMV阳性）中的疫苗效力 猕猴在这里，我们测试病毒和/或细胞IL-10的完全抑制是否可以显著增加功效。 总之，这些研究将提供对IL-10信号传导在RhCMV/SIV疫苗中的作用的清晰理解 有效性，并可能指向新的疫苗方案，是85-100%的有效性。