Effective CMV-based SIV vaccine regimens for newborn infants via IL-10 modulation

通过 IL-10 调节对新生儿有效的基于 CMV 的 SIV 疫苗方案

• 批准号: 10533308
• 负责人: DENNIS J. HARTIGAN-O'CONNOR
• 金额: $ 74万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533308
• 关键词: Acute; Adenovirus Vector; Adenoviruses; Adult; Animals; Anti-Inflammatory Agents; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Blood Cells; Caring; Cell Compartmentation; Cell physiology; Cells; Characteristics; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Disease; Dominant Negative Receptor; Dominant-Negative Mutation; Dose; Ensure; Failure; Frequencies; GAG Gene; Gene Expression Profile; Generations; Genetic Transcription; Goals; Grant; HIV; HIV vaccine; Human; Human Milk; IL10 gene; Immune; Immune response; Immune system; Immunity; Infant; Innate Immune Response; Interleukin-10; Life; Macaca; Measures; Mediating; Medical; Memory; Natural Killer Cells; Newborn Animals; Newborn Infant; Pathway interactions; Persons; Phenotype; Proteins; Regimen; Reporting; Research; SIV; SIV Vaccines; Signal Transduction; T cell response; T-Lymphocyte; TNF gene; Testing; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Viral; Virus; Work; age group; booster vaccine; cytokine; effector T cell; immunoregulation; improved; interleukin-10 receptor; juvenile animal; mature animal; monocyte; postnatal period; protective efficacy; response; restraint; tool; transcription factor; transcriptomics; transmission process; vaccine candidate; vaccine delivery; vaccine efficacy; vector; vector vaccine; vector-based vaccine

The goal of this grant is to develop CMV-vectored SIV and eventually HIV vaccines that are effective in newborn infants. First-generation RhCMV-vectored SIV vaccines (RhCMV/SIV) are effective in adult animals previously infected with wild-type RhCMV but do not protect newborn animals. Possible explanations for this failure include (i) dramatically different function of the developing immune system of newborns and (ii) absence of wild-type RhCMV and its transformative effects on immunity (>98% of newborn babies are CMV uninfected). We demonstrated that a second-generation vaccine lacking the viral IL-10 gene (RhCMVdIL10/SIVgag) does protect RhCMV-seronegative older infants (8-10 months). Protection via RhCMVdIL10/SIVgag is associated with impressive transcriptomic changes similar to those reported for adult animals receiving RhCMV/SIV. Viral IL-10 function is therefore an impediment to RhCMV/SIV efficacy, particularly in younger animals that may have relatively greater function of tolerogenic, anti-inflammatory pathways. Given our favorable results in older infants, it is likely that RhCMVdIL10/SIVgag is capable of priming similar responses in newborns. To counter the possibility that newborn recipients may mount quantitatively lower T- cell responses, we additionally developed an Ad26 vector that delivers SIVgag together with dominant- negative IL-10 receptor. Delivery of antigen with dominant-negative receptor ensures that the relevant APCs, i.e., those presenting antigen, are unaffected by ambient IL-10. This unique vaccine will be used as a boost. We hypothesize that restrained IL-10 signaling in newborns vaccinated with RhCMVdIL10/SIV permits development of high-frequency, fully functional T cells that are protective against SIV. If the hypothesis is correct then this work will dramatically advance research into vaccination of newborns against HIV and other diseases, simultaneously providing measures of the needed responses and new tools to stimulate them. Aim 1: Test protective efficacy of viral IL-10-deficient RhCMV/SIV vaccines in newborn animals while comprehensively profiling innate immune subsets. Our hypothesis predicts that the viral IL-10-deficient vaccine, RhCMVdIL10/SIVgag, stimulates improved T-cell responses and significant protection in newborn animals; furthermore, protection is associated with transcriptional changes concentrated in innate cells and associated with improved T-cell function. Aim 2: Determine if newborn immune responses to RhCMV/SIV can be boosted by Ad26-vectored vaccines delivering vaccine antigen with or without dominant-negative IL-10 receptor. Adenovectors stimulate strong responses acutely and have been shown to boost protective responses to CMV-vectored vaccines. Here we test an Ad26-based booster vaccine that additionally inhibits IL-10 signaling in APCs to evade regulatory responses that are particularly strong in newborns.

这笔赠款的目的是开发有效的CMV Vectored SIV，并最终开发有效的HIV疫苗 新生婴儿。第一代RHCMV向量的SIV疫苗（RHCMV/SIV）对成年动物有效 先前感染了野生型RHCMV，但不能保护新生动物。可能的解释 失败包括（i）发育中的新生儿免疫系统的功能截然不同，并且（ii）缺席 野生型RHCMV及其对免疫力的变化作用（> 98％的新生婴儿是CMV未感染的）。 我们证明了缺乏病毒IL-10基因的第二代疫苗（Rhcmvdil10/sivgag） 保护RHCMV seronegatigation老年婴儿（8-10个月）。通过RHCMVDIL10/SIVGAG进行保护 具有令人印象深刻的转录组变化，类似于接受RHCMV/SIV的成年动物报告的变化。病毒性的 因此，IL-10功能是RHCMV/SIV功效的障碍，尤其是在可能的年轻动物中 具有耐受性，抗炎途径的功能相对较大。 鉴于我们在老年婴儿中的好成绩，Rhcmvdil10/sivgag可能能够启动相似 新生儿的反应。为了应对新生儿可能在定量降低t-上安装的可能性 细胞反应，我们还开发了一个AD26载体，该载体可提供Sivgag以及主要 阴性IL-10受体。用显性阴性受体递送抗原可确保相关的APC， 即，呈现抗原的人不受环境IL-10的影响。这种独特的疫苗将被用作提升。 我们假设用Rhcmvdil10/SIV允许接种的新生儿中约束IL-10信号传导 开发具有保护性SIV的高频，功能性的T细胞。如果假设是 纠正然后这项工作将大大提高对新生儿疫苗接种艾滋病毒和其他的研究 疾病，同时提供所需的反应和新工具来刺激它们的疾病。 AIM 1：测试新生动物中病毒IL-10缺陷RHCMV/SIV疫苗的保护性疗效，而 全面分析先天免疫子集。我们的假设预测病毒IL-10缺陷率 疫苗，RHCMVDIL10/SIVGAG，刺激了新生儿的T细胞反应和显着保护 动物;此外，保护与固有细胞的转录变化有关，并 与改善的T细胞函数有关。 AIM 2：确定新生儿免疫反应是否可以通过AD26矢量增强RHCMV/SIV的反应 输送带有或没有显性阴性​​IL-10受体的疫苗抗原的疫苗。 adenovectors 刺激强烈的反应，并已被证明可以增强对CMV vectored的保护性反应 疫苗。在这里，我们测试了一种基于AD26的增强疫苗，该疫苗还抑制APC中的IL-10信号转导至 逃避新生儿特别强烈的监管反应。