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

基本信息

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
项目类别：
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

项目摘要

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.

这笔赠款的目标是开发 CMV 载体的 SIV 疫苗，并最终开发出有效的 HIV 疫苗刚出生的婴儿。第一代 RhCMV 载体 SIV 疫苗 (RhCMV/SIV) 对成年动物有效以前感染过野生型 RhCMV，但不能保护新生动物。对此的可能解释失败包括（i）新生儿免疫系统发育中的功能显着不同，以及（ii）缺乏野生型 RhCMV 及其对免疫的转化作用（> 98% 的新生儿未感染 CMV）。我们证明，缺乏病毒 IL-10 基因 (RhCMVdIL10/SIVgag) 的第二代疫苗确实可以保护 RhCMV 血清阴性较大婴儿（8-10 个月）。通过 RhCMVdIL10/SIVgag 进行的保护相关令人印象深刻的转录组变化类似于接受 RhCMV/SIV 的成年动物所报道的变化。病毒性的因此，IL-10 功能是 RhCMV/SIV 功效的一个障碍，特别是在年轻动物中，可能具有相对较大的耐受性、抗炎途径功能。鉴于我们在较大婴儿中取得的良好结果，RhCMVdIL10/SIVgag 很可能能够启动类似的作用。新生儿的反应。为了应对新生儿接受者 T- 数量可能较低的可能性细胞反应，我们还开发了一种 Ad26 载体，可将 SIVgag 与显性- IL-10 受体阴性。使用显性失活受体递送抗原可确保相关 APC、即那些呈递抗原的细胞不受环境 IL-10 的影响。这种独特的疫苗将用作加强疫苗。我们假设，在接种 RhCMVdIL10/SIV 的新生儿中，IL-10 信号传导受到抑制，从而允许开发可预防 SIV 的高频、功能齐全的 T 细胞。如果假设是如果正确的话，这项工作将极大地推进新生儿艾滋病毒和其他疾病疫苗接种的研究疾病，同时提供所需应对措施和刺激这些措施的新工具。目标 1：测试病毒性 IL-10 缺陷型 RhCMV/SIV 疫苗对新生动物的保护功效，同时全面分析先天免疫子集。我们的假设预测病毒 IL-10 缺陷疫苗 RhCMVdIL10/SIVgag 可刺激改善 T 细胞反应并为新生儿提供显着保护动物;此外，保护与集中在先天细胞中的转录变化有关与 T 细胞功能的改善有关。目标 2：确定 Ad26 载体是否可以增强新生儿对 RhCMV/SIV 的免疫反应提供具有或不具有显性失活 IL-10 受体的疫苗抗原的疫苗。腺病毒载体急性刺激强烈反应，并已被证明可以增强对 CMV 载体的保护性反应疫苗。在这里，我们测试了一种基于 Ad26 的加强疫苗，该疫苗还抑制 APC 中的 IL-10 信号传导，从而逃避对新生儿特别强烈的监管反应。