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

这笔赠款的目标是开发以CMV为载体的SIV，并最终开发出在 新生婴儿。第一代RhCMV载体SIV疫苗(RhCMV/SIV)在成年动物中有效 以前感染野生型RhCMV但不保护新生动物。对此可能的解释 失败包括(I)新生儿发育中的免疫系统功能显著不同和(Ii)缺失 野生型RhCMV及其对免疫的转化作用(&gt；98%的新生儿未感染CMV)。 我们证明了缺乏病毒IL-10基因的第二代疫苗(RhCMVdIL10/SIVgag)可以 保护RhCMV血清阴性的大龄婴儿(8-10个月)。通过RhCMVdIL10/SIVgag关联的保护 令人印象深刻的转录变化类似于报道的接受RhCMV/SIV的成年动物。病毒式传播 因此，IL-10的功能阻碍了RhCMV/SIV的疗效，特别是在可能 具有相对较大的耐受、抗炎通路功能。 考虑到我们在较大婴儿中的有利结果，RhCMVdIL10/SIVgag很可能能够启动类似的 新生儿的反应。为了应对新生儿受者可能会在数量上降低T- 细胞反应，我们另外开发了一种AD26载体，它能将SIVgag与优势基因一起传递- IL-10受体阴性。带有显性-负性受体的抗原传递确保了相关的APC， 即那些提呈抗原的，不受环境IL-10的影响。这种独特的疫苗将被用作助推剂。 我们推测，在接种了RhCMVdIL10/SIV许可的新生儿中，IL-10信号受到抑制 开发对SIV具有保护作用的高频、全功能T细胞。如果假设是 正确地说，这项工作将极大地推进新生儿预防艾滋病毒和其他疾病疫苗的研究 同时提供必要的应对措施和新的工具来刺激这些疾病。 目的1：检测IL-10基因缺陷的RhCMV/SIV疫苗对新生动物的保护效果 全面剖析先天免疫亚群。我们的假设预测病毒的IL-10缺陷 RhCMVdIL10/SIVgag疫苗刺激改善T细胞反应并显著保护新生儿 动物；此外，保护与集中在天然细胞和 与改善T细胞功能有关。 目的2：确定Ad26载体能否增强新生儿对RhCMV/SIV的免疫应答 带有或不带有显性阴性IL-10受体的疫苗。Adenovectors 敏锐地刺激强烈的反应，并已被证明增强对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，它另外抑制了APC中的IL-10信号转导 避开对新生儿尤为强烈的监管反应。

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.