Persistent modulation of microbiota to enhance HIV vaccination

 描述(由申请人提供)：鉴于艾滋病毒的高度复杂性质，包括保护粘膜表面免受传播和病毒高度变异性的挑战，开发创新的疫苗接种战略至关重要。事实上，尽管进行了广泛的研究，但预防艾滋病毒传播的完全有效的疫苗仍然难以捉摸，而且对保护的相关性了解有限，特别是在粘膜表面。最近，微生物组在粘膜免疫中的重要性已经得到重视，在这里我们假设我们可以利用微生物组来诱导保护性疫苗反应。 在这里，我们提出了一种新的HIV疫苗接种方法，它使用持续的益生菌疗法作为佐剂，以增强免疫原性和由有效的联合疫苗策略诱导的保护。我们的疫苗由同时注射的SIV(Gag P55)和HIV(Gp140)DNA HIV gp140三聚体蛋白组成。最近的研究表明，DNA和蛋白质联合接种可以提高疫苗的特异性细胞免疫和体液免疫。此外，我们的初步研究还发现，在未感染SIV的猕猴中，益生菌治疗会导致淋巴中T滤泡辅助细胞增加，粘膜组织中表达IgA的B细胞增加，粘膜组织中的抗原提呈细胞增加，多功能T细胞增加，以及CD4T细胞的增殖和激活减少。因此，我们假设，将有益的微生物区系操作的强大免疫调节作用与应能诱导强大的细胞和体液免疫的新型疫苗平台相结合，将在粘膜和系统组织中产生前所未有的高水平的疫苗特异性反应，从而保护人们免受直肠SIV攻击。 这种疫苗设计有几个创新方面，包括：(I)用益生菌调节微生物区系以增强粘膜疫苗的反应；新型双SIV DNA-HIV gp140蛋白疫苗接种平台的应用除了疫苗接种的标准相关因素(抗体和T细胞反应)外，还将测量潜在疫苗接种相关因素的新测量，包括微生物组形态发生、动态平衡粘膜反应、先天免疫反应、T毛囊助手和生发中心B细胞反应。

 DESCRIPTION (provided by applicant): Given the highly complex nature of HIV, including the challenges of protecting mucosal surfaces from transmission and high variability of the virus, developing innovative vaccination strategies is crucial. Indeed, despite extensive research, a fully efficacious vaccine to prevent HIV transmission remains elusive, and there is limited understanding of correlates of protection, particularly at mucosal surfaces. Recently, the importance of the microbiome in mucosal immunity have become appreciated, and here we hypothesize that we can exploit the microbiome to induce protective vaccine responses. Here we propose a novel HIV vaccination approach that uses persistent probiotic therapy as an adjuvant to enhance immunogenicity and protection induced by a potent combined vaccine strategy. Our vaccine consists of concurrently administered SIV (gag p55) and HIV (gp140) DNA + HIV gp140 trimer protein. Recent studies have provided evidence that combining DNA and protein for vaccination elicits increased vaccine specific cellular and humoral immunity, In addition, our preliminary studies provocatively demonstrated that probiotic treatment in SIV-uninfected macaques results in increased T follicular helper cells in lymph nodes, IgA expressing B cells in mucosal tissues, increased antigen presenting cells in mucosal tissues, and increased multifunctional T cells, as well as decreased proliferation and activation of CD4+ T cells. Thus, we hypothesize that combining the potent immunomodulatory effects of beneficial microbiota manipulation with a novel vaccine platform that should induce robust cellular and humoral immunity will result in unprecedented high levels of vaccine specific responses in both mucosal and systemic tissues, resulting in protection from rectal SHIV challenge. There are several innovative aspects of this vaccine design, including: (i.) Modulation of the microbiota with probiotics to enhance mucosal vaccine responses; (ii.) utilization of a novel dual SHIV DNA-HIV gp140 protein vaccination platform; (iii.) novel measurements of potential vaccination correlates will be measured including microbiome morphogenesis, homeostatic mucosal responses, innate immune responses, and T follicular helper and germinal center B cell responses, in addition to standard correlates of vaccination (antibody and T cell responses).