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，包括 保护粘膜表面免受病毒传播和高度变异性的挑战，开发创新的疫苗接种策略至关重要。事实上，尽管进行了广泛的研究，但预防HIV传播的完全有效的疫苗仍然难以捉摸，并且对保护相关性的理解有限，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应答。 在这里，我们提出了一种新的艾滋病毒疫苗接种方法，使用持续的益生菌治疗作为佐剂，以提高免疫原性和保护诱导的一个有效的联合疫苗策略。我们的疫苗由同时施用的SIV（gagp 55）和HIV（gp 140）DNA + HIV gp 140三聚体蛋白组成。最近的研究已经提供了证据表明，将DNA和蛋白质组合用于疫苗接种可以增强疫苗特异性细胞和体液免疫。此外，我们的初步研究证明，在未感染SIV的猕猴中进行益生菌治疗导致淋巴结中T滤泡辅助细胞增加、粘膜组织中IgA表达B细胞增加、粘膜组织中抗原呈递细胞增加以及多功能T细胞增加，以及CD 4 + T细胞的增殖和活化降低。因此，我们假设，将有益微生物群操作的有效免疫调节作用与应诱导稳健的细胞和体液免疫的新型疫苗平台相结合，将在粘膜和全身组织中产生前所未有的高水平疫苗特异性应答，从而保护免受直肠SHIV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群以增强粘膜疫苗应答;（ii.）利用新型双重SHIV DNA-HIV gp 140蛋白疫苗接种平台;（iii.）除了标准的疫苗接种相关物（抗体和T细胞应答）之外，还将测量潜在的疫苗接种相关物的新测量，包括微生物组形态发生、稳态粘膜应答、先天免疫应答和T滤泡辅助细胞和生发中心B细胞应答。

 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).