Chlamydial Vaccine Testing in Mice and Guinea Pigs

沙眼衣原体(CT)是美国输卵管阻塞和不孕症的主要原因。 全球范围内。与人类相似，啮齿动物模型中的原发衣原体感染会诱导免疫，即 对后续挑战的部分保护。产生干扰素的T细胞(Th1细胞)是 对于解决感染和抵抗再感染是必不可少的。CD8 T细胞可以促进分辨率 通过产生干扰素和抗体增强抵抗力。小鼠和豚鼠的实验研究 研究表明，感染或接种诱导FGT中的Th1细胞与 保护。组织驻留记忆干扰素分泌的CD4T细胞(Th1TRM)被证明是关键 用于小鼠的长期免疫力。这些发现支持我们的假设，即一种有效的衣原体 因此，疫苗需要同时诱导全身性Th1和FGT Th1 TRM。动物模型是 对疫苗的迭代测试至关重要，以提供基本的免疫原性、机制和 将疫苗推向临床的疗效数据。我们有标准化的小鼠和豚鼠 用于检测衣原体疫苗的生殖道挑战模型。我们将检查两个领先的T细胞 在开发新型衣原体疫苗方面，疫苗形式已被证明在人类身上是安全的。第一 是一种由黑猩猩腺病毒(乍得)组成的异源病毒载体Prime Boost方案 PRIME和改良的痘苗病毒安卡拉(MVA)免疫后，显示出诱导高频率的 CD4和CD8T细胞。我们将生产和测试第一批乍得/MVA衣原体疫苗。这个 第二个平台使用专利纳米乳液Nanovax来佐剂重组蛋白。 纳米疫苗是专门为鼻腔给药而研制的，可以有效地诱导粘膜 CD4T细胞和抗体。我们将开发和测试三价纳米疫苗，以预防 衣原体。所使用的免疫原将是CT蛋白的物种特异性同源物 抵抗再感染或限制其CT感染范围的妇女的记录免疫原性 感染。我们将使用这些疫苗模式来实现三个具体目标：目标1.评估 表达衣原体的复制缺陷病毒载体的免疫原性和保护作用 小鼠体内的抗原。目的2.评价重组疫苗的免疫原性和保护效果 衣原体抗原经鼻腔NE传递的小鼠及其联合疫苗的免疫效果 加强保护。目的3.测定CHAD/MVA Prime-Boost和NE-Boost的免疫原性 佐剂衣原体疫苗在雌性豚鼠中的免疫效果及其对人工和 单独和联合性传播鼠尾丝虫。该项目将确定新的衣原体 具有高度可行的临床测试和许可途径的疫苗。

Chlamydia trachomatis (CT) is the leading cause of tubal obstruction and infertility in the US and globally. Similar to humans, primary chlamydial infection in rodent models induces immunity that is partially protective against subsequent challenge. IFN-producing CD4 T cells (Th1 cells) are essential for resolving infection and resisting reinfection. CD8 T cells can contribute to resolution through production of IFN, and antibodies augment resistance. Studies in mice and guinea pigs demonstrated that the induction of Th1 cells in the FGT by infection or vaccination correlate with protection. Tissue resident memory IFN-secreting CD4 T cells (Th1 TRM) were shown to be critical for long-term immunity in mice. These findings support our hypothesis that an efficacious chlamydial vaccine will therefore need to induce both systemic Th1 and FGT Th1 TRM. Animal models are essential for iterative testing of vaccines to provide essential immunogenicity, mechanistic, and efficacy data for progressing vaccines to the clinic. We have standardized mouse and guinea pig genital tract challenge models for testing chlamydial vaccines. We will examine two leading T cell vaccine modalities proven safe in humans for the development of novel chlamydial vaccines. The first is a heterologous virus vector prime boost regimen comprised of a chimpanzee adenovirus (ChAd) prime followed by a Modified vaccinia virus Ankara (MVA) boost shown to induce high frequencies of CD4 and CD8 T cells. We will generate and test the first ChAd/MVA vaccines against chlamydia. The second platform uses a proprietary nanoemulsion Nanovax to adjuvant recombinant proteins. Nanovax vaccines are specifically formulated for intranasal delivery and efficiently induce mucosal CD4 T cells and antibodies. We will develop and test trivalent Nanovax vaccines against Chlamydia. The immunogens used will be species-specific homologs of CT proteins that have documented immunogenicity in women who resisted reinfection or limited the extent of their CT infection. We will use these vaccine modalities to pursue three specific aims: Aim 1. Evaluate the immunogenicity and protective efficacy of replication-deficient viral vectors expressing chlamydial antigens in mice. Aim 2. Evaluate the immunogenicity and protective efficacy of recombinant chlamydial antigens delivered intranasally via NE in mice and the ability of combined vaccines to improve protection. Aim 3. Determine the immunogenicity of ChAd/MVA prime-boost and NE- adjuvanted chlamydial vaccines in female guinea pigs and their ability to protect from artificial and sexual transmission of C. caviae alone and in combination. This project will identify novel chlamydial vaccines with a highly feasible path to clinical testing and licensure.