Chlamydial Vaccine Testing in Mice and Guinea Pigs

小鼠和豚鼠衣原体疫苗测试

• 批准号: 10615098
• 负责人: Nilu Goonetilleke
• 金额: $ 69.52万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615098
• 关键词: Adenoviruses; Adjuvant; Africa; Animal Model; Antibodies; Antigens; Attenuated; Bacteria; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cavia; Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Chlamydophila; Clinic; Clinical Trials; Combined Vaccines; Data; Development; Ebola; Europe; Female; Female genitalia; Frequencies; Genital; Genitalia; Goals; HIV; Hepatitis C virus; Herpes Simplex Virus Vaccines; Homologous Gene; Human; Human Development; Immunity; Immunization; Infection; Influenza; Licensure; Malaria; Mammalian Oviducts; Mediating; Memory; Modality; Modeling; Modified Vaccinia Virus Ankara; Mucous Membrane; Mus; North Carolina; Pan Genus; Pathology; Persons; Plasmids; Pre-Clinical Model; Production; Proteins; Recombinant Proteins; Recombinants; Regimen; Resistance; Resolution; Rodent Model; Route; Safety; Sexual Transmission; Simplexvirus; Standardization; T-Lymphocyte; Testing; Th1 Cells; Tissues; Translating; Tubal Obstructions; Tuberculosis; Universities; Vaccination; Vaccines; Viral Vector; Virus; Woman; booster vaccine; chlamydia vaccine; immunogenic; immunogenicity; improved; nanoemulsion; novel; pathogen; prevent; protective efficacy; reproductive tract; research clinical testing; subcutaneous; tubal infertility; vaccine evaluation; vaccine platform; vector

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.

沙眼衣原体（CT）是美国输出反对和不孕症的主要原因 全球。与人类类似，啮齿动物模型中的原发性衣原体感染会影响免疫力 部分保护了后来的挑战。产生IFN的CD4 T细胞（Th1细胞）是 解决感染和抵抗再感染至关重要。 CD8 T细胞可以有助于解决 通过生产IFN和抗体增强了抗性。对小鼠和豚鼠的研究 证明通过感染或疫苗接种与FGT中Th1细胞的诱导与 保护。组织居民的记忆IFN分泌CD4 T细胞（TH1 TRM）被证明是关键的 为了长期免疫。这些发现支持我们有效的衣原体的假设 因此，疫苗将需要诱导全身性TH1和FGT TH1 TRM。动物模型是 疫苗的迭代测试至关重要，以提供必要的免疫原性，机械性和 疫苗到诊所的疗效数据。我们有标准化的鼠标和豚鼠 测试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 疫苗模式证明了人类开发新的衣原体疫苗的安全。第一个 是一种异源病毒载体素的增强疗法，完成了黑猩猩腺病毒（CHAD） Prime，其次是修饰的离甲状腺病毒Ankara（MVA）的增强剂，以诱导高频 CD4和CD8 T细胞。我们将生成和测试针对衣原体的第一种乍得/MVA疫苗。这 第二个平台使用专有的纳米乳液纳米诺瓦克斯来调整重组蛋白。 纳米诺瓦疫苗是针对鼻内递送的特异性配制的，并有效诱导粘膜 CD4 T细胞和抗体。我们将开发和测试三价纳米诺瓦疫苗 衣原体。所使用的免疫剂将是具有特定于具有的CT蛋白的特定规格的同源物 抗拒再感染或限制其CT程度的女性中有记录的免疫原性 感染。我们将使用这些疫苗方式来追求三个具体目标：目标1。评估 免疫原性和表达衣原体的复制病毒载体的受保护效率 小鼠中的抗原。目标2。评估重组的免疫原性和保护效率 衣原体抗原在小鼠中通过NE进行鼻内递送，合并疫苗的能力 改善保护。 AIM 3。确定乍得/MVA Prime-Boost和Ne-的免疫原性 雌性豚鼠的调整后疫苗及其免受人造和保护的能力 单独和组合的C. C. C. c.c。这个项目将确定新颖的衣原体 具有高度可行的临床测试和许可途径的疫苗。