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）是美国输卵管阻塞和不孕症的主要原因， 在全球与人类相似，啮齿动物模型中的原发性衣原体感染诱导免疫， 部分保护随后的挑战。产生IFN γ的CD 4 T细胞（Th 1细胞）是 对解决感染和抵抗再感染至关重要。CD 8 T细胞可有助于缓解 通过产生IFN γ和抗体增强抵抗力。小鼠和豚鼠研究 证明了通过感染或疫苗接种诱导FGT中的Th 1细胞与 保护组织驻留记忆IFN γ分泌性CD 4 T细胞（Th 1 TRM）被证明是关键的 用于小鼠的长期免疫。这些发现支持了我们的假设， 因此，疫苗需要诱导全身性Th 1和FGT Th 1 TRM。动物模型是 对于疫苗的迭代测试至关重要，以提供基本的免疫原性，机制， 有效性数据，用于将疫苗推向临床。我们已经标准化了小鼠和豚鼠 生殖道攻击模型测试衣原体疫苗。我们将研究两种主要的T细胞 已证明在人类中安全的疫苗模式，用于开发新型衣原体疫苗。第一 是由黑猩猩腺病毒（ChAd）组成的异源病毒载体初免加强方案， 致敏，然后是改良的安卡拉牛痘病毒（MVA）加强，显示出诱导高频率的 CD 4和CD 8 T细胞。我们将生产和测试第一批针对衣原体的ChAd/MVA疫苗。的 第二个平台使用专有的纳米乳液Nanovax ™来辅助重组蛋白。 Nanovax鼻内疫苗是专门配制用于鼻内递送，并有效诱导粘膜感染。 CD 4 T细胞和抗体。我们将开发和测试三价Nanovax疫苗， 衣原体所用的免疫原将是CT蛋白的物种特异性同源物， 在抵抗再感染或限制CT范围的女性中记录了免疫原性 感染我们将利用这些疫苗模式来实现三个具体目标：目标1。评价 表达衣原体复制缺陷型病毒载体的免疫原性和保护效力 小鼠体内的抗原目标2.评价重组疫苗的免疫原性和保护效力 衣原体抗原在小鼠中通过NE鼻内递送，以及联合疫苗 加强保护。目标3.测定ChAd/MVA初免-加强免疫和NE- 在雌性豚鼠中的含佐剂衣原体疫苗及其保护免受人工和 性传播C.单独的和组合的卡巴拉汀。该项目将确定新的衣原体 疫苗具有高度可行的临床试验和许可证途径。