Development of a Chlamydia trachomatis Vaccine in an Outbred Pre-exposed Swine Animal Model

在远交预暴露猪动物模型中开发沙眼衣原体疫苗

• 批准号: 10432122
• 负责人: Tobias E Kaeser
• 金额: $ 57.59万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-16 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432122
• 关键词: Adjuvant; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Antigens; Azithromycin; Bacterial Sexually Transmitted Diseases; Biological Assay; Biomedical Research; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chlamydia; Chlamydia trachomatis; Clinical; Clinical Trials; Color; Cross Reactions; Data; Development; Disease; Ectopic Pregnancy; Enzyme-Linked Immunosorbent Assay; Exposure to; Family suidae; Flow Cytometry; Generations; Genital; Genitalia; Goals; HIV Infections; Health; Health Care Costs; Homing; Hormonal; Human; Immune; Immune response; Immune system; Immunity; Immunofluorescence Immunologic; Immunoglobulin A; Immunohistochemistry; In Vitro; Inbred Mouse; Infection; Infertility; Interferon Type II; Intramuscular; Intranasal Administration; Lead; Literature; Memory; Miniature Swine; Modeling; Mucous Membrane; Mus; Neutralizing antibody assay; Patients; Pelvic Inflammatory Disease; Peptide antibodies; Peptides; Phase; Phase III Clinical Trials; Physiology; Population; Prevalence; Proteins; Regimen; Reproducibility; Research; Research Personnel; Resolution; Risk; Sexual Transmission; Streptococcus suis; Subunit Vaccines; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Target Populations; Technology; Testing; Tissues; Vaccination; Vaccine Research; Vaccines; base; cell mediated immune response; cross reactivity; efficacy testing; exposed human population; immunogenic; immunogenicity; improved; major outer membrane protein; mouse model; nanoemulsion; novel; novel vaccines; particle; pathogen; porcine model; pre-clinical; reproductive; reproductive tract; response; single-cell RNA sequencing; standard of care; success; vaccination outcome; vaccination strategy; vaccine access; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine formulation; vaccine immunogenicity; vaccine trial; γδ T cells

Chlamydia trachomatis (Ct) is the most frequent bacterial sexually transmitted pathogen, and can lead to ectopic pregnancy and infertility. Antibiotics cure infection but may not ameliorate disease and a vaccine is urgently needed. Success in preclinical animal studies is essential for vaccines to move to human clinical trials. Pigs are affordable, highly biologically relevant, and the natural host to the prevalent pathogen Chlamydia suis (Cs) – a chlamydia species closely related to Ct. Pigs are also susceptible to Ct; and protective CD4 T cells from Cs pre- exposed pigs cross-react to Ct. This cross-reaction makes Cs pre-exposed pigs a highly valuable animal model for Ct vaccine development: Vaccination of Cs-pre-exposed outbred pigs can simulate Ct vaccination of Ct pre- exposed humans – the target population of clinical phase III Ct vaccination trials. Dr. Kaeser has expertise in performing Cs and Ct vaccination and challenge trials in Cs pre-exposed pigs and in detailed analyses of Ct infection and immunity. Our long-term goal is to use this model to develop Ct vaccines and to offer the model to other researchers as a Ct vaccine testing platform. This study has two main goals: Use Cs pre-exposed pigs to develop a Ct vaccine candidate with novel vaccine formulations and Ct antigens, and provide an in-depth understanding of protective vaccine-induced immune mechanisms. The study is divided into three phases: Phase I will determine the most immunogenic parenteral/mucosal, prime/ boost vaccination strategy using whole-cell inactivated Ct either in a nanoemulsion or adjuvanted with the TriAdj adjuvant. Phase II will then use the most immunogenic vaccination strategy to determine the immunogenicity of proven and novel antigen combinations – likely MOMP, CFAMP, OmcB, and pgp3. Vaccine immunogenicity and the humoral and cell mediated immune responses will be analyzed both systemically and locally using state-of- the art technologies including multi-peptide antibody ELISAs, multi-color T cell flow cytometry, tissue clearance in combination with fluorescent immunohistochemistry and single-cell RNAseq analyses of adaptive T cells. These first two phases will develop our vaccine candidate - the most immunogenic vaccination strategy and Ct antigen combination. In Phase III, we will test the efficacy and immunogenicity of this vaccine candidate in two identical animal trials, demonstrating rigor and reproducibility to evaluate our Ct vaccine candidate. This study will contribute in three ways to further Ct vaccine research and human health: i) It will improve our understanding of the immune response relevant for protection against Ct; ii) it will develop a novel Ct vaccine candidate; iii) it will provide a proof-of-principle vaccination study to fully establish the Cs pre-exposed pig model. This highly relevant large animal model can be used to test new candidates and improve on current regimens with the goal to develop a vaccine that results in sterilizing immunity in humans.

沙眼衣原体 (Ct) 是最常见的细菌性性传播病原体，可导致异位 怀孕和不孕症。抗生素可以治愈感染，但可能无法改善疾病，因此迫切需要疫苗 需要。临床前动物研究的成功对于疫苗进入人体临床试验至关重要。猪是 经济实惠、具有高度生物学相关性，并且是流行病原体猪衣原体 (Cs) 的天然宿主 – 与 Ct 密切相关的衣原体物种。猪也对 Ct 敏感；和来自Cs预-的保护性CD4 T细胞 暴露的猪与 Ct 发生交叉反应。这种交叉反应使 Cs 预暴露猪成为非常有价值的动物模型 用于Ct疫苗开发：对Cs预暴露的近交猪进行疫苗接种可以模拟Ct预暴露的Ct疫苗接种 暴露人群——临床 III 期 Ct 疫苗接种试验的目标人群。 Kaeser 博士拥有以下方面的专业知识： 在预先暴露于 Cs 的猪中进行 Cs 和 Ct 疫苗接种和激发试验，并对 Ct 进行详细分析 感染和免疫力。我们的长期目标是利用这个模型来开发Ct疫苗，并将该模型提供给 其他研究人员作为Ct疫苗测试平台。这项研究有两个主要目标： 使用 Cs 预暴露猪 开发具有新型疫苗配方和 Ct 抗原的候选 Ct 疫苗，并提供深入的研究 了解保护性疫苗诱导的免疫机制。 该研究分为三个阶段：第一阶段将确定最具免疫原性的肠胃外/粘膜、初免/ 使用纳米乳剂中的全细胞灭活 Ct 或以 TriAdj 佐剂的加强疫苗接种策略 佐剂。然后，第二阶段将使用最具免疫原性的疫苗接种策略来确定疫苗的免疫原性。 经过验证的新型抗原组合 – 可能是 MOMP、CFAMP、OmcB 和 pgp3。疫苗的免疫原性和 体液和细胞介导的免疫反应将使用状态进行系统和局部分析 先进技术，包括多肽抗体 ELISA、多色 T 细胞流式细胞术、组织清除 结合荧光免疫组织化学和适应性 T 细胞的单细胞 RNAseq 分析。 前两个阶段将开发我们的候选疫苗 - 最具免疫原性的疫苗接种策略和 Ct 抗原组合。在第三阶段，我们将分两个阶段测试该候选疫苗的功效和免疫原性 相同的动物试验，证明了评估我们的 Ct 候选疫苗的严谨性和可重复性。 这项研究将从三个方面为进一步的 Ct 疫苗研究和人类健康做出贡献： i) 它将改善我们的 了解与预防 Ct 相关的免疫反应； ii) 将开发一种新型 Ct 疫苗 候选人; iii) 它将提供原理验证疫苗接种研究，以全面建立铯预暴露猪模型。 这种高度相关的大型动物模型可用于测试新的候选药物并改进当前的治疗方案 目标是开发一种能够消除人类免疫力的疫苗。