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: 10274870
• 负责人: Tobias E Kaeser
• 金额: $ 61.65万
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274870
• 关键词: Adjuvant; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Antigens; Azithromycin; Bacterial Sexually Transmitted Diseases; Biological; 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; 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; neutralizing antibody; 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 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（Chlamydia trachomatis，Ct）是最常见的细菌性性传播病原体，可导致异位妊娠 怀孕和不孕。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。 needed.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 价格实惠，高度生物相关，是流行病原体猪衣原体（Cs）的天然宿主- a 与Ct密切相关的衣原体种类。猪也易受Ct的影响，并且保护性CD 4 T细胞免受Cs前 暴露猪对Ct有交叉反应。这种交叉反应使Cs预暴露猪成为一种极有价值的动物模型 对于Ct疫苗开发：接种Cs预暴露的远系杂交猪可以模拟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。凯瑟博士擅长 在Cs预暴露猪中进行Cs和Ct疫苗接种和攻毒试验，并进行Ct的详细分析 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，并提供这个模型， 其他研究人员作为Ct疫苗测试平台。本研究有两个主要目标：使用Cs预暴露猪， 开发具有新型疫苗制剂和Ct抗原的Ct疫苗候选物，并提供深入的 了解疫苗诱导的免疫机制。 该研究分为三个阶段：第一阶段将确定免疫原性最强的胃肠外/粘膜，初免/免疫接种。 使用纳米乳剂或TriAdj佐剂中的全细胞灭活Ct的加强疫苗接种策略 佐剂。然后，II期将使用最具免疫原性的疫苗接种策略来确定 经证实的新型抗原组合-可能是MOMP、CFAMP、OmcB和pgp 3。疫苗免疫原性和 体液和细胞介导的免疫应答将使用状态- 现有技术包括多肽抗体ELISA、多色T细胞流式细胞术、组织清除 结合适应性T细胞的荧光免疫组织化学和单细胞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 抗原结合在第三阶段，我们将在两个阶段测试这种候选疫苗的有效性和免疫原性。 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。 这项研究将在三个方面为进一步的Ct疫苗研究和人类健康做出贡献：i）它将提高我们的免疫力， 了解与预防Ct相关的免疫反应; ii）它将开发一种新的Ct疫苗 iii）其将提供原理证明疫苗接种研究以完全建立Cs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 其目标是开发一种疫苗，导致人类的绝育免疫。