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

基本信息

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
项目类别：
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

项目摘要

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）是最常见的细菌性传播病原体，可以导致生态怀孕和不育。抗生素治愈感染，但可能无法改善疾病，并且疫苗是紧急的需要。临床前动物研究中的成功对于疫苗进行人类临床试验至关重要。猪是负担得起的，高度与生物学相关的，并且是普遍的病原体衣原体Suis（CS）的天然宿主 - A 衣原体物种与Ct密切相关。猪也容易受到CT的影响；并保护CD4 T细胞来自CS 暴露的猪交叉反应到CT。这种交叉反应使CS预先暴露的猪成为高度有价值的动物模型为了开发CT疫苗：疫苗接种了CS-PRE暴露的爆炸猪可以模拟CT疫苗的CT疫苗暴露的人类 - 临床III期CT疫苗接种试验的目标人群。 Kaeser博士拥有专业知识在CS预先暴露的猪中进行CS和CT疫苗接种和挑战试验以及CT的详细分析感染和免疫力。我们的长期目标是使用该模型开发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预先暴露的猪用新型的疫苗配方和CT抗原开发CT疫苗候选者，并提供深入了解受保护的疫苗诱导的免疫力学。该研究分为三个阶段：第一阶段将确定最免疫原性的肠胃外/粘膜，Prime/ 在纳米乳液中使用全细胞灭活CT或使用Triadj进行调整，以提高疫苗接种策略佐剂。然后，第二阶段将使用最免疫原性的疫苗接种策略来确定证明和新颖的抗原组合 - 可能是MOMP，CFAMP，OMCB和PGP3。疫苗免疫原性和体液和细胞介导的免疫反应将在系统和本地分析艺术技术包括多肽抗体ELISA，多色T细胞流式细胞仪，组织清除率结合荧光免疫组织化学和自适应T细胞的单细胞RNASEQ分析。前两个阶段将发展我们的疫苗候选者 - 最免疫原性的疫苗策略和CT 抗原组合。在第三阶段中，我们将在两个中测试该疫苗候选者的效率和免疫原性相同的动物试验，证明了评估我们CT疫苗候选者的严格性和可重复性。这项研究将以三种方式做出进一步的CT疫苗研究和人类健康：i）它将改善我们的了解与保护CT有关的免疫响应； ii）它将开发一种新型的CT疫苗候选人; iii）它将提供原本疫苗接种研究，以完全建立CS预先暴露的猪模型。这种高度相关的大型动物模型可用于测试新候选者并改善当前方案目的是开发一种疫苗，从而导致对人类的免疫力进行消毒。