Group A Streptococcus Vaccination to prevent Strep throat in an NHP model

A 组链球菌疫苗接种可预防 NHP 模型中的链球菌性咽喉炎

• 批准号: 10507934
• 负责人: Jennifer Marie Dan
• 金额: $ 35.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-16 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507934
• 关键词: Acute; Antibodies; Antibody Affinity; Autoimmune; Autoimmune Diseases; B-Lymphocytes; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cellular Assay; Child; Childhood; Clinical; Collaborations; Cytotoxic T-Lymphocytes; Data; Development; Disease; Etiology; Funding; Goals; Heart Valves; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunoglobulin G; Infection; Knowledge; Lead; Left; Lymphoid Tissue; Macaca mulatta; Measures; Mediating; Memory B-Lymphocyte; Modeling; Molecular Mimicry; Mus; Names; Nature; Persons; Pharyngeal structure; Pharyngitis; Phosphoserine; Play; Primates; Process; Proteins; Recurrence; Research; Resources; Rheumatic Fever; Rheumatic Heart Disease; Risk; Role; Streptococcal Infections; Streptococcal Vaccines; Streptococcus pyogenes; Structure of germinal center of lymph node; Superantigens; T-Cell Receptor; T-Lymphocyte; Tonsil; Tonsillectomy; Tonsillitis; Toxic Shock Syndrome; Toxoids; United States National Institutes of Health; Up-Regulation; Vaccinated; Vaccination; Vaccines; Virulence Factors; World Health Organization; acquired immunity; adaptive immune response; aluminum sulfate; antigen-specific T cells; clinical development; cohort; cross reactivity; erythrogenic toxin; experimental study; heart damage; humanized mouse; immunogenicity; in vivo; mouse model; nonhuman primate; prevent; recurrent infection; response; vaccination outcome

Project Summary: There are currently no approved vaccines for Group A Streptococcus (GAS). GAS is a widespread pediatric problem causing an estimated 616 million cases of strep throat each year worldwide. Untreated strep throat can lead to serious autoimmune sequelae such as rheumatic heart disease (RHD) which inadvertently develops out of molecular mimicry from the host immune response to GAS infection. RHD results from damaged heart valves, claiming the lives of 288,000 people each year worldwide, per the World Health Organization. Therefore there is a critical need for a GAS vaccine. We had first studied why some children get recurrent strep throat by studying the tonsillar germinal center response in children who had undergone tonsillectomy for either recurrent strep tonsillitis or non-recurrent tonsillitis. Tonsils are the lymphoid tissue which likely mount the first adaptive immune response to GAS. We observed that children with recurrent strep throat had a deficit in circulating antibodies against a critical GAS virulence factor streptococcus pyrogenic exotoxin A (SpeA). This was an interesting finding as there has been a long clinical association demonstrating the protective nature of SpeA antibodies against the development of GAS toxic shock syndrome. SpeA is a superantigen which is necessary to establish infection in a humanized mouse model. We discovered that SpeA induced CD4+ T cells with the capacity to kill instead of help B cells within germinal centers. We named these cells “killer T follicular helper (Tfh)” cells. We found that children with recurrent strep throat had more SpeA induced “killer Tfh” cells and significantly smaller germinal centers, likely explaining their propensity for recurrent strep infections. We hypothesize that an SpeA toxoid vaccination will protect against GAS pharyngitis or tonsillitis by limiting the development of SpeA-induced “killer Tfh” cells and allowing for the development of GAS-specific germinal center responses to quickly clear a GAS tonsillar infection. This proposal focuses on evaluating whether an SpeA toxoid vaccine will prevent GAS tonsillitis and pharyngitis in a non- human primate model and understanding the impact of SpeA toxoid vaccination in altering the GAS germinal center response. The long term objective is to demonstrate the utility of GAS toxoid vaccinations in preventing disease.

项目总结： 目前还没有针对A组链球菌(GAS)的批准疫苗。天然气是一种广泛存在的 据估计，全球每年有6.16亿例链球菌性咽喉炎。未经治疗的链球菌病 喉咙会导致严重的自身免疫后遗症，如风湿性心脏病(RHD)，不经意间 从宿主对GAS感染的免疫反应发展出分子模仿。风湿性心脏病由损坏引起 心脏瓣膜，夺走了每年28.8万人的生命，根据世界卫生组织的数据。 因此，迫切需要一种气体疫苗。 我们首先通过研究扁桃体生发中心来研究为什么有些儿童会患上复发性链球菌性咽喉炎。 复发性链球菌性扁桃体炎和非复发性扁桃体炎行扁桃体切除术后儿童的反应 扁桃体炎。扁桃体是淋巴组织，很可能对GAS产生第一次适应性免疫反应。我们 观察到，患有复发性链球菌性咽喉炎的儿童在循环中抗关键气体抗体方面存在缺陷。 毒力因子链球菌热原外毒素A(SPEA)。这是一个有趣的发现，因为有一个 SPEA抗体对GAS发展具有保护作用的长期临床关联 中毒性休克综合征。SPEA是一种超抗原，在人源化小鼠中建立感染是必要的 模特。我们发现，SPEA诱导的CD4+T细胞具有杀伤能力，而不是体内的辅助B细胞 生发中心。我们将这些细胞命名为“杀伤T滤泡辅助细胞(TFH)”。我们发现，反复发作的儿童 链球菌性咽喉炎有更多的SPEA诱导的“杀伤Tfh”细胞和明显较小的生发中心，这可能解释了 他们有反复感染链球菌的倾向。我们假设SPEA类毒素疫苗可以预防 气性咽炎或扁桃体炎通过限制SPEA诱导的“杀伤Tfh”细胞的发展，并允许 发展气体特异性生发中心反应，以快速清除气体扁桃体感染。这项建议 重点评估SPEA类毒素疫苗是否可以预防非典型肺炎患者的气性扁桃体炎和咽炎 人类灵长类动物模型及SPEA类毒素疫苗对气体生发改变的影响 中心回应。长期目标是证明气体类毒素疫苗在预防 疾病。