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.

项目概要： 目前还没有批准的 A 组链球菌 (GAS) 疫苗。 GAS是一种广泛存在的 据估计，全世界每年有 6.16 亿例链球菌性咽喉炎病例由儿科问题引起。未经治疗的链球菌 喉咙可能会导致严重的自身免疫性后遗症，例如风湿性心脏病（RHD）。 源自宿主对 GAS 感染的免疫反应的分子模拟。 RHD 因损坏而导致 据世界卫生组织统计，心脏瓣膜每年夺走全球 288,000 人的生命。 因此，迫切需要 GAS 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孩子会复发链球菌性咽喉炎 因复发性或非复发性链球菌扁桃体炎而接受扁桃体切除术的儿童的反应 扁桃体炎。扁桃体是淋巴组织，可能对 GAS 产生第一个适应性免疫反应。我们 观察到患有复发性链球菌性咽喉炎的儿童体内针对关键 GAS 的循环抗体存在缺陷 毒力因子链球菌致热性外毒素 A (SpeA)。这是一个有趣的发现，因为有一个 长期临床关联证明 SpeA 抗体对 GAS 发展具有保护作用 中毒性休克综合症。 SpeA 是一种超抗原，是在人源化小鼠中建立感染所必需的 模型。我们发现 SpeA 诱导 CD4+ T 细胞具有杀死而不是帮助体内 B 细胞的能力 生发中心。我们将这些细胞命名为“滤泡辅助杀伤性 T (Tfh)”细胞。我们发现患有反复发作的孩子 链球菌性咽喉炎有更多的 SpeA 诱导的“杀伤性 Tfh”细胞和显着更小的生发中心，这可能解释 他们反复感染链球菌的倾向。我们假设 SpeA 类毒素疫苗接种可以预防 通过限制 SpeA 诱导的“杀伤性 Tfh”细胞的发育并允许 发展 GAS 特异性生发中心反应，以快速清除 GAS 扁桃体感染。这个提议 重点评估 SpeA 类毒素疫苗是否能预防非 GAS 扁桃体炎和咽炎 人类灵长类动物模型并了解 SpeA 类毒素疫苗接种对改变 GAS 生发的影响 中心回应。长期目标是证明 GAS 类毒素疫苗接种在预防 疾病。