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A组链球菌（GAS）的批准疫苗。GAS是一种广泛的 儿科问题，每年在全世界造成估计6.16亿例链球菌性咽喉炎。未经治疗的链球菌 咽喉可能导致严重的自身免疫后遗症，如风湿性心脏病（RHD）， 从宿主对GAS感染的免疫反应的分子模拟中发展出来。RHD是由损坏的 据世界卫生组织统计，心脏瓣膜每年夺去全球28.8万人的生命。 因此，迫切需要一种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应答。我们 观察到患有复发性链球菌性咽喉炎的儿童缺乏针对关键GAS的循环抗体， 毒力因子链球菌致热外毒素A（SpeA）。这是一个有趣的发现， 长期的临床关联证明SpeA抗体对GAS发展的保护性 中毒性休克综合征SpeA是在人源化小鼠中建立感染所必需的超抗原 模型我们发现SpeA诱导的CD4+ T细胞具有杀死体内B细胞的能力， 老年中心我们将这些细胞命名为“杀伤性T滤泡辅助（Tfh）”细胞。我们发现， 链球菌咽喉炎有更多的SpeA诱导的“杀手Tfh”细胞和明显较小的生发中心，这可能解释了 他们反复感染链球菌的倾向我们假设SpeA类毒素疫苗可以预防 通过限制SpeA诱导的“杀伤Tfh”细胞的发展， GAS特异性生发中心反应的发展，以快速清除GAS扁桃体感染。这项建议 重点是评估SpeA类毒素疫苗是否能预防非GAS患者的GAS扁桃体炎和咽炎。 人类灵长类动物模型和理解SpeA类毒素疫苗接种在改变GAS基因中的影响 中心响应长期目标是证明GAS类毒素疫苗在预防 疾病