An RNA vaccines systems approach to Group A streptococcus vaccine discovery

摘要/摘要 目前还没有临床使用的疫苗来对抗A组链球菌感染，尽管 可归因于这种病原体的相当大的全球急慢性疾病负担。 这项工作的长期目标是开发一种能够对抗 A群链球菌咽炎在全球范围内，没有疫苗逃逸的风险，以期根除 未来风湿性心脏病的病例和减少侵袭性感染的风险。 这项建议的目标是使用自扩增RNA(SARNA)技术来识别 一种新的、广泛作用的A组链球菌Sarna的最佳抗原组合 预防实验性鼻咽和软组织感染的疫苗。 成人对A组链球菌性咽炎普遍免疫，而年幼的儿童则 高度敏感。我们方法的基本原理是，理解成人对群体的免疫力 链球菌会直接告知儿童对免疫的要求。池化 成人捐赠的免疫球蛋白含有促进A组清除的抗体 人类血液和实验模型中的链球菌。已确定并排名 这些抗体的抗原靶点，本项目将使用Sarna来评估每个抗原 单独的，也有组合的。具体目标是：(1)开发Sarna结构，以表达 一组新的链球菌抗原。(2)基于保护性的对单个SANA抗原进行排序 实验性小鼠软组织感染攻击和鼻咽部感染的疗效 挑战。(3)通过配对评价顶级Sarna抗原之间的二阶相互作用 软组织和鼻咽部感染模型的组合。(4)预测最优 使用计算机结合最多5种Sarna抗原来对抗鼻咽部感染- 在体内辅助建模和测试优化组合，采用标准化和人性化 小鼠感染模型，以及随后的鼻腔免疫。 这项工作的成果将是一种优化的组合Sarna疫苗，它可以提供 实验性A组链球菌感染的预防和发展方法学 未来联合疫苗的发现。对人类健康的长期影响将是 相当可观：消除A组链球菌性咽炎将减少抗菌药 消费，减少链球菌疾病的健康和社会经济负担，减少 未来的侵袭性链球菌感染和风湿性心脏病病例，因此 减少这种感染造成的全球死亡率。

Abstract/summary There is currently no vaccine in clinical use to combat group A streptococcal infection, despite the considerable global burden of acute and chronic disease attributable to this pathogen. The long-term goal of this work is the development of a combination vaccine that can combat group A streptococcal pharyngitis worldwide, without risk of vaccine escape, in order to eradicate future cases of rheumatic heart disease and reduce the risk of invasive infections. The objective of this proposal is to use self-amplifying RNA (saRNA) technology to identify the optimum combination of antigens to include in a new, broad-acting group A streptococcal saRNA vaccine that protects against experimental nasopharyngeal and soft tissue infection. Adults are broadly immune to group A streptococcal pharyngitis, whereas younger children are highly susceptible. The rationale for our approach, is that understanding adult immunity to group A streptococcus will directly inform the requirements for immunity in children. Pooled immunoglobulin donated by adults contains antibodies that promote clearance of group A streptococcus, both in human blood and in experimental models. Having identified and ranked the antigenic targets of these antibodies, this project will use saRNA to evaluate each antigen alone, and in combination. The specific aims are: (1) Develop saRNA constructs that express the new panel of streptococcal antigens. (2) Rank individual saRNA antigens based on protective efficacy in experimental murine soft tissue infection challenge and in nasopharyngeal infection challenge. (3) Evaluate second order interactions between top-ranking saRNA antigens via paired combinations in soft tissue and nasopharyngeal models of infection. (4) Predict the optimum combination of up to 5 saRNA antigens to combat nasopharyngeal infection, using computer- assisted modelling and test the optimized combination in vivo, using standard and humanized murine models of infection, as well as following nasal immunization. Deliverables from the work will be an optimized combination saRNA vaccine that provides protection from experimental group A streptococcal infection, and a methodology to advance combination vaccine discovery in the future. The longer-term impact on human health would be considerable: Elimination of group A streptococcal pharyngitis would reduce antimicrobial consumption, reduce the health and socio-economic burden of streptococcal disease, reduce future cases of invasive streptococcal infection and rheumatic heart disease and therefore reduce global mortality from this infection.