An RNA vaccines systems approach to Group A streptococcus vaccine discovery

发现 A 组链球菌疫苗的 RNA 疫苗系统方法

基本信息

批准号：
10577082
负责人：
ROBIN J SHATTOCK
金额：
$ 34.16万
依托单位：
IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-13 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577082
关键词：
Acute Disease Address Adult Antibiotics Antibodies Antigens Autoimmune Autoimmune Responses Bacterial Infections Blood Cessation of life Child Chronic Disease Clinical Combined Vaccines Computer Assisted Consumption Coupled Development Disease Economic Burden Experimental Models Foundations Fright Future Genetic Recombination Genome Genotype Goals Health Horizontal Gene Transfer Human Immune Immunity Immunization Immunoglobulins Individual Infection Intravenous Immunoglobulins Investigation Life Methodology Modeling Mus Mutation Nasopharynx Necrotizing fasciitis Nose Pharyngitis Predisposition Preparation Proteins Public Health RNA amplification RNA vaccine Rheumatic Fever Rheumatic Heart Disease Risk Risk Reduction Series Serotyping Soft Tissue Infections Streptococcal Infections Streptococcus Streptococcus pyogenes System Technology Testing Toxic Shock Syndrome Vaccinated Vaccine Antigen Vaccines Work antimicrobial combat experimental group health economics human pathogen in vivo innovation interest lead candidate mortality mouse model multiple myeloma M Protein pathogen prevent protective efficacy socioeconomics soft tissue vaccine development vaccine discovery

项目摘要

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.

摘要/总结尽管目前临床上还没有用于对抗 A 组链球菌感染的疫苗这种病原体造成的急性和慢性疾病给全球带来了相当大的负担。这项工作的长期目标是开发一种可以对抗这种疾病的组合疫苗世界范围内的 A 组链球菌性咽炎，无疫苗逃逸风险，以便根除未来的风湿性心脏病病例并降低侵袭性感染的风险。该提案的目标是利用自扩增 RNA (saRNA) 技术来识别包含在新的、广泛作用的 A 组链球菌 saRNA 中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 组链球菌性咽炎具有广泛的免疫力，而年幼的儿童则对 A 组链球菌性咽炎具有免疫力。高度敏感。我们方法的基本原理是了解成人对群体的免疫力链球菌将直接告知儿童的免疫力要求。汇集成人捐赠的免疫球蛋白含有促进 A 组清除的抗体链球菌，存在于人类血液和实验模型中。确定并排名后这些抗体的抗原靶标，该项目将使用 saRNA 来评估每种抗原单独的，和组合的。具体目标是：（1）开发表达新的链球菌抗原组。 (2) 根据保护性对个体 saRNA 抗原进行排序实验性小鼠软组织感染挑战和鼻咽感染的功效挑战。 (3) 通过配对评估顶级 saRNA 抗原之间的二阶相互作用软组织和鼻咽感染模型中的组合。 (4) 预测最优值使用计算机组合多达 5 种 saRNA 抗原来对抗鼻咽感染使用标准和人源化辅助建模并在体内测试优化的组合小鼠感染模型以及鼻腔免疫接种后。这项工作的成果将是一种优化的组合 saRNA 疫苗，它可以提供防止实验 A 组链球菌感染的保护，以及推进的方法未来联合疫苗的发现。对人类健康的长期影响将相当重要：消除 A 组链球菌性咽炎会减少抗菌药物消费，减少链球菌疾病的健康和社会经济负担，减少未来侵袭性链球菌感染和风湿性心脏病的病例，因此降低这种感染的全球死亡率。