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

• 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
• 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

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/概要 目前临床上还没有疫苗用于对抗A组链球菌感染，尽管 这种病原体造成的急性和慢性疾病给全球造成的巨大负担。 这项工作的长期目标是开发一种联合疫苗， A组链球菌性咽炎在全球范围内，没有疫苗逃逸的风险，为了根除 未来的风湿性心脏病的病例，并减少侵袭性感染的风险。 本提案的目的是使用自扩增RNA（saRNA）技术来鉴定 抗原的最佳组合，以包含在新的、广泛作用的A组链球菌saRNA中 预防实验性鼻咽和软组织感染的疫苗。 成人对A组链球菌咽炎具有广泛的免疫力，而年幼的儿童则对A组链球菌咽炎具有免疫力。 非常敏感我们的方法的基本原理是，了解成人对群体的免疫力， 一份传单将直接告知儿童免疫的要求。合并 成人捐赠的免疫球蛋白含有促进A组清除的抗体 在人血和实验模型中，经过鉴定和排名 这些抗体的抗原靶点，该项目将使用saRNA来评估每种抗原 单独的，和组合的。具体的目标是：（1）开发表达SARNA的saRNA构建体， 一组新的链球菌抗原(2)基于保护性的单个saRNA抗原排序 在实验性小鼠软组织感染攻击和鼻咽感染中有效性 挑战. (3)通过配对的方法评估顶级saRNA抗原之间的二级相互作用 在软组织和鼻咽感染模型中的组合。(4)预测最优值 最多5种saRNA抗原的组合，以对抗鼻咽感染，使用计算机- 辅助建模和测试优化的组合在体内，使用标准的和人源化的 感染的鼠模型，以及鼻免疫后。 这项工作的成果将是一种优化的组合saRNA疫苗， 保护免受实验性A组链球菌感染，以及促进 联合疫苗的研发。对人类健康的长期影响将 值得注意的是：消除A组链球菌咽炎将减少抗菌 消费，减少链球菌疾病的健康和社会经济负担， 侵袭性链球菌感染和风湿性心脏病的未来病例， 降低全球因这种感染造成的死亡率。