Development of novel protein-based vaccine formulations to prevent pneumococcal colonization and disease

开发新型蛋白质疫苗制剂以预防肺炎球菌定植和疾病

• 批准号: 10057035
• 负责人: Norberto Gonzalez Juarbe
• 金额: $ 25.86万
• 依托单位: J. CRAIG VENTER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057035
• 关键词: 5 year old; Adjuvant; Antibodies; Antibody Response; Antigens; Antimicrobial Resistance; Area; Bacteremia; Carrier Proteins; Cessation of life; Child; Cleaved cell; Conjugate Vaccines; Dendritic Cells; Development; Disadvantaged; Disease; Elderly; Equipoise; Formulation; Generations; Goals; Immune; Immune Sera; Immunity; Immunization; Immunocompromised Host; Immunologic Adjuvants; In Vitro; Incidence; Individual; Infection; Invaded; Knowledge; Lead; Link; Mediating; Membrane Proteins; Memory; Meningitis; Modeling; Otitis Media; Patients; Pneumococcal Colonization; Pneumococcal Infections; Pneumonia; Polysaccharides; Populations at Risk; Predisposition; Protein Microchips; Proteins; Research; Resistance; Serotyping; Severity of illness; Specificity; Streptococcus pneumoniae; Subunit Vaccines; T-Cell Activation; T-Lymphocyte; Temperature; Testing; Vaccines; Virulence; Work; World Health Organization; adaptive immune response; adaptive immunity; antigen binding; base; capsule; cost; disorder risk; efficacy testing; experience; human subject; immunogenic; immunogenicity; improved; in vitro testing; in vivo; innovation; macromolecule; mouse model; novel; pathogen; pathogenic bacteria; polyphosphazene; prevent; response; transmission process; vaccine development; vaccine efficacy

Project Summary/Abstract One of the major problems of the great burden of Streptococcus pneumoniae infections is the acquisition of antimicrobial resistance and the global spread of resistant clones. This problems get enhanced by the major disadvantages of the current capsular polysaccharide based vaccines, such as cost, serotype specificity, and the resulting incomplete coverage. While the use of polysaccharide vaccines, specially the conjugate vaccine, had significantly reduced the amount of invasive disease caused Spn, it only has reduced that of the represented serotypes. This occurs mainly because of disease being caused by serotypes not present in the vaccine (maximum of 23 of the >97 capsule types, only 13 in the conjugate vaccine) and replacement carriage. Our rationale is that development of a subunit based vaccine utilizing novel conserved antigenic proteins in conjunction with novel polyphosphazene (PPZ) adjuvants, proven to induce adaptive immunity will deepen the current toolkit to prevent pneumococcal disease without serotype limitations. Thus, we hypothesize that addition of conserved immunogenic proteins to the PPZ molecule will provide the groundwork for the development of a broadly protective pneumococcal subunit based vaccine. The gaps in knowledge we aim to bridge are to define and characterize novel pneumococcal antigenic proteins and polyelectrolyte adjuvants formulations that will initiate adaptive immune responses and lead to protection against disease in a serotype independent manner. The proposed work is significant due to the high incidence serotype replacement that current polysaccharide based vaccines are prone to, which leads to increase susceptibility of children and the elderly to Spn carriage and severe infections (e.g. pneumonia, bacteremia, and meningitis); and innovative since it will use novel formulations of antigenic and conserved pneumococcal proteins to induce potent adaptive immune responses, that will not be serotype dependent.

项目摘要/摘要 肺炎链球菌感染的巨大负担的主要问题之一是收购 抗菌素耐药性和抗性克隆的全局传播。专业的问题得到了加强 当前基于胶囊多糖的缺点，例如成本，血清型特异性和 由此产生的不完整覆盖范围。使用多糖疫苗，特别是结合疫苗，而 已经大大减少了侵袭性疾病引起的SPN的量，它仅减少了所代表的疾病 血清型。这主要是由于疫苗中不存在的血清型引起的疾病 （> 97胶囊类型中的最多23个，在结合疫苗中只有13种）和更换载体。我们的 理由是利用新型保守抗原蛋白在中的基于亚基的疫苗的开发 与新型聚磷酸（PPZ）佐剂的结合，被证明诱导适应性免疫将加深 当前的工具包可预防无血清型限制的肺炎球菌疾病。因此，我们假设加法 保守的免疫原性蛋白到PPZ分子将为开发A提供基础 广泛的保护性肺炎球菌亚基疫苗。我们旨在桥接的知识差距是定义 并表征新型的肺炎球菌抗原蛋白和聚电解质佐剂制剂 启动适应性免疫反应并以独立的血清型方式保护疾病。 由于电流多糖的高发血清型替代量，提出的工作很重要 基于基于的疫苗很容易发生，这会增加儿童和老年人对SPN运输的敏感性 和严重的感染（例如肺炎，菌血症和脑膜炎）；和创新，因为它将使用小说 抗原和保守肺炎球菌蛋白的制剂可诱导有效的适应性免疫反应， 这不会取决于血清型。