Utilization of the adjuvant effect of CRM197 protein to develop a trivalentprotein-vaccine against Streptococcus pneumoniae infections

利用CRM197蛋白的佐剂作用开发肺炎链球菌感染的三价蛋白疫苗

• 批准号: 10218838
• 负责人: Nadeem Khan
• 金额: $ 21.15万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218838
• 关键词: A549; Adherence; Adjuvant; Adult; Animal Model; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Bacteria; Binding; Biological Assay; Biological Process; CD4 Positive T Lymphocytes; Cells; Child; Clinical Trials; Data; Development; Diphtheria; Disease; Elderly; Epithelial Cells; Flow Cytometry; Formulation; Genetic; Geography; Human; Immune Sera; Immune response; Immunocompromised Host; Individual; Lead; Life; Lung; Measures; Medical; Memory B-Lymphocyte; Meningitis; N-terminal; Otitis Media; Pneumococcal Infections; Pneumococcal conjugate vaccine; Pneumococcal vaccine; Pneumonia; Pneumovax; Polysaccharides; Proteins; Publishing; Role; Sepsis; Serotyping; Severities; Sinusitis; Streptococcus pneumoniae; Streptococcus pneumoniae plY protein; Structure; T cell response; T memory cell; T-Lymphocyte; Target Populations; Testing; Toxin; Vaccination; Vaccine Antigen; Vaccines; Work; base; burden of illness; capsule; cross reacting material 197; effectiveness testing; experimental study; immunogenic; immunogenicity; memory CD4 T lymphocyte; mouse model; natural antibodies; novel; pneumococcal surface protein A; protective effect; protective efficacy; respiratory pathogen; vaccine access; vaccine candidate; vaccine development

Abstract Streptococcus pneumoniae (Spn) is a major respiratory pathogen that causes a spectrum of non-invasive (otitis media, sinusitis, pneumonia) as well as invasive (sepsis, meningitis) diseases. Despite a decline in the overall Spn disease burden caused by currently available vaccines (Spn/pneumococcal conjugate vaccines: PCVs), Spn diseases continue to occur and remain a significant medical problem. Due to the emergence of new, replacement serotypes (STs), Spn protein-based vaccines that aim to protect against Spn diseases in a serotype-independent manner are considered to be the best solution. However, there is a pressing need to develop novel adjuvants that can enhance antibody response and its biological function directed against Spn proteins antigens, given the target populations of these vaccines are children, elderly, and immunocompromised individuals. We developed a trivalent protein vaccine involving two well-known Spn vaccine candidates, N-terminal pneumococcal surface protein A (PspA) and domain 4 of pneumolysin (PlyD4), genetically fused with diphtheria The purpose of choosing N-PspA and PlyD4 is based on their prior characterization in animal models of vaccination with demonstratable efficacy against Spn colonization and sepsis. Therefore, genetic fusion of CRM197 to proven Spn candidates will help compare the CRM197 driven enhancement of immunogenicity and protective efficacy with published work and to expand the platform to include other promising vaccine candidates subsequently. detoxified antigen CRM197 (CRM197-N-PspA-PlyD4). Our preliminary data shows that the genetic fusion of CRM197 significantly enhanced (several folds) the antibody titers against N-terminal PspA. Additionally, the genetic fusion (trivalent vaccine) led to a significant increase in the binding of antisera to Spn bacteria, a measure of antibody functionality. Furthermore, the incubation of Spn bacteria with trivalent antisera significantly reduced Spn adherence to A549 cells. Based on our preliminary data, we hypothesize that “Genetic fusion of CRM197 enhances the memory T-cell response to Spn antigens, leading to enhanced antibody functionality and protection against Spn colonization and disease.” This hypothesis will be tested in two structured aims that will establish the role of CRM197 in enhancing the immunogenic and protective efficacy of Spn antigens, N-PspA and PlyD4. The findings of the proposed work could lead to a broader utilization of the adjuvant effect of CRM197 in enhancing the immune response to Spn as well as non-Spn protein antigens, leading to a more robust T-cell dependent immune response and protective effect.

抽象的 肺炎链球菌（SPN）是一种主要的呼吸道病原体，可引起多种非侵入性（耳炎） 培养基，鼻窦炎，肺炎）以及侵入性（败血症，脑膜炎）疾病。尽管总体下降 SPN疾病伯恩当前可用的疫苗（SPN/肺炎球菌缀合物疫苗：PCVS），PCVS， SPN疾病继续发生，并且仍然是一个重大的医学问题。由于新出现 替代血清型（STS），基于SPN蛋白的疫苗，旨在防止SPN疾病 血清型独立的方式被认为是最好的解决方案。但是，迫切需要 开发可增强抗体反应及其针对SPN的生物学功能的新型调节器 鉴于这些疫苗的目标种群是儿童的蛋白质抗原，较早和免疫功能低下 个人。 我们开发了一种三价蛋白疫苗，涉及两种众所周知的SPN疫苗N-末端 肺炎球菌表面蛋白A（PSPA）和肺炎的结构域4（Plyd4），与白喉融合 选择N-PSPA和PLYD4的目的是基于 它们在疫苗接种动物模型中的先前表征，证明了对SPN定殖的易于 和败血症。因此，CRM197的遗传融合以证明SPN候选者将有助于比较CRM197驱动器 通过发表的工作增强免疫原性和受保护效率的保护，并将平台扩展到 随后包括其他承诺疫苗候选者。 排毒抗原CRM197（CRM197-N-PSPA-PLYD4）。 我们的初步数据表明， CRM197显着增强了针对N端PSPA的抗体滴度。另外， 遗传融合（三价疫苗）导致抗血清与SPN细菌的结合显着增加，这是一种度量 抗体功能。此外，SPN细菌与三价抗血清的孵育显着降低 SPN遵守A549细胞。 根据我们的初步数据，我们假设“ CRM197的遗传融合增强了内存T细胞T细胞 对SPN抗原的反应，从而增强了抗体功能和针对SPN定殖的保护 和疾病。 增强SPN抗原，N-PSPA和PLYD4的免疫原性和受保护的效率。的发现 拟议的工作可能导致更广泛地利用CRM197在增强免疫力方面的可调效应 对SPN以及非SPN蛋白抗原的反应，导致更强的T细胞免疫 反应和保护效果。