Enhanced immunogenicity and protection study of lipid modified protein vaccine candidates of Nontypeable Haemophilus influenzae

不可分型流感嗜血杆菌脂质修饰蛋白候选疫苗的增强免疫原性和保护性研究

• 批准号: 10042550
• 负责人: Ravinder Kaur
• 金额: $ 24万
• 依托单位: ROCHESTER GENERAL HOSPITAL (NY)
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-21 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042550
• 关键词: Acute; Adherence; Adoptive Transfer; Adult; Antibodies; Antibody Response; Antibody-mediated protection; Antigens; Blood; Carrier Proteins; Cells; Child; Chronic Obstructive Airway Disease; Clinical Research; Clinical Trials; Conjugate Vaccines; Conjunctivitis; Defect; Ear; Epithelial Cells; Goals; Haemophilus Vaccines; Herd Immunity; Immune; Immune Sera; Immune response; Immunity; In Vitro; Infant; Infection; Interleukin-17; Knockout Mice; Lipids; Lipoprotein Receptor; Lipoproteins; Low Grade Fever; Measures; Mediating; Memory; Methods; Modeling; Modification; Molecular; Mucous Membrane; Mus; Nasopharynx; Neisseria meningitidis; Neutrophil Infiltration; Nontypable Haemophilus influenza; Nose; Otitis; Otitis Media; Outcome; Phase; Pneumococcal conjugate vaccine; Population; Prevention; Proteins; Recombinant Proteins; Recombinants; Recurrence; Regulation; Role; Safety; Sampling; Sinusitis; Streptococcus pneumoniae; T-Lymphocyte; TLR2 gene; Testing; Vaccinated; Vaccination; Vaccines; Virulence; base; co-infection; cytokine; delta protein; efficacy trial; immunogenic; immunogenicity; improved; interest; middle ear; mouse model; natural antibodies; neutrophil; prevent; response; restoration; vaccine candidate; vaccine development

Abstract: In the conjugate vaccine era, Nontypeable Haemophilus influenzae (NTHi) has become the leading cause of acute otitis media (AOM), recurrent AOM, acute sinusitis and conjunctivitis in children and adults and acute exacerbations of chronic obstructive pulmonary disease (COPD) in adults. There is need to develop a vaccine against NTHi. Various vaccine candidates have been explored but still there is need for enhancement of antibody and Th17 immunity response for NTHi vaccines that will help prevent nasopharyngeal colonization and infection. In this project we will compare immunogenicity of recombinant proteins P6 and OMP26 and their fusion constructs in their lipidated and non-lipidated form in a mouse coinfection model of NTHi-AOM, we developed. Two proteins were selected based on their different function and considering P6 is naturally lipidated and native OMP26 is not but is known to induce Th17 immunity. We will test our hypothesis that lipidated protein antigens elicit higher blood and mucosal antibody levels as well as Th17 immune response (via toll-like receptor 2 activation) than non lipidated proteins. Lipidated protein antigens will elicit greater reduction in ear and nasal bacterial loads compared to nonlipidated antigens against NTHi. The contribution and mechanism of antibody mediated and TH17-mediated immunity in protection against NTHi will be compared in infant and adult mice as well as in TLR2-knock out mice using lipidated, nonlipidated and fusion constructs of vaccine candidates P6 and OMP26. We will test whether lipidated proteins produce a more robust IL-17A response from memory Th17 cells in the nasopharynx that helps traffic neutrophils and show enhanced NTHi clearance compared to nonlipidated protein antigens. Overall, the proposed studies will significantly advance our understanding of enhanced immunogenicity of recombinant proteins and molecular mechanisms underlying the lipidation regulation of TLR-2 dependent Th17- immunity in NTHi vaccine development.

抽象的： 在共轭疫苗时代，不可用的流感嗜血杆菌（NTHI）已成为 急性中耳炎（AOM），复发性AOM，急性鼻窦炎和结膜炎的主要原因 儿童和成人以及慢性阻塞性肺疾病（COPD）的急性加重 成年人。需要开发针对NTHI的疫苗。各种候选疫苗 经过探索，但仍需要增强抗体和Th17免疫反应的NTHI 有助于预防鼻咽定植和感染的疫苗。在这个项目中，我们将 比较重组蛋白P6和OMP26的免疫原性及其融合构建体中的免疫原性 我们在nthi-aom的小鼠共感染模型中进行了脂化和非脂化形式，我们开发了。 根据它们的不同功能选择了两种蛋白质，并且自然考虑P6是 脂化和天然的OMP26不是，但已知会诱导Th17免疫力。我们将测试我们的 脂化蛋白抗原也会引起较高的血液和粘膜抗体水平的假设 与非脂肪蛋白相比，作为Th17免疫反应（通过Toll样受体2激活）。脂化 与 针对NTHI的非脂肪抗原。抗体介导的贡献和机制和机制 在婴儿和成年小鼠中，将比较Th17介导的针对NTHI的免疫力 以及在TLR2敲除疫苗的脂化，非脂化和融合构建体中的小鼠 候选人P6和OMP26。我们将测试脂肪蛋白是否产生更强大的IL-17A 鼻咽内存中记忆Th17细胞的响应，有助于中性粒细胞并显示 与非脂肪蛋白抗原相比，NTHI清除率增强。总体而言，提议 研究将大大提高我们对重组免疫原性增强的理解 蛋白质和分子机制的脂化调节依赖性脂化调节的基础 Th17- NTHI疫苗开发中的免疫力。