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： 在结合疫苗时代，不可分型流感嗜血杆菌（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病 (COPD) 的急性加重 成年人。需要开发针对 NTHi 的疫苗。多种候选疫苗已被 已探索但仍需要增强 NTHi 的抗体和 Th17 免疫反应 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 及其融合构建体的免疫原性 我们开发了 NTHi-AOM 小鼠共感染模型中的脂质化和非脂质化形式。 根据其不同的功能选择了两种蛋白质，并考虑到 P6 自然是 脂化的天然 OMP26 不会诱导 Th17 免疫，但已知它能诱导 Th17 免疫。我们将测试我们的 假设脂化蛋白抗原也会引起更高的血液和粘膜抗体水平 Th17 免疫反应（通过 Toll 样受体 2 激活）优于非脂化蛋白。脂化 与相比，蛋白质抗原将导致耳部和鼻部细菌负荷的更大减少 针对 NTHi 的非脂化抗原。抗体介导的贡献和机制 TH17 介导的免疫对 NTHi 的保护作用将在婴儿和成年小鼠中进行比较： 以及使用脂质化、非脂质化和融合疫苗构建体的 TLR2 敲除小鼠 候选人 P6 和 OMP26。我们将测试脂化蛋白是否产生更强大的 IL-17A 鼻咽中记忆 Th17 细胞的反应有助于中性粒细胞的运输并显示 与非脂化蛋白抗原相比，NTHi 清除率增强。总体而言，建议 研究将显着增进我们对重组蛋白增强免疫原性的理解 TLR-2依赖性脂质化调节的蛋白质和分子机制 NTHi 疫苗开发中的 Th17- 免疫。