Single Antigen Strategy for Prevention of Recurrent and Chronic Suppurative Otitis

预防复发性和慢性化脓性中耳炎的单一抗原策略

• 批准号: 9105737
• 负责人: Stephen I. Pelton
• 金额: $ 21.75万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105737
• 关键词: Acetates; Acetylation; Animals; Antibodies; Antigens; Bacterial Model; Bacteroides fragilis; Binding; Carrier Proteins; Child; Chinchilla (genus); Chronic; Collaborations; Complement; Conjugate Vaccines; Country; Developed Countries; Developing Countries; Development; Disease; Economics; Effectiveness; Escherichia coli; Extracellular Space; Frequencies; Future; Glucosamine; Goals; Haemophilus influenzae; Health; Hearing; Hemophilus; Human; In Vitro; Link; Mediating; Microbial Biofilms; Modeling; Monoclonal Antibodies; Moraxella; Morbidity - disease rate; Nontypable Haemophilus influenza; Oligosaccharides; Organism; Otitis; Otitis Media; Outcome; Pathogenesis; Phase I Clinical Trials; Polysaccharides; Population; Populations at Risk; Prevention; Prevention strategy; Publishing; Quality of life; Recurrence; Reporting; Resistance; Staphylococcus epidermidis; Streptococcus pneumoniae; Suppurative Otitis Media; Surface; Tube; Tympanostomy; Vaccines; antimicrobial; bactericide; base; capsule; deafness; ear infection; immunogenicity; in vivo; killings; middle ear; middle ear disorder; pathogen; poly-N-acetyl glucosamine; polyclonal antibody; prophylactic; protective efficacy; respiratory; vaccine efficacy

 DESCRIPTION (provided by applicant): The goal of this proposal is to evaluate the prophylactic potential of antibodies to the conserved bacterial surface polysaccharide poly-N-acetyl glucosamine (PNAG) for prevention of recurrent and chronic suppurative otitis media (CSOM) specifically caused by the two most common pathogens of otitis media (OM), Streptococcus pneumoniae (SP) and non-typeable Haemophilus influenzae (NTHi). Both of these organisms produce surface PNAG, a molecule recognized to be essential for several bacterial biofilms. Drs. Pier and Pelton and collaborators have already published evidence that PNAG is expressed as a capsule-like antigen, intercalated within the known capsules of SP and NTHi on isolates obtained directly from the middle ear in children and in chinchillas. The unique aspect of this proposal will be targeting one antigen, present on both pathogens that could impact the reduced quality of life associated with recurrent OM and the profound deafness and suppurative complications associated with CSOM. As PNAG is produced by many commensal organisms (E. coli, S. epidermidis, B. fragilis), natural antibody to PNAG is commonly found in humans5. However, natural antibodies bind to the highly acetylated glycoform of PNAG (>60% acetylation) and are of low efficiency for mediating opsonic or bactericidal killing and show littl protective efficacy against infection5. Pier and colleagues have reported that by reducing the levels of acetylation to <30%, the glycoform of PNAG produced, called deacetylated PNAG (dPNAG), induces opsonic and/or bactericidal antibodies when conjugated to carrier proteins against both SP and NTHi. Importantly, these antibodies appear to have no effect on normal flora as evidenced by results from a phase 1 clinical trial of a MAb to PNAG in humans and multiple other lines of evidence including long-term animal studies. This project will evaluate the in vivo efficacy of passively transferred polyclonal and monoclonal antibody to PNAG for protection against pneumococcal and nontypable haemophilus influenzae middle ear disease in a well-established chinchilla model of bacterial otitis media, define a protective antibody concentration of anti- PNAG antibody for future studies of PNAG-conjugate vaccine efficacy, and evaluate immunogenicity of a 9GlcNH2-TT conjugate vaccine to demonstrate the potential of a passive-active strategy for reducing the burden of middle ear disease in children.

 描述（由适用提供）：该提案的目的是评估抗体对保守细菌表面多糖多糖多糖多糖葡萄糖（PNAG）的预防潜力不可用的嗜血杆菌影响（NTHI）。这两种生物都产生了表面PNAG，这是一种对几种细菌生物膜必不可少的分子。博士。 Pier和Pelton以及合作者已经发表了证据，表明PNAG表示为类似胶囊的抗原，在SP和NTHI的已知胶囊中插入了直接从儿童和Chinchillas的中耳中获得的分离株。该提案的独特方面将针对一种抗原，这两种病原体都可能影响与经常性OM相关的生活质量以及与CSOM相关的深刻聋和补充并发症。由于PNAG是由许多共生生物（大肠杆菌，表皮，B。fragilis）产生的，因此在人类中常见于pNAG的天然抗体5。然而，天然抗体与PNAG高度乙酰化的糖型（乙酰化> 60％）结合，对于介导OPSONIC或杀菌杀伤的效率低，并显示出针对感染的LITTL保护有效性5。 Pier及其同事报告说，通过将乙酰化水平降低到<30％，即产生的PNAG糖型（称为脱乙酰化PNAG（DPNAG）），当将opsonic和/或杀菌性抗体诱导与SP和NTHI抗载体蛋白时，诱导了Opsonic和/或杀菌性抗体。重要的是，这些抗体似乎对正常菌群没有影响，这是由人类中mAb到PNAG的1阶段临床试验以及包括长期动物研究在内的其他多种证据的结果所证明的。该项目将评估 在良好的细菌性炎培养基中，在较成熟的龙虾模型中，对PNAG的被动转移多克隆和单克隆抗体的体内效率可防止肺炎球菌和不可抑制的嗜血性嗜血杆菌中耳病，定义了一种抗PNAG抗体的保护性抗体，以未来的抗体和评估抗体的研究。 9GLCNH2-TT结合疫苗的免疫原性，以证明一种被动活跃策略的潜力减少儿童中耳病的燃烧。