Development of a model of Gonococcal conjunctivitis for vaccine evaluations

开发用于疫苗评估的淋菌性结膜炎模型

• 批准号: 10740430
• 负责人: Gerald B Pier
• 金额: $ 26.47万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740430
• 关键词: Active Immunization; Active Immunotherapy; Address; Adult; Antibacterial Response; Antibiotic Resistance; Antibiotics; Antibodies; Antibody-mediated protection; Antigens; Antimicrobial Resistance; Bacteria; Biological Assay; Blindness; Cattle; Cells; Cicatrix; Coculture Techniques; Collaborations; Communicable Diseases; Communities; Complement Factor H; Conjunctivitis; Cornea; Country; Development; Diagnosis; Disease; Dose; Edema; Epithelial Cells; Epithelium; Estradiol; Exclusion; Eye; Eye Infections; Female; Germ-Free; Goals; Gonorrhea; Growth; Human; Human Activities; Immune; Immune response; Immunity; Immunology; Immunotherapeutic agent; Immunotherapy; In Vitro; Income; Infant; Infection; Inflammatory; Laboratory Animal Models; Letters; Licensing; Literature; Lymphocytic Infiltrate; Measures; Mediating; Membrane Proteins; Microbiology; Modeling; Monoclonal Antibodies; Mus; Natural Immunity; Needs Assessment; Neisseria gonorrhoeae; Neonatal; Neonatal meningitis; Ophthalmia Neonatorum; Organism; Passive Immunization; Passive Immunotherapy; Pathogenesis; Pathology; Physiology; Polysaccharides; Prevention approach; PubMed; Publishing; Research Project Grants; Resistance; Serology; Serum; Site; Specificity; Standardization; Study models; Surface; System; Testing; Therapeutic; Therapeutic antibodies; Transgenic Animals; Treatment Efficacy; Uterus; Vaccination; Vaccine Antigen; Vaccines; Validation; Virulence; Virulence Factors; Visual; Work; acquired immunity; antimicrobial; bactericide; clinically relevant; complement 4b-binding protein; corneal epithelium; effective therapy; experience; genital microbiota; healthcare community; human monoclonal antibodies; human pathogen; immunogenic; in vitro Model; in vivo; lipooligosaccharide; low and middle-income countries; microbial; mouse model; neonatal mice; novel; novel strategies; ocular surface; passive antibodies; pathogen; poly-N-acetyl glucosamine; preservation; prophylactic; protective efficacy; reproductive tract; response; success; tool; transmission process; vaccine candidate; vaccine evaluation; vaccine trial; vaccine-induced antibodies

Abstract The serious concerns of the health-care community around the current state of worldwide N. gonorrhoeae infec- tions are well known and documented in the infectious diseases, microbiology and immunology communities and literature. The major manifestations of gonococcal (GC) infection worldwide are genital tract infections and conjunctivitis, the latter a major problem in infants born in low and middle income countries, diagnosed as oph- thalmia neonatorum. There is a global concern about effective treatments due to antimicrobial resistance and the threat of pan-resistant, untreatable GC infections is high. Thus, new approaches, strategies and tools are needed to address the consequences from this exceedingly successful human pathogen. At the top of this list are vaccines and immunotherapeutics to control GC infection and transmission. Yet, unlike its cousin, N. men- ingitides, where vaccine-preventable disease has been obtained by targeting the immunogenic, serologically variable capsular polysaccharides or, more recently, surface proteins for serogroup B, such vaccine targets have not been identified on N. gonorrhoeae cells. Indeed, there are no known correlates of human immunity mediating resistance to GC infection. Furthermore, reinfection with N. gonorrhoeae seems to occur sufficiently frequently to suggest that vaccine antigens are either serologically variable and differ markedly among strains, or, infection with GC simply does not engender sufficient protective immune responses. The goal of this research project is to develop and validate a murine model of N. gonorrhoeae conjunctivitis in both adult and neonatal mice to study virulence and immunity to this pathogen in a readily accessible laboratory animal model. A second goal will be to evaluate the prophylactic and therapeutic potential of antibody therapeu- tics to N. gonorrhoeae to substantiate the utility of the conjunctival infection model for such studies. These targets include the conserved bacterial surface polysaccharide poly-N-acetyl glucosamine (PNAG) that we have shown surrounds the outer surface of N. gonorrhoeae and serves as a target for bactericidal antibody, and the surface lipooligosaccharide (LOS) recognized by monoclonal antibody (MAb) 2C7. We propose to take advantage of our extensive experience with murine models of ocular infections to study N. gonorrhoeae conjunctivitis in adult and neonatal mice. We will determine the growth and dose parameters needed to establish infection in both of these murine settings, the latter as a model for ophthalmia neonatorum. We will evaluate pathogenesis of multiple N. gonorrhoeae strains, test active and passive immunotherapies for impacting bacterial burdens and conjunctival pathology, and determine some of the in vitro and in vivo immune effectors needed to impact these measures of infection and disease. Success would open up the potential to readily study additional vaccines and therapies, as well as virulence factors and host innate and acquired im- munity to N. gonorrhoeae in a clinically-relevant setting. Thus, an in vivo murine model for GC conjunctival infection would fill in the gaps currently limiting the study of virulence and immunity to N. gonorrhoeae infections.

摘要 医疗界对全球淋病奈瑟菌感染现状的严重关切 在传染病、微生物学和免疫学领域，传染病已广为人知并被记录在案。 和文学。全世界淋球菌(GC)感染的主要表现是生殖道感染和 结膜炎，后者是低收入和中等收入国家出生的婴儿的主要问题，被诊断为眼球突出症。 新生儿地中海贫血症。由于抗菌素耐药性，全球都在关注有效的治疗 对泛素耐药、无法治疗的GC感染的威胁很高。因此，新的方法、战略和工具正在 需要解决这种极其成功的人类病原体的后果。在这份榜单的首位 是控制GC感染和传播的疫苗和免疫疗法。然而，与它的表亲N.Men不同的是- 通过针对免疫原性，从血清学上获得疫苗可预防的疾病的脑膜炎 B群的可变被膜多糖或最近的表面蛋白，这样的疫苗靶标 在淋病奈瑟菌细胞上未鉴定。事实上，目前还没有已知的与人类免疫有关的因素。 对GC感染的抵抗性。此外，淋病奈瑟菌的再感染似乎相当频繁。 表明疫苗抗原要么在血清学上是可变的，而且在不同菌株之间存在显著差异，要么就是感染 GC根本不能产生足够的保护性免疫反应。 本研究的目的是建立和验证淋球菌结膜炎的小鼠模型。 成年和新生小鼠在容易接近的实验室研究对这种病原体的毒力和免疫力 动物模型。第二个目标是评估抗体疗法的预防和治疗潜力。 TICS对淋病奈瑟菌的作用，以证实结膜感染模型在此类研究中的实用性。这些目标 包括我们已经显示的保守的细菌表面多糖聚N-乙酰氨基葡萄糖(PNAG) 环绕淋病奈瑟氏菌的外表面，并作为杀菌抗体的目标，该表面 单抗2C7识别的脂寡糖(LOS)。 我们建议利用我们在小鼠眼部感染模型方面的丰富经验来研究N. 成年和新生小鼠的淋病结膜炎。我们将确定生长和剂量参数 需要在这两种小鼠环境中建立感染，后者作为新生儿眼炎的模型。 我们将评估多种淋病奈瑟菌的致病机制，测试主动和被动免疫疗法 影响细菌负荷和结膜病理，并测定部分体内外免疫 效应者需要影响这些感染和疾病的衡量标准。成功将开启一种潜力 随时研究其他疫苗和治疗方法，以及毒力因素，并掌握先天和后天免疫。 在临床相关环境中对淋病奈瑟菌的免疫。因此，建立了一种活体小鼠结膜GC模型 感染将填补目前限制淋球菌感染的毒力和免疫力研究的空白。