Proteomics-driven reverse vaccinology for gonorrhea.

蛋白质组学驱动的淋病反向疫苗学。

• 批准号: 8865005
• 负责人: Aleksandra Elzbieta Sikora
• 金额: $ 60.66万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8865005
• 关键词: Address; Adjuvant; Aerobic; Affect; Antibiotic Resistance; Antibiotics; Antibodies; Antigenic Variation; Antigens; Biological Process; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Clinical; Collection; Communicable Diseases; Communities; Data; Developed Countries; Developing Countries; Development; Economic Burden; Ectopic Pregnancy; Effectiveness; Evaluation; Fluoroquinolones; Functional disorder; Generations; Genital system; Goals; Gonorrhea; HIV; Health; Human; Immunization; In Vitro; Incidence; Infection; Infertility; Iron; Laboratory Animal Models; Measures; Mediating; Membrane Proteins; Mining; Modeling; Mothers; Mus; Neisseria gonorrhoeae; Neonatal; Newborn Infant; Oxygen; Pathogenesis; Pelvic Inflammatory Disease; Penicillin Resistance; Permeability; Phase; Play; Preventive; Proteins; Proteome; Proteomics; Public Health; Reporting; Research; Resistance; Role; Serum; Sexually Transmitted Diseases; Site; Solutions; Stimulus; Surface; Surface Antigens; Testing; Tetracyclines; United States; Vaccine Antigen; Vaccine Design; Vaccines; Woman; bactericide; base; burden of illness; cell envelope; deprivation; design; disorder prevention; gonorrhea vaccine; health economics; in vitro Assay; men; novel; novel therapeutic intervention; novel vaccines; pathogen; programs; protective efficacy; public health relevance; reproductive; research study; response; vaccine candidate; vaccine development; vaccinology

 DESCRIPTION (provided by applicant): Gonorrhea occurs at high incidence worldwide and has a major impact on reproductive and neonatal health worldwide. Alarmingly, with each new antibiotic introduced for gonorrhea, resistance has emerged, including resistance to penicillin, tetracycline, fluoroquinolones, and recently the third-generation cephalosporins. Treatment options are currently seriously limited and the development of a gonorrhea vaccine is a critical, long- term solution to this problem. Progress on gonorrhea vaccines has been slow, however, in part due to the high number of surface molecules in Neisseria gonorrhoeae (GC) that undergo phase or antigenic variation and a lack of understanding of protective responses. Gonorrhea vaccine development can therefore benefit from a comprehensive, unbiased approach for antigen discovery. We hypothesize that many constituents of the GC cell envelope are stable and important for biological functions, and thus represent attractive vaccine targets. Moreover, there is growing evidence that Th1 responses protect against gonorrhea and we have preliminary data using the vaccine candidate MtrE that supports the effectiveness of Th1-inducing adjuvants in inducing vaccine-mediated protection. Accordingly, here we propose to 1) identify novel conserved vaccine candidates using a proteomics-guided discovery program. High-throughput proteomic studies will be performed to broaden the array of potential antigens that are expressed in response to stimuli encountered at different infection sites including: oxygen availability (aerobic and anaerobic), iron deprivation, and the presence of human serum; 2) evaluate the selected proteins as vaccine candidates. Nineteen protein candidates will be subjected to rigorous evaluation for their potential as vaccine targets by verifying their surface exposure and conservation using a diverse collection of contemporary GC clinical isolates, examining pathophysiological functions in vitro and during experimental murine infection, and by assessing their capacity to elicit functional antibodies in mice; 3) determine the protective capabilities of candidate antigens in a murine genital tract infection model. The three most promising antigens will be tested alone or in combination with each other and with MtrE, to determine their protective potential against GC in the murine infection model. Completion of these proposed studies will provide a starting point for preventive vaccine(s) against GC infections and guide next-generation vaccine design, as well as identify novel proteins that may play a role in GC pathogenesis.

 描述（由申请人提供）：淋病在全世界发病率很高，对全世界的生殖和新生儿健康产生重大影响。令人担忧的是，随着每种新的淋病抗生素的出现，耐药性也随之出现，包括对青霉素、四环素、氟喹诺酮类药物的耐药性，以及最近对淋病的耐药性。第三代头孢菌素的治疗选择目前严重有限，而开发淋病疫苗是解决这一问题的关键、长期的解决方案。然而，淋病疫苗的研发进展缓慢，部分原因是淋病奈瑟菌 (GC) 中存在大量的表面分子，这些分子会发生相变或抗原变异，并且缺乏对淋病疫苗开发的了解，因此可以从全面、公正的疫苗开发中受益。我们发现 GC 细胞包膜的许多成分是稳定的并且对生物学功能很重要，因此代表了有吸引力的疫苗靶标。此外，越来越多的证据表明 Th1 反应可以预防淋病。使用候选疫苗 MtrE 的数据支持 Th1 诱导佐剂在诱导疫苗介导的保护方面的有效性。因此，我们建议 1) 使用蛋白质组学指导的发现计划鉴定新型保守疫苗候选物。进行扩大潜在抗原的阵列，这些抗原是针对不同感染部位遇到的刺激做出反应而表达的，包括：氧气可用性（需氧和厌氧）、缺铁和人血清的存在； 2) 评估选定的候选蛋白作为疫苗候选物，将通过使用多种当代 GC 临床分离株验证其表面暴露和保守性、在体外和实验过程中检查病理生理功能，对其作为疫苗靶标的潜力进行严格评估。小鼠感染，并通过评估它们在小鼠中引发功能性抗体的能力；3) 确定候选抗原在小鼠生殖道感染模型中的保护能力，将单独或相互组合以及与 MtrE 一起测试三种最有希望的抗原。 ， 到确定它们在小鼠感染模型中对 GC 的保护潜力，完成这些拟议的研究将为预防 GC 感染的疫苗提供起点，指导下一代疫苗设计，并确定可能发挥作用的新型蛋白质。在GC发病机制中。