Proteomics-Driven Reverse Vaccinology for Gonorrhea

蛋白质组学驱动的淋病逆向疫苗学

• 批准号: 10446940
• 负责人: Aleksandra Elzbieta Sikora
• 金额: $ 70.37万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446940
• 关键词: Address; Adjuvant; Antibiotic Resistance; Antibodies; Antibody Formation; Antigen Targeting; Antigens; B-Lymphocytes; Binding; Bioinformatics; COVID-19 prevention; Capsid Proteins; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Trials; Complement; Complex; Control Groups; Country; Coupling; Data; Disease; Ensure; FDA approved; Female; Fimbriae Proteins; Formulation; Funding; Future; Geography; Goals; Gonorrhea; Gram-Negative Bacteria; Health; Helper-Inducer T-Lymphocyte; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Immune; Immune response; Immune system; Immunization; Immunize; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunology; In Vitro; Incidence; Infection; Knock-out; Lead; Length; Lipoproteins; Lymphoid Tissue; Measures; Memory; Metabolic Clearance Rate; Mining; Molecular Conformation; Morbidity - disease rate; Mucous Membrane; Multi-Drug Resistance; Mus; Neisseria gonorrhoeae; Outcome; Particulate; Pathogenesis; Physiology; Plasma; Protein Subunits; Proteins; Proteomics; Psychological Impact; Public Health; Recombinants; Reproductive Health; Research; Resistance; Resources; SARS-CoV-2 spike protein; Serum; Sexually Transmitted Diseases; Standardization; Structure of germinal center of lymph node; Subunit Vaccines; Superbug; Surface; System; T cell response; Vaccines; Vagina; Viral Antigens; Virus-like particle; aluminum sulfate; antigen-specific T cells; antimicrobial; bactericide; base; clinical development; cohort; comparative; cost effective; density; design; efficacy evaluation; efficacy study; ethnic minority; gender minority; gonorrhea vaccine; his6 tag; immunogenicity; innovation; male; mouse model; neonatal health; neutrophil; novel vaccines; preclinical efficacy; preclinical study; priority pathogen; protein folding; racial minority; receptor binding; research and development; response; self assembly; sexual minority; statistics; vaccine candidate; vaccine development; vaccine evaluation; vaccine platform; vaccinology; vaginal mucosa

ABSTRACT Neisseria gonorrhoeae (Ng), the gram-negative bacterium responsible for the sexually transmitted infection gonorrhea, is categorized as a high-priority pathogen for research and development efforts. In the US, over 50% of Ng isolates are resistant to at least one antimicrobial and the CDC has ranked Ng as one of the top 5 urgent antibiotic resistant threats. Gonorrhea outcomes are especially devastating in sexual, gender, racial, and ethnic minorities and resource-limited countries. Ng’s “superbug” status, its high morbidity, and the serious health and psychological impacts of gonorrhea necessitate vaccine development. To address the urgent need for an effective and safe vaccine against gonorrhea, we propose to use a powerful Virus-like-Particle (VLP) vaccine platform with a highly effective split-protein conjugation system to deliver promising Ng antigens (Ag) as full- length and natively folded proteins. We selected for this proposal six promising lipoproteins based on their: 1) exceptional conservation in >5K sequenced Ng isolates worldwide; 2) surface-exposure; 3) ability to elicit bactericidal antibodies (Abs); 4) expression in geographically and temporally diverse Ng strains, during different in vitro conditions and Ng infection in the gonorrhea mouse model; and 5) important functions in Ng pathogenesis and physiology. We will: 1) Design and produce antigen-VLP formulations; 2) Identify Ag-VLP and adjuvant combinations that generate robust immune responses; and 3) Evaluate efficacy of promising vaccines and elucidate the immune correlates of protection. Our approach presents conceptual and technical innovations in the gonorrhea vaccine field by pioneering VLP-display of conserved, full-length Ng lipoproteins, which will be comparatively assessed for efficacy and potential mechanisms of protection.

抽象的 Neisseria Gonorrhoeae（NG），革兰氏阴性的双支性，负责性传播感染 淋病被归类为50％的研究和开发工作的高度优势病原体。 NG分离株的抗性至少一种抗菌剂，CDC已将NG排名为前5名紧急情况之一 抗生素耐药线。 少数民族和资源有限的国家。 淋病的心理影响需要疫苗开发。 有效且安全的疫苗疫苗针对淋病，我们建议使用强大的样粒子（VLP）疫苗 具有高效的分裂蛋白结合系统的平台，以提供有希望的ngastigens（Ag） 长度和天然折叠蛋白。 在> 5k的NG隔离材料中，全球的特殊保护； 2） 在不同 淋病小鼠模型中的体外条件和NG感染； 和生理学。 产生强大免疫反应的组合； 3）评估有希望的疫苗的功效 阐明保护的免疫相关性。 淋病疫苗通过开创的VLP-DISPLAY的全长NG脂蛋白，这将是 比较评估了保护的功效和潜在的保护机制。