Novel vaccine antigens against N. gonorrhoeae

针对淋病奈瑟菌的新型疫苗抗原

• 批准号: 10700802
• 负责人: Paola Massari
• 金额: $ 55.13万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700802
• 关键词: Adjuvant; Adjuvant Study; Amino Acid Sequence; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Formation; Antibody Specificity; Antigens; Avidity; Bacteria; Bacterial Adhesion; Binding; Bioinformatics; CD4 Positive T Lymphocytes; Ceftriaxone; Cells; China; Clinical; Combined Vaccines; Complement; Detection; Disease; Dose; Drug-resistant Neisseria Gonorrhoeae; Epithelial Cells; Epitopes; FDA approved; Female; Gene Proteins; Genes; Goals; Gonorrhea; Growth; Human; Hydrogen Peroxide; Hypothetical Protein; IL17 gene; IL8 gene; Immune; Immune response; Immunity; Immunize; Immunoglobulin A; Immunoglobulin G; In Vitro; Inbred BALB C Mice; Individual; Infection; Infertility; Inflammatory; Interferon Type II; Interleukin-1 beta; Interleukin-4; Interleukin-6; Invaded; Irrigation; Knowledge; Lead; Lipid A; Measures; Mediating; Membrane; Messenger RNA; Metals; Monoclonal Antibodies; Morbidity - disease rate; Mucous Membrane; Multi-Drug Resistance; Mus; Neisseria gonorrhoeae; Nutrient Depletion; Oxygen; Phylogenetic Analysis; Probability; Production; Property; Proteins; Reporting; Research Design; Sampling; Serum; Sexually Transmitted Agents; Sexually Transmitted Diseases; Site; Specimen; Splenocyte; Structure; Subgroup; Surface; T-Cell Proliferation; T-Lymphocyte; TNF gene; Therapeutic; Time; Urethra; Vaccine Antigen; Vaccines; Vagina; Vaginal Douching; Vesicle; Virulence; Woman; Work; aluminum sulfate; antimicrobial peptide; bacterial fitness; bactericide; cervicovaginal; cohort; cross reactivity; cytokine; design; efficacy evaluation; fitness; immunogenicity; improved; in vivo; lipooligosaccharide; mRNA Expression; male; mouse model; mutant; novel; novel vaccines; peptidomimetics; pharmacologic; pre-clinical; reproductive tract; response; tool; transcriptome; transcriptome sequencing; vaccine candidate; vaccine evaluation; vaccine formulation

Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection (STI) gonorrhea, a disease with high morbidity worldwide, estimated at 87 million cases annually, and severe reproductive tract complications in women. Current treatment approaches against gonorrhea are compromised by recent onset of antibiotic resistance. There is a pressing need for an effective vaccine against N. gonorrhoeae, but protective antigens have been limited, so far. Our previous work on the gonococcal transcriptome during human natural infection has described differences in mRNA expression of gonococcal genes in urethral and vaginal lavage samples fromnaturally-infected subjects as compared to mRNA expression when the correspondinggonococcal strains were cultured in vitro. We termed those genes “in vivo-expressed factors” (IVEFs). We also reported that ~30% of the gonococcal genes expressed during infection are hypothetical proteins. We hypothesized that gonococcal hypothetical proteins expressed and regulated during infection include new candidate antigens for a vaccine against N. gonorrhoeae. Through a bioinformatics-based candidate antigen selection strategy (CASS) that examined predicted immunogenicity, cellular localization, conservation in N. gonorrhoeae and structure features of the gonococcal hypothetical proteins, we identified 36 new potential targets (ongoing R21AI131004). We investigated an initial group of 6 antigens, confirming 3 as surface-exposed proteins (NGO0690, NGO0948 and NGO1701) that induced cross-reactive antibodies with complement-mediated serum bactericidal activity (SBA) against diverse N. gonorrhoeae strains. In preliminary studies, a combination of these antigens showed promise as protective vaccine candidates in a mouse model of gonococcal infection. Correlates of protection against gonorrhea in humans are not known but SBA and reduced vaginal colonization in mice are stepping- stones in preclinical gonococcal vaccine evaluation. An example is the (currently most advanced) N. gonorrhoeae vaccine candidate, the 2C7 LOS epitope (and its mimotope TCMP2). Other cited mechanisms of protection include antibody-dependent inhibition of bacterial adhesion or invasion of host cells at the colonization site, but these have yet to be confirmed in human studies. The goal of this project is to validate and improve the efficacy of our three candidates as gonococcal vaccine antigens. In Aim 1, we propose antigen dosing and adjuvant studies to achieve optimal immune responses to our candidates and SBA; in Aim 2 we will validate protection in the available female mouse model of gonococcal vaginal colonization, broaden strain coverage by including TMCP2, and correlate immune effector mechanisms and protection; in Aim 3, we will define the function of the hypothetical protein candidates and their impact on N. gonorrhoeae virulence, fitness and Immunity, a necessary complement for their selection as vaccine candidates. Our studies will provide new tools and knowledge towards the unmet goal of a successful vaccine against N. gonorrhoeae.

淋病奈瑟菌是性传播感染 (STI) 淋病的病原体，这是一种疾病 全球发病率很高，估计每年有 8700 万例，且生殖道严重 目前针对淋病的治疗方法因最近出现的淋病而受到影响。 迫切需要针对淋病奈瑟菌的有效疫苗，但具有保护性。 到目前为止，我们之前对人类自然过程中淋球菌转录组的研究还很有限。 感染描述了尿道和阴道灌洗液中淋菌基因 mRNA 表达的差异 自然感染受试者的样本与相应淋球菌感染时的 mRNA 表达相比 我们还报道了这些基因在体外培养的“体内表达因子”（IVEF）。 感染期间表达的淋球菌基因中约 30% 是假设的蛋白质。 淋球菌在感染过程中表达和调节的假设蛋白包括新的候选抗原 通过基于生物信息学的候选抗原选择策略（CASS）。 检查预测的免疫原性、细胞定位、淋病奈瑟菌的保守性和结构 根据淋球菌假设蛋白的特征，我们确定了 36 个新的潜在靶点（正在进行的 R21AI131004）。 我们研究了最初的 6 种抗原组，确认 3 种为表面暴露蛋白（NGO0690、NGO0948） 和 NGO1701）诱导具有补体介导的血清杀菌活性的交叉反应抗体 (SBA) 针对多种淋病奈瑟菌菌株 在初步研究中，这些抗原的组合显示。 有望作为淋球菌感染小鼠模型的保护性疫苗候选物。 人类对抗淋病的效果尚不清楚，但 SBA 和减少小鼠阴道定植正在逐步发展- 临床前淋球菌疫苗评估中的结石就是一个例子（目前最先进的）N. 淋病疫苗候选物，2C7 LOS 表位（及其模拟表位 TCMP2）。 保护包括抗体依赖性抑制细菌在定植时粘附或入侵宿主细胞 网站，但这些尚未在人体研究中得到证实，该项目的目标是验证和改进。 我们的三种候选淋球菌疫苗抗原的功效在目标 1 中，我们建议抗原剂量。 以及辅助研究，以最佳地实现对我们的候选者和 SBA 的免疫反应，我们将在目标 2 中进行验证； 在现有的淋球菌阴道定植雌性小鼠模型中提供保护，广泛的菌株覆盖 包括 TMCP2，以及目标 3 中的相关免疫效应机制和保护； 假设的候选蛋白质的功能及其对淋病奈瑟菌毒力、适应性和影响的影响 免疫力是选择候选疫苗的必要补充，我们的研究将提供新的工具。 以及关于成功研制淋病奈瑟菌疫苗这一未实现目标的知识。

项目成果

In Vitro Pre-Clinical Evaluation of a Gonococcal Trivalent Candidate Vaccine Identified by Transcriptomics.

通过转录组学鉴定的淋球菌三价候选疫苗的体外临床前评估。

• 发表时间: 2023-12-13
• 影响因子: 7.8
• 作者: Roe, Shea K;Felter, Brian;Zheng, Bo;Ram, Sanjay;Wetzler, Lee M;Garges, Eric;Zhu, Tianmou;Genco, Caroline A;Massari, Paola
• 通讯作者: Massari, Paola