Novel vaccine antigens against N. gonorrhoeae

针对淋病奈瑟菌的新型疫苗抗原

基本信息

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
项目类别：
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

项目摘要

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.

淋病奈瑟氏菌是性传播感染（STI）淋病的病因，一种疾病全球发病率高，每年估计为8700万例，严重的生殖道女性的并发症。当前针对淋病的治疗方法因最近的发作而受到损害抗生素抗性。迫切需要针对淋病猪笼草的有效疫苗，但受到保护到目前为止，抗原一直受到限制。我们以前关于人类自然淋球菌转录组的工作感染描述了尿道和阴道灌洗中淋球菌基因的mRNA表达差异与MRNA表达相比，来自自然感染受试者的样本当在体外培养菌株。我们称这些基因为“体内表达因素”（IVEFS）。我们还报告了在感染期间表达的淋球菌基因的〜30％是假设的蛋白质。我们假设了这一点感染期间表达和调节的淋球菌假设蛋白包括A的新候选者疫苗针对N. Gonorrhoeae。通过基于生物信息学的候选抗原选择策略（CASS）研究了预测的免疫原性，细胞定位，淋病乳杆菌和结构中的保存淋球菌假设蛋白的特征，我们确定了36个新的潜在靶标（正在进行的R21AI131004）。我们研究了一组6种抗原，证实了3种暴露于表面蛋白（NGO0690，NGO0948） NGO1701）诱导具有补体介导的血清细菌活性的交叉反应性抗体（SBA）对抗淋病菌的菌株。在初步研究中，这些抗原的组合显示在淋球菌感染的小鼠模型中，有望作为受保护的疫苗候选物。保护的关联在人类中反对淋病是不知道的，但是SBA和小鼠的阴道定植减少是阶梯临床前淋球菌疫苗评估中的石头。一个例子是（当前最高级的）N。 Gonorrhoeae疫苗候选，2C7 LOS发作（及其MIMOTOPE TCMP2）。其他引用的机制保护包括抗体依赖性抑制细菌粘合剂或在定植处的宿主细胞侵袭站点，但是这些尚未在人类研究中得到证实。该项目的目的是验证和改进我们三个候选者作为淋球菌疫苗抗原的效率。在AIM 1中，我们提出抗原给药并调整研究以实现对我们的候选人和SBA的最佳免疫回应；在AIM 2中，我们将验证在可用的淋球菌阴道定植的可用雌鼠模型中保护，通过包括TMCP2，并将免疫效应器机制和保护相关联；在AIM 3中，我们将定义假设蛋白质候选物的功能及其对淋病病毒，适应性和的影响免疫，是他们选择作为疫苗候选者的必要完成。我们的研究将提供新工具并知道成功采用淋病。