A novel vaccine against multidrug-resistant gonorrhea

一种针对多重耐药性淋病的新型疫苗

• 批准号: 10542795
• 负责人: SANJAY RAM
• 金额: $ 29.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542795
• 关键词: Active Immunization; Address; Adjuvant; Affect; Animals; Antibiotic Resistance; Antibiotics; Antigens; Attenuated; Azithromycin; Binding; Biological Assay; Case Study; Ceftriaxone; Chlamydia; Chlamydia Infections; Clinical; Clinical Protocols; Clostridium difficile; Complement; Complement Factor H; Complement Inactivators; Cyclic GMP; Development; Development Plans; Disease; Ectopic Pregnancy; Ensure; Enzyme-Linked Immunosorbent Assay; Epitopes; Event; Goals; Gonorrhea; HIV; Human; Immune; Immune Sera; Immunization; Immunize; In Vitro; Incidence; Infection; Infection prevention; Infectious Diseases Research; Infertility; International; Knowledge; Laboratories; Libraries; Lipid A; Macaca mulatta; Manufacturer; Methods; Modeling; Monoclonal Antibodies; Multi-Drug Resistance; Mus; National Institute of Allergy and Infectious Disease; Nature; Neisseria gonorrhoeae; New Zealand; Oligosaccharides; Oryctolagus cuniculus; Passive Immunization; Peptides; Phase; Polylysine; Production; Public Health; Qualifying; Recommendation; Reporting; Reproductive Health; Research Design; Research Institute; Resistance; Safety; Serum; Sexually Transmitted Diseases; Specific qualifier value; Superbug; Surface; Technology Transfer; Testing; Toxic effect; Toxicology; Transgenic Mice; United States; United States National Institutes of Health; Vaccine Antigen; Vaccines; Vagina; Vertebral column; Virulence; Woman; Women' s Health; bactericide; carbapenem-resistant Enterobacteriaceae; chronic pelvic pain; co-infection; complement 4b-binding protein; design; drug-resistant gonorrhea; efficacy testing; experimental study; immunogenicity; in vivo; infection burden; lipooligosaccharide; manufacture; manufacturing process; manufacturing scale-up; microorganism; nonhuman primate; novel; novel vaccines; peptide structure; peptidomimetics; polypeptide; pre-IND studies; pre-Investigational New Drug meeting; product development; programs; public health priorities; research clinical testing; scale up; stability testing; transmission process; trend; vaccine candidate; vaccine efficacy; vaccine evaluation

ABSTRACT Gonorrhea is the second most common bacterial sexually transmitted infection – the most common is chlamydia, which often coinfects with gonorrhea. About 80 million new cases of gonorrhea occur worldwide annually. Over 450,000 cases are reported yearly in the U.S. Serious sequelae of gonorrhea in women includes infertility, ectopic pregnancy and chronic pelvic pain. Neisseria gonorrhoeae (Ng), the causative agent of gonorrhea, has become resistant to almost every antibiotic in clinical use. Resistance to ceftriaxone and azithromycin – the recommended first-line of treatment –portends an era of untreatable gonorrhea. The CDC has listed Ng as a microorganism with a threat level of “Urgent”. Development of a safe and effective vaccine against gonorrhea is a public health priority. Furthermore, Ng and chlamydia coinfection is a frequent event and a successful gonococcal vaccine will prevent infection even when chlamydia infection is present. We identified a monoclonal antibody (mAb) called 2C7 that recognizes a lipooligosaccharide (LOS) epitope expressed by >95% of Ng in vivo and is critical for virulence in mice. mAb 2C7 is bactericidal and significantly reduces the duration and burden of Ng infection in mice. Its ubiquitous expression, key role in virulence, and the bactericidal nature of Ab against the 2C7 epitope makes it an attractive vaccine antigen. To circumvent limitations of LOS as a vaccine antigen, we identified a peptide mimic of the 2C7 epitope, which when configured as a multi-antigen peptide (MAP), elicited bactericidal Abs and attenuated Ng infection in mice. A Product Development Plan overseen by NIAID/NIH partnered us with ABL Inc., Peptides International and the Infectious Diseases Research Institute (IDRI). The objectives of the PDP have been met and has resulted in design of a novel tetra-MAP structure (TMCP2) and identification of GLA-SE as the optimal adjuvant based on immunogenicity in mice. In Aim 1, Peptides International will produce TMCP2, perform stability testing and transfer technology to the cGMP manufacturer. In Aim 2 (UMass), mice and non-human primates will be immunized with development-grade TMCP2 plus GLA-SE to evaluate i) immunogenicity and ii) functionality of elicited Ab in Ng infected or (separately) in Ng/chlamydia co-infected mice. Ng bind the complement inhibitors, factor H (FH) and C4b-binding protein (C4BP) in a human-specific manner, which dampens activity of vaccine Ab. Therefore, we will test vaccine efficacy in novel transgenic mice that express human FH and C4BP to simulate conditions in humans. Anti-LOS Ab purified from immunized Rhesus macaques will be assayed for bactericidal activity and for its ability to attenuate colonization in single Ng and Ng/chlamydia coinfected mice. ABL Inc. will qualify ELISAs and SBAs. A GLP-grade safety and toxicology study in New Zealand White Rabbits (ABL, Inc.) which is essential for product development will be performed in Aim 3. Pre-IND enabling studies will be carried out in Aim 4. Successful completion of these Aims will ready our vaccine candidate for human studies

抽象的 淋病是第二常见的细菌性传播感染 - 最常见的是 衣原体，通常与淋病同时感染。全球新增淋病病例约 8000 万例 每年。美国每年报告超过 45 万例女性淋病严重后遗症 包括不孕症、宫外孕和慢性盆腔疼痛。淋病奈瑟菌 (Ng)，病原体 淋病已对临床使用的几乎所有抗生素产生耐药性。对头孢曲松钠耐药 阿奇霉素——推荐的一线治疗药物——预示着淋病无法治愈的时代即将来临。疾病预防控制中心 已将 Ng 列为威胁级别为“紧急”的微生物。开发安全有效的疫苗 防治淋病是一项公共卫生优先事项。此外，吴氏菌和衣原体合并感染是常见事件 即使存在衣原体感染，成功的淋球菌疫苗也能预防感染。 我们鉴定出一种名为 2C7 的单克隆抗体 (mAb)，它可识别脂寡糖 (LOS) 表位 体内 Ng 的表达量超过 95%，对于小鼠的毒力至关重要。 mAb 2C7 具有杀菌作用，并且显着 减少小鼠 Ng 感染的持续时间和负担。它的普遍表达、毒力的关键作用以及 Ab 针对 2C7 表位的杀菌特性使其成为一种有吸引力的疫苗抗原。规避 由于 LOS 作为疫苗抗原的局限性，我们鉴定了 2C7 表位的肽模拟物，当 配置为多抗原肽 (MAP)，在小鼠中引发杀菌抗体并减弱 Ng 感染。 由 NIAID/NIH 监督的产品开发计划与我们与 ABL Inc.、Peptides International 和 传染病研究所 (IDRI)。 PDP 的目标已经实现并取得了成果 设计新型 tetra-MAP 结构 (TMCP2) 并鉴定 GLA-SE 作为最佳佐剂 关于小鼠的免疫原性。在目标 1 中，Peptides International 将生产 TMCP2，进行稳定性测试并 将技术转让给 cGMP 制造商。在目标 2（麻省大学）中，小鼠和非人类灵长类动物将 使用开发级 TMCP2 加 GLA-SE 进行免疫，以评估 i) 免疫原性和 ii) 功能 在 Ng 感染的小鼠或（分别）在 Ng/衣原体共感染的小鼠中引发抗体。 Ng 结合补体抑制剂， H 因子 (FH) 和 C4b 结合蛋白 (C4BP) 以人类特异性方式抑制疫苗活性 阿布。因此，我们将在表达人 FH 和 C4BP 的新型转基因小鼠中测试疫苗功效 模拟人类的条件。从免疫恒河猴中纯化的抗 LOS Ab 将用于检测 杀菌活性及其减弱单个 Ng 和 Ng/衣原体共感染小鼠定植的能力。 ABL Inc. 将验证 ELISA 和 SBA 的资格。新西兰白葡萄酒的 GLP 级安全性和毒理学研究 对产品开发至关重要的 Rabbits (ABL, Inc.) 将在目标 3 中进行。Pre-IND 启用 研究将在目标 4 中进行。成功完成这些目标将使我们的候选疫苗做好准备 人类研究

项目成果

Preclinical efficacy of a cell division protein candidate gonococcal vaccine identified by artificial intelligence.

• DOI: 10.1128/mbio.02500-23
• 发表时间: 2023-12-19
• 期刊: mBio
• 影响因子: 6.4

Neisseria gonorrhoeae Infection in Women Increases With Rising Gonococcal Burdens in Partners: Chlamydia Coinfection in Women Increases Gonococcal Burden.

女性淋球菌感染随着伴侣淋球菌负担的增加而增加：女性衣原体合并感染会增加淋球菌负担。

• DOI: 10.1093/infdis/jiac408
• 发表时间: 2022
• 期刊: The Journal of infectious diseases
• 作者: Su,Xiaohong;Le,Wenjing;Zhu,Xiaofeng;Li,Sai;Wang,Baoxi;Madico,Guillermo;Yang,Zhaoyan;Chaisson,ChristineE;McLaughlin,RobertE;Gandra,Sumanth;Yoon,Jungwon;Zheng,Bo;Lewis,LisaA;Gulati,Sunita;Reed,GeorgeW;Ram,Sanjay;Rice,Pet
• 通讯作者: Rice,Pet