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: 10322115
• 负责人: SANJAY RAM
• 金额: $ 65.31万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322115
• 关键词: Active Immunization; Address; Adjuvant; Affect; Animals; Antibiotic Resistance; Antibiotics; Antigens; Attenuated; Azithromycin; Binding; Biological Assay; Case Study; Ceftriaxone; Centers for Disease Control and Prevention (U.S.); 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 Name; 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; Reporting; Reproductive Health; Research Design; Research Institute; Resistance; Safety; Serum; Sexually Transmitted Diseases; 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; base; carbapenem-resistant Enterobacteriaceae; chronic pelvic pain; co-infection; complement 4b-binding protein; design; efficacy testing; experimental study; immunogenicity; in vivo; infection burden; lipooligosaccharide; manufacturing process; meetings; microorganism; nonhuman primate; novel; novel vaccines; peptide structure; peptidomimetics; polypeptide; 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 淋病是第二种最常见的细菌性传播感染 - 最常见的是 衣原体经常与淋病共同感染。大约8000万例新淋病发生 每年在美国淋病的严重后遗症中报告超过450,000例 包括不育，生态妊娠和慢性骨盆疼痛。淋病奈瑟氏菌（NG），病因 在淋病中，几乎对临床使用中的每种抗生素都具有抵抗力。对头孢曲松的抵抗力和 阿奇霉素（推荐的一线治疗）是一个不可治疗的淋病时代。 CDC 已将NG列为一种微生物，其威胁水平为“紧急”。开发安全有效的疫苗 反对淋病是公共卫生的重点。此外，NG和衣原体共感染是一个经常的事件 即使存在衣原体感染，成功的淋球菌疫苗也会防止感染。 我们确定了一种称为2C7的单克隆抗体（MAB），该抗体识别含脂糖酸（LOS）表位 由> 95％的NG体内表达，对于小鼠的病毒至关重要。 mAb 2c7是细菌剂，明显 减少小鼠NG感染的持续时间和燃烧。它无处不在的表达，在病毒中的关键作用和 AB针对2C7发作的细菌性质使其成为吸引人的疫苗抗原。绕开 LOS作为疫苗抗原的局限性，我们鉴定出一种模仿2C7表位的肽 构成为多抗原肽（MAP），引起细菌ABS并减弱小鼠的NG感染。 NIAID/NIH监督的产品开发计划与ABL Inc.，International和 传染病研究所（IDRI）。 PDP的对象已经满足并导致 在设计新型TETRA-MAP结构（TMCP2）和GLA-SE作为最佳调整的识别中 关于小鼠的免疫原性。在AIM 1中，国际肽将产生TMCP2，进行稳定性测试和 将技术转移到CGMP制造商。在AIM 2（UMass）中，小鼠和非人类灵长类动物将是 免疫原性和II）TMCP2和GLA-SE的功能以评估i） 在NG/衣原体共感染的小鼠中引起NG感染或（分别）的AB。 NG结合补体抑制剂， 因子H（FH）和C4B结合蛋白（C4BP）以人为特异性的方式抑制了疫苗的活性 ab。因此，我们将测试表达人FH和C4BP的新型转基因小鼠的疫苗效率 模拟人类的条件。将分配免疫恒河猕猴纯净的抗LOS AB 杀菌活性及其在单个NG和NG/衣原体共感染小鼠中衰减定殖的能力。 ABL Inc.将符合Elisas和SBAS的资格。新西兰白色的GLP级安全性和毒理学研究 对于产品开发至关重要的兔子（ABL，Inc。）将在AIM 3中进行。 研究将在AIM 4中进行。这些目标的成功完成将为我们的疫苗候选者做好准备 人类研究