Outer membrane vesicle vaccine against gonococcal and meningcoccal disease

针对淋球菌和脑膜炎球菌疾病的外膜囊泡疫苗

• 批准号: 9981532
• 负责人: Lisa Ann Lewis
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981532
• 关键词: Address; Adolescent and Young Adult; Antibiotic Resistance; Antibiotics; Antigens; Attenuated; Azithromycin; Binding; Binding Proteins; Ceftriaxone; Centers for Disease Control and Prevention (U.S.); Chlamydia; Clinical; Clostridium difficile; Combined Vaccines; Complement; Complement Factor H; Complement Inactivators; Complement component C5; Crowding; Detergents; Development; Disease; Economics; Ectopic Pregnancy; Effectiveness; Engineering; Ensure; Environment; Epidemic; Epitopes; Equipment; Evaluation; Genetic Complementation Test; Gonorrhea; HIV; Human; Immunize; In Vitro; Incidence; Infection; Infertility; Lipoproteins; Logistics; Membrane; Membrane Proteins; Meningococcal vaccine; Methods; Monoclonal Antibodies; Mus; Mutate; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; New Zealand; Peptides; Phase; Play; Polymers; Reagent; Reporting; Resistance; Role; Serial Passage; Serum; Sexually Transmitted Diseases; Sialic Acids; Surface; Testing; Transgenic Mice; United States; Vaccine Antigen; Vaccines; Vagina; Variant; Vesicle; Virulence; Woman; Work; age group; bactericide; carbapenem-resistant Enterobacteriaceae; chronic pelvic pain; combat; complement 4b-binding protein; complement system; design; efficacy evaluation; efficacy testing; experimental study; fitness; human pathogen; immunogenicity; improved; in vivo; infection burden; innovation; lipooligosaccharide; major outer membrane protein; microorganism; mutant; optimism; overexpression; peptidomimetics; product development; public health priorities; social stigma; transmission process; trend; vaccination schedule; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation

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 555,000 cases were reported in the U.S. in 2017. Serious sequelae of gonorrhea in women include 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. Our group has shown that a monoclonal antibody (mAb) called 2C7 that targets a widely-expressed Ng lipooligosaccharide (LOS) epitope (the 2C7 epitope) is bactericidal. A peptide mimic (mimitope) of the 2C7 epitope, when configured as a polymer (a ‘multiantigen peptide’) elicits bactericidal Abs and attenuates Ng vaginal colonization in mice. Encouraged by the recent retrospective observation that a group B meningococcal vaccine composed of detergent-extracted outer membrane vesicles (MeNZB) designed to curtail a meningococcal epidemic in New Zealand also reduced incident gonococcal disease by 31%, we will incorporate the gonococcal 2C7 epitope into meningococcal outer membrane vesicles to target both meningococci and gonococci. This innovative approach is advantageous because both diseases are highly prevalent in adolescents and young adults. In addition to the economic advantages, a ‘pan- Neisseria’ vaccine would help address an already crowded vaccination schedule and may mitigate the stigma associated with vaccines against STIs. In Aim 1, we will develop meningococcal native outer membrane vesicles (NOMVs) containing LOS that displays the 2C7 epitope. Meningococcal FH-binding protein (FHbp) will be mutated to abrogate binding of human FH and thereby elicit higher bactericidal Ab against Nm than wild- type FHbp. We will also delete Rmp and H.8, which may elicit blocking Ab against Ng and Nm, respectively. Elicited Abs will be tested for complement-dependent bactericidal activity against homologous and heterologous Ng strains and tested for efficacy versus Ng in transgenic mice we have developed that express the human complement inhibitors, FH and C4BP, to better simulate the complement environment in humans. We will use mice deficient in C9 (the last step in formation of the bacteriolytic pore) or mice depleted of PMNs to elucidate the mechanism of action of the candidate vaccine, which will also define correlates of protection. In Aim 2, we will develop detergent-extracted outer membrane vesicle vaccines (dOMVs) that display the 2C7 mimitope peptide in the framework of the major outer membrane protein, PorA. Immunogenicity and efficacy of this vaccine will be evaluated as described in Aim 1.

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 2017年美国报告了超过555,000例。 包括不育，异位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）预示着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。我们的小组表明单克隆抗体（mAb）称为 2C7靶向广泛表达的Ng lipoligosacaCaChide（LOS）表位（2C7表位）是杀菌性的。一个 2C7表位的肽模拟物（Mimitope），当配置为聚合物（一种“多蛋白胡椒”）引发 杀菌性ABS和减弱小鼠的阴道定植。最近的回顾展鼓励 观察到B组脑膜炎球疫苗由检测器提取的外膜蔬菜组成 （MENZB）旨在减少新西兰的脑膜炎球菌流行，也减少了事件的淋球菌 疾病降低了31％，我们将淋球菌2C7表位纳入脑膜外膜蔬菜 靶向脑膜炎球菌和淋球菌。这种创新的方法是有利的，因为这两种疾病 在青少年和年轻人中非常普遍。除了经济优势外， Neisseria的疫苗将有助于解决已经拥挤的疫苗时间表，并可能减轻污名 与针对性传播感染的疫苗有关。在AIM 1中，我们将开发脑膜炎脑膜天然外膜 蔬菜（NOMV）包含显示2C7表位的LOS。脑膜炎球菌FH结合蛋白（FHBP）将 被突变以消除人类FH的结合，从而比野生物引起更高的杀菌剂AB与NM的结合 键入FHBP。我们还将删除RMP和H.8，这可能会分别引起对NG和NM的阻止。 引起的ABS将测试针对同源和 异源NG菌株并测试了效率与转基因小鼠的NG，我们已经开发了表达的 人类补充抑制剂FH和C4BP，以更好地模拟人类的补体环境。 我们将使用缺乏C9的小鼠（形成细菌孔的最后一步）或PMN耗尽的小鼠 阐明候选疫苗的作用机理，这也将定义保护的相关性。在 AIM 2，我们将开发显示2C7的检测器提取的外膜囊泡疫苗（DOMV） Mimitope在主要外膜蛋白Pora的框架内。免疫原性和效率 该疫苗将如AIM 1所述进行评估。