Gonococcal peptide vaccine candidate display using HPV virus-like particles

使用 HPV 病毒样颗粒展示候选淋球菌肽疫苗

基本信息

批准号：
10390991
负责人：
SANJAY RAM
金额：
$ 24.1万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-27 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390991
关键词：
Affect Antibiotic Resistance Antibiotics Antibodies Antibody Response Antigens Attenuated Azithromycin Binding Cancer Burden Ceftriaxone Centers for Disease Control and Prevention (U.S.)Cessation of life Chlamydia Clinical Complement Complement Factor H Complement Inactivators Data Developing Countries Development Disease Ectopic Pregnancy Ensure Epitopes Equipment Female Genetic Complementation Test Gonorrhea HIV Human Human Papilloma Virus Vaccine Human Papillomavirus Human papillomavirus 16 Human papillomavirus HPV L1 protein Immune Immunize Immunoglobulin A Immunoglobulin G In Vitro Inbred BALB C Mice Incidence Infection Infertility Inflammation Lead Luciferases Malignant Neoplasms Malignant neoplasm of cervix uteri Mammalian Cell Measures Methodology Modeling Monoclonal Antibodies Mucous Membrane Mus Neisseria gonorrhoeae Peptide Vaccines Peptides Persons Plants Play Population Production Reagent Reporter Genes Reporting Resistance Resources Role Serum Sexually Transmitted Diseases Sialic Acids Study models Surface System Testing Tobacco Transgenic Mice United States Vaccinated Vaccination Vaccines Vagina Virulence Virulence Factors Virus-like particle Woman Work bacterial resistance bactericide cervicovaginal chronic pelvic pain complement 4b-binding protein complement system cost efficacy testing immunogenicity improved in vivo infection burden lipooligosaccharide male microorganism mutant peptidomimetics product development prophylactic public health priorities receptor reproductive tract response sialic acid binding Ig-like lectin social stigma socioeconomic disadvantage success transmission process trend vaccine candidate vaccine efficacy vaccine evaluation

项目摘要

ABSTRACT About 87 million new cases of gonorrhea occur globally, annually. In 2018, 583,405 cases were reported in the U.S, an 82.6% increase in disease incidence since the historic low in 2009. Human papillomaviruses (HPVs) are the causative agents of cervical cancer, the 4th most common cancer in women globally, resulting in ~567,000 cases and 311,000 deaths every year. About 80% of these cases occur in resource-poor developing countries. There are currently three licensed effective prophylactic HPV vaccines. Despite the great success of these vaccines, the cervical cancer burden remains high, particularly in developing countries, as these vaccines are expensive and type-specific. Neisseria gonorrhoeae (Ng), the causative agent of gonorrhea, has become resistant to almost every antibiotic in clinical use and portends an era of untreatable gonorrhea. Development of a safe and effective vaccine against gonorrhea is a global public health priority. Lipooligosaccharide (LOS) is the most abundant molecule on the gonococcal surface and plays multifaceted roles in bacterial virulence. A LOS epitope recognized by mAb 2C7 (therefore called the 2C7 epitope) is expressed by >95% of Ng in vivo; Ng mutants that do not express the 2C7 epitope are attenuated in mice. This is because the 2C7 LOS epitope can be modified with sialic acid, which increases resistance of the bacteria to complement-dependent killing and engages Siglec receptors to down-regulate host inflammation. We have developed a peptide mimic (mimitope) of the 2C7 epitope, which when configured as a multi-antigen peptide (MAP) elicits bactericidal Abs and attenuates Ng colonization in mice in a complement-dependent manner. This project will leverage the HPV virus-like particle (VLP) platform to deliver the 2C7 mimitope. VLPs are an excellent platform to enhance immunogenicity of peptides. We have already produced HPV VLPs that express the Ng mimitope peptide (called HPV-Ng) in tobacco plants and in mammalian cells on a small scale. Production in tobacco plant expression could reduce costs, an important consideration for vaccines against STIs that disproportionately affect socio-economically underprivileged populations. In Aim 1 we will test the immunogenicity and in vitro function of antibodies (Abs) elicited by HPV-Ng. We will measure Ab responses in male and female BALB/c, C57BL/6 and CD1 mice against i) the 2C7 LOS epitope and ii) against HPV16. An intact complement system is necessary and sufficient for activity in vivo of Ab against the 2C7epitope. Therefore, we will test complement-dependent bactericidal activity of immune Ab against Ng. The ability of anti-HPV Ab to neutralize pseudovirions (PsVs) – an in vitro measure of efficacy against HPV – will be measured. In Aim 2, the efficacy of HPV-Ng against Ng will be tested in a gonococcal vaginal colonization model in mice that express human complement inhibitors, to better simulate the complement system of humans and provide a more stringent test of vaccine efficacy. Efficacy of HPV-Ng against HPV16 will be tested in a HPV PsV cervicovaginal model in mice.

抽象的全球每年约有 8700 万新发淋病病例，2018 年报告了 583,405 例病例。美国的发病率自 2009 年历史最低点以来增加了 82.6%。人乳头瘤病毒 (HPV) 是宫颈癌的病原体，宫颈癌是全球女性第四大常见癌症，导致每年约 567,000 例病例和 311,000 例死亡，其中约 80% 发生在资源贫乏的发展中国家。尽管取得了巨大成功，但目前已有三种有效的预防性 HPV 疫苗获得许可。尽管使用这些疫苗，宫颈癌负担仍然很高，特别是在发展中国家，因为这些疫苗疫苗价格昂贵且具有特定类型的淋病奈瑟菌 (Ng)。对临床使用的几乎所有抗生素都产生耐药性，预示着淋病无法治愈的时代即将来临。开发安全有效的淋病疫苗是全球公共卫生的首要任务。脂寡糖（LOS）是淋球菌表面最丰富的分子，具有多方面的作用 mAb 2C7 识别的 LOS 表位（因此称为 2C7 表位）是体内超过 95% 的 Ng 表达；不表达 2C7 表位的 Ng 突变体在小鼠中减弱。是因为2C7 LOS表位可以用唾液酸修饰，从而增加细菌对细菌的抵抗力补体依赖性杀伤并与 Siglec 受体结合来下调宿主炎症。开发了 2C7 表位的肽模拟物（模拟表位），当配置为多抗原肽时 (MAP) 以补体依赖性方式引发杀菌 Abs 并减弱小鼠体内的 Ng 定植。该项目将利用 HPV 病毒样颗粒 (VLP) 平台来提供 2C7 模拟表位。增强肽免疫原性的优秀平台我们已经生产了表达 HPV VLP。烟草植物和小规模哺乳动物细胞中的 Ng 模拟肽（称为 HPV-Ng）。烟草植物表达生产可以降低成本，这是疫苗的一个重要考虑因素性传播感染对社会经济弱势群体的影响尤为严重在目标 1 中，我们将测试我们将测量 HPV-Ng 引发的抗体 (Ab) 的免疫原性和体外功能。雄性和雌性 BALB/c、C57BL/6 和 CD1 小鼠针对 i) 2C7 LOS 表位和 ii) 针对 HPV16。完整的补体系统对于抗体针对 2C7 表位的体内活性是必要且充分的。因此，我们将测试针对 Ng 的免疫抗体的补体依赖性杀菌活性。中和假病毒颗粒 (PsV) 的抗 HPV 抗体（一种针对 HPV 功效的体外测量方法）将在目标 2 中，将在淋球菌阴道定植中测试 HPV-Ng 对 Ng 的功效。表达人类补体抑制剂的小鼠模型，以更好地模拟补体系统人类并提供更严格的疫苗功效测试 HPV-Ng 针对 HPV16 的功效。在小鼠 HPV PsV 宫颈阴道模型中。