Meningococcal serogroup B vaccine to prevent invasive disease and carriage

用于预防侵袭性疾病和携带的 B 群脑膜炎球菌疫苗

基本信息

批准号：
9097516
负责人：
Dan M. Granoff
金额：
$ 64.17万
依托单位：
CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-05 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9097516
关键词：
Accounting Active Immunization Address Adherence Adhesions Animal Model Antibodies Antibody Response Antibody-mediated protection Antigens Attenuated Avidity Bacteriolysis Binding Binding Proteins Biological Models CEACAM1 Cell Culture Techniques Cell Line Cells Clinical Trials Collection Complement Complement Activation Complement Factor H Complex Conjugate Vaccines Country Data Detergents Development Disease Endotoxins Engineering Epithelial Cells Epitopes Europe Exposure to Failure Glycoconjugates Goals Health Herd Immunity Human Immune system Immunization In Vitro Individual Infant Investigation Knowledge Laboratories Licensing Life Measures Mediating Membrane Meningitis Meningococcal vaccine Modeling Mus Neisseria meningitidis Nose Organism Persons Policy Maker Polysaccharides Population Prevention Primates Proteins Recombinant Proteins Recombinants Risk Role Septicemia Serum Specificity Testing Tissues Transgenic Mice Transgenic Organisms Vaccinated Vaccination Vaccine Antigen Vaccines Vesicle bactericide base carcinoembryonic antigen-related cell adhesion molecules complement deficiency disease transmission disorder control human tissue humanized mouse immunogenicity improved in vitro Model in vivo in vivo Model insight mouse model mutant neutrophil nonhuman primate novel novel vaccines prevent receptor response transmission process university student vaccine evaluation vaccine-induced immunity

项目摘要

DESCRIPTION (provided by applicant): Neisseria meningitidis (Nm) is a major cause of meningitis and septicemia. Serogroup B (NmB) strains account for 30 to 80 percent of invasive disease in different populations. Capsular polysaccharide-protein conjugate vaccines are available against all of the major serogroups except for NmB, which cross-reacts with host antigens. A protein antigen-based vaccine (referred to as 4CMenB) that targets NmB strains recently was licensed in Europe. However, failure of 4CMenB vaccination to decrease asymptomatic NmB carriage was instrumental in a preliminary decision by policy makers not to recommend routine vaccination in the UK. While considerable data indicate that glycoconjugate vaccines prevent both invasive disease and decrease nasopharyngeal colonization, there are important gaps in knowledge about the underlying mechanisms, and how protein-based vaccines can be improved to decrease carriage more effectively. Our hypotheses are that improving serum antibody quantity and quality (i.e, avidity, breadth of epitope reactivity, and functional activity) and/or targeting additional antigens, will increase the ability of NmB vaccine to decrease carriage. The major challenges that impede investigation of these questions are, 1) the specificity of Nm for the human host, and 2) the lack of appropriate in vitro and in vivo models. For example, human CEACAM1 specifically mediates adhesion of Nm to airway epithelial cells, and human complement factor H (fH) specifically down-regulates complement activation and permits meningococci to evade bacteriolysis in humans. Our laboratory has developed a broadly protective meningococcal native outer membrane vesicle vaccine (NOMV) from mutants with genetically attenuated endotoxin and over-expressed factor H binding protein (fHbp). Data indicate that the quality of the antibody responses to fHbp when over-expressed in an NOMV vaccine is greater than to recombinant fHbp vaccines. To determine the effect of NOMV-fHbp immunization on carriage, and to identify additional antigens that might be added to the vaccine to decrease carriage, we propose to: 1) develop in vitro airway models of meningococcal colonization, 2) generate a transgenic mouse model of human colonization that expresses both human CEACAM1 and human fH, and 3) use these model systems to evaluate the ability our NOMV-fHbp vaccine and new antigens to prevent colonization. The results will increase our understanding of the mechanisms by which vaccination decreases meningococcal carriage, and will further development of a broadly protective serogroup B meningococcal vaccine that prevents both invasive disease and asymptomatic carriage.

描述（由申请人提供）：脑膜炎奈瑟菌（Nm）是脑膜炎和败血症的主要原因。 B 血清群 (NmB) 菌株占不同人群侵袭性疾病的 30% 至 80%。荚膜多糖-蛋白结合疫苗可针对除 NmB 以外的所有主要血清群，NmB 会与宿主抗原发生交叉反应。一种针对 NmB 菌株的基于蛋白抗原的疫苗（简称 4CMenB）最近在欧洲获得许可。然而，4CMenB 疫苗接种未能减少无症状 NmB 携带，这有助于政策制定者初步决定不建议在英国进行常规疫苗接种。虽然大量数据表明复合糖疫苗可以预防侵袭性疾病并减少鼻咽定植，但对于其潜在机制以及如何改进基于蛋白质的疫苗以更有效地减少携带的知识仍存在重大差距。我们的假设是，提高血清抗体的数量和质量（即亲合力、表位反应范围和功能活性）和/或靶向其他抗原，将增加 NmB 疫苗减少携带的能力。阻碍这些问题研究的主要挑战是，1）Nm 对人类宿主的特异性，2）缺乏适当的体外和体内模型。例如，人 CEACAM1 特异性介导 Nm 与气道上皮细胞的粘附，而人补体因子 H (fH) 特异性下调补体激活并允许脑膜炎球菌逃避人体溶菌。我们的实验室开发了一种具有广泛保护性的脑膜炎球菌天然外膜囊泡疫苗 (NOMV)，该疫苗来自具有基因减毒内毒素和过表达 H 因子结合蛋白 (fHbp) 的突变体。数据表明，当在 NOMV 疫苗中过表达 fHbp 时，抗体对 fHbp 的反应质量优于重组 fHbp 疫苗。为了确定 NOMV-fHbp 免疫对携带的影响，并确定可能添加到疫苗中以减少携带的其他抗原，我们建议：1) 开发脑膜炎球菌定植的体外气道模型，2) 生成转基因小鼠模型表达人类 CEACAM1 和人类 fH 的人类定植的能力，以及 3) 使用这些模型系统来评估我们的 NOMV-fHbp 疫苗和新抗原预防定植的能力。这些结果将加深我们对疫苗接种减少脑膜炎球菌携带的机制的了解，并将进一步开发具有广泛保护性的 B 血清群脑膜炎球菌疫苗，以预防侵袭性疾病和无症状携带。