Improved mutant meningococcal factor H binding protein vaccines

改进的突变型脑膜炎球菌 H 因子结合蛋白疫苗

基本信息

批准号：
8433338
负责人：
Peter T. BEERNINK
金额：
$ 44.64万
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：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433338
关键词：
Amino Acid Sequence Amino Acid Substitution Amputation Antibodies Antibody Formation Antigens Autoantibodies Autoimmune Diseases Bacteremia Bacteria Bacteriolysis Binding Binding Proteins Biological Assay Blocking Antibodies Brain Injuries Clinical Complement Complement Factor H Complement Inactivators Detection Development Disease Drug Formulations Epitopes Escherichia coli Europe Family Homology Modeling Host Defense Mechanism Human Human Factor H Immunity Immunization Infant Kidney Kidney Diseases Lead Libraries Licensing Ligand Binding Mediating Meningitis Minor Modeling Modification Mus Mutagenesis Mutation Neisseria meningitidis Organism Pathology Peptide Sequence Determination Predisposition Prevention Protein Binding Proteins Rattus Recombinants Resistance Risk Factors Safety Sepsis Serum Site Site-Directed Mutagenesis Sorting - Cell Movement Testing Transgenic Animals Transgenic Mice Transgenic Organisms Vaccine Antigen Vaccines Variant Wild Type Mouse bactericide disorder prevention immunogenicity improved killings mutant protein complex response vaccine candidate vaccine development vaccine efficacy vaccine safety

项目摘要

DESCRIPTION (provided by applicant): Factor H-binding protein (fHbp) is part of two vaccines in clinical development for prevention of group B meningococcal disease for which currently there is no licensed vaccine. Meningococci use fHbp to bind complement factor H (fH) to evade host immunity; binding is specific for human fH. Antibodies to fHbp can inhibit binding of fH and increase susceptibility of the organisms to complement-mediated bacteriolysis. Our preliminary studies in newly created human fH transgenic mice showed that binding of human fH to fHbp decreased the protective antibody responses. A single amino acid substitution in fHbp eliminated fH binding and increased the protective responses. In Aim 1 we will use random mutagenesis to identify and investigate the vaccine potential of additional mutants that eliminate fH binding. Sequence variants of fHbp are classified in two antigenic sub-families; the mutation that eliminated fH binding in one sub-family had no effect in the other. Therefore in Aim 2 we will use site-specific and random mutagenesis to generate mutants in the fHbp from the other sub- family. Binding of fH to fHbp may create neoantigens capable of eliciting autoantibodies to fH. In Aim 3, we will test whether the native fHbp that binds human fH elicits autoantibodies in transgenic animals, which would provide a strong rationale for the use of fH non-binding fHbp mutants as vaccines. By making relatively minor modifications to fHbp antigens already in clinical development, the proposed studies will illuminate the relationship between binding of fH to a vaccine antigen and vaccine safety and efficacy.

描述（由申请人提供）： H 因子结合蛋白 (fHbp) 是两种处于临床开发阶段的疫苗的一部分，用于预防 B 组脑膜炎球菌病，目前尚无获得许可的疫苗。脑膜炎球菌利用fHbp结合补体因子H（fH）来逃避宿主免疫；结合对人类 fH 具有特异性。 fHbp 抗体可以抑制 fH 的结合并增加生物体对补体介导的溶菌作用的敏感性。我们对新创建的人 fH 转基因小鼠的初步研究表明，人 fH 与 fHbp 的结合降低了保护性抗体反应。 fHbp 中的单个氨基酸取代消除了 fH 结合并增加了保护反应。在目标 1 中，我们将使用随机诱变来识别和研究消除 fH 结合的其他突变体的疫苗潜力。 fHbp 的序列变体分为两个抗原亚家族；消除一个亚家族中 fH 结合的突变对另一个亚家族没有影响。因此在目标 2 中我们将使用位点特异性和随机诱变在来自其他亚家族的 fHbp 中产生突变体。 fH 与 fHbp 的结合可能产生能够引发针对 fH 的自身抗体的新抗原。在目标 3 中，我们将测试结合人类 fH 的天然 fHbp 是否会在转基因动物中引发自身抗体，这将为使用 fH 非结合 fHbp 突变体作为疫苗提供强有力的理由。通过对临床开发中的 fHbp 抗原进行相对较小的修改，拟议的研究将阐明 fH 与疫苗抗原的结合与疫苗安全性和有效性之间的关系。