Improved protein-based meningococcal serogroup B vaccines

改进的基于蛋白质的 B 群脑膜炎球菌疫苗

基本信息

批准号：
10180889
负责人：
Peter T. BEERNINK
金额：
$ 74.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180889
关键词：
Adolescent and Young Adult Affect Age-Years Amino Acid Substitution Animal Model Animals Antibody Formation Antibody-mediated protection Antigenic Diversity Antigens Bacteremia Bacteria Bacterial Meningitis Binding Binding Proteins Cell Separation Cessation of life Child Cohort Studies Combined Vaccines Complement Complement Factor H Crystallization DNA Shuffling Data Development Disease Engineering Enzyme-Linked Immunosorbent Assay Epitopes Exhibits Family Generations Genes Genetic Polymorphism Goals Human Immune Evasion Immunity In Vitro Individual Infant Ligands Macaca mulatta Measures Mediating Membrane Proteins Meningitis Microbe Modeling Mus Mutagenesis Neisseria meningitidis Nervous System Trauma Persons Prevention Primates Proteins Rattus Recombinant Proteins Recommendation Reporter Sepsis Serogroup B Neisseria meningitidis Serum Solubility Structure Surface Surface Plasmon Resonance System Terminator Codon Testing Transgenic Mice Transgenic Organisms Vaccines Variant Virulence Wild Type Mouse aged bactericide base deafness extracellular first-in-human high risk immunogenicity improved in vivo limb amputation microbial mutant next generation nonhuman primate preservation prototype recruit vaccine development virtual

项目摘要

Project Summary/Abstract Two protein-based vaccines are licensed in the U.S. for prevention of meningococcal group B (MenB) disease in adolescents and young adults. One vaccine contains two Factor H binding protein (FHbp) Ags, one from each of the two phylogenic sub-families; the other contains one FHbp sub-family B Ag and three other potentially protective Ags. The former vaccine has limitations in protection against strains with no or low FHbp expression (10-20% of strains) and the latter has limitations against the ~40% of strains with FHbp in sub-family A and lacking another matched Ag. Our previous studies in human complement Factor H (FH) transgenic mice and infant rhesus macaques showed that binding of FH to FHbp decreases the magnitude of the protective Ab responses. Further, our colleagues have shown that human FH decreases the protective Ab responses to an alternative FH ligand known as Neisserial surface protein A (NspA), which is present in virtually all MenB strains. Since recruitment of the complement down-regulator FH to the bacterial surface contributes to immune evasion, a vaccine that targets both of these FH ligands would elicit Abs that effectively defeat this virulence mechanism. In Aim 1, we will incorporate FHbp amino acid substitutions to decrease binding of FH into optimally cross-protective FHbp sequence variants in each sub-family. In Aim 2, we will introduce substitutions to decrease binding of human FH to NspA based on the known crystal structure of NspA and to increase solubility of the recombinant protein using random mutagenesis and a fluorescent reporter system. For both Aims 1 and 2, we will test the optimized antigens for FH and MAb binding in vitro, evaluate immunogenicity in wild-type and human FH transgenic mice and test the serum Ab protective activity. In Aim 3, we will develop a combination FHbp-NspA vaccine that will combine an engineered FHbp sequence variant from each sub-family and an engineered NspA Ag. We will test the combination vaccine compared to a licensed MenB vaccine, first in human FH transgenic mice then in infant rhesus macaques with high binding of FH to wild-type FHbp and NspA. For each of these studies, we will determine the magnitudes of the bactericidal Ab responses against MenB strains that are specific for each of the two Ags (i.e. lacking or with very low expression of one of the two Ags). We also will test passive Ab protection in human FH transgenic infant rats. The data will support development of a second-generation MenB vaccine that elicits higher and more sustained protective Ab responses and broader protection than the currently licensed vaccines. Since binding of complement regulators is a common microbial virulence mechanism, the results also will have broad implications for the development of vaccines against other microbes that bind complement regulators or other host molecules.

项目概要/摘要两种基于蛋白质的疫苗在美国获得许可用于预防 B 组脑膜炎球菌 (MenB) 青少年和年轻人的疾病。一种疫苗含有两个 H 因子结合蛋白 (FHbp) Ags，两个系统发育亚科各一个；另一个包含一个 FHbp 亚家族 B Ag 以及其他三种具有潜在保护作用的抗原。以前的疫苗在预防方面有局限性没有或低 FHbp 表达的菌株（10-20% 的菌株），后者对约 40% 的菌株具有 A 亚科中的 FHbp，但缺乏另一种匹配的 Ag。我们之前的研究人补体因子 H (FH) 转基因小鼠和幼年恒河猴表明结合 FH 变为 FHbp 会降低保护性抗体反应的强度。此外，我们的同事还表明人类 FH 降低了对替代 FH 配体（称为奈瑟菌表面蛋白 A (NspA)，几乎存在于所有 MenB 菌株中。自招聘以来补体下调因子 FH 到达细菌表面有助于免疫逃避，针对这两种 FH 配体的疫苗将引发有效抵抗这种毒力的抗体机制。在目标 1 中，我们将合并 FHbp 氨基酸取代以减少 FH 的结合成每个亚家族中最佳交叉保护性 FHbp 序列变体。在目标 2 中，我们将介绍基于已知的 NspA 晶体结构，进行取代以减少人 FH 与 NspA 的结合并使用随机诱变和荧光增加重组蛋白的溶解度记者系统。对于目标 1 和 2，我们将测试 FH 和 MAb 结合的优化抗原体外评价野生型和人 FH 转基因小鼠的免疫原性并检测血清抗体保护活动。在目标 3 中，我们将开发一种 FHbp-NspA 组合疫苗，该疫苗将结合来自每个亚家族的工程化 FHbp 序列变体和工程化 NspA Ag。我们将测试该组合疫苗与获得许可的 MenB 疫苗相比，首先在人类 FH 转基因小鼠中进行比较然后在幼年恒河猴中，FH 与野生型 FHbp 和 NspA 高度结合。对于每个通过这些研究，我们将确定针对 MenB 的杀菌抗体反应的强度对这两种抗原具有特异性的菌株（即缺乏或表达非常低的其中一种抗原）两个 Ag）。我们还将测试人类 FH 转基因幼鼠的被动抗体保护。数据将支持开发第二代 MenB 疫苗，该疫苗可引发更高、更持久的效果保护性抗体反应和比目前许可的疫苗更广泛的保护。自从绑定补体调节因子是微生物常见的毒力机制，其结果也会有广泛的影响对开发针对结合补体调节因子的其他微生物的疫苗的影响或其他宿主分子。