Identification of bactericidal antibody specificities for the development of novel broad-coverage vaccine candidates against Neisseria meningitidis

鉴定杀菌抗体特异性，用于开发针对脑膜炎奈瑟菌的新型广泛覆盖候选疫苗

• 批准号: 10256250
• 负责人: Joseph J Campo
• 金额: $ 30万
• 依托单位: IMMPORT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-12 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256250
• 关键词: Address; Adhesions; Adult; Animal Model; Animal Testing; Annual Reports; Antibodies; Antibody Repertoire; Antibody Specificity; Antigen Targeting; Antigens; Applications Grants; Baculovirus Expression System; Binding Proteins; Biological Assay; Blood Circulation; Blood specimen; Cells; Child; Childhood; Cloning; Collaborations; Communities; Complement; Complement Activation; Coupled; Data; Deposition; Development; Disease; Escherichia coli; Female; Foundations; Future; Generations; Genes; Genetic Transcription; Goals; Gold; Gram-Negative Bacteria; Healthcare; Hospitals; Human; Immune Sera; Immunity; Immunoassay; Immunoglobulin G; In Vitro; Individual; Infection; Infection prevention; Invaded; Length; Libraries; London; Manufacturer Name; Measurement; Measures; Meninges; Meningitis; Meningococcal vaccine; Microarray Analysis; Mucous Membrane; Neisseria meningitidis; Open Reading Frames; Operative Surgical Procedures; Patients; Phase; Plasmablast; Printing; Protein Array; Proteins; Proteome; Recombinant Proteins; Research; Sampling; Septicemia; Serum; Slide; Small Business Innovation Research Grant; Specificity; System; Target Populations; Technology; Therapeutic Intervention; Tissues; Transgenic Mice; Translations; Vaccine Antigen; Vaccines; Validation; antigen antibody binding; antigen binding; bactericide; base; clinical development; college; commercialization; cross reactivity; human monoclonal antibodies; immunogenic; immunogenicity; in silico; interest; male; mouse model; next generation; novel; novel vaccines; pediatric patients; preclinical development; prevent; safety testing; synergism; tool; vaccination outcome; vaccine candidate; vaccine discovery; vaccinology

ABSTRACT Neisseria meningitidis (Nm) is a Gram-negative bacterium that commonly colonizes the human pharyngeal mucosa, but can also cause invasive meningococcal disease (IMD), a devastating disease that presents as septicemia and meningitis. More than 70,000 cases of IMD are reported annually worldwide with case fatality ratios between 5% and 15%. Bactericidal anti-Nm antibodies may prevent infection and colonization and can be identified by the serum bactericidal assay (SBA), which is the gold standard in vitro surrogate of protection. Vaccination that results in protective bactericidal IgG is, therefore, considered a crucial control measure for IMD. A “Reverse Vaccinology” approach that starts with in silico prediction of vaccine antigens has led to licensed protein-based vaccines such as the multicomponent 4CMenB (Bexsero®). However, all licensed anti- Nm vaccines have limited breadth of coverage, leaving vaccinees susceptible to IMD caused by non-vaccine type strains. There is an urgent need for continued discovery of vaccine candidates that will provide full coverage, either individually or in synergy with existing vaccines. We hypothesize that the next generation of Reverse Vaccinology (“RV 2.0”), whereby SBA-active human monoclonal antibodies (hmAbs) are generated from convalescent IMD patients, will provide the platform for discovery of vaccine antigens against Nm. The team of Prof. Paul Langford and Dr. Fadil Bidmos of Imperial College London have generated novel broadly protective bactericidal hmAbs from convalescing patients. The current challenge with RV 2.0 is identifying the cognate antigens of bactericidal hmAbs. Antigen Discovery, Inc. (ADI) of Irvine, CA has established panproteome microarray technology for identification of the protein targets of antibodies associated with protective immunity. A proteome-scale platform for profiling antibody specificity has never before been available to the Nm research community, and this technology has the power to rapidly advance discovery of vaccine candidates. This project aims to identify the antigens targeted by bactericidal antibodies. A Neisseria meningitidis panproteome microarray will be developed for use in an RV 2.0 approach to screen hmAbs and convalescent sera from pediatric IMD patients characterized as having SBA and other in vitro functional antibody activity, such as complement activation, opsonophagocytosis and adhesion inhibition. The most promising antigens will be validated by producing and purifying recombinant proteins, which will be used to develop Luminex assays for confirmation in orthologous immunoassays. At least 5 vaccine candidate antigens that bind antibodies that recognize diverse Nm strains, are broadly immunogenic in the target population and are not currently included in any licensed vaccine will be taken forward for preclinical development in a Phase 2 SBIR application. This grant application addresses the significant problem of IMD in children and adults by laying the foundation for a broad-coverage vaccine through identification of the protein targets of bactericidal antibodies.

抽象的 Neiserseria脑膜炎（NM）是一种革兰氏阴性菌，通常在人咽部殖民地 粘膜，但也可能引起侵入性脑膜炎球菌疾病（IMD），这是一种毁灭性的疾病，呈现为 败血病和脑膜炎。每年在全球范围内报告了超过70,000例IMD，病例死亡 比率在5％至15％之间。杀菌性抗NM抗体可能会阻止感染和定殖，并且可以是 通过血清细菌测定（SBA）鉴定，这是保护的金标准。 因此，导致受保护的细菌IgG的疫苗被认为是至关重要的控制措施 对于IMD。从疫苗抗原预测开始的“反疫苗学”方法已导致 基于许可的蛋白质疫苗，例如多组分4CMENB（BEXSERO®）。但是，所有许可的反 - NM疫苗的覆盖率有限，使疫苗易受非疫苗感染的IMD 类型应变。迫切需要继续发现候选疫苗，这些疫苗将提供全部覆盖范围， 单独或与现有疫苗协同作用。我们假设下一代反向 疫苗接种学（“ RV 2.0”），从而从SBA活跃的人类单克隆抗体（HMAB）中产生 疗养IMD患者将为发现NM发现疫苗抗原的平台。团队 伦敦帝国学院的Paul Langford教授和Fadil Bidmos博士已经产生了广泛保护的小说 康复患者的杀菌性HMAB。 RV 2.0的当前挑战是识别同源 细菌HMAB的抗原。加利福尼亚州欧文市的Antigen Discovery，Inc。（ADI）建立了Panproteome 微阵列技术，用于鉴定与保护性免疫相关的抗体的蛋白质靶标。 用于分析抗体特异性的蛋白质组规模平台从未在NM上使用 研究社区，这项技术有能力快速提高疫苗的发现 候选人。该项目旨在鉴定细菌抗体靶向的抗原。奈瑟氏菌 将开发脑膜炎薄膜微阵列用于RV 2.0筛选HMAB和 小儿IMD患者的康复血清，其特征为具有SBA和其他体外功能抗体 活性，例如完成激活，调查性胞毒性和粘附性抑制作用。最有前途的 抗原将通过产生和净化重组蛋白来验证，该蛋白将用于开发 Luminex分析用于直系同源免疫测定。至少有5种结合的疫苗候选物 识别潜水NM菌株的抗体在目标群中具有广泛的免疫原性，并且不是 目前将在任何许可的疫苗中纳入任何许可疫苗 应用。该赠款申请通过奠定了儿童和成人的IMD的重大问题 通过鉴定细菌抗体的蛋白质靶标的宽覆盖疫苗的基础。