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: 10404598
• 负责人: Joseph J Campo
• 金额: $ 29.6万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404598
• 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; Vaccinee; 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 脑膜炎奈瑟菌 (Nm) 是一种革兰氏阴性细菌，通常定植于人类咽部 粘膜，但也可引起侵袭性脑膜炎球菌病 (IMD)，这是一种破坏性疾病，表现为 全世界每年报告超过 70,000 例 IMD 病例并导致死亡。 比率在 5% 到 15% 之间，杀菌性抗 Nm 抗体可以预防感染和定植。 通过血清杀菌测定 (SBA) 进行鉴定，这是体外保护替代的金标准。 因此，产生保护性杀菌 IgG 的疫苗接种被认为是一项重要的控制措施 IMD 的“逆向疫苗学”方法从疫苗抗原的计算机预测开始。 获得许可的基于蛋白质的疫苗，例如多组分 4CMenB (Bexsero®) 然而，所有获得许可的抗疫苗均是基于蛋白质的疫苗。 Nm疫苗的覆盖范围有限，使得疫苗容易受到非疫苗引起的IMD 迫切需要继续发现能够提供全面覆盖的候选疫苗， 无论是单独使用还是与现有疫苗协同使用，我们都敢于推出下一代反向疫苗。 疫苗学（“RV 2.0”），其中 SBA 活性人单克隆抗体 (hmAb) 是从 康复期 IMD 患者将为发现 Nm 疫苗抗原提供平台。 伦敦帝国理工学院的 Paul Langford 教授和 Fadil Bidmos 博士提出了新颖的广泛保护措施 RV 2.0 目前面临的挑战是识别同源抗体。 加利福尼亚州欧文市的 Antigen Discovery, Inc. (ADI) 已建立了泛蛋白质组。 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。 Nm 从未提供过用于分析抗体特异性的蛋白质组规模平台 研究界，这项技术有能力迅速推进疫苗的发现 该项目旨在鉴定杀菌抗体所针对的抗原。 将开发脑膜炎球菌泛蛋白质组微阵列，用于 RV 2.0 方法筛选 hmAb 和 来自儿科 IMD 患者的恢复期血清，具有 SBA 和其他体外功能性抗体 最有前途的活性，例如补体激活、调理吞噬作用和粘附抑制。 抗原将通过生产和纯化重组蛋白进行验证，该重组蛋白将用于开发 Luminex 测定用于在直系同源免疫测定中确认至少 5 种结合的疫苗候选抗原。 识别不同 Nm 菌株的抗体，在目标人群中具有广泛的免疫原性，并且不 目前包含在任何许可疫苗中的药物将在第 2 阶段 SBIR 中进行临床前开发 该拨款申请通过提出以下要求来解决儿童和成人的 IMD 重大问题。 通过鉴定杀菌抗体的蛋白质靶标，为广泛覆盖的疫苗奠定了基础。