Development of an anti-idiotype based vaccine for respiratory syncytial virus

呼吸道合胞病毒抗独特型疫苗的研制

• 批准号: 10302873
• 负责人: Andrew McGuire
• 金额: $ 18.8万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302873
• 关键词: Adopted; Adult; Affinity; Age; Anti-Idiotypic Antibodies; Antibodies; Antibody Response; Antigens; Area; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Cessation of life; Child; Chimeric Proteins; Clinical; Developed Countries; Development; Disease; Elderly; Engineering; Epitopes; Face; Frequencies; Genes; Health Benefit; Health Priorities; Human; Immune response; Immune system; Immunization; Immunoglobulin Class Switching; Immunoglobulin Idiotypes; Immunologics; Infant; Label; Lead; Light; Lower Respiratory Tract Infection; Lung diseases; Maps; Masks; Maternal antibody; Mediating; Modeling; Molecular Conformation; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nature; Peripheral Blood Mononuclear Cell; Physiological; Population; Process; Prophylactic treatment; Proteins; Recombinant Antibody; Recombinants; Reproducibility; Research; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Risk; Somatic Mutation; Specificity; Structure; Subunit Vaccines; T-Lymphocyte; Time; Umbilical Cord Blood; Vaccination; Vaccine Antigen; Vaccines; Variant; Viral Fusion Proteins; Virus; Vulnerable Populations; Wild Type Mouse; base; cellular engineering; cost; cost effective; effective therapy; experience; global health; high risk infant; immunogenic; infant infection; mortality; mouse model; neutralizing antibody; neutralizing monoclonal antibodies; novel vaccines; pathogen; pre-B cell receptor; preclinical development; response; success; vaccination outcome; vaccine development

PROJECT SUMMARY/ABSTRACT Respiratory Syncytial Virus (RSV) is a common pathogen that causes lower respiratory tract infections leading to significant morbidity and mortality at the extremes of age. Primary RSV infection is responsible for ~60,000 deaths in children under 5. Passive transfer of a monoclonal neutralizing antibody that targets the RSV fusion protein (F) is the only prophylactic treatment for infant RSV infection that has proven to be protective, but its widespread use is limited due to cost limitations. Thus, a vaccine that could elicit protective neutralizing antibodies would have a significant, cost effective, global health benefit. However, the development of an RSV subunit vaccine that is efficacious in infants has remained elusive. This is in part due to the metastable nature of recombinant RSV F, and to the unique challenges facing infant immunization including the presence of pre-existing maternal antibodies that can interfere with infant immune responses, and limited ability of the immature infant immune system to respond to vaccination. A class of antibodies that potently neutralize RSV has recently been identified. These antibodies arise from the chromosomally encoded VH3-21/VL1-40 antibody genes and are unique in that they are structurally pre-configured to bind to and neutralize RSV and do not need to undergo affinity maturation to achieve potent neutralizing activity. A vaccine that can selectively engage B cells capable of producing VH3-21/VL1-40- derived antibodies would hence lead to rapid RSV neutralization following immunization. Here we propose to develop anti-idiotypic monoclonal antibodies (ai-mAbs) that have a high affinity and specificity for B cells expressing re-arranged, unmutated BCRs derived from VH3-21/VL1-40 pairs and use these to develop vaccine immunogens. This unconventional approach is well suited to selectively engage target B cells while at the same time being completely antigenically distinct from RSV F. Importantly since VH3-21/VL1-40 do not require affinity maturation to achieve potent neutralizing activity an ai-mAb-based vaccine could be effective in infants, whose affinity maturation processes are still inefficient. The antigenic disparity between RSV F and ai-mAbs presents additional advantages in the context of infant vaccination, as it should eliminate the ability of maternal antibodies to interfere with the infant humoral response through the masking or disruption of relevant epitopes on RSV F. Moreover, ai-mAbs should eliminate or reduce the risk of vaccine-enhanced disease by not presenting irrelevant RSV F epitopes, which has been attributed to the elicitation of non-neutralizing anti-RSV F antibodies in previous vaccine formulations. Herein we will use complementary approaches to develop and evaluate ai-mAb derived vaccines. If successful, these approaches will provide a crucial proof of concept and clear path for the development of an ai-mAb- derived RSV vaccine for the most vulnerable population.

项目概要/摘要 呼吸道合胞病毒（RSV）是引起下呼吸道感染的常见病原体 导致极端年龄的显着发病率和死亡率。原发性 RSV 感染是造成 约 60,000 名 5 岁以下儿童死亡。针对 RSV 融合蛋白 (F) 是唯一已被证明有效的婴儿 RSV 感染预防性治疗方法。 保护性，但由于成本限制，其广泛使用受到限制。因此，一种可以引起保护作用的疫苗 中和抗体将具有显着的、具有成本效益的全球健康益处。然而， 对婴儿有效的 RSV 亚单位疫苗的开发仍然难以实现。这部分是由于 重组 RSV F 的亚稳态性质，以及婴儿免疫面临的独特挑战 包括预先存在的母体抗体的存在，这些抗体可能会干扰婴儿的免疫反应，以及 不成熟的婴儿免疫系统对疫苗接种的反应能力有限。 最近已经鉴定出一类能够有效中和 RSV 的抗体。这些抗体出现 来自染色体编码的 VH3-21/VL1-40 抗体基因，其独特之处在于它们在结构上 预先配置为结合并中和 RSV，无需经过亲和力成熟即可实现有效效果 中和活性。一种可以选择性地接触能够产生 VH3-21/VL1-40- 的 B 细胞的疫苗 因此，衍生的抗体将导致免疫后快速中和 RSV。在此我们建议 开发对 B 细胞具有高亲和力和特异性的抗独特型单克隆抗体 (ai-mAb) 表达源自 VH3-21/VL1-40 对的重新排列、未突变的 BCR，并使用它们来开发疫苗 免疫原。这种非常规方法非常适合选择性地参与目标 B 细胞 同时在抗原性上与 RSV F 完全不同。重要的是，因为 VH3-21/VL1-40 不需要 亲和力成熟以实现有效的中和活性，基于 ai-mAb 的疫苗可能对婴儿有效， 其亲和力成熟过程仍然效率低下。 RSV F 和 ai-mAb 之间的抗原差异在以下方面呈现出额外的优势： 婴儿疫苗接种，因为它应该消除母体抗体干扰婴儿体液的能力 通过掩蔽或破坏 RSV F 上的相关表位来做出反应。此外，ai-mAb 应该 通过不呈现不相关的 RSV F 表位来消除或降低疫苗增强疾病的风险，这 归因于先前疫苗配方中产生非中和性抗 RSV F 抗体。 在此，我们将使用补充方法来开发和评估 ai-mAb 衍生疫苗。如果成功的话， 这些方法将为 ai-mAb 的开发提供重要的概念验证和明确的路径。 针对最脆弱人群的 RSV 疫苗。