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.

项目摘要/摘要 呼吸综合病毒（RSV）是一种常见的病原体，引起下呼吸道感染 导致年龄极端的发病率和死亡率明显。原发性RSV感染负责 5岁以下儿童死亡约60,000人。单克隆中和抗体的被动转移针对 RSV融合蛋白（F）是婴儿RSV感染的唯一预防性治疗 保护性，但由于成本限制，其广泛使用受到限制。因此，一种可能引起保护性的疫苗 中和抗体将具有重要的，具有成本效益的全球健康益处。但是， 在婴儿中有效的RSV亚基疫苗的开发仍然难以捉摸。这是部分原因 重组RSV F的亚稳性，以及婴儿免疫面临的独特挑战 包括存在可能干扰婴儿免疫反应的孕产妇抗体以及 未成熟婴儿免疫系统对疫苗接种的反应能力有限。 最近已经确定了有效中和RSV的一类抗体。这些抗体出现 从染色体编码的VH3-21/VL1-40抗体基因中，它们是独特的，因为它们在结构上是 预先配置以结合并中和RSV，并且不需要经历亲和力成熟即可实现有效 中和活性。可以选择性地接合能够产生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RSV中和。在这里我们建议 开发具有高亲和力和特异性的抗IDIOTYPIC单克隆抗体（AI-MAB） 表达源自VH3-21/VL1-40对的重新安排的未分离的BCR，并使用它们开发疫苗 免疫原子。这种非常规的方法非常适合选择性地与目标B细胞接合 同一时间与RSV F完全不同。重要的是，由于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 婴儿疫苗接种，因为它应消除母体抗体干扰婴儿体液的能力 通过在RSV F上掩盖或破坏相关表位的响应。此外，AI-MAB应该 通过不提出无关的RSV f表位来消除或降低疫苗增强疾病的风险， 已归因于先前疫苗制剂中非中和抗RSV F抗体的诱导。 在此，我们将使用互补方法开发和评估AI-MAB衍生的疫苗。如果成功， 这些方法将为AI-mab-的发展提供至关重要的概念证明和清晰的道路 针对最脆弱的人群派生的RSV疫苗。