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

项目摘要/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 在极端年龄导致严重的发病率和死亡率。原发呼吸道合胞病毒感染是 5岁以下儿童死亡约60,000人。被动转移针对 RSV融合蛋白(F)是唯一已被证明是婴儿RSV感染的预防性治疗 具有保护性，但由于成本限制，其广泛使用受到限制。因此，一种可能引发保护性的疫苗 中和抗体将对全球健康产生显著的、具有成本效益的好处。然而， 对婴儿有效的RSV亚单位疫苗的开发仍然难以捉摸。这部分是由于 重组RSV F的亚稳性，以及婴儿免疫面临的独特挑战 包括预先存在的母体抗体可能干扰婴儿的免疫反应，以及 未成熟的婴儿免疫系统对接种疫苗的反应能力有限。 最近发现了一类能中和呼吸道合胞病毒的抗体。这些抗体会产生 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的结构 预先配置为与RSV结合并中和RSV，不需要经历亲和力成熟即可实现有效 中和活性。一种可以选择性地结合能够产生VH3-21/VL1-40的B细胞的疫苗- 因此，衍生抗体将导致免疫后快速中和RSV。在此，我们建议 研制对B细胞具有高亲和力和特异性的抗独特型单抗 表达VH3-21/VL1-40重组未突变BCR并用于疫苗研制 免疫原。这种非常规的方法非常适合于选择性地接触目标B细胞 同时与RSV F在抗原性上完全不同。重要的是，因为VH3-21/VL1-40不需要 亲和力成熟以获得强大的中和活性基于AI-mAb的疫苗可能在婴儿中有效， 其亲和力成熟过程仍然效率低下。 在RSV F和AI-mAb之间的抗原性差异在以下背景下表现出额外的优势 婴儿接种疫苗，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上的相关表位来应答。 通过不呈现不相关的RSV F表位来消除或降低疫苗增强型疾病的风险，这 被归因于在以前的疫苗配方中诱导了非中和的抗RSV F抗体。 在这里，我们将使用互补的方法来开发和评估AI-mAb衍生疫苗。如果成功， 这些方法将为AI-mAb的发展提供关键的概念证明和明确的途径。 为最脆弱的人群研制RSV疫苗。

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.