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

项目总结/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 导致极端年龄段的发病率和死亡率很高。原发性RSV感染导致 5岁以下儿童死亡约60，000人。被动转移单克隆中和抗体，其靶向 RSV融合蛋白（F）是唯一的预防性治疗婴儿RSV感染，已被证明是 保护性，但由于成本限制，其广泛使用受到限制。因此，一种疫苗，可以引发保护性 中和抗体将具有显著的、成本有效的全球健康益处。但 在婴儿中有效的RSV亚单位疫苗的开发仍然是难以捉摸的。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， 包括存在可干扰婴儿免疫反应的预先存在的母体抗体，以及 不成熟的婴儿免疫系统对疫苗接种的反应能力有限。 最近已经鉴定了一类有效中和RSV的抗体。这些抗体产生于 来自染色体编码的VH 3 -21/VL 1 -40抗体基因，其独特之处在于它们在结构上 预配置为结合并中和RSV，并且不需要经历亲和力成熟以实现有效的免疫应答。 中和活性一种疫苗，其可选择性地接合能够产生VH 3 -21/VL 1 -40的B细胞。 因此，衍生的抗体将导致免疫后的快速RSV中和。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） 表达来自VH 3 -21/VL 1 -40对的重排的未突变的BCR，并使用这些BCR开发疫苗 免疫原这种非常规的方法非常适合于选择性地接合靶B细胞，同时在靶向细胞中进行免疫调节。 同时与RSV F在抗原性上完全不同。重要的是，由于VH 3 -21/VL 1 -40不需要 亲和力成熟以获得有效的中和活性基于α 1-mAb的疫苗在婴儿中可能是有效的， 其亲和力成熟过程仍然是低效的。 RSV F和ai-mAb之间的抗原差异在RSV感染的背景下呈现出额外的优势。 婴儿接种疫苗，因为它应该消除母体抗体干扰婴儿体液免疫的能力。 通过掩蔽或破坏RSV F上的相关表位来产生应答。此外，ai-mAbs应 通过不呈递不相关的RSV F表位，消除或降低疫苗增强疾病的风险， 已归因于在先前的疫苗制剂中引发非中和性抗RSV F抗体。 在此，我们将使用互补方法来开发和评估ai-mAb衍生的疫苗。如果成功， 这些方法将为ai-mAb的开发提供关键的概念验证和明确的途径， 为最脆弱的人群提供RSV衍生疫苗。

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.