Epitope focusing by molecular grafting of subdominant epitopes to achieve a universal-influenza vaccine

项目摘要 抗原变异和病毒进化阻碍了传统的流感疫苗接种策略。这个 研制“通用流感疫苗”是当前流感研究的目标之一。概念的定义 “通用”应包括一种能够在流通中的h1和h3内诱导广泛免疫的疫苗。 亚型，b)跨亚型(异亚型)和c)大流行前。循序渐进的方法 实现这些标准是本提案的目标。由一种普遍的 流感疫苗很可能来自引起针对保守区的体液反应的免疫原 病毒血凝素(HA)上的表位，如受体结合部位(RBS)和“茎”。这个 这项建议的重点是前者。RBS使用保守的“核心”来协调唾液酸 残留物和周围的外围限制了保护性反应的范围。我们将使用结构- 引导表面处理将循环H1和H3的RBS移植到外来的、非循环的HAS上。 这些“受体”HAS将作为分子支架呈现保守的H1和H3RBS核心， 但有一个异源的外围。这种方法将迫使引发的反应保持核心联系， 同时适应外国外围国家，从而扩大反应范围。我们将设计嵌合体， 二硫化物稳定的，只有头部的三聚体，呈现接枝的H1和H3 RBS。三聚化将 隐藏单体上存在的新表位，外来受体将移除表位 以有免疫经验的个体的菌株特异性反应为靶点。设计的免疫原 将进行体内疗效测试。我们的策略将为全球流感提供候选免疫原 疫苗，通过利用保守的RBS的免疫原性。它们也将适用于其他 快速进化的病原体以及种群中先前存在的免疫必须 这是疫苗设计中的一个重要因素。

Project Summary Antigenic variation and viral evolution have thwarted traditional influenza vaccination strategies. The development of a “universal influenza vaccine” is a goal of current influenza research. The definition of “universal” should include a vaccine that can induce broad immunity a) within circulating H1 and H3 subtypes, b) across subtypes (heterosubtypic) and c) pre-pandemic. A stepwise approach to accomplishing these criteria are goals of this proposal. The broad protection afforded by a universal influenza vaccine will likely come from immunogens that elicit humoral responses targeting conserved epitopes on the viral hemagglutinin (HA), such as the receptor binding site (RBS) and the “stem”. The focus of this proposal is on the former. The RBS coordinates sialic acid using conserved “core” residues and the surrounding periphery limits the range of protective responses. We will use structure- guided resurfacing to graft the RBS from circulating H1 and H3 HAs onto exotic, non-circulating HAs. These “acceptor” HAs will serve as molecular scaffolds to present the conserved H1 and H3 RBS core, but with a heterologous periphery. This approach will force elicited responses to maintain core contacts, while adapting to the foreign periphery and thus broadening the response. We will design chimeric, disulfide-stabilized, head-only trimers that present the grafted H1 and H3 RBS. Trimerization will conceal neo-epitopes present on monomers, and the exotic, acceptor HAs will remove epitopes targeted by strain-specific responses in immune-experienced individuals. The designed immunogens will be tested for in vivo efficacy. Our strategies will provide candidate immunogens for a universal flu vaccine, by exploiting the immunogenicity of the conserved RBS. They will also be applicable to other rapidly evolving pathogens and to contexts in which preexisting immunity within the population must be factored into vaccine design.