Current seasonal influenza virus vaccines only provide limited, short-lived protection, and antigenic drift in the hemagglutinin surface glycoprotein necessitates their annual re-formulation and re-administration. To overcome these limitations, universal vaccine strategies that aim at eliciting broadly protective antibodies to conserved epitopes of the hemagglutinin show promise for protecting against diverse and drifted influenza viruses. Here a vaccination strategy that focuses antibody responses to conserved epitopes of the H3 hemagglutinin is described. The approach is based on antigenic silencing of the immunodominant major antigenic sites of an H3 protein from 2014 by replacing them with corresponding sequences of exotic avian hemagglutinins, yielding “mosaic” hemagglutinins. In mice, vaccination with inactivated viruses expressing mosaic hemagglutinins induced highly cross-reactive antibodies against the H3 stalk domain that elicited Fc-mediated effector functions in vitro. In addition, the mosaic viruses elicited head-specific antibodies with neutralizing and hemagglutination-inhibiting activity against recent H3N2 viruses in vitro. Immune sera protected mice from heterologous challenge with viruses carrying H3 proteins from 1968 and 1982, whereas immune sera generated with a seasonal vaccine did not protect. Consequently, the mosaic vaccination approach provides a promising avenue toward a universal influenza virus vaccine.

当前的季节性流感病毒疫苗仅提供有限的，短暂的保护，并且血凝素表面糖蛋白的抗原性漂移使得它们需要每年重新配制和重新施用。为了克服这些局限性，旨在引发针对血凝素保守表位的广泛保护性抗体的通用疫苗策略显示出有望预防多种多样且漂移的流感病毒。在此描述了一种疫苗接种策略，该策略将抗体应答集中在H3血凝素的保守表位上。该方法基于2014年以来H3蛋白的免疫主要主要抗原性位点的抗原沉默，方法是将它们替换为外来禽血凝素的相应序列，产生“马赛克”血凝素。在老鼠中 用表达花椰菜血凝素的灭活病毒接种疫苗诱导了针对H3茎结构域的高度交叉反应抗体，该抗体在体外引起Fc介导的效应子功能。此外，花叶病毒在体外引发了具有针对中和H2N2病毒抑制作用的具有中和和血凝抑制活性的头部特异性抗体。从1968年到1982年，免疫血清可以保护小鼠免受携带H3蛋白的病毒的异源攻击，而季节性疫苗产生的免疫血清则不能保护小鼠。因此，镶嵌疫苗接种方法为通用流感病毒疫苗提供了有希望的途径。花叶病毒在体外引发了针对中性和血凝抑制活性的头部特异性抗体。从1968年到1982年，免疫血清可以保护小鼠免受携带H3蛋白的病毒的异源攻击，而季节性疫苗产生的免疫血清则不能保护小鼠。因此，镶嵌疫苗接种方法为通用流感病毒疫苗提供了有希望的途径。花叶病毒在体外引发了针对中性和血凝抑制活性的头部特异性抗体。从1968年到1982年，免疫血清可以保护小鼠免受携带H3蛋白的病毒的异源攻击，而季节性疫苗产生的免疫血清则不能保护小鼠。因此，镶嵌疫苗接种方法为通用流感病毒疫苗提供了有希望的途径。