The conserved region of influenza hemagglutinin (HA) stalk (or stem) has gained attention as a potent target for universal influenza vaccines^1,2,3,4,5. Although the HA stalk region is relatively well conserved, the evolutionarily dynamic nature of influenza viruses⁶ raises concerns about the possible emergence of viruses carrying stalk escape mutation(s) under sufficient immune pressure. Here we show that immune pressure on the HA stalk can lead to expansion of escape mutant viruses in study participants challenged with a 2009 H1N1 pandemic influenza virus inoculum containing an A388V polymorphism in the HA stalk (45% wild type and 55% mutant). High level of stalk antibody titers was associated with the selection of the mutant virus both in humans and in vitro. Although the mutant virus showed slightly decreased replication in mice, it was not observed in cell culture, ferrets or human challenge participants. The A388V mutation conferred resistance to some of the potent HA stalk broadly neutralizing monoclonal antibodies (bNAbs). Co-culture of wild-type and mutant viruses in the presence of either a bNAb or human serum resulted in rapid expansion of the mutant. These data shed light on a potential obstacle for the success of HA-stalk-targeting universal influenza vaccines—viral escape from vaccine-induced stalk immunity.

流感血凝素 (HA) 茎（或茎）的保守区域作为通用流感疫苗^1,2,3,4,5的有效靶标而受到关注。尽管 HA 茎区相对保守，但流感病毒的进化动态特性⁶引起人们对在足够的免疫压力下可能出现携带茎逃逸突变的病毒的担忧。在这里，我们表明，HA 茎上的免疫压力可导致研究参与者的逃逸突变病毒扩大，这些参与者受到 2009 年 H1N1 大流行性流感病毒接种物挑战，HA 茎中含有 A388V 多态性（45% 野生型和 55% 突变体）。高水平的茎抗体滴度与人类和体外突变病毒的选择有关。尽管突变病毒在小鼠中的复制略有减少，但在细胞培养物、雪貂或人类挑战参与者中并未观察到。A388V 突变赋予了对一些有效的 HA 茎广泛中和单克隆抗体 (bNAb) 的抗性。在存在 bNAb 或人血清的情况下，将野生型病毒和突变病毒共培养导致突变体的快速扩增。这些数据揭示了靶向 HA 茎的通用流感疫苗成功的潜在障碍——病毒从疫苗诱导的茎免疫中逃逸。