Since 2013, a total of 167 human infections with swine-origin (variant) influenza A viruses of A(H1N1)v, A(H1N2)v, and A(H3N2)v subtypes have been reported in the United States. Analysis of 147 genome sequences revealed that nearly all had S31N substitution, an M2 channel blocker-resistance marker, whereas neuraminidase inhibitor–resistance markers were not found. Two viruses had a polymerase acidic substitution (I38M or E199G) associated with decreased susceptibility to baloxavir, an inhibitor of viral cap-dependent endonuclease (CEN). Using phenotypic assays, we established subtype-specific susceptibility baselines for neuraminidase and CEN inhibitors. When compared with either baseline or CEN-sequence–matched controls, only the I38M substitution decreased baloxavir susceptibility, by 27-fold. Human monoclonal antibodies FI6v3 and CR9114 targeting the hemagglutinin’s stem showed variable (0.03 to >10 µg/mL) neutralizing activity toward variant viruses, even within the same clade. Methodology and interpretation of laboratory data described in this study provide information for risk assessment and decision-making on therapeutic control measures.

自 2013 年以来，美国共报告了 167 例人感染甲型（H1N1）v、甲型（H1N2）v 和甲型（H3N2）v 亚型的猪源（变体）甲型流感病毒。对 147 个基因组序列的分析显示，几乎所有基因组序列都具有 S31N 取代，这是一种 M2 通道阻滞剂-耐药标志物，而未发现神经氨酸酶抑制剂-耐药标志物。两种病毒具有聚合酶酸性取代 （I38M 或 E199G），与对病毒帽依赖性核酸内切酶 （CEN） 抑制剂 baloxavir 的易感性降低有关。使用表型分析，我们建立了神经氨酸酶和 CEN 抑制剂的亚型特异性易感基线。与基线或 CEN 序列匹配的对照相比，仅 I38M 替代使 baloxavir 敏感性降低了 27 倍。靶向血凝素茎的人单克隆抗体 FI6v3 和 CR9114 对变异病毒显示出可变的 （0.03 至 >10 μg/mL） 中和活性，即使在同一分支中也是如此。本研究中描述的实验室数据的方法和解释为风险评估和治疗控制措施的决策提供了信息。