Background Influenza virus remains a threat to human health, but gaps remain in our knowledge of the humoral correlates of protection against influenza virus A/H3N2, limiting our ability to generate effective, broadly protective vaccines. The role of antibodies against the hemagglutinin (HA) stalk, a highly conserved but immunologically sub-dominant region, has not been established for influenza virus A/H3N2. Methods Household transmission studies were conducted in Managua, Nicaragua across three influenza seasons. Household contacts were tested for influenza virus infection using RT-PCR. We compared pre-existing antibody levels against full-length hemagglutinin (FLHA), HA stalk, and neuraminidase (NA) measured by enzyme-linked immunosorbent assay (ELISA), along with HA inhibition assay (HAI) titers, between infected and uninfected participants. Results A total of 899 individuals participated in household activation, with 329 infections occurring. A four-fold increase in initial HA stalk titers was independently associated with an 18% decrease in the risk of infection (OR=0.82, 95%CI 0.68-0.98, p=0.04). In adults, anti-HA stalk antibodies were independently associated with protection (OR=0.72, 95%CI 0.54-0.95, p=0.02). However, in 0-14-year-olds, anti-NA antibodies (OR=0.67, 95%CI 0.53-0.85, p<0.01) were associated with protection against infection, but anti-HA stalk antibodies were not. Conclusions The HA stalk is an independent correlate of protection against A/H3N2 infection, though this association is age dependent. Our results support the continued exploration of the HA stalk as a target for broadly protective influenza vaccines but suggest that the relative benefits may depend on age and influenza virus exposure history.

中文翻译：

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预防甲型 H3N2 流感病毒感染的体液相关性

背景流感病毒仍然对人类健康构成威胁，但我们对 A/H3N2 流感病毒防护的体液相关性的了解仍然存在差距，限制了我们生产有效的、具有广泛保护性的疫苗的能力。针对 A/H3N2 流感病毒的血凝素 (HA) 茎（高度保守但免疫学次优势区域）的抗体的作用尚未确定。方法 在尼加拉瓜马那瓜三个流感季节进行了家庭传播研究。使用 RT-PCR 对家庭接触者进行流感病毒感染检测。我们比较了感染者和未感染者之间通过酶联免疫吸附测定 (ELISA) 测量的全长血凝素 (FLHA)、HA 茎和神经氨酸酶 (NA) 的现有抗体水平以及 HA 抑制测定 (HAI) 滴度。结果 共有899人参与家庭激活，发生感染329例。初始 HA 茎滴度增加四倍与感染风险降低 18% 独立相关（OR=0.82，95%CI 0.68-0.98，p=0.04）。在成人中，抗 HA 茎抗体与保护独立相关（OR=0.72，95%CI 0.54-0.95，p=0.02）。然而，在0-14岁儿童中，抗NA抗体(OR＝0.67，95％CI 0.53-0.85，p＜0.01)与预防感染相关，但抗HA茎抗体则不然。结论 HA 茎是 A/H3N2 感染保护的独立相关性，尽管这种相关性具有年龄依赖性。我们的结果支持继续探索 HA 茎作为广泛保护性流感疫苗的目标，但表明相对益处可能取决于年龄和流感病毒暴露史。