Immunity to influenza viruses can be long-lived, but reinfections with antigenically distinct viral strains and subtypes are common. Reinfections can boost antibody responses against viral strains first encountered in childhood through a process termed “original antigenic sin.” It is unknown how initial childhood exposures affect the induction of antibodies against the hemagglutinin (HA) stalk domain of influenza viruses. This is an important consideration since broadly reactive HA stalk antibodies can protect against infection, and universal vaccine platforms are being developed to induce these antibodies. Here we show that experimentally infected ferrets and naturally infected humans establish strong “immunological imprints” against HA stalk antigens first encountered during primary influenza virus infections. We found that HA stalk antibodies are surprisingly boosted upon subsequent infections with antigenically distinct influenza A virus subtypes. Paradoxically, these heterosubtypic-boosted HA stalk antibodies do not bind efficiently to the boosting influenza virus strain. Our results demonstrate that an individual’s HA stalk antibody response is dependent on the specific subtype of influenza virus that they first encounter early in life. We propose that humans are susceptible to heterosubtypic influenza virus infections later in life since these viruses boost HA stalk antibodies that do not bind efficiently to the boosting antigen.

流感病毒的免疫力可以长期存在，但是抗原性截然不同的病毒株和亚型的再感染很常见。再感染可以通过称为“原始抗原性罪过”的过程来增强针对童年时期首次遇到的病毒株的抗体反应。尚不清楚童年初期接触如何影响针对流感病毒血凝素（HA）茎结构域的抗体的诱导。这是一个重要的考虑因素，因为具有广泛反应性的HA茎杆抗体可以防止感染，并且正在开发通用疫苗平台来诱导这些抗体。在这里，我们表明，实验感染的雪貂和自然感染的人类对原发性流感病毒感染期间首次遇到的HA杆抗原形成了强大的“免疫印迹”。我们发现，HA茎杆抗体在随后感染抗原性不同的甲型流感病毒亚型后会令人惊讶地得到增强。矛盾的是，这些异亚型增强的HA茎抗体不能有效地与加强型流感病毒株结合。我们的结果表明，个人的HA茎抗体反应取决于他们生命早期首次遇到的流感病毒的特定亚型。我们建议人类在生命的晚些时候易受异型流感病毒感染，因为这些病毒会增强不能有效结合增强抗原的HA秸秆抗体。这些异亚型增强的HA茎杆抗体无法有效地与加强型流感病毒株结合。我们的结果表明，个人的HA茎抗体反应取决于他们生命早期首次遇到的流感病毒的特定亚型。我们建议人类在生命的晚些时候易受异型流感病毒感染，因为这些病毒会增强不能有效结合增强抗原的HA秸秆抗体。这些异亚型增强的HA茎杆抗体无法有效地与加强型流感病毒株结合。我们的结果表明，个人的HA茎抗体反应取决于他们生命早期首次遇到的流感病毒的特定亚型。我们建议人类在生命的晚些时候易受异型流感病毒感染，因为这些病毒会增强无法有效结合增强抗原的HA茎抗体。