Background: Multiple clades of H1N1 influenza A viruses (IAVs) circulated during the 2019-2020 season. Here, we completed serological assays to determine the specificities of serum antibodies from humans infected with viruses from different H1N1 clades during the 2019-2020 season.

Methods: We collected nasopharyngeal (NP) swabs and serum from influenza-infected individuals who received care within the University of Pennsylvania Health System (UPHS). We sequenced H1N1 viruses from NP swabs and completed hemagglutination inhibition assays using serum and viruses from different H1N1 clades that we identified from NP swabs. We also collected serum samples from influenza B virus (IBV)-infected patients at UPHS, allowing us to examine antibody titers associated with H1N1 versus IBV infection.

Results: Sequence analyses revealed that most IAV-infected individuals were infected with clade 6B.1A.5a.1 and 6B.1A.5a.2 H1N1 viruses that possessed substitutions at major antigenic sites of hemagglutinin. We found that antibodies from both H1N1- and IBV-infected individuals recognized the 6B.1A.1 H1N1 vaccine component of the 2019-2020 vaccine more efficiently compared to the circulating 6B.1A.5a.1 and 6B.1A.5a.2 H1N1 viruses. Patients infected with 6B.1A.5a.2 clade H1N1 viruses had significantly higher titers against the vaccine strain virus, suggesting that the 6B.1A.5a.2 virus evaded antibodies elicited from previous vaccinations or infections.

Conclusions: These studies suggest that most individuals, irrespective of whether they were infected with H1N1 virus or IBV during the 2019-2020 season, possessed antibodies that poorly reacted to circulating H1N1 strains.