Atypical Influenza A(H3N2) Activity Patterns in Germany, 2021-2023, and Characterization of Newly Emerged Virus Clades

Abstract

The first waves of the COVID-19 pandemic were accompanied by an unprecedented decrease of influenza activity which persisted throughout the 2020/21 and 2021/22 winter seasons. Here, we report on the unusual influenza circulation patterns that followed in the year 2022, which was dominated throughout by A(H3N2) influenza viruses. After a delayed spring wave in 2022, A(H3N2) influenza viruses circulated at low levels throughout the summer and rose to a prominent, prematurely-timed fall/winter wave peaking in December, with highest positivity rates observed in 10-12-years old children. This winter wave ended abruptly with the national school holidays, when positivity rates decreased sharply not only in children but also in other age groups. Genetic analysis of influenza virus hemagglutinin (HA) showed cocirculation of 10 A(H3N2) clades, of which three (2a.1b, 2a.3a.1, and 2b) became dominant in late 2022. All A(H3N2) viruses, including those assigned to the new clades, displayed high titers in HA inhibition tests with postinfection ferret antiserum raised against the A(H3N2) vaccine strains A/Cambodia/e0826360/2020 and A/Darwin/9/2021. All viruses were susceptible to neuraminidase inhibitors and the polymerase inhibitor baloxavir marboxil, but carried the M2-S31N substitution conferring adamantane resistance. Our findings shed light on disturbed seasonality of A(H3N2) circulation in the post-COVID-19 era.

Keywords: antigenic analysis; influenza, surveillance; inhibition test; phylogenetic analysis; resistance; respiratory infection; vaccine; virological analysis.

Figure 1

Influenza A(H3N2) detections in the German ARI sentinel, 2021/22–2022/23. Absolute numbers of sentinel samples testing positive for influenza A(H3N2) (red bars) in comparison to total sentinel samples tested (shadow bars) per week. The reporting period for each influenza season starts in Week 40 and extends through Week 39 of the following year; the X‐axis is labeled accordingly.

Figure 2

Circulation of influenza A(H3N2) viruses from 2009/10 to 2022/23 in the German ARE sentinel. Shown are the PR of influenza A(H3N2) per calendar week. The reporting period for each influenza season starts in Week 40 and extends through Week 39 of the following year; the X‐axis is labeled accordingly.

Figure 3

Influenza A(H1N1pdm09) circulation patterns in 2008/09–2009/10 compared with those of influenza A(H3N2) in 2021/22–2022/23. Shown are the percentages of influenza A(H1N1pdm09) and A(H3N2) positive sentinel samples, respectively, per calendar week. The reporting period for each influenza season starts in Week 40 and extends through Week 39 of the following year.

Figure 4

Age distribution of influenza A(H3N2) sentinel cases in the 2022/23 season. Color codes indicate influenza A(H3N2) PR of ARI sentinel patients per age group (Y‐axis) and week (X‐axis). This figure corresponds to the 12th panel shown in Figure S2, which provides numerical values for each heatmap cell.

Figure 5

Age distribution of polymerase chain reaction‐confirmed influenza sentinel cases in relevant preceding influenza seasons. (A) A(H3N2), 2011/12, 2014/15, and 2016/17. (B) A(H3N2), 2019/20 influenza season before the COVID‐19 pandemic and A(H3N2), 2021/22 after COVID‐19‐associated restrictions ceased. (C) A(H1N1pdm09), 2009/10. Color codes indicate influenza‐positive percentages of ARI sentinel patients per age group (Y‐axis) and week (X‐axis). A and B correspond to panels 2, 5, 7, and 10, 12 of Figure S2, respectively.

Figure 6

Phylogenetic analysis of the gene coding for hemagglutinin of A(H3N2) influenza viruses circulating in Germany, 2021/22–2022/23. Selected A(H3N2) viruses collected within the German ARI sentinel during the 2021/22 (n = 34, black) and 2022/23 (n = 40, blue) seasons are shown with ECDC/WHO reference viruses (in italics) and clades according to www.gisaid.org. Clade‐characteristic deduced amino acid substitutions within HA1, HA2, and the signal peptide (SigPep) are displayed at the root of the respective branch. The analysis was performed with Mega (NJ, K2, bootstrap test with 1000 replicates, partial deletion: site coverage cutoff 5%).

Figure 7

Antigenic analysis of A(H3N2) influenza viruses circulating in Germany 2021/22 and 2022/23. Reactivity of A(H3N2) influenza viruses with antisera raised against the vaccine strains; red circles: reactivity of vaccine viruses; blue circles: reactivity of 699 influenza A(H3N2) viruses isolated in seasons 2021/22 and 2022/23, based on the month of primary sample collection. Shown is for each month the mean ± SEM of the log₂‐transformed reciprocal titer values.

Figure 8

Seroprevalences against A(H3N2) from the move‐in area of Berlin in August 2024.