Human seasonal influenza under COVID-19 and the potential consequences of influenza lineage elimination

Abstract

Annual epidemics of seasonal influenza cause hundreds of thousands of deaths, high levels of morbidity, and substantial economic loss. Yet, global influenza circulation has been heavily suppressed by public health measures and travel restrictions since the onset of the COVID-19 pandemic. Notably, the influenza B/Yamagata lineage has not been conclusively detected since April 2020, and A(H3N2), A(H1N1), and B/Victoria viruses have since circulated with considerably less genetic diversity. Travel restrictions have largely confined regional outbreaks of A(H3N2) to South and Southeast Asia, B/Victoria to China, and A(H1N1) to West Africa. Seasonal influenza transmission lineages continue to perish globally, except in these select hotspots, which will likely seed future epidemics. Waning population immunity and sporadic case detection will further challenge influenza vaccine strain selection and epidemic control. We offer a perspective on the potential short- and long-term evolutionary dynamics of seasonal influenza and discuss potential consequences and mitigation strategies as global travel gradually returns to pre-pandemic levels.

Fig. 1. Streamgraph showing temporal changes in influenza lineage circulation.

Lineage prevalence was estimated using sample collection dates of all sequences submitted to the Global Initiative for Sharing All Influenza Data (GISAID) from December 2018 to August 2021. Lineages detected since April 2020 are labeled in black; lineages that have not been detected since April 2020 are labeled in gray.

Fig. 2. Virological surveillance of seasonal influenza viruses.

A Time series comparing FluNet data on seasonal influenza activity in the Northern and Southern Hemispheres from 2015 to July 2021, with the COVID-19 pandemic shaded in gray. Stacked bar chart (left-hand y-axis) represents the number of influenza-positive cases per week colored by subtype. Black trend-line (right-hand y-axis) shows the number of specimens tested per week. B Magnified view of the gray-shaded bar charts in A showing influenza-positive specimens from April 2020 to July 2021. Note: y-axis scales differ in each panel.

Fig. 3. Comparison of seasonal influenza virus evolution before and since COVID-19 emergence.

A Evolutionary relationships and divergence times of HA genes inferred using maximum likelihood (see Online Methods section). Tips are colored by WHO clade designations. Phylogenetic trees of major clades that continued to circulate during 2020/2021 (marked in A) are shown in Supplementary Figs. 1–4, including A(H3N2) clades A1b/94N and A1b/186D; A(H1N1) clade 6b1.A/187A lineages in West Africa; and B/Victoria lineages from several regions around the world. B Timeline of recently circulating seasonal influenza virus HA clades from mean estimated divergence time to most recent sequence. Time since the onset of the COVID-19 pandemic is shaded in gray.

Fig. 4. Geographic distribution of influenza HA sequences before (left) and after (right) COVID-19 emergence.

From April 2020 to July 2021, A(H3N2) (590 sequences from 32 countries), A(H1N1) (254 sequences from 18 countries), and B/Victoria (834 sequences from 34 countries) were available for analysis. In comparison to the 16-month period before April 2020 (December 2018 to March 2020), there was a reduction in sequences of 97% for A(H3N2), 99% for A(H1N1), 92% for B/Victoria, and 100% for B/Yamagata. Last updated on 24 August 2021; for an interactive visualization of current seasonal influenza circulation, we refer the reader to the Nextstrain platform.

Fig. 5. Cluster size and duration of influenza transmission lineages that originated before the COVID-19 pandemic.

Each colored bar represents a monophyletic transmission lineage inferred from maximum-likelihood phylogenetic analyses of seasonal influenza HA gene sequences in GISAID (see Online Methods section). Labels indicate sequence counts per transmission lineage.

Fig. 6. Historical circulation of influenza viruses in the last century.

Dots indicate emergence of pandemic strains that replaced previously circulating influenza viruses.