Figure 3. Influenza A(H3N2) antigenic drift correlates with larger, more intense annual epidemics.

A(H3N2) epidemic size, peak incidence, transmissibility (effective reproduction number, $R_t$), and epidemic intensity increase with antigenic drift, measured by (A) hemagglutinin (H3) epitope distance, (B) neuraminidase (N2) epitope distance, and (C) hemagglutination inhibition (HI) log₂ titer distance. Seasonal antigenic drift is the mean titer distance or epitope distance between viruses circulating in the current season ${\displaystyle t}$ and viruses circulating in the prior season (${\displaystyle t}$ – 1) or two prior seasons ago (${\displaystyle t}$ – 2). Distances are scaled to aid in direct comparison of evolutionary indicators. Point color indicates the dominant influenza A virus (IAV) subtype based on CDC influenza season summary reports (red: A(H3N2), blue: A(H1N1), purple: A(H1N1)pdm09, orange: A(H3N2)/A(H1N1)pdm09 co-dominant), and vertical bars are 95% confidence intervals of regional estimates (pre-2009 seasons: 9 regions; post-2009 seasons: 10 regions). Seasonal mean A(H3N2) epidemic metric values were fit as a function of antigenic or genetic distance using LMs (epidemic size, peak incidence), Gaussian GLMs (effective $R_t$: inverse link), or Beta GLMs (epidemic intensity: logit link) with 1000 bootstrap resamples. In each plot, the black dashed line represents the mean regression fit, and the gray shaded band shows the 95% confidence interval, based on 1000 bootstrap resamples. The R² and associated p-value from the mean regression fit are in the top left section of each plot.

Figure 3—figure supplement 1. Univariate correlations between influenza A(H3N2) evolutionary indictors and epidemic impact.

Mean Spearman’s rank correlation coefficients, 95% confidence intervals of correlation coefficients, and corresponding p-values of bootstrapped (N=1000) evolutionary indicators (rows) and epidemic metrics (columns). Point color indicates the strength and direction of the association, from dark red (strong positive correlation) to dark blue (strong negative correlation), and stars indicate statistical significance (* p<0.05, ** p<0.01, *** p<0.001). Abbreviations: ${\displaystyle t}$ – 1, one-season lag; ${\displaystyle t}$ – 2, two-season lag; RBS, receptor binding site; HI, hemagglutination inhibition; s.d., standard deviation; LBI, local branching index.

Figure 3—figure supplement 2. Excess influenza A(H3N2) mortality increases with H3 and N2 epitope distance, but correlations are not statistically significant.

Relationships between seasonal excess influenza A(H3N2) mortality and epitope distance are organized by gene segment and age group: (A) H3 epitope distance and all age groups, (B) H3 epitope distance and individuals aged ≥65 years, (C) N2 epitope distance and all age groups, and (D) N2 epitope distance and individuals aged ≥65 years. The number of excess influenza deaths attributable to A(H3N2) (per 100,000 people) were estimated from a seasonal regression model fit to weekly pneumonia and influenza-coded deaths in the United States (Hansen et al., 2022). Seasonal epitope distance is the mean distance between viruses circulating in the current season ${\displaystyle t}$ and viruses circulating in the prior season (${\displaystyle t}$ – 1) or two prior seasons ago (${\displaystyle t}$ – 2). Distances are scaled to aid in direct comparison of evolutionary indicators. Point color indicates the dominant influenza A subtype based on CDC influenza season summary reports (red: A(H3N2), blue: A(H1N1), purple: A(H1N1)pdm09, orange: A(H3N2)/A(H1N1)pdm09 co-dominant), and vertical bars are 95% confidence intervals of excess mortality model estimates. Seasonal national excess mortality estimates were fit as a function of H3 or N2 epitope distance using Gaussian GLMs (log link) with 1000 bootstrap resamples. In each plot, the black dashed line represents the mean regression fit, and the gray shaded band shows the 95% confidence interval, based on 1000 bootstrap resamples. The R² and associated p-value from the mean regression fit are in the top left section of each plot.

Figure 3—figure supplement 3. Low seasonal diversity in the clade growth rates of circulating A(H3N2) viruses, as measured by the standard deviation of local branching index values, correlates with higher transmissibility and greater epidemic intensity.

A(H3N2) effective $R_t$ and epidemic intensity negatively correlate with the seasonal diversity of local branching index (LBI) values among circulating A(H3N2) lineages in the current season, measured by the standard deviation (s.d.) of (A) H3 LBI values, and (B) N2 LBI values. LBI values are scaled to aid in direct comparisons of H3 and N2 s.d. LBI values. Point color indicates the dominant influenza A subtype based on CDC influenza season summary reports (red: A(H3N2), blue: A(H1N1), purple: A(H1N1)pdm09, orange: A(H3N2)/A(H1N1)pdm09 co-dominant), and vertical bars are 95% confidence intervals of regional estimates (pre-2009 seasons: 9 regions; post-2009 seasons: 10 regions). Seasonal mean A(H3N2) epidemic metric values were fit as a function of H3 or N2 LBI diversity using Gaussian GLMs (effective $R_t$: inverse link) or Beta GLMs (epidemic intensity: logit link) with 1000 bootstrap resamples. In each plot, the black dashed line represents the mean regression fit, and the gray shaded band shows the 95% confidence interval, based on 1000 bootstrap resamples. The R² and associated p-value from the mean regression fit are in the top right section of each plot.

Figure 3—figure supplement 4. Low seasonal diversity in the clade growth rates of circulating A(H3N2) viruses, as measured by the Shannon diversity of local branching index values, correlates with higher transmissibility and greater epidemic intensity.

A(H3N2) effective $R_t$ and epidemic intensity negatively correlate with the seasonal diversity of local branching index (LBI) values among circulating A(H3N2) lineages in the current season, measured by the Shannon diversity of (A) H3 LBI values, and (B) N2 LBI values. LBI values are scaled to aid in direct comparisons of H3 and N2 LBI diversity values. Point color indicates the dominant influenza A subtype based on CDC influenza season summary reports (red: A(H3N2), blue: A(H1N1), purple: A(H1N1)pdm09, orange: A(H3N2)/A(H1N1)pdm09 co-dominant), and vertical bars are 95% confidence intervals of regional estimates (pre-2009 seasons: 9 regions; post-2009 seasons: 10 regions). Seasonal mean A(H3N2) epidemic metric values were fit as a function of H3 or N2 LBI diversity using Gaussian GLMs (effective $R_t$: inverse link) or Beta GLMs (epidemic intensity: logit link) with 1000 bootstrap resamples. In each plot, the black dashed line represents the mean regression fit, and the gray shaded band shows the 95% confidence interval, based on 1000 bootstrap resamples. The R² and associated p-value from the mean regression fit are in the top right section of each plot.