Distinct evolution patterns of influenza viruses and implications for vaccine development

Influenza A (H5N1), particularly the clade 2.3.4.4b, caused a panzootic outbreak starting in 2022, resulting in 40 human infections from January 2022 to September 2024. Among these cases, 15 have been confirmed to be of the clade 2.3.4.4b. Despite the availability of three FDA-approved A(H5N1) vaccines, these vaccines, based on earlier strains of other clades, have shown reduced hemagglutination inhibition (HAI) titers against clade 2.3.4.4b due to antigenic drift.1 In 2023, the EMA approved a vaccine containing an A(H5N8) strain of clade 2.3.4.4b. However, a recent study reported a decrease in HAI titers of serum induced by this strain against recent 2.3.4.4b strains.1 These findings highlight the urgent need for developing an effective vaccine.

Distinct evolution patterns of influenza viruses

Monitoring antigenic evolution is crucial to mitigate the impact of antigenic drift on future vaccine development (Figures 1A and 1B). The antigenic maps of A(H1N1) and A(H3N2) (Figures 1C and 1D) show a unidirectional evolution with multiple clusters of strains over time, indicating a punctuated antigenic evolution driven by significant alterations in the hemagglutinin (HA) protein. This evolution trajectory is reflected in their “ladder-like” phylogenetic trees, resulting from strong immune selection of seasonal influenza viruses.2 Dominant strains in one season can generate immune selection against circulating strains in humans, leading to the emergence of immune escape-driven “winner” strains in the next season, creating a ladder-like evolutionary tree and a punctuated antigenic trajectory. Thus, it is theoretically possible to select well-matched vaccine strains when a new ladder of strains appears in the phylogenetic tree or a new punctuated strain emerges on the antigenic map.