A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine

Abstract

The effectiveness of the annual influenza vaccine has declined in recent years, especially for the H3N2 component, and is a concern for global public health. A major cause for this lack in effectiveness has been attributed to the egg-based vaccine production process. Substitutions on the hemagglutinin glycoprotein (HA) often arise during virus passaging that change its antigenicity and hence vaccine effectiveness. Here, we characterize the effect of a prevalent substitution, L194P, in egg-passaged H3N2 viruses. X-ray structural analysis reveals that this substitution surprisingly increases the mobility of the 190-helix and neighboring regions in antigenic site B, which forms one side of the receptor binding site (RBS) and is immunodominant in recent human H3N2 viruses. Importantly, the L194P substitution decreases binding and neutralization by an RBS-targeted broadly neutralizing antibody by three orders of magnitude and significantly changes the HA antigenicity as measured by binding of human serum antibodies. The receptor binding mode and specificity are also altered to adapt to avian receptors during egg passaging. Overall, these findings help explain the low effectiveness of the seasonal vaccine against H3N2 viruses, and suggest that alternative approaches should be accelerated for producing influenza vaccines as well as isolating clinical isolates.

Author summary

Seasonal influenza vaccine does not always confer protection in vaccinated individuals. Vaccine candidates are selected from clinical isolates based on their antigenic properties. It is common to use chicken eggs for culturing clinical isolates and for large-scale production of vaccines. However, influenza virus often mutates to adapt to being grown in chicken eggs, which can influence antigenicity and hence vaccine effectiveness. Here, we structurally characterize an egg-adaptive substitution, namely L194P, in H3N2 virus hemagglutinin. Our results reveal that the L194P substitution substantially increases the flexibility of an epitope region that is commonly targeted by antibodies. Based on the binding affinity of a broadly neutralizing antibody and a panel of human serum antibodies, we further show that the L194P substitution dramatically changes the HA antigenicity. The change of the receptor-binding mode associated with the L194P substitution provides an explanation for its ability to successfully grow in eggs. Our study describes a mechanism for the low influenza vaccine effectiveness and reaffirms the urgency for replacing the egg-based production of influenza vaccines.