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.
Highlights
Recognition and neutralization of influenza virus by the immune system has been a subject of extensive research due to its profound implications for vaccine design
Influenza virus often mutates to adapt to being grown in chicken eggs, which can influence antigenicity and vaccine effectiveness
The HA L194P substitution rapidly emerges in human H3N2 viruses during passaging in chicken eggs [19, 23,24,25]
Summary
Recognition and neutralization of influenza virus by the immune system has been a subject of extensive research due to its profound implications for vaccine design. The majority of human antibodies against influenza virus that are elicited by natural infection or vaccination target the globular head domain of the hemagglutinin (HA) glycoprotein. In H3N2 viruses, five major antigenic sites A-E are the primary targets [1,2,3]. Most of the globular head domain has an intrinsically high mutational tolerance [4, 5] that facilitates escape from the immune system. The receptor-binding site (RBS) is conserved but can still accommodate some level of mutation to evade antibody recognition. Rapid antigenic drift of influenza viruses can occur without perturbing vital functions and necessitates almost annual reformulation of the influenza vaccine
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