Hemagglutinin destabilization in H3N2 vaccine reference viruses skews antigenicity and prevents airborne transmission in ferrets

Abstract

During influenza virus entry, the hemagglutinin (HA) protein binds receptors and causes membrane fusion after endosomal acid activation. To improve vaccine efficiency and pandemic risk assessment for currently-dominant H3N2 influenza viruses, we investigated HA stability of 6 vaccine reference viruses and 42 circulating viruses. Recent vaccine reference viruses had destabilized HA proteins due to egg-adaptive mutation HA1-L194P. Virus growth in cell culture was independent of HA stability. In ferrets, the vaccine reference viruses and circulating viruses required a relatively stable HA (activation and inactivation pH < 5.5) for airborne transmissibility. The recent vaccine reference viruses with destabilized HA proteins had reduced infectivity, had no airborne transmissibility unless reversion to HA1-P194L occurred, and had skewed antigenicity away from the studied viruses and circulating H3N2 viruses. Other vaccine reference viruses with stabilized HAs retained infectivity, transmissibility, and antigenicity. Therefore, HA stabilization should be prioritized over destabilization in vaccine reference virus selection to reduce mismatches between vaccine and circulating viruses.

A naturally occurring HA-stabilizing amino acid (HA1-Y17) in an A(H9N2) low-pathogenic influenza virus contributes to airborne transmission

“…Generally, most avian and swine IAVs have a higher threshold pH for HA activation compared to human isolates within the same subtype ( 4 , 5 ), indicating that an acid-stable IAV may have a fitness advantage in infecting and transmitting among humans. A link between virus acid stability and airborne transmission has also been observed for 2009 pandemic H1N1 (2009pdmH1N1), swine-origin A(H1N1), and human A(H3N2) IAVs ( 6 – 8 ). Currently circulating 2009pdmH1N1 viruses share HA activation values ranging from 5.2 to 5.4, which are lower compared with early pandemic strains in humans (pH 5.5) and precursor H1N1 viruses in swine (pH 5.5–6.0) ( 9 ).…”