Abstract
Influenza A virus (subtype H3N2) causes seasonal human influenza and is included as a component of influenza vaccines. The majority of vaccine viruses are isolated and propagated in eggs, which commonly results in amino acid substitutions in the haemagglutinin (HA) glycoprotein. These substitutions can affect virus receptor-binding and alter virus antigenicity, thereby, obfuscating the choice of egg-propagated viruses for development into candidate vaccine viruses. To evaluate the effects of egg-adaptive substitutions seen in H3N2 vaccine viruses on sialic acid receptor-binding, we carried out quantitative measurement of virus receptor-binding using surface biolayer interferometry with haemagglutination inhibition (HI) assays to correlate changes in receptor avidity with antigenic properties. Included in these studies was a panel of H3N2 viruses generated by reverse genetics containing substitutions seen in recent egg-propagated vaccine viruses and corresponding cell culture-propagated wild-type viruses. These assays provide a quantitative approach to investigating the importance of individual amino acid substitutions in influenza receptor-binding. Results show that viruses with egg-adaptive HA substitutions R156Q, S219Y, and I226N, have increased binding avidity to α2,3-linked receptor-analogues and decreased binding avidity to α2,6-linked receptor-analogues. No measurable binding was detected for the viruses with amino acid substitution combination 156Q+219Y and receptor-binding increased in viruses where egg-adaptation mutations were introduced into cell culture-propagated virus. Substitutions at positions 156 and 190 appeared to be primarily responsible for low reactivity in HI assays with post-infection ferret antisera raised against 2012–2013 season H3N2 viruses. Egg-adaptive substitutions at position 186 caused substantial differences in binding avidity with an insignificant effect on antigenicity.
Highlights
Influenza A virus (IAV), subtype H3N2, causes seasonal human influenza and is included in trivalent and tetravalent vaccines containing H1N1, H3N2 and influenza B virus components
Encoding the major protein target for immune responses, to evade pre-existing immunity. Accumulation of these mutations can result in the emergence of antigenicallydistinct groups if certain amino acid substitutions are introduced in the HA glycoprotein
The recommended virus from which candidate vaccine viruses (CVV) were produced for the Northern Hemisphere season 2012–2013 was A/Victoria/361/2011 (Vic361)
Summary
Influenza A virus (IAV), subtype H3N2, causes seasonal human influenza and is included in trivalent and tetravalent vaccines containing H1N1, H3N2 and influenza B virus components. A recent study has used BLI and glycan arrays to examine the receptor-binding properties of baculovirus-expressed H3N2 HA proteins from seasonal vaccine components up until 2013 (Yang et al, 2015), no complementary antigenic analysis was done and the viruses have continued to change in the intervening period and are highly likely to do so in future seasons To our knowledge this is the first time that quantitative receptorbinding assays and HI assays have been used together to investigate the correlative effects on receptor-binding and antigenicity of defined AA substitutions in H3N2 CVVs
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