Abstract
SummaryEgg-based seasonal influenza vaccines are the major preventive countermeasure against influenza virus. However, their effectiveness can be compromised when antigenic changes arise from egg-adaptive mutations on influenza hemagglutinin (HA). The L194P mutation is commonly observed in egg-based H3N2 vaccine seed strains and significantly alters HA antigenicity. An approach to prevent L194P would therefore be beneficial. We show that emergence of L194P during egg passaging can be impeded by preexistence of a G186V mutation, revealing strong incompatibility between these mutations. X-ray structures illustrate that individual G186V and L194P mutations have opposing effects on the HA receptor-binding site (RBS), and when both G186V and L194P are present, the RBS is severely disrupted. Importantly, wild-type HA antigenicity is maintained with G186V, but not L194P. Our results demonstrate that these epistatic interactions can be used to prevent the emergence of mutations that adversely alter antigenicity during egg adaptation.
Highlights
Seasonal influenza vaccines offer protection against two influenza A virus subtypes, H1N1 and H3N2, as well as against influenza B virus
Since the HA receptor-binding site (RBS) partially overlaps with several major antigenic sites (Wiley et al, 1981; Wilson et al, 1981; Wu and Wilson, 2017), egg-adaptive mutations can dramatically alter HA antigenicity and reduce the effectiveness of seasonal influenza vaccines (Raymond et al, 2016; Skowronski et al, 2014; Wu et al, 2017b; Zost et al, 2017)
Namely H156Q, H156R, H183L, G186V, L194P, S219Y, S219F, N246H, and N246S, were classified as the major egg-adaptive mutations. These observations are consistent with previous studies, which showed that growth of the H3N2 virus in eggs can be enhanced by H183L (Lu et al, 2005), G186V (Barman et al, 2015; Lu et al, 2005; Stevens et al, 2010; Widjaja et al, 2006), L194P
Summary
Seasonal influenza vaccines offer protection against two influenza A virus subtypes, H1N1 and H3N2, as well as against influenza B virus. Since the HA RBS partially overlaps with several major antigenic sites (Wiley et al, 1981; Wilson et al, 1981; Wu and Wilson, 2017), egg-adaptive mutations can dramatically alter HA antigenicity and reduce the effectiveness of seasonal influenza vaccines (Raymond et al, 2016; Skowronski et al, 2014; Wu et al, 2017b; Zost et al, 2017) While such problems can be resolved by cell-based or recombinant influenza vaccines, most influenza vaccines available on the market remain egg based because of low production cost and existing infrastructure for their annual production (Harding and Heaton, 2018)
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