Reproducible and later vaccine strain selection can improve vaccine match to A/H3N2 seasonal influenza viruses

Twice per year, the World Health Organization (WHO) recommends strains for seasonal influenza vaccines to ensure vaccine strains match circulating viruses. However, new variants can emerge after vaccine strain selection, leading to mismatches between vaccine and circulating viruses. New vaccine platforms could enable later than currently practiced strain selection, which could reduce mismatch frequency. Here, we investigated whether delaying vaccine strain selection by three months could improve vaccine match. We compared haemagglutinin epitope mutations and hemagglutination inhibition (HI) titers of historical and hypothetical vaccine strains selected using a reproducible method against dominant circulating viruses during 63 influenza seasons in the United States, Europe, and Australia and New Zealand between 2002 and 2023. Vaccine match to circulating viruses, based on epitope mutations, could be improved in 51/63 seasons by our reproducible strain selection method while preserving WHO timing. Delaying selection could have further improved the match in 14/63 seasons. Based on a ≥4-fold match improvement in HI titer, our reproducible strain selection with WHO timing could have improved the match in 12/63 seasons and a further 7/63 seasons if selected later. Improvements in vaccine match can be achieved while preserving the current WHO timing, with further improvements possible by delaying strain selection.