To improve the effectiveness of vaccines, several attempts have been made to predict the major amino acid
sequence of HA1 in the target season of vaccination (Bush et al., 1999; Xia et al., 2009; He and Deem, 2010; Ito
et al., 2011; Suzuki, 2013b; Luksza and Lassig, 2014). However, the precision of prediction was limited by the
random genetic drift, the incomplete sampling of epidemic viruses, the occurrence of de novo mutations, and
the lack of knowledge on the mechanism of sequence evolution. In addition, the usefulness of predicted
sequence was unclear because its relationship to the antigenicity was unknown.