Comparison of log2-fold change in HAI GMT, and 50 and 80% FRA neutralization titers between VLP-vaccinated and preimmune vaccinated ferrets. Fold changes in HAI and FRA at day 182 were compared between immunologically naive ferrets (n = 4) vaccinated two times (days 84 and 168) with one of the four COBRA H3N3 VLP vaccines (T6, T7, T10, or T11) or H3N3 VLP vaccines expressing wild-type HA proteins from Wisc/05 or TX/12 and preimmune ferrets that were vaccinated two times (days 84 and 168) with H3N3 VLP vaccines expressing the same HA proteins used to immunize the naive ferrets. Fold change differences were compared against four H3N2 viruses isolated between 2012 and 2015 representing clades 3c.1 (TX/12) (A), 3c.3a (Sz/13) (B), 3c.2a (HK/14) (C), and 3c.2a1 (Sing/16) (D). Statistical analyses were performed using unpaired parametric t tests to determine significance of vaccination in the preimmune setting compared to naive ferrets. P values of <0.05 are considered significant and are colored blue.