(A, B) meta-analysis of A/H3N2 viruses from next-generation sequencing studies of naturally-infected individuals (Debbink et al., 2017; McCrone et al., 2018). (A) Fraction of infections with one or more observed amino acid polymorphisms in the hemagglutinin (HA) protein, stratified by likelihood of affecting antigenicity: infections with a substitution in the ‘antigenic ridge’ of 7 key amino acid positions found by Koel et al., 2013 in red, infections with a substitution in a classically-defined ‘antigenic site’, (Wiley et al., 1981) in blue, infections with HA substitutions only in non-antigenic regions in gray, infections with no HA substitutions in cream. Infections grouped by whether individuals had been (left) vaccinated in a year that the vaccine matched the circulating strain, (center) vaccinated in a year that the vaccine did not match the circulating strain, or (right) not vaccinated. (B) Distribution of plotted polymorphic sites from (A) by within-host frequency of the minor variant. (C, D) heatmaps showing model probability of new antigenic variant selection to the NGS detection threshold of 1% (C) and to 50% (D) by 3 days post infection given the strength of immune selection , the antibody response time and a founding population composed of old variant virions. Probabilities calculated from Equation 27 in the Materials and methods. Calculated with , but for , replication selection probabilities are approximately equal for all trios that yield a given (see Materials and methods). Star denotes a plausible influenza-like parameter regime: 25% escape from sterilizing-strength immunity () with a recall response at 2.5 days post infection. Black lines are probability contours. (E–H) example model trajectories. Upper row: absolute counts of virions and target cells. Lower row: variant frequencies for old antigenic variant (blue) and new variant (red). Dashed line shows 1% frequency, the detection limit of NGS. Dotted line shows an analytical prediction for new variant frequency according to Equations 15 and 16 (see Materials and methods). Model scenarios: (E) naive; (F) experienced with ; (G) experienced with ; (H) experienced with and new antigenic variant virion incoulated. Lines faded when infection is below 5% transmission probability—approximately 107 virions with default parameters. All parameters as in Table 1 unless otherwise stated.