Early prediction of antigenic transitions for influenza A/H3N2

Influenza A/H3N2 is a rapidly evolving virus which experiences major antigenic transitions every two to eight years. Anticipating the timing and outcome of transitions is critical to developing effective seasonal influenza vaccines. Using a published phylodynamic model of influenza transmission, we identified indicators of future evolutionary success for an emerging antigenic cluster and quantified fundamental trade-offs in our ability to make such predictions. The eventual fate of a new cluster depends on its initial epidemiological growth rate––which is a function of mutational load and population susceptibility to the cluster––along with the variance in growth rate across co-circulating viruses. Logistic regression can predict whether a cluster at 5% relative frequency will eventually succeed with ~80% sensitivity, providing up to eight months advance warning. As a cluster expands, the predictions improve while the lead-time for vaccine development and other interventions decreases. However, attempts to make comparable predictions from 12 years of empirical influenza surveillance data, which are far sparser and more coarse-grained, achieve only 56% sensitivity. By expanding influenza surveillance to obtain more granular estimates of the frequencies of and population-wide susceptibility to emerging viruses, we can better anticipate major antigenic transitions. This provides added incentives for accelerating the vaccine production cycle to reduce the lead time required for strain selection.Author summary: The efficacy of annual seasonal influenza vaccines depends on selecting the strain that best matches circulating viruses. This selection takes place 9–12 months prior to the influenza season. To advise this decision, we used an influenza A/H3N2 phylodynamic simulation to explore how reliably and how far in advance can we identify strains that will dominate future influenza seasons? What data should we collect to accelerate and improve the accuracy of such forecasts? And importantly, what is the gap between the theoretical limit of prediction and prediction based on current influenza surveillance? Our results suggest that even with detailed virological information, the tight race between the antigenic turnover dynamics and the vaccine development timeline limits early detection of emerging viruses. Predictions based on current influenza surveillance do not achieve the theoretical limit and thus our results provide impetus for denser sampling and the development of rapid methods for estimating viral fitness.