Science Spotlight

Have you gotten your shot? Understanding the origins of seasonal flu (H3N2)

Bedford lab (Vaccine and Infectious Disease Division)
Graph showing data produced from the model.
Output from a single stimulation showing the phylogeny of the pathogen (a), the antigenic drift away from the founding strain (b), and prevalence of each strain (c). Colors for the three populations are shown in (d) representing the temperate north, tropics, and temperate south. Image provided by Dr. Bedford

Influenza virus is the cause of the seasonal flu here in the United States, but have you ever wondered where it comes from? New strains emerge and spread based on antigenic drift or the accumulation of novel mutations causing the virus to evade host immunity, leading to more successfully transmitted strains. Currently antigenically novel strains of seasonal H3N2 have disproportionally originated in Asia where the population is large, dense, and has a high turnover rate creating newly susceptible hosts. Another proposed reason is Asia’s tropical climate, which allows the virus to circulate year-round avoiding transmission bottlenecks seen in temperate zones. Since about 2000 the trunk of the influenza phylogenic tree has been in Asia 87% of the time; the trunk is made up of strains that are often the most evolutionarily successful and seed the branches.

In a recent article in the Proceedings of the Royal Society B, Dr. Bedford (Vaccine and Infectious Disease Division) and colleagues simulated flu infection in a global metapopulation to look at which ecologic factors caused Asia’s disproportional contributions to the evolution and spread of the virus. In Dr. Bedford’s words, “These strains are often the best strains to use in the seasonal influenza vaccine as they represent the "future" of the virus population. However… there was little real understanding of why this was the case. There were various hypotheses, like population size, seasonality, etc... but nothing completely clear. Here, we took a modeling approach to distinguish between these possibilities”. By gaining a more complete understanding of the contributions needed for spread, the group hope to better inform viral forecasting, including predictions of upcoming variance leading to more informed vaccine strain choices. The researchers tested multiple factors for their effect on antigenic dynamics and spatial evolution, looking for patterns similar to observed data. The mathematical model was designed to look at the effects of population size, turnover, conditions, transmission rate and seasonality.

Using three connected populations representing the temperate north and south and tropics, Bedford and his team created a simple model that produced results similar to observed outcomes. They found that higher transmission rates (Ro) were the largest contributor to more antigenic variation resulting in greater drift. Seasonality influenced the strains coming out of each region but alone did not contribute to the fitness seen in the tropic strains. Climate does however create bottlenecks in temperate zone strains, which contribute less competition for tropic strains allowing them to spread into other regions. Other factors, including population size, age and turnover rate can influence global strains but to a lesser extent. Overall by increasing transmission rates in the tropics over the temperate zones, the model produced results very similar to observed data in incidence, drift rate, trunk location and antigenic lead. From this data we can hypothesize that areas with high transmission rates would disproportionally contribute to influenza strain evolution on a global scale and thus, vaccine strain selection should target these strains.

This work was supported by the National Institutes of Health.

Wen F,Bedford T,Cobey S. 2016. Explaining the geographical origins of seasonal influenza A (H3N2). Proc Biol Sci, 283(1838).