Influenza viruses evolve rapidly, making it hard to develop protective vaccines against them. Despite a great deal of effort, scientists have found it difficult to forecast which way the virus’ evolution would take it. Now, thanks to improvements in our ability to study viruses and a new mathematical model, anticipating influenza’s next move appears possible.

Making the jump

In addition to the rapid evolution of genes within human flu strains, the viruses have the ability to jump from animals to humans, a move that can spark global pandemics like the 2009 swine flu, which killed thousands from Mexico to China.

But a pandemic does not always follow from these jumps. For example, there have been numerous reports of humans being infected with the H5N1 bird flu, yet it doesn’t seem to spread from human to human. Researchers are still trying to understand why some influenza viruses are unable to spread within human populations, while others have taken off.

One of the successful jumps was made by a subtype called H3N2 in 1968. H3N2 evolves quickly enough that its entire population is replaced every few years. It exemplifies the other type of evolutionary challenge: predicting, from year to year, which of the many circulating strains will take over.

Because influenza is a major cause of death (it can result in pneumonia), understanding this evolution is more than an academic exercise—developing the right vaccines can save lives. Predicting which strain will be widespread nearly a year into the future is the central challenge of the World Health Organization’s vaccine strain selection committee. It meets twice a year to review the evidence on circulating viruses and pick the likeliest candidates for the next flu seasons. The challenge the committee faces is that it is difficult to build a compelling case against any one strain.

Slow and costly

Measuring how well different strains have evaded the immune system has been a slow and costly process. Traditionally, ferrets are experimentally infected with common flu strains to see whether they develop antibodies that can cross react to other circulating strains—including those targeted by vaccines. These are then compared with measures from human samples. Often, several strains show some ability to escape immunity.

For more than a decade, different groups have attempted to find genetic shortcuts to predict the winners in advance. Mutations in certain parts of the virus are more likely to lead to immune escape than others. But in the past, every time a rule based on these mutations was derived, the virus seemed to break it.

Over time, however, a pattern gradually became clear, one that’s been a recurring theme in evolution: the impact of a mutation depends heavily on the genetic background in which it occurs. In other words, it’s not just the new mutations; it’s how they interact with the rest of the virus’ genetic material. For fast-evolving viruses such as influenza, the combinatorial possibilities of mutations and backgrounds have made prediction seem like a daunting task.

A new model

But a recent study, published last week in Nature, shows that in the case of H3N2, we perhaps can predict its evolution after all. The study's authors, Marta Łuksza and Michael Lässig, showed that the future success of related H3N2 strains, known as clades, could be predicted by a relatively simple model.

The model considers only three types of information when assessing a clade’s future: mutations in sites that are targeted by antibodies (generally thought to be helpful to the virus), mutations in sites not binding antibodies (generally thought to be harmful), and the recent frequencies of the clade and competing clades. The authors showed the model can be used to predict strain frequencies on a time scale useful for creating vaccines. This could greatly increase the effectiveness of flu jabs.

In addition to its ability to identify strains, the model also reveals important information about the way influenza evolves. It reinforces that the immunity acquired by host populations shapes the virus' evolution. This suggests that widespread vaccination could also shape the evolution of influenza.

The study also supports the idea that strains emerging from Asia tend to be inordinately successful. Why this is, and whether the trend will continue, are unanswered questions. Finally, the model suggests that influenza follows a narrow path between beneficial mutations to escape immunity and harmful ones that affect its ability to stably infect the populations it targets.

How do we know the virus won’t break the rules of this model too? In a way, we don’t, but the authors took steps to show that their model balanced the trade-off between complexity and predictive power. Their ability to find this sweet spot comes entirely from the large and growing number of publicly available influenza genome sequences.

This article was originally published on The Conversation.