Ever wondered why some of us get knocked badly by the flu while others don’t get sick at all, even without getting the vaccine?

A major new study, drawing on a trove of data from Kiwi patients, has taken scientists closer to solving this enduring mystery – and highlights how there’s much more to the puzzle than the immune boost we get from our annual flu shot.

Their findings suggest some immune cells are linked with increased protection against the virus – while others appear to make us more susceptible to developing symptoms.

They might now point the way to better flu vaccines, and smarter ways of measuring our individual risk – even months before flu season begins.

While the flu’s impact has been somewhat overshadowed by Covid-19, it remains a huge burden globally, with seasonal epidemics causing around three to five million cases of severe illness, and 290,000 to 650,000 deaths, each year.

In New Zealand, researchers have estimated the flu’s annual toll at around 500 deaths – making it our single biggest infectious disease killer after a coronavirus that’s likely to claim twice that many lives in 2023, in formally Covid-attributed deaths alone.

Though there’s more than enough evidence to show vaccination offers the best defence against flu, there’s plenty more to understand about how our bodies fight it.

“We’ve been struggling for decades, if not centuries, with why some people get sick with infections and some don’t,” said the new study’s lead author, Dr Richard Webby, of St Jude Children’s Research Hospital in the US.

“This is one of the best attempts to try and figure that out for influenza.”

For Webby and his US and Kiwi collaborators, a wealth of data long been collected here proved invaluable.

That came from the SHIVERS-II study – the Southern Hemisphere’s largest and most comprehensive flu research initiative – which has been tracking hundreds of Kiwi patients over time.

As part of the programme, collaboratively run by St Jude and New Zealand’s ESR, volunteers regularly had their blood drawn so scientists could characterise their immune cells, to find out which were linked with protection from flu symptoms.

“We were able to measure many different immune parameters from a single blood draw and correlate them with protection from, or susceptibility to, infection symptoms,” Webby said.

One of the biggest insights was that having a more “functionally diverse” set of immune cells appeared to help.

The researchers pinpointed these specific cells by comparing those present in the blood of patients who had symptoms from flu infection with those who were asymptomatic or uninfected.

The blood samples, taken up to six months before flu season, showed very different sets of immune cells in the two groups.

Those without symptoms not only had a more functionally diverse set of immune cells but those cells were also associated with an influenza-specific long-term response – sometimes called memory response.

Patients with symptoms tended to have a more similar set of inflammatory immune cells, which were more likely to be involved in a non-specific, “functionally narrow” and short-term response.

“Our results show that the balance of different immune cells in people can be extremely biased,” St Jude immunologist and study author Dr Paul Thomas said.

“You might build up an immune cell army that is exceptional at fighting off one kind of infection, but then that can make you feel sicker from another kind of infection.

“By understanding which immune cells are the best for fighting the flu, we can start designing vaccines to push for those populations that are most protective.”

Fellow author and St Jude researcher, Dr Aisha Souquette, added that, before vaccination, the baseline state of our immunity varied heavily depending on factors like our sex, age, vaccination status and infection history.

“By understanding the different types of immune profiles that can provide protective responses, we can tailor and optimise our vaccine platforms for populations with distinct baseline immune states.”

In doing so, targeting particular cell or antibody types, they found, might actually be less important than evaluating the collective contribution of all immune cells.

In a less surprising finding, the study showed that those vaccinated for the flu generally had increased protective anti-flu immune cells, improving their chance of avoiding symptoms.

But those rarer individuals who were unvaccinated and avoided symptoms appeared to have a set of immune cells that effectively mimicked the functions of the protective cells in the vaccinated population.

This, the researchers concluded, might explain why some people were less affected by the flu than others – even when unvaccinated.

Looking to the future, the team pointed to the possibility of predicting people’s flu risk more accurately than with today’s approaches, which typically involved testing only for levels of anti-flu antibodies in the bloodstream.

Smarter tests could instead look for a diverse set of immune cells, together with a high proportion of T cells that help B cells with long-term immune response.

“We may have the tools to understand susceptibility to infection already in our hands,” Webby said.

“We can only do it in the lab now, but it’s surprising and potentially exciting that, someday, we may get to a point where we can easily identify at-risk people and provide targeted support.”

It was similarly exciting that, even months out from the flu season, his team correctly predicted those patients most likely to have flu symptoms.

“I don’t think we’ve really been in a position to even think about that before – this could open up new opportunities to prevent flu-based morbidity.”

At the same time, he said the results, just published in the journal Nature Immunology, confirmed a long-standing message from virology and immunology.

“Our results re-emphasise that vaccination prevents influenza symptoms, and now we can point to the increased levels of those immune cells correlated with that protection,” Thomas said.

“Get your annual flu vaccine.”

ESR virologist and study co-author Dr Sue Huang meanwhile paid tribute to the participants of the SHIVERS platform, whose willingness to stay involved had made it “tremendously successful”.

“It is great to see their efforts coming to fruition.”