Designing a flu vaccine that protects against a broad array of influenza viruses is going to be a tougher nut to crack than some might have thought, the findings of a new study suggest.

It’s generally believed a so-called universal vaccine will need to trigger a production of antibodies — the immune system’s ammunition — that aim for a different target on flu viruses than the current vaccines do. But the new research shows that people’s previous experiences with influenza — both the viruses that make them sick and the vaccines that aim to prevent illness — limit their ability to produce that kind of antibody.

“I think they’re showing us that the path forward has to be really thoughtfully considered,” Paul Thomas, an immunology expert at St. Jude Children’s Hospital in Memphis, Tenn., said of the paper, which was published in this week’s issue of Science Translational Medicine.

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A universal flu vaccine is often referred to as influenza’s Holy Grail. That’s because these wily viruses mutate constantly, giving them the capacity to infect people multiple times over a lifetime.

Because the viruses keep changing, vaccines targeting them need to be updated too. Some years the viruses selected for the vaccine are a good match for those making people sick, in which case the vaccine offers pretty good protection. But sometimes the viruses give the vaccine the slip.

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And occasionally a brand new strain of flu emerges, one to which no one has immunity. Those strains trigger flu pandemics, which can be mild, like the 2009 H1N1 outbreak, or severe, like the 1918 Spanish flu, which killed upwards of 50 million people. Or they can be somewhere in between.

In recent years the research into a universal flu vaccine has homed in on an approach experts hope might achieve the goal. They think by redirecting the vaccine’s aim they can produce a product that is more effective and longer lasting.

The vaccine triggers the immune system to create antibodies, preparing the body for viral battle. Alex Hogan/STAT

The surface of flu viruses are studded with proteins called hemagglutinin. This protein is the part of the virus that latches onto cells in a person’s respiratory tract, initiating infection. Hemagglutinins are shaped a bit like a lollypop — they have globe-like head attached to a stalk.

When the immune system sees a flu hemagglutinin protein — either on a virus or in a vaccine — it produces antibodies to it. Most of those antibodies target the head of the protein, which is the part that changes continuously to try to evade the immune system’s defenses. The stalk, on the other hand, doesn’t change much and is pretty similar from strain to strain. Antibodies that recognize and neutralize the hemagglutinin stalk would, in theory, work against multiple strains of flu.

But people don’t generate a lot of antibodies that target the stalk. The research in this new paper explores that phenomenon by vaccinating some subjects a number of times against H1N1 — the 2009 pandemic strain.

The work was conducted by scientists from the University of Chicago, the Icahn School of Medicine at Mount Sinai in New York, and Emory University in Atlanta. It was supported in part by grants from the National Institutes of Health. Corresponding author Patrick Wilson of the University of Chicago did not reply to requests for an interview.

When the virus was new, people produced a range of antibodies targeting both the head and the stalk. But subsequent vaccinations spurred production of antibodies that target the head only. And those antibodies seemed to impede the production of stalk antibodies, explained Thomas, who was not involved in the research.

“They’re just so much better, they get there first. And then there’s no room for the stalk antibodies to get boosted, or recalled, or used, even,” Thomas said.

Michael Osterholm, an infectious disease expert who has long argued for the need for substantially more effective flu vaccines — he uses the term “game-changing vaccines” — said he doesn’t think these findings dash hopes for a broadly protective influenza vaccine.

But they do highlight hurdles that will need to be cleared.

“So one of the key questions is going to be for any kind of game-changing flu vaccine is how do you overcome that?” asked Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy. “And to the extent that that occurs, when does it jeopardize protection if, for example, you create a vaccine against the … stalk versus the head?”

Osterholm, who was not involved in the research, noted the findings are consistent with an observation some research groups have reported: that repeated vaccinations may produce diminishing returns.

Thomas pointed out another challenge the study revealed. The neutralizing antibodies that target the hemagglutinin stalk can attach to things other than just flu viruses — for instance insulin and DNA.

That raises the possibility that people don’t produce many of these types of antibodies because they might have the capacity to mistake things that aren’t invaders — that are necessary substances in the body — as threats, Thomas said. “It raises a little bit of a concern about the safety of generating really high levels of these antibodies.”

The upshot? Claims that a universal flu vaccine may be within sight should probably be taken with a grain of salt, Osterholm and Thomas suggested.