Despite push for a universal flu vaccine, the ‘holy grail’ stays out of reach

It is the holy grail of influenza science: a universal flu vaccine that could provide protection against virtually all strains instead of a select few.

A burst of recent headlines have suggested that we might get one soon. Just last week, the National Institute of Allergy and Infectious Diseases released a strategic plan for the development of a universal flu vaccine, prompting the White House science office to proclaim on Twitter that the goal is “closer than ever.”

Experts, however, say we’re really not there yet. And to be honest, we can’t necessarily even see there from here.

“I don’t think we’re that close at all,” Michael Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy. “I think the kind of work that’s gone on has been critical and important, but it’s only the first 5 feet of what would need to be a 100-foot rope.”

There’s no doubt that there is some momentum. The release of the strategic plan — which outlines for scientists the research that NIAID sees as critical and that it would be willing to help finance — signals renewed interest in the quest for a universal vaccine. So, too, does a bill — introduced by Sen. Edward Markey, a Democrat from Massachusetts — calling for $1 billion in government spending for the project.

“This is a real sign that the [National Institutes of Health] is ready to make this push. So I’m excited about it,” said Scott Hensley, a professor of immunology at the University of Pennsylvania whose laboratory has explored why flu vaccines don’t work well some years.

But Dr. Arnold Monto, a flu vaccine expert at the University of Michigan, agreed with Osterholm, saying there are some basic questions that must be answered before scientists can devise more effective and long-lasting flu shots.

“There is a lot of work going on, but it is still relatively early because what we have to do is do a better job in identifying why vaccines work or why vaccines do not work,” Monto insisted.

A lot of hope is pinned on research that proposes a new target for vaccines, sites on the main viral protein that don’t change much from virus to virus. But our immune systems don’t generate a lot of antibodies to these in response to vaccine or flu infections and the clinical trials needed to show vaccines made this way actually work haven’t yet been undertaken.

Likewise, it isn’t clear if antibodies are enough to protect against flu. It could be that other parts of the immune arsenal — T cells, for instance — have to be harnessed if a vaccine is to be more broadly effective.

There are also many questions about the impact of “imprinting” on our ability to respond effectively to flu vaccines. That term refers to the shaping of each individual’s immune profile, created by the flu viruses each of us encountered, both through infection and vaccination — and the order in which they happened. It’s thought, for instance, that we will always generate the best response to the type of flu virus that triggered our first infection.

It has been clear for a while that existing flu vaccines are not as effective as they ought to be. The official line is that the vaccines protect about 50 percent or 60 percent of the time, although effectiveness is lower in years — like this one — when H3N2 viruses are most dominant, or when the viruses selected for inclusion in the vaccine aren’t well-matched to those causing illness. This year it was estimated that the H3N2 component of the flu shot protected only 1 out of every 4 Americans who was vaccinated.

Scientists have been searching for over a decade for ways to make more effective flu vaccines, always with the elusive goal of producing a universal version.

Based on the current understanding of flu, there are 198 possible combinations of influenza A viruses, the ones identified with names including numbered Hs and Ns. There are 18 known hemagglutinins or Hs, and 11 known neuraminidases or Ns.

(A hemagglutinin is a protein on the exterior of a flu virus that allows it to invade cells in your respiratory tract, where it hijacks the inner workings of those cells to make copies of itself. The neuraminidase protein helps those new viruses escape so they can invade other cells.)

The hemagglutinins are divided into two groups, which signal how closely or distantly related they are from one another, genetically.

The reality is that some H and N combinations have never been seen, even in wild water birds, the original source of all flu viruses. And in a recent interview with STAT, Dr. Anthony Fauci, director of the NIAID, said he thinks a single vaccine that could protect against all these potential viruses is currently “unattainable.”

He does, however, think that it is possible to make vaccines that could protect more broadly against common viruses, like H3N2. If scientists could make an effective H3N2 vaccine that would help the immune system recognize all H3 viruses, regardless of the constant shape-shifting the virus undertakes to evade our immune defenses, that would substantially lessen the toll that virus takes.

Fauci described a scenario in which a better H3N2 vaccine could be developed, one that might also provide protection against one of the bird flu viruses that are seen as pandemic threats, like H7N9. Later, a better vaccine to protect against the H1N1 virus — the other influenza A virus that causes human illness — could be developed, which would include a different bird flu virus, such as H5N1. The timeline for development of these types of products — if industry moves to develop them — could be years rather than a decade or two, he suggested.

These would be major contributions to the effort to blunt flu’s annual assault, but they would definitely constitute a redefining of the term “universal vaccine.”

“The end goal is still to get a bona fide universal flu vaccine,” said Hensley, who along with Osterholm and Monto attended a meeting of experts NIAID held last June to develop the strategic plan.

“But I’d take a vaccine that was universally awesome against H1N1, or a vaccine that was universally awesome against H3N2. Give me that vaccine any day of the week. And if we could end up developing a vaccine that protects against all the different subtypes, that’s gravy.”

In the strategic plan Fauci’s agency published last week, universal was defined as meeting four must-have criteria. The vaccine would have to be at least 75 percent effective, be suitable for people of all ages, protect against viruses from both hemagglutinin groups (though it does not say all), and generate protection for at least a year. Influenza B viruses — which cause a substantial amount of illness most years — are left for another iteration.

The notion that a universal vaccine would provide protection for a year also breaks with traditional ideas.

Osterholm was the lead author of a 2012 report that laid out the problems with existing flu vaccines and mapped out what would be needed to develop “game-changing” alternatives. (Osterholm prefers that term to “universal.”)

That report suggested a universal vaccine should provide at least a decade’s worth of protection. Breaking away from the annual vaccination cycle for flu is crucial, Osterholm said.

“It’s causing actually almost an erosion of confidence in vaccines as opposed to increasing confidence. … If you look at over the past five years, the number of people being vaccinated has actually leveled off or in some groups actually decreased,” he said. “And that’s because I think people are really confused about this vaccine and what it does.”

Monto, too, thinks a long-lasting vaccine is a key component in this effort, but for a different reason.

Evidence is emerging that getting vaccinated against flu year after year appears to sometimes — not always — undermine the benefit of the vaccine, with people who are repeatedly vaccinated developing fewer antibodies after vaccination than people who haven’t recently received a flu shot. Monto thinks moving away from the need to vaccinate annually could improve the impact of next-generation vaccines.

There are many complexities, such as the repeat vaccination question, that stand between us and those better flu vaccines.

“It’s not coming any time soon,” Monto warned. “We have a lot of work to do. But in the meantime, we can improve flu vaccine. We have low-hanging fruit.”