Some flu vaccines may work better than others, but public could use better guidance

Last fall some people in the know about influenza science got picky when it came time to get their flu shots.

They didn’t want to roll up their sleeve for any old vaccine on offer at their doctor’s office or workplace clinic. They sought specific products, the ones licensed for older adults that contain a performance-boosting compound called an adjuvant or more notably one of the two brands of vaccine not made — as most flu vaccines are — in eggs.

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“My colleagues who are over age 65, everybody wanted basically the Fluad or the Protein Sciences vaccine, Flublok,” said Dr. Michael Osterholm, director of the Center for Infectious Diseases Research and Policy at the University of Minnesota. (Fluad, made by Seqirus, contains an adjuvant; Flublok is produced in insect cells.)

The pickiness of flu experts underlines a truth not widely known to the general public: There are a host of different kinds of flu shots, and not all are created equal. In fact, in an incredibly crowded sector, four companies offered a total of 12 different influenza vaccines this year, bringing to market roughly 152 million doses.

The proliferation of products, many of which have a tweak or two on the standard three-in-one shot used for years, has left some people wondering whether public health officials should do more to steer flu vaccine consumers towards Vaccine X or Vaccine Y.

Interest in that kind of advice has likely grown as evidence on how well — or how inadequately — individual components of the vaccines work has been amassed over the past decade or so. In short, many in the field believe some flu vaccines may provide better protection than others.

At the most recent meeting of the Advisory Committee on Immunization Practices — which guides the vaccine recommendations set by the Centers for Disease Control and Prevention — veteran vaccine researcher Stanley Plotkin urged the committee to consider issuing preferential recommendations for flu vaccines that appear to have performance advantages over the competition.

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And Robin Robinson, the former director of the government’s Biomedical Advanced Research and Development Authority, told STAT recently that it was a market failure that more people did not get one of the two vaccines not grown in eggs, Flublok (recently acquired by Sanofi Pasteur) and Flucelvax, made by Seqirus.

But influenza experts at the CDC argue they aren’t in a position to indicate a preference for some vaccines, because there simply isn’t much evidence to say with certainty that the vaccines people believe are more protective truly are.

And given that the vaccines in question make up a fraction of the total market, that evidence may not be be forthcoming in the near future, they suggested. There were only 300,000 doses of Flublok produced this year and Seqirus made just over 20 million doses of Flucelvax. Those two products combined made up only 13 percent of the vaccine delivered to the U.S. market in 2017-2018.

Late next week the CDC is expected to release interim estimates of how well flu vaccine is working this year, and will follow up at the end of the season. But those studies aren’t large enough to assess how each individual brand of vaccine performed; they would need to be substantially larger to generate enough data to answer those questions, said Osterholm, who argued for increasing the sample size to prize out detailed effectiveness information.

“I would be very surprised if we had enough [use] in our network to actually look at those two specific vaccines this year,” lamented Alicia Fry, head of epidemiology for the CDC’s influenza division.

Dr. Dan Jernigan, director of CDC’s influenza division, said companies may at a point decide they want to conduct studies themselves to show these vaccines are more protective, in a bid to stand out from the crowd. He noted that Sanofi did just that with a high-dose vaccine it wanted to target to adults 65 and older — a key flu shot demographic.

Flu vaccines produced in eggs have been shown not to protect especially well against H3N2 viruses, with protection rates from that component generally hovering around 30 percent or lower.

To grow in eggs the viruses must mutate; the changes that take place can undermine the vaccine’s effectiveness by training the immune system to be on the lookout for the wrong viruses. It’s as if a police artist sketched a suspect with skinny sideburns when in fact the perpetrator sported a ZZ Top beard.

Those mutations don’t arise — or at least don’t arise as often and to the same degree — with vaccines produced in other mediums. Hence the interest in Flucelvax and Flublok.

But they are more expensive. And without expert guidance on why the extra cost might be worth it, individuals and people planning workplace flu shot clinics might be inclined to go for the lower priced option.

A regular flu shot might cost in the $15 to $18 range. But Flucelvax costs a bit more, a little over $20. And Flublok is at the far end of the price spectrum, at $45 a dose.

Robinson, who is now a consultant with a British biotech called IntraBio, argued that the government could play a role in encouraging more use of these more expensive vaccines by offering coupons or rebates.

Still, some experts suggest the CDC needs to be careful about issuing preferential recommendation. If it’s not based on evidence, the advice could well turn out to be misguided. With always-complicated influenza, what seems intuitive could still be wrong.

Case in point: For years flu vaccines targeted three viruses — the influenza A viruses H1N1 and H3N2, plus one of two families of influenza B viruses. Seeing a chance to stand out in a crowded market, some companies turned their 3-in-1 shot into a 4-in-1, adding the other B.

But in Canada, the trivalent vaccine — the 3-in-1 — is still most commonly used. This year’s formulation included the wrong B virus; the experts who advised on which vaccines should go into the flu shot predicted wrong. And yet, a study released last week suggested Canadians who got the flu shot got protection against flu B that was virtually as good as what was seen in Australia’s last winter — and Australia only uses the 4-in-1 shot.

“The strain isn’t in the damn vaccine, and it’s giving cross protection,” Osterholm said.

Dr. Danuta Skowronski, an influenza epidemiologist at the British Columbia Center for Disease Control, led the study that showed this flu B cross protection; she noted it’s not the first time this puzzling flu B phenomenon has been seen. It just goes to show how careful one needs to be about drawing conclusions about the effectiveness of flu vaccines, she said.

“I think it’s OK for individuals to make that decision,” Skowronski said of people who decide they want to choose the specific flu shot that they get.

“But on a population level, we have to be much more fastidious about the level of evidence available,” she said. “I think we’ve learned previously that when you jump to conclusions with influenza you pay for it later.”