The FluMist mystery: Why was it effective one year but not now?

What led to the abrupt fall of FluMist, until recently the preferred alternative to the injectable influenza vaccine for younger children?

No one is quite sure, but there were hints of trouble for the past three flu seasons.

In June, an advisory panel to the Centers for Disease Control and Prevention decided that the nasal spray was so ineffective that it should not be used by anyone during the 2016-2017 flu season.

Just two years ago, after reviewing several studies from 2006-2007 that suggested the spray was more effective in kids than the injectable forms of the vaccine, that same panel had recommended FluMist as the preferred alternative for most kids ages 2 to 8.

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What changed?

“We don’t understand what it is,” said David Kimberlin, a professor of pediatrics at the University of Alabama at Birmingham, adding that academics and researchers at MedImmune, which makes the vaccine, are working to get answers.

FluMist is a live attenuated vaccine, which means it contains a weakened version of the virus that does not make the recipient ill. Instead, it – like injectable forms of the vaccine, which contain killed versions of the virus – sparks the body’s immune system to create antibodies.

Among several studies the panel considered when it made its 2014 recommendation was a 2004 randomized controlled trial that found a 55 percent reduction in the number of flu cases among children who received the nasal spray compared with those who got the shot. Those results were reported in the New England Journal of Medicine in 2007.

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Three months after it made the recommendation, however, the CDC received some troubling data: During the 2013-2014 flu season, the nasal spray showed no measurable effectiveness in kids ages 2 to 8 against the pandemic H1N1 virus, the predominant type of influenza virus circulating that year.

As a result, the panel in February 2015 did not renew its preference for FluMist for the next flu season, although it was still considered a viable option.

At that meeting, the panel also heard that the spray had performed poorly in the 2014-2015 season.

Because vaccine makers have to guess months ahead of time what the predominant strains of the virus will be, designing the correct combination is always a gamble.

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That time, they guessed wrong. More than two-thirds of the H3N2 versions of the virus circulating in the United States during the 2014-2015 season were different from the H3N2 versions in both the nasal spray and the injectable vaccines. So all versions of the vaccine – shots and spray – performed poorly.

Now, looking at this winter’s flu season, the CDC says data shows that FluMist’s efficacy among children 2 to 17 was only 3 percent, essentially providing no protective benefit.

AstraZeneca, the parent company of MedImmune, said the CDC’s data for 2015-2016 is in sharp contrast with its own studies as well as preliminary findings by public health officials abroad.

“These findings demonstrate that FluMist . . . was 46-58 percent effective overall against the circulating influenza strains during the 2015-2016 season,” the firm said in a release last month.

U.S. sales of FluMist in 2015 totaled $206 million.

In any given flu season, vaccine effectiveness varies. One factor is how well the vaccines match the virus that is actually prevalent. Other factors include the age and general health of the recipient. In the overall population, the CDC says studies show vaccines can reduce the risk of flu by about 50 to 60 percent when the vaccines are well matched.

Now, researchers are trying to find a common factor behind FluMist’s recent incidents of poor performance.

There’s not a clear answer, said Henry Bernstein, a professor of pediatrics at Hofstra Northwell School of Medicine in New York and an ex-officio member of the committee on infectious diseases for the American Academy of Pediatrics.

“We know that the influenza virus itself is totally unpredictable from one year to the next,” he said.

Among the questions researchers are considering is why the strain of pandemic H1N1 used in the 2013-2014 flu season didn’t perform well. The manufacturer’s attempt to fix it in following seasons also did not work.

Several years ago, the vaccine also went from incorporating three flu virus strains to four. Did that somehow reduce its effectiveness? The earlier studies demonstrating that the spray was more effective than the shots were based on the three-virus vaccine, not the four-virus version.

Researchers will investigate whether the vaccine loses effectiveness for some reason when given to children who have had many previous flu vaccinations.

Uncertainty comes with the territory for researchers. But it’s harder for the general public, especially kids.

“Once they found out about the nasal vaccine instead of the shot, they strongly, strongly preferred the nasal one,” said Elizabeth Howton of Falls Church, Va., who has an 8-year-old and a 10-year-old.

Howton said she fears the doubts surrounding the nasal spray will add to the skepticism some parents have about vaccines in general.

For her kids, there will be no skipping the vaccine, even though it means a shot. Howton said she expects to offer “copious bribes” to sweeten the deal.

“I know they will be very disappointed, but I will still get them vaccinated,” she said.

The recommendation not to offer FluMist shows that public health agencies are watching carefully, Bernstein said, and that should be reassuring for the public.

“People need to recognize and applaud the idea that this type of monitoring and evaluation happens continuously,” he said. “The CDC does evaluate the effectiveness of these public health initiatives, including vaccine effectiveness and safety.”

While people who don’t like needles will be disappointed, FluMist’s absence is not likely to lead to a vaccine shortage, experts say.

According to the CDC, the spray made up about 8 percent of the total projected supply of 176 million doses of vaccine being prepared for the upcoming flu season.

And despite the loss of this form of the vaccine, the CDC and other experts continue to strongly recommend that just about everyone 6 months and older get vaccinated because influenza can cause serious illness and is blamed for thousands of deaths each year.

“The importance of preventing flu hasn’t changed,” Kimberlin said. “What has changed is we have one less tool.”