If you had a flu shot last fall or winter, you might have learned the hard way that the vaccine didn’t work as well as usual. Now, researchers think they know why: a mutation that enabled some flu viruses to beat the vaccine.
When we get a flu shot, our immune cells crank out antibodies that recognize and attach to a viral protein known as hemagglutinin, thus disabling the virus. However, flu viruses continually evolve new versions of hemagglutinin that the antibodies don’t recognize. That means the protection provided by one year’s shot typically doesn’t carry over into the next year, and manufacturers regularly have to upgrade their formulations.
To determine the composition of each year’s vaccine, scientists with the World Health Organization (WHO) survey the virus strains that are on the loose and then try to forecast which ones will be making people sick when flu season hits. Even though patients don’t start getting the shots until the fall, WHO has to deliver its recommendations in February (or September for the Southern Hemisphere) to allow enough time for preparation and delivery of the vaccine. “It’s very hard to predict what [viral strains] will be circulating the next season,” says viral immunologist Scott Hensley of the Wistar Institute in Philadelphia, Pennsylvania. “It’s a bit of a guessing game.”
Last year, WHO was missed the mark: The vaccine conferred only 19% protection, versus as much as 60% in other years.
Researchers know what some of the problems were. A flu vaccine contains a mixture of virus strains, and the 2014 to 2015 shots included a strain of the H3N2 flu virus first isolated in Texas in 2012. The WHO scientists thought the Texas strain would predominate through the winter, but instead three other H3N2 varieties surged. Although researchers have uncovered several hemagglutinin-modifying mutations in these renegade H3N2 viruses, they weren’t sure which enabled the viruses to dodge the vaccine.
To find out, Hensley and colleagues created a lab version of the Texas strain as their standard of comparison. The team then engineered several varieties of this virus, each of which carried one of the candidate mutations in hemagglutinin. Next, the researchers mixed the viruses with blood from sheep and ferrets that had recovered from infections with the control Texas strain. This test is a common way to determine how tightly antibodies attach to the viruses, an indicator of how much protection they provide against infection.
As Hensley and colleagues expected, antibodies in the blood samples reacted strongly to the control Texas virus. But as the researchers conclude online today in Cell Reports, the antibodies were a poor match for several of the viruses that harbored mutations. The mutation with the most powerful effect, known as F159S, switches the identity of a single amino acid on the top of hemagglutinin.
The scientists saw a similar picture when they tested blood samples from people who had been immunized with the 2014 to 2015 vaccine. Antibodies in the blood latched onto the standard Texas virus, but modified viruses carrying the F159S mutation triggered a much weaker effect. “They were able to escape or avoid human antibody responses,” Hensley says, suggesting that this mutation is largely responsible for the poor performance of last year’s vaccine.
For this year’s vaccine, WHO recommended that manufacturers replace the Texas strain with one nabbed in 2013 in Switzerland. It contains several of the mutations the researchers tested, such as F159S. Hensley and colleagues found that antibodies from sheep that had recovered from a bout with the Swiss strain reacted strongly to all of the mutation-carrying viruses, including those with the F159S mutation.
“This is a solid piece of work,” says immunologist Alain Townsend of the University of Oxford in the United Kingdom. But it’s not the final word on which mutations allowed the viruses to escape the vaccine, he says. “There’s a lot more [research] that can be done with more mutations.”
In the meantime, production of this year’s vaccine containing the Swiss strain is already underway, and patients should be lining up to receive their shots in a few months. Says Gillian Air, a virologist at the University of Oklahoma College of Medicine in Oklahoma City: “We are hopeful that this year’s outcome will be better.”