Somewhere in the world right now there is one person harboring an important strain of the flu.
“In just two or three years … millions of infections will descend from that single person’s sneeze,” said Fred Hutchinson Cancer Research Center virologist Dr. Trevor Bedford.
That’s partly because flu spreads easily and partly because the virus evolves very rapidly. Its speedy evolution is the reason we need flu vaccines every year instead of one jab in childhood that confers lifelong protection like the measles shot, said Dr. Jesse Bloom, an evolutionary biologist and assistant member in Fred Hutch’s Basic Sciences Division.
“The measles viruses that we were at risk for in 1980 look to our immune systems pretty much like the same ones we’re at risk for now, and that’s not the case for flu,” Bloom said. “The reason we have to get this flu vaccine every year is that we have to try to make our vaccines to keep up with the virus’ evolution.”
The challenge for the many researchers around the world who work on flu vaccine development and production is predicting which of the thousands of flu strains floating around in the world will be the seminal bugs. These strains need to be included in yearly flu vaccines to protect the maximum number of people from infection. Depending on the type of vaccine, three or four strains from three different kinds of flu make up the annual flu shot: one each out of the hundreds of strains of influenza A subtypes H1N1 and H3N2, and one or two out of the hundreds of influenza B strains.
Choose wrong, and the vaccines will lose some or much of their precious efficacy, as happened in the 2003-2004 flu season, when a variant of H3N2 emerged too late to be part of the yearly shot. That strain caused the majority of human flu infections that year, according to the Centers for Disease Control and Prevention.
A global game of cat and mouse
Picking the strains to include in the vaccine is a massive global effort organized by the World Health Organization, fed by thousands of samples from 130 different influenza centers in 101 countries.
“The whole world is involved,” said Bedford, an assistant member in Fred Hutch’s Vaccine and Infectious Disease Division.
Scientists at central WHO Collaborating Centers then determine the genetic sequences of sampled strains and use laboratory tests to determine whether previous vaccines match these strains. They’re looking not only for strains that show up in sample after sample, but those that are recently on the rise and against which last year’s shot won’t protect.
That process takes months and has to be complete by mid-February the winter before the Northern Hemisphere’s flu season to give manufacturers the necessary six months to produce the vaccines. And then the effort starts all over again for the Southern Hemisphere’s winter.
Researchers like Bedford are working on ways to forecast the future of flu and help ease the burden of this huge endeavor. To do that, he has to understand how the virus evolves. It’s a unique way to study evolution, because unlike with most living creatures, viruses evolve quickly enough for scientists to watch them transform in real time.
“You can actually see the changes happening every year,” Bedford said. “If you really understand what’s going on, you should be able to predict, out of the strains that are circulating this year, which one will take over next year.”
Although Bedford emphasizes that today’s WHO-led flu vaccine design process works very well, he thinks that approaches like his that use mathematical models to predict next year’s most common strains could lead to more effective and cheaper vaccines. That’s because modeling relies specifically on sequencing viral genes, which costs less than the laboratory tests used now. Computational modeling could especially help pick out small but important differences in flu strains and therefore allow scientists to more precisely match strains included in the vaccine to circulating viruses, Bedford said.
“My suspicion is that we could eke out a few more points in efficacy on average,” he said, “which is not to say that the current vaccine is bad by any means.”
A lifelong flu vaccine?
Not only does flu evolve quickly, it turns out that the human immune system recognizes and targets those pieces of the virus that are among the fastest shape-shifters. In a recent study, Bloom and his colleagues put flu through the evolutionary wringer by making more than 10,000 different mutations, one at a time, to a single viral protein, hemagglutinin. This lollipop-shaped protein dots the surface of flu particles and is necessary both for the virus to attach to cells (the first step in a successful infection) and for our immune systems to recognize the bug.
Bloom’s team found that, overall, mutations in the lollipop-head piece of hemagglutinin were less likely to interfere with the virus’ ability to infect cells than mutations to the protein’s stick. And that outer head is the same portion of the protein that the immune system recognizes, whether it’s via immunity to natural infection or boosted by the flu vaccine.
“It’s not so much that our immune system isn’t able to target the virus, it’s that it targets parts of the virus that then change,” Bloom said.
Scientists don’t know whether that’s just unfortunate coincidence or if flu has evolved to trick our immune systems, Bloom said. But figuring out how to get a vaccine to direct our immune systems to recognize that less-variable lollipop stick of hemagglutinin would mean a shot that could protect for years, or maybe even a lifetime.
It’s not as simple as just adding that stick to current vaccine formulations though – most flu vaccines are made from live attenuated strains, meaning the entire virus is present in the shot with only minor changes so that it doesn’t make us sick. For whatever reason, the human immune system mostly ignores other parts of the virus.
Fred Hutch immunology researcher Dr. Justin Taylor hopes to lay the groundwork for a universal flu vaccine by finding those rare immune cells that recognize slower-changing parts of flu and figuring out how to use vaccination to boost those cells. Taylor, who opened his laboratory in Fred Hutch’s Vaccine and Infectious Disease Division earlier this year, studies the immune cells that produce antibodies, immune proteins that can bind and neutralize foreign invaders like the flu.
Antibodies that bind unchanging parts of flu exist – scientists have found people who produce antibodies that can bind many different flu strains because they target these stable areas common across strains. But it’s not clear why most people fail to produce similar antibodies, Taylor said.
Once Taylor finds the rare immune cells that could produce such antibodies, or at least better antibodies, he’ll be able to figure out whether vaccines do anything to these cells and, hopefully, how to ramp up vaccination’s effects on these cells to the point of creating a lifelong vaccine.
“I think that’s where we’d all like to get, where it’s a childhood vaccine – you give that series and you’re done,” Taylor said. “Even if … you needed a boost every 10 years, that would be a huge gain.”
But until that day, Taylor will line up every year for his annual flu shot.
“Wanting to make a better vaccine doesn’t mean that the current vaccine doesn’t work,” he said. “For me, better safe than sorry. I don’t like being sick.”
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Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.
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