A multifaceted immune response to the flu

Vaccines work by triggering an immune response to a bacteria or virus so that our bodies are already protected when we encounter it. Many vaccines, like the measles vaccine, produce protective immunity that can last rest of our lives. So, how come we need to get the flu shot every year?

It’s because, unlike the measles virus, flu is constantly evolving to escape our defenses. It mutates rapidly every year, changing so much that new strains make last year’s immune response old news. To do this, the flu needs to change so much that it’s no longer recognized by anti-flu antibodies, immune proteins that can bind to viruses and block their ability to infect us.

“Our immune system is famous for is making a lot of different antibodies,” Bloom said, noting that other studies have estimated that humans can make at least a trillion different possible antibodies. “Obviously they’re not all binding to flu, but even if a small fraction does, there’s going to be a lot of antibodies binding to flu.”

In theory, the more multifaceted our antibodies, the harder it should be for the virus to evolve a way past them. So, Bloom wondered, how can a virus, even one as ever-changing as flu, outrun all those antibodies?

Flu’s escape route

“That was really our question: What are the mutations that help the virus escape human immunity?” Bloom said.

To address this, Lee zeroed in on hemagglutinin, or HA, a viral protein that flu uses to infect our cells. She used human sera, a blood fraction rich in many different antibodies, to examine the effects of different mutations in HA. She tested whether each possible mutation to HA allowed the virus to survive treatment with human sera and go on to infect cells. She then sequenced the gene for HA to pinpoint the mutation that made it possible for flu to pass the antibody gauntlet.

Lee used sera drawn from blood that was donated by 16 healthy volunteers between 2009 and 2010 and banked in Fred Hutch’s Infectious Disease Sciences Biospecimen Repository. The HA she used was derived from a flu strain that was included in the flu vaccine from 2010 to 2012.

The results startled Lee and Bloom. In most cases, they found that a single mutation to HA allowed the virus to escape 90% of the sera’s neutralizing power.

“This viral protein has over 500 different positions that antibodies could be binding to. By changing just one of those, the potency of the [anti-flu] immunity goes down 10-fold,” Bloom said, though it’s not yet clear why.

Different person, different route

When Lee performed the same experiment using sera from different volunteers, she saw that flu escaped immunity via a different mutation in every person. So she tested whether a mutation that enabled immune escape in one person gave flu the same advantage in a different person.

The outcome of this experiment really surprised the team. They found that a mutation that helped flu slip past the antibody blockade in one person had little effect against the antibodies from another.

“It’s a remarkable finding that suggests that from the perspective of all the viral mutants that are constantly appearing, people look very, very different even if they all have good immunity to the specific strain in the flu vaccine,” Bloom said. “It could be the case that for some viral mutants, there are pockets of the population that will then be much more susceptible to that mutation.”

It doesn’t mean that you shouldn’t get vaccinated. Instead, Bloom hopes that someday this work will help scientists improve the vaccine.

“The ultimate goal of vaccine research is to induce immunity that the virus cannot escape,” he said. “By understanding how flu escapes current human immunity, hopefully we can understand how to tailor new vaccines that make this escape harder.”

Seeking the source of human variation in immunity

In collaboration with Dr. Scott Hensley at the University of Pennsylvania, Lee and Bloom also began investigating why the immunity of people may look so different, even among those who received the same flu vaccine.

For that, they used ferrets, which are not as genetically similar as inbred strains of laboratory mice. Lee found that, in contrast to humans, vaccinated ferrets that had never been previously exposed to the flu shared gaps in immunity.

The ferrets had identical histories of flu exposure. People, however, do not. This preliminary finding (with the caveat, of course, that ferrets are not humans) supports the idea that our immune history — the times each person has been exposed to flu, when, and to which strains — shapes the variation in our immune responses to the virus, Bloom said.

The team is currently exploring this hypothesis by looking at anti-flu immunity in sera from young children who (like the ferrets) have only been exposed to flu once. They would also like to repeat the work from this paper using sera from people from whom the infecting flu virus strain is known.

The upshot of Bloom and Lee’s findings — you met a flu strain ideally evolved to slip past your antibodies — may be cold comfort as you shiver under your five layers of quilts. Unfortunately, a vaccine that protects from all flu variants has yet to be translated from hot research topic to real-life vaccine. But as you watch your family sail through flu season, take this to heart: next time, it could be them.