Flu season comes around like clockwork every year, and sooner or later everyone gets infected. The annual flu shot is a key part of public health efforts to control the flu, but the vaccine's effectiveness is notoriously poor, falling somewhere from 40% to 60% in a typical year.

A growing body of evidence suggests that a history of exposure to influenza virus might be undermining the effectiveness of the annual flu vaccine. Partial immunity developed during prior flu seasons—either through natural infection or vaccination—might interfere with the body's response to a new vaccine, such that vaccination mainly boosts the recognition of prior influenza strains but does little to create the ability to fight new strains.

Now, a research team has developed an approach to assess whether a vaccine activates the kind of immune cells needed for long-lasting immunity against new influenza strains. Using this technique, the researchers showed that the flu vaccine is capable of eliciting antibodies that protect against a broad range of flu viruses, at least in some people. These findings could aid efforts to design an improved flu vaccine that provides protection not only against old influenza viruses but also new ones.

The key to long-lasting immunity lies in lymph nodes, minuscule organs of the immune system positioned throughout the body. Easy to miss in healthy people, lymph nodes become swollen and tender during an infection as immune cells busily interact and multiply within them.

The first time a person is exposed to a virus—either by infection or vaccination—immune cells capture the virus and bring it to the nearest lymph node. There, the virus is presented to so-called naïve B cells, causing them to mature and start producing antibodies to fight the infection. Once the virus is successfully routed, most of the immune cells that take part in the battle die off, but a few continue circulating in the blood as long-lived memory B cells.

The second time a person is exposed to a virus, memory B cells quickly reactivate and start producing antibodies again, bypassing naive B cells. This rapid response quickly builds protection for people who have been reinfected with the exact same strain of virus, but it's not ideal for people who have received a vaccine designed to build immunity against a slightly different strain, as in the annual flu vaccine.

"If our influenza vaccine targets memory cells, those cells will respond to the parts of the virus that haven't changed from previous influenza strains," Ellebedy said. "Our goal is to get our immune system up to date with the new strains of influenza, which means we want to focus the immune response on the parts of the virus that are different this year."

To get decades-long immunity against the new strains, the flu strains from the vaccine need to be taken to the lymph nodes, where they can be used to train a new set of naïve B cells and induce long-lived memory B cells specifically tailored to recognize the unique features of the vaccine strains.

Our study shows that the influenza vaccine can engage both kinds of cells  in the germinal centers, but we still don't know how often that happens," Ellebedy said. "But given that influenza vaccine effectiveness hovers around 50%, it probably doesn't happen as often as we would like. That brings up the importance of promoting strategies to boost the germinal centers as a step toward a universal influenza vaccine.

Nature (2020). DOI: 10.1038/s41586-020-2711-0

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