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Researchers led by a team at Washington University School of Medicine in St. Louis have developed an approach to assess whether a flu vaccine activates the types of immune cells that will be needed for long-lasting immunity against new influenza strains. The team demonstrated in human volunteers that the flu vaccine is capable of eliciting antibodies that protect against a broad range of flu viruses, at least in some people. Their findings, published in Nature, could help efforts to design an improved flu vaccine that provides protection not only against old influenza viruses but also new ones.

“Every year, about half of the U.S. adult population gets vaccinated against influenza,” said Ali Ellebedy, PhD, an assistant professor of pathology and immunology at Washington University. “It’s necessary for public health, but it’s also incredibly expensive and inefficient. What we need is a one-and-done influenza shot, but we are not there yet. Anything that helps us understand how immunity develops in the context of prior exposures would be important as we try to make a better vaccine.” Ellebedy is senior author of the team’s paper, which is titled, “Human germinal centres engage memory and naïve B cells after influenza vaccination.”

Flu season comes around every year, and sooner or later anyone may get 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. Seasonal influenza vaccination in humans primarily stimulates pre-existing B cells. “Seasonal influenza viruses kill 290,000 to 650,000 people globally every year,” the authors wrote. As the virus drifts, novel antigenic targets emerge, creating a pressing need for the annual vaccine to engage new B cell clones that recognize such targets.”

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.

The key to long-lasting immunity lies in lymph nodes. The first time a person is exposed to a virus, whether due to infection or through 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 recall response contributes to ‘original antigenic sin’ [OAS], the selective boosting of antibody specificities from prior exposures to influenza virus antigens,” the authors noted. But while this rapid response swiftly builds protection for people who have been reinfected with the exact same strain of virus, 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. To find out what happens inside lymph nodes after influenza vaccination, Ellebedy, teamed up with co-authors Rachel Presti, MD, PhD, an associate professor of medicine, and Sharlene Teefey, MD, a professor of radiology at Washington University.

Presti led a team at the Infectious Disease Clinical Research Unit that coordinated the sampling of blood and lymph nodes from healthy volunteers before and after vaccination. Guided by ultrasound imaging, Teefey carefully extracted the germinal centers (GCs) that hold immune cells from underarm lymph nodes of eight healthy, young volunteers who were vaccinated with the 2018–19 quadrivalent influenza vaccine. That vaccine was designed to protect against four different strains of influenza virus. The immune cells were extracted prior to vaccination, and again at one, two, four and nine weeks after vaccination.

Ellebedy and colleagues then analyzed the immune cells in the germinal centers to find the ones that had been activated by vaccination. ­The results showed that in three volunteers, both memory B cells and naïve B cells in the lymph nodes responded to the vaccine strains, indicating that the vaccine had initiated the process of inducing long-lasting immunity against the new strains. “To our knowledge, the current study provides the first direct evidence of vaccine-induced GC responses in humans, but it does have some limitations,” they acknowledged. “We detected HA-binding GC B cells in only three participants despite readily detectable peripheral B cell responses in all eight participants.” It is possible that the lymph nodes sampled in the other five participants were not the primary draining lymph nodes, they noted. It’s also possible that vaccination just didn’t elicit a GC response in these other participants.

“We propose that suboptimal GC B cell responses after influenza vaccination result in a more pronounced OAS due to inefficient engagement of naïve B cells targeting novel epitopes,” the team further commented. “High levels of baseline antibodies against conserved influenza epitopes may interfere with the formation or continued maintenance of vaccination-induced GC responses in humans. If so, new vaccine formulations that promote robust GC reactions are more likely to induce a more diverse antibody response against circulating and emerging influenza virus strains.”

As Ellebedy noted, “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. 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.”

Elledeby and the team’s colleagues for the study included co-senior authors Steven Kleinstein, PhD, a professor of pathology at Yale University School of Medicine, and Andrew Ward, PhD, a professor of integrative structural and computational biology at Scripps Research Institute, as well as co-first authors Jackson Turner, PhD, a postdoctoral researcher who works with Ellebedy, Julian Zhou, a graduate student in Kleinstein’s lab, and Julianna Han, PhD, who works with Ward.

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