Every year, some unlucky people get the flu even though they’ve had their seasonal shot. One reason, according to a new study, might be their gut bacteria. Researchers have shown that, at least in mice, a strong immune response to the flu vaccine relies in part on signals from intestinal microbes. The findings could help explain variation in the response to the vaccine and suggest ways to maximize its effectiveness.
The microbes that inhabit our bodies—collectively known as the microbiome—may influence everything from obesity risk to food allergies. Recent studies have also shown that resident microbes affect how our immune system responds to infection. For example, mice with depleted microbiomes appear to be more susceptible to the flu. But it wasn’t clear what role the microbiome plays in the response to vaccines.
The new evidence came out of a curious observation that researchers revealed in a 2011 paper. Bali Pulendran, an immunologist at Emory University in Atlanta, and colleagues were looking for genetic signatures in the blood of people injected with the trivalent inactivated influenza vaccine—a mixture of three flu strains. They wanted to know whether the expression of specific genes in the immune system’s white blood cells correlated with the amount of vaccine—specific antibodies in the blood—which indicates how strongly a person’s immune system responds to the shot, and how much protection that person will gain against future infections. In a long list of genes associated with strong vaccine response, the researchers found an unexpected one: the gene that codes for a protein called toll-like receptor 5 (TLR5).
“We thought this must just be a coincidence,” Pulendran says. TLR5 is a sensor of flagellin, a protein that makes up the appendages of bacteria. Why would a receptor that interacts with bacteria in the gut have anything to do with the body’s response to a virus injected into muscle? Maybe, the group thought, B cells—the white blood cells that produce antibodies—receive a signal from bacteria that boosts their activity.
To explore that possibility, the researchers designed a new study using mice. They gave the flu vaccine to three different groups: mice genetically engineered to lack the gene for TLR5, germ-free mice with no microorganisms in their bodies, and mice that had spent 4 weeks drinking water laced with antibiotics to obliterate most of their microbiome.
Seven days after vaccination, all three groups showed significantly reduced concentrations of vaccine-specific antibodies in their blood—up to an eightfold reduction compared with vaccinated control mice, the group reports online today in Immunity. The reduction was less marked by day 28, as blood antibody levels appeared to rebound. But when the researchers observed the mice lacking Tlr5 on the 85th day after vaccination, their antibodies seemed to have dipped again, suggesting that without this bacterial signaling, the effects of the flu vaccine wane more quickly.
The researchers saw similar results when they gave mice a polio vaccine, which, like the flu shot, uses an inactivated virus and doesn’t contain so-called adjuvants—additives that boost the body’s immune response. Pulendran and colleagues suggest that these weaker, adjuvant-lacking vaccines rely more heavily on bacterial signaling. (They didn’t see the same results with the live virus in the yellow fever vaccine, for example.)
No specific type of bacteria seemed more important than another in prompting the vaccine response. But further experiments showed a major role for macrophages—immune cells that display pieces of the virus to activate B cells and that can also recognize flagellin. Pulendran’s favored explanation is that flagellin manages to break through the lining of the intestines to circulate in the body and activate B cells and macrophages, amping up antibody production. But where and how the interaction happens “is a huge mystery,” he says. “We don’t have the full answer.”
However, what they do know presents some interesting possibilities for human vaccines. “I think the implications of the work are fairly broad,” says David Artis, an immunologist at Weill Cornell Medical College in New York City who was not involved in the study. “It tells us that the microbiome is an additional component [of the vaccine response] that we didn’t previously appreciate.” He notes that people in industrialized countries seem to get more protection from flu vaccines than do residents of developing countries—a phenomenon that could be partially explained by variations in their microbiomes, though genetics, diet, and previous infections probably also play a role.
He cautions that the group would need to expose the mice to flu after vaccination to confirm that bacterial signals influence the vaccine-induced resistance to the virus. But if it does, future vaccines could try to mimic the effect of bacteria to prompt a bigger immune response. Several groups are already exploring flagellin as a possible adjuvant, though Artis suspects it’s not the only important microbial protein in play.
The results also raise questions about the role of antibiotics in vaccine response, says Paul Thomas, an immunologist at St. Jude Children’s Research Hospital in Memphis, Tennessee. People who are taking antibiotics when they get vaccinated could see depressed antibody levels “for a long time after,” he says. He suggests a follow-up study to measure antibody levels in people who start antibiotic treatment before getting the flu vaccine. Pulendran says his group plans to do just that for their next experiment.