Annual flu epidemics cause millions of cases of severe illness and up to half a million deaths every year around the world, despite widespread vaccination programs. A study published by Cell Press in Immunity reveals that gut microbes play an important role in stimulating protective immune responses to the seasonal flu vaccine in mice, suggesting that differences in the composition of gut microbes in different populations may impact vaccine immunity. The study paves the way for global public health strategies to improve the effectiveness of the flu vaccine.

"Our findings raise the possibility that antibiotic treatment prior to or during vaccination may impact immunity," says senior study author Bali Pulendran of the Emory Vaccine Research Center. "Another potential implication of our study is that we may be able to manipulate gut microbes in order to improve immune responses to the vaccine."

Vaccines are less effective in many parts of developing countries compared to industrialized areas, and a significant proportion of vaccinated individuals, especially the young and elderly, remain susceptible to infection. The underlying reasons for the lack of complete protection have not been clear, in part because relatively little is known about how vaccines elicit host immune responses.

In a previous study, Pulendran and his team found that the antibody response in healthy human adults vaccinated with the seasonal flu vaccine, known as trivalent inactivated influenza vaccine (TIV), depended on expression of a gene called Toll-like receptor 5 (TLR5). Because this gene encodes a cell-surface receptor that detects bacterial flagellin - a protein that makes up the whip-like appendage that helps bacteria move - the researchers suspected that gut microbes may influence immunity to flu vaccination.

Pulendran and his collaborators tested this possibility in the new study. Upon vaccination with TIV, mice that were genetically manipulated to lack TLR5 showed significantly reduced antibody responses compared with normal mice. Moreover, mice that were either raised in a germ-free environment or treated with antibiotics showed lower vaccine-induced antibody levels compared with germ-exposed mice. TLR5-deficient mice also showed reduced antibody responses to the polio vaccine, which is composed of specific viral molecules rather than an active virus, similar to TIV.

Taken together, the findings suggest that the effectiveness of inactivated, subunit vaccines in eliciting protective immune responses strongly depends on gut microbes. "In the future, it will be important to determine the impact of antibiotic treatment on immunity to vaccination in humans and to study whether differences in the composition of gut microbes in different populations can impact vaccine immunity," Pulendran says.