In a new study, NIAID-supported researchers describe in mice how the bacteria that naturally colonize the gut may help mount a strong immune response to a seasonal flu vaccine. Their findings also suggest that antibiotic treatment, which decreases the number and diversity of resident gut bacteria, may reduce the immune response to the vaccine. Understanding how gut bacteria affect vaccine responses may help scientists develop new strategies to enhance vaccine-induced immunity. The researchers report their results in the Sept. 2014 issue of Immunity.
One type of seasonal flu vaccine approved by the Food and Drug Administration primarily contains hemagglutinin, an influenza protein, from three different flu strains predicted to circulate that year. Known as a subunit vaccine because it contains only a component of the influenza virus, it also does not contain an adjuvant, a substance included in some vaccines to boost protective immune responses.
In a 2011 study of healthy adults’ immune responses to this seasonal flu vaccine, researchers led by Bali Pulendran, Ph.D., of Emory University uncovered an association between antibody responses to the vaccine and expression of Toll-like receptor 5 (TLR5). TLR5 stimulates an immune response by detecting flagellin, a component of the tail-like appendages, or flagella, used by some bacteria—including those naturally found in the gut—to propel themselves. The potential role of TLR5 in immune responses to a viral vaccine was unclear but intriguing, because flagellin is not a component of viruses.
Results of Study
In the current study, Dr. Pulendran and colleagues compared immune responses to the flu vaccine in various groups of mice. They found that mice lacking TLR5, germ-free mice—those born and raised with no microbes—and mice treated with antibiotics all had poor antibody responses to the vaccine compared to normal mice.
Antibiotic treatment affected multiple microbial communities, and no single bacterial species was associated with changes in the immune response. However, antibiotic treatment that specifically killed bacteria in the gut led to poor antibody responses to the vaccine, similar to those of mice given multiple antibiotics. Colonizing germ-free or antibiotic-treated mice with flagellated bacteria before vaccination or administering flagellin with the vaccine restored strong vaccine-induced antibody responses.
Further experiments revealed that flagellin interacted with TLR5 on two different types of white blood cells critical for the production of antibody: macrophages, which help coordinate immune responses, and B cells, which develop into antibody-producing cells.
Responses to vaccines that contained an adjuvant or weakened viruses appeared to be less affected by the microbiota. For example, treating mice with antibiotics did not affect the animals’ immune responses to the adjuvanted tetanus-diphtheria-pertussis (Tdap) vaccine or the yellow fever vaccine, which contains weakened virus. This suggests that subunit vaccines without adjuvants rely more heavily on the microbiota to activate antibody production by signaling through TLR5.
The researchers describe in mice how the intestinal microbiota plays a critical role in generating antibody responses to subunit vaccines. Their findings suggest that antibiotic treatment before vaccination may reduce vaccine-induced protective immunity in people. They also raise the possibility of developing strategies to improve immune responses to vaccines by modifying the microbiota.
Additional studies are needed in people to determine whether the microbiota has a similar effect on vaccine-induced immune responses and to examine the impact of antibiotic treatment on immune responses to vaccines.
Oh JZ, Ravindran R, Chassaing B, Carvalho FA, Maddur MS, Bower M, Hakimpour P, Gill KP, Nakaya HI, Yarovinsky F, Sartor RB, Gewirtz AT, Pulendran B. TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity (2014)