We have recently shown that, in mice, early life antibiotic-driven imbalance of the gut microbiota leads to significantly dysregulated B and T cell responses to vaccines that are routinely administered to infants worldwide. However, the mechanisms by which the gut microbiota influence vaccine responses remain poorly understood.
We assessed antigen-specific antibody responses to multiple different vaccines including the PCV13, Infanrix Hexa, BCG, influenza, and meningococcal B vaccines in germ-free (GF) mice and assessed whether colonising GF mice via fecal microbiota transplant (FMT), probiotics, or with specific bacterial cultures altered responses to vaccination. To assess changes in immune cell populations induced by colonisation, we used multiparameter flow cytometry to assess a range of B cell and Tfh cell populations in the mediastinal lymph nodes, spleen and the peritoneum. Finally, to determine the role of pattern recognition receptors (PRRs), we assessed vaccine responses in mice deficient in key PRR signalling pathways.
We found that GF mice had impaired antibody responses to the PCV13, BCG, Infanrix Hexa and influenza vaccines but interestingly, not the meningococcal B vaccine. Responses to the polysaccharide conjugate vaccine, PCV13, were particularly impaired but could be restored to levels comparable to normally colonised (SPF) mice by administering the probiotic, Infloran, but not other bacterial monocultures, to GF mice. We found that GF mice had significantly fewer B-1a and B-1b cells in the peritoneum following immunisation with PCV13 compared to SPF mice. B-1 cells are innate-like B cells which have recently been shown play an important role in Ig responses to polysaccharide antigens via a Myd88-/- dependent pathway. Consistent with these data Myd88-/- mice had significantly impaired antibody responses to the PCV13 vaccine.
Our findings indicate that the microbiota modulates the immune response to the PCV13 vaccine through a B-1 cell and MyD88 dependent pathway.