Vaccines that could effectively prevent Pseudomonas aeruginosa pulmonary
infections in the settings of
cystic fibrosis (CF) and
nosocomial pneumonia could be exceedingly useful, but to date no effective
immunotherapy targeting this pathogen has been successfully developed for routine use in humans. Evaluations using animals and limited human trials of
vaccines and their associated immune effectors against different P. aeruginosa
antigens have suggested that antibody to the conserved surface
polysaccharide alginate, as well as the flagellar
proteins, often give high levels of protection. However,
alginate itself does not elicit protective antibody in humans, and flagellar
vaccines containing the two predominant serotypes of this
antigen may not provide sufficient coverage against variant flagellar types. To evaluate if combining these
antigens in a
conjugate vaccine would be potentially efficacious, we conjugated
polymannuronic acid (PMA), containing the blocks of
mannuronic acid conserved in all P. aeruginosa
alginates, to type a
flagellin (FLA) and evaluated immunogenicity, opsonic killing activity, and passive protective efficacy in mice. The PMA-FLA conjugate was highly immunogenic in mice and rabbits and elicited opsonic
antibodies against mucoid but not nonmucoid P. aeruginosa, but nonetheless rabbit antibody to PMA-FLA showed evidence of protective efficacy against both types of this organism in a mouse lung
infection model. Importantly, the PMA-FLA
conjugate vaccine did not elicit
antibodies that neutralized the
Toll-like receptor 5 (TLR5)-activating activity of
flagellin, an important part of innate immunity to flagellated microbial pathogens. Conjugation of PMA to FLA appears to be a promising path for developing a broadly protective
vaccine against P. aeruginosa.