Abstract
Despite numerous efforts to develop an effective vaccine against Pseudomonas aeruginosa, no vaccine has yet been approved for human use. This study investigates the utility of the P. aeruginosa inherently produced polyhydroxyalkanaote (PHA) inclusions and associated host–cell proteins (HCP) as a particulate vaccine platform. We further engineered PHA inclusions to display epitopes derived from the outer membrane proteins OprF/OprI/AlgE (Ag) or the type III secretion system translocator PopB. PHA and engineered PHA beads induced antigen-specific humoral, cell-mediated immune responses, anti-HCP and anti-polysaccharide Psl responses in mice. Antibodies mediated opsonophagocytic killing and serotype-independent protective immunity as shown by 100% survival upon challenge with P. aeruginosa in an acute pneumonia murine model. Vaccines were stable at 4 °C for at least one year. Overall, our data suggest that vaccination with subcellular empty PHA beads was sufficient to elicit multiple immune effectors that can prevent P. aeruginosa infection.
Highlights
P. aeruginosa is a frequently multiple drug-resistant Gram-negative bacterium that is a ubiquitous opportunistic human pathogen causing life-threatening nosocomial infections, affecting immunocompromised people worldwide [1,2]
The recent Phase II/III clinical trial testing the translational fusion of the OMPs OprF and OprI recombinantly produced by Escherichia coli (IC43 vaccine) was unsuccessful to induce the desired immune responses and reduce mortality
PHA beads induced functional antibodies leading to opsonophagocytic killing and an overall serotype-independent immune response that protected mice against acute infection by P. aeruginosa
Summary
P. aeruginosa is a frequently multiple drug-resistant Gram-negative bacterium that is a ubiquitous opportunistic human pathogen causing life-threatening nosocomial infections, affecting immunocompromised people worldwide [1,2] This bacterium, which causes chronic lung infections in people with cystic fibrosis, is extremely adaptive and can survive in a wide range of environments, including different hosts such as plants, animals, and humans [3,4]. We previously bioengineered P. aeruginosa using its inherently assembled polyhydroxyalkanoate (PHA) inclusions as carrier for its own antigens [11] This approach explored engineering of the P. aeruginosa PHA synthase (PhaC1) that catalyzes the polymerization of coenzyme A thioesters of medium chain length 3-hydroxy fatty acids (MCL) to PHA, while PhaC1 remains covalently linked to the surface of the PHA inclusions serving as anchor to display antigens of interest [12]. To properly evaluate the utility of P. aeruginosa-derived antigen-coated PHA beads as the particulate P. aeruginosa vaccine requires the further assessment of the functionality of the immune response, such as the analysis of protective immunity by challenging vaccinated animals with the pathogen
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