Hospital acquired infections such as Pseudomonas aeruginosa (PA) affect up to 10% of patients admitted to acute care hospitals, representing upwards of 10 million hospital days annually in North America. PA infection results in significant patient morbidity and mortality (ca. 80,000 deaths in North America per year due to PA ventilator-associated pneumonia in intensive care unit (ICU) patients). Patients considered being at risk of PA infections are those whose immune systems have been weakened because of accident, disease or other causes. PA infections are commonly found in patients with cancer, cystic fibrosis, AIDS, burn wounds or who have a long history of hospitalization. Although antibiotic therapy is employed in treatment it is often incapable of resolving the infection. This lack of effectiveness is due in part to antibiotic resistance of the bacteria, difficulty in establishing an exact diagnosis, and, paradoxically, antibiotic use which selects resistant bacteria. New approaches are needed to control infection which are based on prevention. The research described here is such an approach. Our laboratory has investigated PA infection for the last 10 years and has demonstrated the feasibility of preventing PA infection by using novel approaches to both active vaccination or by passive use of antibody therapeutics. Both these methods attack the infection process at its initial stage: attachment of the bacterium to the host's cell surfaces. However, the problem exists that there are multiple strains of PA bacteria and an efficacious vaccine or antibody therapeutic must account for all existing strains of this pathogen. In this proposal we are developing 1) a novel consensus sequence vaccine approach forcoverage against all strains of PA, 2) a constrained peptidomimetic of the immunogen to enhance immunogenicity when used as an active peptide vaccine to block bacteria attachment and 3) monoclonal antibodies (prepared to selected peptide immunogens) that are broadly cross-reactive with maximal affinity for use as an antibody therapeutic.
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