Prevention of Staphylococcus aureus infections by glycoprotein vaccines synthesized in Escherichia coli.

BACKGROUND: Staphylococcus aureus is a leading cause of superficial and invasive human disease that is often refractory to antimicrobial therapy. Vaccines have the potential to reduce the morbidity, mortality, and economic impact associated with staphylococcal infections. However, single-component vaccines targeting S. aureus have failed to show efficacy in clinical trials. METHODS: A novel glycoengineering technology for creation of a multicomponent staphylococcal vaccine is described. Genes encoding S. aureus capsular polysaccharide (CP) biosynthesis, PglB (a Campylobacter oligosaccharyl transferase), and a protein carrier (detoxified Pseudomonas aeruginosa exoprotein A or S. aureus α toxin [Hla]) were coexpressed in Escherichia coli. Recombinant proteins N-glycosylated with S. aureus serotype 5 or 8 CPs were purified from E. coli. RESULTS: Rabbits and mice immunized with the glycoprotein vaccines produced antibodies that were active in vitro in functional assays. Active and passive immunization strategies targeting the CPs protected mice against bacteremia, and vaccines targeting Hla protected against lethal pneumonia. The CP-Hla bioconjugate vaccine protected against both bacteremia and lethal pneumonia, providing broad-spectrum efficacy against staphylococcal invasive disease. CONCLUSIONS: Glycoengineering technology, whereby polysaccharide and protein antigens are enzymatically linked in a simple E. coli production system, has broad applicability for use in vaccine development against encapsulated microbial pathogens.

StaphVAX (Nabi).

StaphVAX is a bivalent polysaccharide- and protein-conjugated vaccine, directed against capsular Staphylococcus aureus types 5 and 8, which are associated with 80 to 90% of S aureus clinical infections. The vaccine is being developed by Nabifor the potential treatment of infections in kidney patients who are receiving peritoneal dialysis and are prone to serious staphylococcal infections [193495], [221403], [222643], [283114]. In February 2001, Nabi revealed that it was movingforward during the second quarter of 2001 with previously stated plans to conduct a boosting study of StaphVAX in patients with end-stage renal disease (ESRD). This study would be conducted in patients who were enrolled in the first phase III trial and the company expected completion by early 2002 [283114]. The company was also progressing with scale-up of the manufacturing process for commercial production of the vaccine. Nabi met with the FDA in December 2000 to review results from its phase III trial of StaphVAX in patients with ESRD. The FDA stated that a definitive demonstration of preventative efficacy in another well-designed, randomized and controlled clinical study would be required for licensing. At this time, Nabi was making plans for this second phase III trial, despite plans to appeal the FDA's decision [397729].