Immunogenicity and safety of a tetravalent E. coli O-antigen bioconjugate vaccine in animal models

Background: Extra-intestinal pathogenic Escherichia coli (ExPEC) are major human pathogens; however, no protective vaccine is currently available. We assessed in animal models the immunogenicity and safety of a 4-valent E. coli conjugate vaccine (ExPEC-4V, serotypes O1, O2, O6 and O25 conjugated to Exotoxin A from Pseudomonas aeruginosa (EPA)) produced using a novel in vivo bioconjugation method. Methods: Three doses of ExPEC-4V (with or without aluminum hydroxide) were administered to rabbits (2 mu g or 20 mu g per O-antigen, subcutaneously), mice (0.2 mu g or 2 mu g per O-antigen, subcutaneously) and rats (0.4 mu g or 4 mu g per O-antigen, intramuscularly). Antibody persistence and boostability were evaluated in rats using O6-EPA monovalent conjugate (0.4 mu g O-antigen/dose, intramuscularly). Toxicity was assessed in rats (16 mu g total polysaccharide, intramuscularly). Serum IgG and IgM antibodies were measured by ELISA. Results: Robust antigen-specific IgG responses were observed in all animal models, with increased responses in rabbits when administered with adjuvant. O antigen-specific antibody responses persisted up to 168 days post-priming. Booster immunization induced a rapid recall response. Toxicity of ExPEC-4V when administered to rats was considered to be at the no observed adverse effect level. Conclusions: ExPEC-4V conjugate vaccine showed good immunogenicity and tolerability in animal models supporting progression to clinical evaluation. (C) 2016 Elsevier Ltd. All rights reserved.