An mRNA-based FimH nanoparticle vaccine against uropathogenic Escherichia coli confers protection in a mouse model of recurrent urinary tract infection

Abstract

Background Increasing antimicrobial resistance and the high health and economic burden of frequent, recurring urinary tract infections (rUTIs) drive the need for an efficacious UTI vaccine. Most UTIs are caused by uropathogenic E. coli (UPEC) expressing the virulence factor FimH, which mediates bladder colonisation. We have developed a lipid nanoparticle (LNP) mRNA vaccine, FimHDG-Ferritin, as a UPEC vaccine candidate. Methods FimHDG-Ferritin mRNA constructs were introduced into HeLa cells through mRNA-transfection to assess the generation of immune-accessible protein nanoparticles (PNPs) in vitro by native polyacrylamide gel electrophoresis and negative stain electron microscopy. Following this, induction of humoral and cellular responses were evaluated in female BALB/c AnNRj mice and Wistar rats following either 2 or 3 intramuscular administrations of the FimHDG-Ferritin mRNA vaccine. Finally, protective efficacy was assessed in a clinically relevant mouse model of rUTI. Results In vitro PNP formation of the FimHDG-Ferritin fusion protein with intact functional epitopes was confirmed. Immunogenicity was demonstrated in mice and rats; equivalent functional antibody levels were raised against homologous and heterologous UPEC strains. In a rUTI mouse model, FimHDG-Ferritin mRNA vaccine administration induced the highest levels of functional antibodies among protein subunit comparators and significantly reduced bladder bacterial load versus negative controls. Conclusion These preclinical data in rodents establish the FimHDG-Ferritin mRNA vaccine as a protective candidate vaccine to prevent UTI caused by UPEC, supporting consideration for phase 1 clinical evaluation.