The development and early clinical testing of the ExPEC4V conjugate vaccine against uropathogenic Escherichia coli.

OBJECTIVES: In this 'how it was done' narrative review, we provide a description of, and context for, the early development of a conjugate vaccine targeting extra-intestinal, pathogenic Escherichia coli (ExPEC), from its creation in the laboratory to its testing in a large, first-in-human phase Ib trial. SOURCES: We searched the Pubmed database for previous attempts to develop vaccines against ExPEC, and we provide data from laboratory and trial databases established during the development of ExPEC4V, the tetravalent conjugate vaccine candidate. CONTENT: Earlier attempts at ExPEC vaccines had mixed success: whole-cell or cell-lysate preparations have limited effectiveness, and though an early conjugate vaccine was immunogenic in animal models, its development stalled before extensive clinical testing could occur. The development of the current conjugate vaccine candidate, ExPEC4V, began at a population level, with an epidemiological survey to determine the most common E. coli serotypes causing urinary tract infections (UTI) in Switzerland, Germany and the USA. The O antigens of the four most prevalent serotypes were selected for inclusion in ExPEC4V. After its creation in the laboratory by means of an in vivo bioconjugation process engineered to occur within E. coli cells, ExPEC4V underwent toxicity and immunogenicity testing in animal models. It then underwent safety and immunogenicity testing in a first-in-human, phase Ib multicentre trial, whose population of healthy women with a history of recurrent UTI allowed for an additional, preliminary assessment of the candidate's clinical efficacy. IMPLICATIONS: Laboratory development and early phase I testing were successful, as the vaccine candidate emerged with strong safety and immunogenicity profiles. The clinical trial was ultimately underpowered to detect a significant reduction in vaccine-specific E. coli UTI, though it showed a significant decrease in the incidence of UTI caused by E. coli of any serotype. We discuss the findings, including the lessons learned.