A bioconjugate vaccine containing the O-antigens of four Escherichia coli serotypes (ExPEC4V) was well tolerated and elicited functional antibody responses against all vaccine serotypes in healthy adult women with a history of recurrent urinary tract infection (UTI), according to results from a phase 1b trial published ahead of print in Lancet Infectious Diseases.1 E coli is the pathogen responsible for 80% to 85% of uncomplicated UTIs.2 Prophylactic vaccines targeting uropathogenic E coli or UTIs in general are not presently available, nor are any candidates in late-phase clinical trials.
In an email interview with Infectious Disease Advisor, lead investigator Angela Huttner, MD, of the Geneva University Hospitals and Faculty of Medicine in Geneva, Switzerland explained the rationale for the development of an E coli vaccine. “E coli is by far the leading cause of urinary tract infections, but it is also the most frequent cause of bloodstream infections. Like other Gram-negative bacteria, E coli is becoming increasingly resistant to antibiotics, so preventive measures are needed. Meanwhile, antibiotics can have serious side effects and other costs.”
In the study (ClinicalTrials.gov identifier: NCT02289794), Dr Huttner and colleagues randomly assigned 188 patients to receive a single injection of either intramuscular ExPEC4V (n=93) or placebo (n=95). ExPEC4V contains 4 extraintestinal pathogenic E coli serotypes (O1A, O2, O6A, and O25B). Serotypes O1A, O2, O6A, and O25B are the most frequently noted in a pretrial epidemiological survey of Swiss urinary isolates, and are also the E coli serotypes most frequently associated with bacteremia.
The mean age of participants was approximately 42 in both the active-treatment and placebo arms. Patients had a median of 4 UTIs in the year prior to enrollment.
Results showed that the incidence of adverse events, the study’s primary outcome, was similar in the vaccine and placebo recipients in the modified intention-to-treat population. Of the 93 patients who received the target-dose vaccine, 56 (60%) experienced at least 1 adverse event that was possibly, probably, or certainly related to injection, compared with 47 of 95 patients (49%) who received placebo. The most common treatment-related adverse events (occurring in ≥2% of patients) were injection site erythema, injection site pain, and injection site swelling. No severe or serious adverse events related to the vaccine were observed during the 9-month follow-up period.
Immunogenicity, as measured by immunoglobulin G (IgG) geometric mean titres of vaccine-specific serum antibodies; antibody functionality, as assessed by the opsonophagocytic killing (OPK) assay; the number and incidence of UTIs attributable to vaccine-specific serotypes; and the intensity and duration of clinical symptoms were evaluated as secondary outcomes. Significant IgG responses for all serotypes were seen in the active treatment group: at day 30 compared with baseline, O1A, 02, 06A and 025B titres were 4.6 times higher, 9.4 times higher, 4.9 times higher, and 5.9 times higher respectively (overall P <.0001). Activity measured by the OPK assay showed antibody functionality. Vaccine efficacy was not demonstrated for vaccine-specific serotype UTI events, and no statistically significant between-group differences were found for symptom type, severity, and duration.
“In conclusion, the tetravalent ExPEC4V O-conjugate candidate vaccine was well tolerated and safe,” wrote the investigators. “In a proof-of-concept assessment, the candidate vaccine elicited strong, durable, and functional immune responses. Preliminary data demonstrate a reduction in UTIs with high bacterial counts, raising optimism that ExPEC conjugates might be able to prevent invasive disease such as bacteraemia. Further studies of higher doses and different formulations of the candidate vaccine are warranted.”
- Huttner A, Hatz C, van den Dobbelsteen G, et al. Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial [published online February 23, 2017]. Lancet Infect Dis. 2017. doi:10.1016/S1473-3099(17)30108-1
- Nicolle LE. Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis. Urol Clin North Am. 2008;35:1-12, v. doi:10.1016/j.ucl.2007.09.004