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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

https://doi.org/10.1016/S1473-3099(17)30108-1Get rights and content

Summary

Background

Escherichia coli infections are increasing worldwide in community and hospital settings. The E coli O-antigen is a promising vaccine target. We aimed to assess the safety and immunogenicity of a bioconjugate vaccine containing the O-antigens of four E coli serotypes (ExPEC4V).

Methods

In this multicentre phase 1b, first-in-human, single-blind, placebo-controlled trial, we randomly assigned (1:1) healthy adult women with a history of recurrent urinary tract infection (UTI) to receive a single injection of either intramuscular ExPEC4V or placebo. The primary outcome was the incidence of adverse events among vaccine and placebo recipients throughout the study. Secondary outcomes included immunogenicity and antibody functionality, and the incidence of UTIs caused by E coli vaccine serotypes in each group. This study is registered with ClinicalTrials.gov, number NCT02289794.

Findings

Between Jan 20, 2014, and Aug 27, 2014, 93 women received target-dose ExPEC4V and 95 received placebo. The vaccine was well tolerated: no vaccine-related serious adverse events occurred. Overall, 56 (60%) target-dose vaccines and 47 (49%) placebo recipients experienced at least one adverse event that was possibly, probably, or certainly related to injection. Vaccination induced significant IgG responses for all serotypes: at day 30 compared with baseline, O1A titres were 4·6 times higher, O2 titres were 9·4 times higher, O6A titres were 4·9 times higher, and O25B titres were 5·9 times higher (overall p<0·0001). Immune responses persisted at 270 days but were lower than those at 30 days. Opsonophagocytic killing activity showed antibody functionality. No reduction in the incidence of UTIs with 103 or more colony-forming units per mL of vaccine-serotype E coli was noted in the vaccine compared with the placebo group (0·149 mean episodes vs 0·146 mean episodes; p=0·522). In post-hoc exploratory analyses of UTIs with higher bacterial counts (≥105 colony-forming units per mL), the number of vaccine serotype UTIs did not differ significantly between groups (0·046 mean episodes in the vaccine group vs 0·110 mean episodes in the placebo group; p=0·074). However, significantly fewer UTIs caused by E coli of any serotype were noted in the vaccine group compared with the placebo group (0·207 mean episodes vs 0·463 mean episodes; p=0·002).

Interpretation

This tetravalent E coli bioconjugate vaccine candidate was well tolerated and elicited functional antibody responses against all vaccine serotypes. Phase 2 studies have been initiated to confirm these findings.

Funding

GlycoVaxyn, Janssen Vaccines.

Introduction

Extraintestinal pathogenic Escherichia coli is the most frequent cause of bloodstream and urinary tract infections (UTIs),1, 2 and a noteworthy cause of other community-associated and health-care-associated infections.3 The worldwide emergence of multidrug-resistant extraintestinal pathogenic E coli has resulted in increased incidence of treatment failure, hospital admissions, and mortality, and intensified the economic burden on health-care systems and communities.2, 4 With an inadequate antibiotic pipeline5 and annual costs associated with UTIs and septicaemia in the USA of more than US$2 billion and $20 billion, respectively, a prophylactic vaccine targeting extraintestinal pathogenic E coli is urgently needed.6

The surface lipopolysaccharide-linked O-antigen contributes to E coli survival,7 and the production of anti-O-antigen antibodies confers protective effects against E coli infections.8 The clinical efficacy of multivalent glycoconjugate vaccines against Haemophilus influenzae type b, pneumococcal and meningococcal bacteraemia, and meningitis further supports the use of surface polysaccharides in conjugate vaccine development.9, 10, 11, 12 Although chemically conjugated E coli O-antigen vaccines seem to be safe and immunogenic in human beings,13, 14 production of multiple O-conjugates is technically difficult.15 Bioconjugation is an innovative technique allowing in-vivo synthesis and conjugation of polysaccharide structures to carrier proteins via appropriately engineered bacterial cells.16, 17, 18 We previously used the protein glycosylation machinery of E coli to produce a conjugate vaccine incorporating a genetically detoxified form of exoprotein A from Pseudomonas aeruginosa linked to the four O-serotype surface polysaccharide antigens of E coli serotypes.19

Research in context

Evidence before this study

We did a literature review of the cause and epidemiology of urinary tract infections, current therapies, and vaccine candidates. We searched the MEDLINE databases with the terms “urinary tract infection”, “cystitis”, and “uropathogenic Escherichia coli” for articles published in English between Jan 1, 1980, and Jan 13, 2017 (the date of our final search). Search terms were subsequently combined with: “placebo-controlled clinical trial”, “aetiology”, “epidemiology”, “prevalence”, “pathogenesis”, “therapy”, or “vaccine”. Some papers cited in the screened publications were also included, as were guidelines on urological infections, additional articles on antibiotic resistance and uropathogenic E coli pathogenicity, and information from company websites, government agencies, and the ClinicalTrials.gov registry.

Although we identified two vaccine candidates (targeting E coli and Proteus mirabilis, respectively) undergoing testing in murine models, we identified no other vaccine candidates in clinical development (human testing) targeting uropathogenic E coli or urinary tract infections in general. Additionally, we did an epidemiological study of urinary tract infections in community and hospital settings throughout Switzerland to assess the prevalence of E coli associated with urinary tract infections and to identify the O-serogroups of the predominant strains (unpublished). Pathogens associated with more than 3000 urinary tract infections were characterised and more than 1800 E coli strains isolated from urine were collected to identify the main O-serogroups.

Added value of this study

Our study shows a strong safety profile and high immunogenicity with durable and functional immune responses for the parenteral, multivalent E coli O-antigen bioconjugate vaccine. Additionally, this first-in human trial shows moderate protective efficacy against urinary tract infections with bacterial loads of 105 colony-forming units per mL or more. Collectively these findings support an early proof of concept for the development of E coli bioconjugate vaccines.

Implications of all the available evidence

Increases in antibiotic-resistant bacteria causing pyelonephritis and urosepsis call for further development of preventive approaches. Our study suggests that there is the potential for further investigation of a parenteral bioconjugate vaccine for prevention of extraintestinal E coli infections.

We did a multicentre phase 1b first-in-human trial to assess the safety, immunogenicity, and preliminary clinical efficacy of the tetravalent bioconjugate candidate vaccine, ExPEC4V, in healthy women with a history of recurrent UTI.

Section snippets

Study design and participants

We did a phase 1, first-in-human, staggered, randomised, placebo-controlled single-blind trial in 13 medical centres in Switzerland. Eligible participants were healthy women aged 18 to 70 years with a self-reported clinical history of recurrent UTIs (ie, two infections in the past 6 months, or three in the past year) and at least one urine culture with documented E coli growth in the preceding 5 years, and were in general good health, without clinically significant medical history, physical

Results

We recruited participants between Jan 20, 2014, and Aug 27, 2014. 234 women were screened, 196 were included and randomly assigned, and 194 received either reduced-dose vaccine (n=6), target-dose vaccine (n=93), or placebo (n=95; figure 1). 190 participants completed the study (figure 1). Demographic characteristics in the two main treatment groups were similar (table 1). Mean age in both groups was roughly 42 years, women in both groups had a median of four UTIs in the year before inclusion,

Discussion

Our findings suggest that the bioconjugate ExPEC4V candidate vaccine has an acceptable safety profile, consistent with previous studies of other conjugate vaccines,13, 18, 22, 23, 24 and elicits a robust vaccine-specific immune response for all four serotypes in all age groups.

The vaccine was well tolerated; no vaccine-related severe or serious adverse events were noted throughout the study. There were no significant differences among vaccinees and placebo recipients in the frequency or

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