Safety and immunogenicity of a vaccine for extra-intestinal pathogenic Escherichia coli (ESTELLA): a phase 2 randomised controlled trial.

BACKGROUND: ExPEC4V (JNJ-63871860) is a bioconjugate vaccine, containing O-antigens from Escherichia coli serotypes O1A, O2, O6A, and O25B, developed for the prevention of invasive extra-intestinal pathogenic E coli (ExPEC) disease. We aimed to assess safety, reactogenicity, and immunogenicity of ExPEC4V in healthy adults. METHODS: In this phase 2 randomised, double-blind placebo-controlled study, we recruited healthy adults (≥18 years with a body-mass index of 35 kg/m2 or less) between Nov 16, 2015, and Aug 8, 2017, and randomly assigned them to receive a single dose of ExPEC4V (antigen O1A:O2:O6A:O25B content 4:4:4:4 µg [group 1]; 4:4:4:8 µg [group 2], 8:8:8:8 µg [group 3], 8:8:8:16 µg [group 4], or 16:16:16:16 µg [group 5]) or placebo. The primary objectives were evaluation of the safety, tolerability, and immunogenicity of ExPEC4V and determination of its dose-dependent immunogenicity 15 days after vaccination by ELISA in individuals who had received at least one vaccination dose. Antibody titres and safety evaluation were used to select two ExPEC4V doses for assessment up to day 360. This trial is registered at ClinicalTrials.gov, number NCT02546960. FINDINGS: Of 848 enrolled participants, 843 (99%) received the ExPEC4V vaccine (757) or placebo (86) and were included in the safety analysis. Of 757 participants vaccinated with ExPEC4V, 222 (29%) had a solicited local adverse event and 325 (43%) had any solicited systemic adverse event, compared with 11 (13%) and 30 (35%) of 86 participants in the control group. Symptoms were mild-to-moderate. The most frequently reported solicited local adverse event was pain or tenderness (205 [27·1%] of 757 in combined ExPEC4V groups) and the most frequently reported solicited systemic adverse event was fatigue (208 [27·6%] of 757). Only 13 (2%) of 843 had a grade 3 event. At day 15, 80% or more of all participants achieved a two times or greater increase in serotype-specific IgG antibodies (except O25B at the lowest dose, 103 [72%] of 144). At day 360, 66% (95% CI 56·47-74·33) of participants in group 2 and 71% (62·13-78·95) of participants in group 4 selected for long-term follow-up maintained a two times or greater increase in serotype-specific antibody compared with baseline. INTERPRETATION: EXPEC4V seemed well tolerated and elicited robust and functional antibody responses across all serotypes, doses, and age groups. For the two dosages evaluated (4:4:4:8 µg and 8:8:8:16 µg), the immune response persisted for 1 year. FUNDING: Janssen Pharmaceuticals.

Safety, tolerability and immunogenicity of the ExPEC4V (JNJ-63871860) vaccine for prevention of invasive extraintestinal pathogenic Escherichia coli disease: A phase 1, randomized, double-blind, placebo-controlled study in healthy Japanese participants.

This Phase 1, randomized, double-blind, placebo-controlled study was conducted to evaluate the safety, tolerability and immunogenicity of different doses of ExPEC4V conjugate vaccine (4-16µg Polysaccharide [PS]/serotype) in healthy Japanese participants, stratified into younger (≥20 to <50 years) or older age groups (≥50 years). Within each age group, participants were randomized to a single vaccination with 1 of 3 dose levels of ExPEC4V (4, 8 and 16 µg PS/serotype) or placebo. Safety and tolerability were the primary objectives; immunogenicity was secondary. Of the 48 participants, 47 (98%) completed; one (2%) in the placebo group discontinued. A total of 48% participants had ≥1 AE (younger group: n = 13 [54%]; older group: n = 10 [41.7%]). Solicited and unsolicited AEs were reported in 44% and 8% participants, respectively in the combined ExPEC4V groups. Pain/tenderness (n = 11 [31%]) and redness (n = 9 [25%]) were the most frequently reported solicited local AEs, whereas fatigue (n = 4 [11%]), headache (n = 4 [11%]), muscle pain (n = 2 [6%]), and malaise (n = 5 [14%]) were the most common solicited systemic AEs in the combined ExPEC4V group. No serious AEs, deaths, or discontinuation due to AEs were reported. All doses were immunogenic with an increase in IgG (ELISA) geometric mean titers of at least 5-fold from baseline to Days 15 and 30 for all serotypes. Of participants vaccinated with ExPEC4V, 75% - 100% demonstrated an ELISA titer increase of ≥2-fold. Strong correlation observed between ELISA and OPK. ExPEC4V was well tolerated and elicited an immunogenic response at all dose levels (up to 16 µg PS/serotype) in healthy Japanese participants.

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.

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.