A randomized phase 1/2a trial of ExPEC10V vaccine in adults with a history of UTI.

The safety, reactogenicity, and immunogenicity of 3 doses of ExPEC10V (VAC52416), a vaccine candidate to prevent invasive Escherichia coli disease, were assessed in a phase 1/2a study (NCT03819049). In Cohort 1, ExPEC10V was well tolerated; the high dose was selected as optimal and further characterized in Cohort 2. Cohort 2 comprised a maximum 28-day screening, vaccination (Day 1), double-blind 181-day follow-up, and open-label long-term follow-up until Year 1. Healthy participants (≥60 years) with a history of urinary tract infection (UTI) within 5 years were randomized to receive ExPEC10V or placebo. The primary endpoint evaluated the safety and reactogenicity of ExPEC10V (solicited local and systemic AEs [until Day 15]; unsolicited AEs [until Day 30], SAEs [until Day 181], and immunogenicity [Day 30]) via multiplex electrochemiluminescent (ECL) and multiplex opsonophagocytic assay (MOPA). 416 participants (ExPEC10V, n = 278; placebo, n = 138) were included (mean age [SD], 68.8 [6.52] years; female, 79.6%; White, 96.1%). The incidence of solicited AEs was higher with ExPEC10V (local, 50.0% [n = 139]; systemic, 50.0% [n = 139]) than placebo (15.9% [n = 22]; 38.4% [n = 53]); rates of unsolicited AEs were comparable (ExPEC10V, 28.4% [n = 79]; placebo, 26.1% [n = 36]). No vaccine-related SAEs or deaths were reported. ExPEC10V elicited a robust antibody-mediated immunogenic response across all serotypes with ECL (Day 30 geometric mean fold increase, 2.33-8.18) and demonstrated functional opsonophagocytic killing activity across all measured serotypes (Day 30 geometric mean fold increase, 1.81-9.68). ExPEC10V exhibited an acceptable safety profile and a robust vaccine-induced functional immunogenic response in participants with a history of UTI. Clinical trial registration details: https://clinicaltrials.gov/study/NCT03819049 .

Feasibility of tracking invasive Escherichia coli disease among older adults in a community setting: A prospective observational study.

PURPOSE: Invasive Escherichia coli disease (IED) encompasses a diverse range of sterile site infections. This study evaluated the feasibility of capturing IED among community-dwelling older adults to inform the implementation of a phase 3 efficacy trial of a novel vaccine against IED (NCT04899336). METHODS: EXPECT-1 (NCT04087681) was a prospective, multinational, observational study conducted in medically stable participants aged ≥ 60 years. At least 50% of participants were selected based on a history of urinary tract infection (UTI) in the previous 10 years. The main outcomes were the incidence of IED and the number of hospitalisations reported by the site vs participant. The length of follow-up was 12 months. In a US-based substudy, a smartphone-based geofencing was evaluated to track hospital entries. RESULTS: In total, 4470 participants were enrolled (median age, 70.0 years); 59.5% (2657/4469) of participants had a history of UTI in the previous 10 years. Four IED events were captured through deployment of different tracking methods: a self-report, a general practitioner (GP) report, and a follow-up call. The incidence rate of IED was 98.6 events per 100,000 person-years. The number of reported hospitalisations was 2529/4470 (56.6%) by the site and 2177/4470 (48.7%) by participants; 13.8% of hospitalisations would have been missed if utilising only site reports. Geofencing detected 72 hospital entries. CONCLUSION: Deployment of multiple tracking methods can optimise detection of IED among community-dwelling older adults. Older adults with a history of UTI could be feasibly targeted for a phase 3 vaccine efficacy trial through a network of GPs.

Clinical presentation and antimicrobial resistance of invasive Escherichia coli disease in hospitalized older adults: a prospective multinational observational study.

BACKGROUND: Clinical data characterizing invasive Escherichia coli disease (IED) are limited. We assessed the clinical presentation of IED and antimicrobial resistance (AMR) patterns of causative E. coli isolates in older adults. METHODS: EXPECT-2 (NCT04117113) was a prospective, observational, multinational, hospital-based study conducted in patients with IED aged ≥ 60 years. IED was determined by the microbiological confirmation of E. coli from blood; or by the microbiological confirmation of E. coli from urine or an otherwise sterile body site in the presence of requisite criteria of systemic inflammatory response syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), or quick SOFA (qSOFA). The primary outcomes were the clinical presentation of IED and AMR rates of E. coli isolates to clinically relevant antibiotics. Complications and in-hospital mortality were assessed through 28 days following IED diagnosis. RESULTS: Of 240 enrolled patients, 80.4% had bacteremic and 19.6% had non-bacteremic IED. One-half of infections (50.4%) were community-acquired. The most common source of infection was the urinary tract (62.9%). Of 240 patients, 65.8% fulfilled ≥ 2 SIRS criteria, and 60.4% had a total SOFA score of ≥ 2. Investigator-diagnosed sepsis and septic shock were reported in 72.1% and 10.0% of patients, respectively. The most common complication was kidney dysfunction (12.9%). The overall in-hospital mortality was 4.6%. Of 299 E. coli isolates tested, the resistance rates were: 30.4% for trimethoprim-sulfamethoxazole, 24.1% for ciprofloxacin, 22.1% for levofloxacin, 16.4% for ceftriaxone, 5.7% for cefepime, and 4.3% for ceftazidime. CONCLUSIONS: The clinical profile of identified IED cases was characterized by high rates of sepsis. IED was associated with high rates of AMR to clinically relevant antibiotics. The identification of IED can be optimized by using a combination of clinical criteria (SIRS, SOFA, or qSOFA) and culture results.

Safety, Reactogenicity, Immunogenicity, and Dose Selection of 10-Valent Extraintestinal Pathogenic Escherichia coli Bioconjugate Vaccine (VAC52416) in Adults Aged 60-85 Years in a Randomized, Multicenter, Interventional, First-in-Human, Phase 1/2a Study.

Background: ExPEC10V is a bioconjugate vaccine containing O-antigen polysaccharides of 10 extraintestinal pathogenic Escherichia coli (ExPEC) serotypes. This phase 1/2a study (NCT03819049) assessed the safety, reactogenicity, and immunogenicity of ExPEC10V (VAC52416) to prevent invasive E coli disease in elderly adults. Methods: The observer-blind, active-controlled design included a 28-day screening, vaccination, 181-day follow-up, and 1-year follow-up. Participants (60-85 years of age) were randomized to ExPEC10V low dose (antigen dose range, 4-8 µg), ExPEC10V medium dose (4-16 µg), or ExPEC10V high dose (8-16 µg); 4-valent ExPEC vaccine (ExPEC4V); or 13-valent pneumococcal conjugate vaccine (PCV13). The incidence of adverse events (AEs; solicited, day 15; unsolicited, day 30; serious AEs, day 181) and immunogenicity (electrochemiluminescent-based assay [ECL] and multiplex opsonophagocytic assay [MOPA]) were assessed. Optimal ExPEC10V dose was determined from safety data through day 30 and an immunogenicity dose selection algorithm based on day 15 ECL and MOPA results. Results: A total of 416 participants were included (median age, 64.0 years; 54.8% female). The incidences of solicited local and systemic AEs were, respectively, 44.2% and 39.4% for low-dose, 52.9% and 46.1% for medium-dose, 57.7% and 45.2% for high-dose ExPEC10V, and 74.1% and 48.1% for PCV13. Five serious AEs, not vaccine related, were reported. The ECL revealed a robust antibody response to ExPEC10V through year 1. Opsonophagocytic killing activity was detected against all but serotype O8; this lack of response against serotype O8 was linked to low assay sensitivity. Based on the totality of data, high-dose ExPEC10V was considered optimal. Conclusions: ExPEC10V was well tolerated and immunogenic in elderly adults against all but serotype O8.

Epidemiology, Clinical Features, and Antimicrobial Resistance of Invasive Escherichia Coli Disease in Patients Admitted in Tertiary Care Hospitals.

Background: Invasive Escherichia coli disease (IED), including bloodstream infection, sepsis, and septic shock, can lead to high hospitalization and mortality rates. This multinational study describes the clinical profile of patients with IED in tertiary care hospitals. Methods: We applied clinical criteria of systemic inflammatory response syndrome (SIRS), sepsis, or septic shock to patients hospitalized with culture-confirmed E coli from urine or a presumed sterile site. We assessed a proposed clinical case definition against physician diagnoses. Results: Most patients with IED (N = 902) were adults aged ≥60 years (76.5%); 51.9%, 25.1%, and 23.0% of cases were community-acquired (CA), hospital-acquired (HA), and healthcare-associated (HCA), respectively. The urinary tract was the most common source of infection (52.3%). Systemic inflammatory response syndrome, sepsis, and septic shock were identified in 77.4%, 65.3%, and 14.1% of patients, respectively. Patients >60 years were more likely to exhibit organ dysfunction than those ≤60 years; this trend was not observed for SIRS. The case-fatality rate (CFR) was 20.0% (60-75 years, 21.5%; ≥75 years, 22.2%), with an increase across IED acquisition settings (HA, 28.3%; HCA, 21.7%; CA, 15.2%). Noticeably, 77.8% of patients initiated antibiotic use on the day of culture sample collection. A total of 65.6% and 40.8% of E coli isolates were resistant to ≥1 agent in ≥1 or ≥2 drug class(es). A 96.1% agreement was seen between the proposed clinical case definition and physician's diagnoses of IED. Conclusions: This study contributes valuable, real-world data about IED severity. An accepted case definition could promote timely and accurate diagnosis of IED and inform the development of novel preventative strategies.

Global Distribution of O Serotypes and Antibiotic Resistance in Extraintestinal Pathogenic Escherichia coli Collected From the Blood of Patients With Bacteremia Across Multiple Surveillance Studies.

BACKGROUND: Extraintestinal pathogenic Escherichia coli (ExPEC) is the leading cause of bacteremia worldwide, with older populations having increased risk of invasive bacterial disease. Increasing resistance to first-line antibiotics and emergence of multidrug-resistant (MDR) strains represent major treatment challenges. ExPEC O serotypes are key targets for potential multivalent conjugate vaccine development. Therefore, we evaluated the O serotype distribution and antibiotic resistance profiles of ExPEC strains causing bloodstream infections across 4 regions. METHODS: Blood culture isolates from patients aged ≥60 years collected during 5 retrospective E. coli surveillance studies in Europe, North America, Asia-Pacific, and South America (2011-2017) were analyzed. Isolates were O serotyped by agglutination; O genotyping was performed for nontypeable isolates. Antimicrobial susceptibility testing was also conducted. RESULTS: Among 3217 ExPEC blood culture isolates, the most ubiquitous O serotype was O25 (n = 737 [22.9%]), followed by O2, O6, O1, O75, O15, O8, O16, O4, O18, O77 group, O153, O9, O101/O162, O86, and O13 (prevalence of ≥1%). The prevalence of these O serotypes was generally consistent across regions, apart from South America; together, these 16 O serotypes represented 77.6% of all ExPEC bacteremia isolates analyzed. The overall MDR frequency was 10.7%, with limited variation between regions. Within the MDR subset (n = 345), O25 showed a dominant prevalence of 63.2% (n = 218). CONCLUSIONS: Predominant O serotypes among ExPEC bacteremia isolates are widespread across different regions. O25 was the most prevalent O serotype overall and particularly dominant among MDR isolates. These findings may inform the design of multivalent conjugate vaccines that can target the predominant O serotypes associated with invasive ExPEC disease in older adults.

Distribution of extraintestinal pathogenic Escherichia coli O-serotypes and antibiotic resistance in blood isolates collected from patients in a surveillance study in Japan.

INTRODUCTION: Invasive extraintestinal pathogenic Escherichia coli (ExPEC) disease (IED), characterised by sepsis and bacteraemia, is a major global healthcare concern worsened by emerging multidrug resistant (MDR) strains. The development of multivalent prophylactic vaccines targeting E. coli strains of IED-associated O-serotypes could address this. A better understanding of O-serotype distribution is required for this purpose. Here, we characterised O-serotype prevalence and drug resistance among ExPEC bacteraemia isolates in Japan. METHODS: E. coli blood isolates from patients aged ≥60 years with bacteraemia were obtained from a retrospective surveillance study in Japan (2015-2017). O-serotyping was performed by agglutination; for isolates non-typeable by agglutination, O-genotyping was performed. Antimicrobial susceptibility was evaluated by broth microdilution using a 21-antibiotic panel. The frequency of drug resistant (DR) isolates was evaluated by antimicrobial susceptibility testing. RESULTS: Of 401 ExPEC bacteraemia isolates evaluated, the most prevalent O-serotype (≥1%) was O25 (28.7% [n = 115]), followed by O1 (14.2% [n = 57]), O2 (8.5% n = 34]), O6 (5.5% [n = 22]), O75, O18, O13, O16, O15, O4, O46/O134, O86, O8 and O83 (each <5% prevalence). These 14 O-serotypes accounted for 81.5% of isolates collected. In total, 19% (n = 77) of isolates were DR ≥ 3, of which 59.7% were O25. Fluoroquinolone-resistance among all and O25 isolates was most prevalent (35.7% and 84.3%, respectively). Almost all (98%) isolates identified as O25 were of subtype O25B. CONCLUSIONS: E. coli serotype O25B showed the highest prevalence and highest multidrug resistance among ExPEC bacteraemia isolates from patients ≥60 years in Japan. Our data may inform development of multivalent glycoconjugate vaccines to prevent IED.

Epidemiology and O-Serotypes of Extraintestinal Pathogenic Escherichia coli Disease in Patients Undergoing Transrectal Ultrasound Prostate Biopsy: A Prospective Multicenter Study.

PURPOSE: Extraintestinal pathogenic Escherichia coli (ExPEC) are a leading cause of invasive infections in adults. The study aimed to evaluate the incidence of microbiologically confirmed invasive ExPEC disease in patients undergoing transrectal ultrasound-guided prostate needle biopsy (TRUS-PNB), O-serotype distribution and antibiotic resistance profiles of associated E. coli isolates. MATERIALS AND METHODS: Adult men (≥18 years) undergoing TRUS-PNB were enrolled. The TRUS-PNB procedure was performed according to local standard of care, including preferences of prophylactic antibiotics. Clinical and microbiological data were collected. RESULTS: Of the 4,951 patients (mean age 66.9 years) enrolled 4,935 (99.7%) underwent TRUS-PNB (95.1% received prophylactic antibiotics); 98.9% completed the study. Overall incidence of invasive ExPEC disease was 0.67% (33/4,935 patients; 95% CI 0.46-0.94); highest incidence was in the U.S. (0.97%, 14/1,446; 95% CI 0.53-1.62). Prevalence of the 10 selected O-serotypes O1, O2, O4, O6, O8, O15, O16, O18, O25 and O75 was 52.0% (95% CI 31.3-72.2). E. coli isolates showed highest resistance rates to levofloxacin and ciprofloxacin (76%; 95% CI 54.8-90.6 for both). Among fluoroquinolone-resistant ExPEC isolates, prevalence of the 10 selected O-serotypes was 60%. CONCLUSIONS: This study provides an estimate of microbiologically confirmed invasive ExPEC disease incidence following TRUS-PNB. Information on E. coli O-serotype distribution and associated antibiotic resistance profiles from invasive ExPEC disease cases in the first 30 days following TRUS-PNB may help guiding antibiotic use and inform development of a prophylactic ExPEC vaccine.

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.

Immunogenicity and estimation of antibody persistence following vaccination with an inactivated virosomal hepatitis A vaccine in adults: A 20-year follow-up study.

PURPOSE: This was a 20-year follow-up study to assess long-term persistence of protective antibody levels against the hepatitis A virus (HAV) in healthy participants vaccinated with 2 doses of inactivated hepatitis A vaccine (Epaxal®) between 1992 and 1995. METHODS: Blood samples for anti-HAV antibody concentrations were obtained during a follow-up visit 20years after vaccination and were analyzed in parallel with samples still available from previous visits using AxSYM® HAVAB 2.0 assay. RESULTS: Mean (SD) age of the participants was 44.71 (3.905) years at year 20 follow-up (N=95). Participants completing 0/12-month Epaxal® immunization regimen (N=94) had seroprotection rate of 100% (95% CI: 96.2, 100.0) with ⩾10mIU/mL seropositivity cut-off and 98.9% (95% CI: 94.2, 100.0) with ⩾20mIU/mL cut-off. With ⩾10mIU/mL cut-off, the estimated median duration of protection was 77.3years (95% CI: 71.8, 83.5) with 95% of the vaccinated participants predicted to be protected for at least 41.5years. At ⩾20mIU/mL cut-off, the estimated median duration of protection was 64.8years (95% CI: 60.1, 68.4) with 95% of the vaccinated participants predicted to be protected for at least 33years. Anti-HAV antibody geometric mean concentrations were higher in women (277.9; 95% CI: 217.7, 354.7) than in men (167.7; 95% CI: 125.2, 224.6). CONCLUSION: The data from this 20-year follow-up study confirm previous observations that two doses of Epaxal® provide protection against hepatitis A infection for at least 30years in over 95% of healthy participants.

Long-term Serologic Follow-up of Children Vaccinated with a Pediatric Formulation of Virosomal Hepatitis A Vaccine Administered With Routine Childhood Vaccines at 12-15 Months of Age.

BACKGROUND: The aim of this open-label, active-controlled, parallel group, phase 2 follow-up study was to assess the long-term immunogenicity of Epaxal Junior, the pediatric dose of an aluminum-free virosomal inactivated hepatitis A virus (HAV) vaccine, in children receiving routine childhood vaccines (RCV). METHODS: Healthy children (12-15 months old, ≥8 kg weight) were randomized (1:1:1) to group A: Epaxal Junior + RCV (day 1); group B: Epaxal Junior (day 1) + RCV (day 29) and group C: Havrix 720 + RCV (day 1). All 3 groups received 2 doses of HAV vaccines 6 months apart. Children who completed the primary study were followed up from 18 months to 7.5 years post booster. RESULTS: Of 291/327 randomized children who had completed the primary study, 157 were followed for the 7.5-year analysis (group A: 50; group B: 54; and group C: 53). Of these, 152 children had protective levels of anti-HAV antibodies [≥10 mIU/mL; 98% (group A); 96.3% (group B); 96.2% (group C)]. Anti-HAV geometric mean concentrations were similar in groups A and B at all the time points (1.5-, 2.5-, 3.5-, 5.25- and 7.5-year time point) but slightly lower in group C. Predictions of the median duration of persistence of seroprotective antibody levels, using the linear mixed model were similar in all groups: (group A: 19.1 years, group B: 18.7 years, group C: 17.3 years). CONCLUSIONS: Immunization with Epaxal Junior administered with RCVs at 12 months elicited protective response beyond 7.5 years in almost all children. Assessing the kinetic of anti-HAV antibody titers decline over time, the moment to reach antibody concentrations below the accepted protective level may occur earlier than previously estimated.

Safety and Tolerability of Doripenem in Hospitalized Children With Complicated Intra-Abdominal Infection, Complicated Urinary Tract Infections and Pneumonia.

Three multicenter, randomized, controlled studies evaluated doripenem in children 3 months to <18 years of age, with complicated intra-abdominal or urinary tract infections and bacterial pneumonia.In the 66 patients treated with doripenem before early termination of the studies for nonsafety reasons, doripenem was safe and generally well tolerated. Low enrollment limited ability to assess benefits and risks of doripenem in children.

Incidence of diabetes in American Indians of three geographic areas: the Strong Heart Study.

OBJECTIVE: To estimate incidence rates of diabetes and associated risk factors among participants of the Strong Heart Study. RESEARCH DESIGN AND METHODS: Of the 4,549 Strong Heart Study participants examined at baseline, 3,638 returned for a similar examination after an average of 4 years. The 1985 World Health Organization criteria for diabetes were used to identify new diabetes cases. Rates of diabetes among participants who did not have diabetes at baseline examination were determined. The relationships between the incidence rates of diabetes and a number of risk factors measured at baseline examination were studied. RESULTS: Significant variables associated with the development of diabetes included triglycerides, obesity, fasting plasma glucose, insulin, and degree of American Indian blood among participants with NGT at baseline. For those with IGT at baseline, significant predictors included fasting plasma glucose, 2-h glucose, BMI, degree of American Indian blood, and albuminuria. CONCLUSIONS: The high incidence rates found in this study were alarming. To slow down the rapid increase of this disease in the American Indian population, preventive programs must be designed and implemented. Patients with IGT should be treated with diabetes medication or put on a rigid weight-reduction program to reduce the risk of progression to diabetes.