Human Vaccines Project Europe

BackgroundIn the fight against antimicrobial resistance, mathematical transmission models have been shown as a valuable tool to guide intervention strategies in public health.ObjectiveThis review investigates the persistence of modelling gaps identified in earlier studies. It expands the scope to include a broader range of control measures, such as monoclonal antibodies, and examines the impact of secondary infections.MethodsThis review was conducted according to the PRISMA guidelines. Gaps in model focus areas, dynamics, and reporting were identified and described. The TRACE paradigm was applied to selected models to discuss model development and documentation to guide future modelling efforts.ResultsWe identified 170 transmission studies from 2010 to May 2022; Mycobacterium tuberculosis (n = 39) and Staphylococcus aureus (n = 27) resistance transmission were most commonly modelled, focusing on multi-drug and methicillin resistance, respectively. Forty-one studies examined multiple interventions, predominantly drug therapy and vaccination, showing an increasing trend. Most studies were population-based compartmental models (n = 112). The TRACE framework was applied to 39 studies, showing a general lack of description of test and verification of modelling software and comparison of model outputs with external data.ConclusionDespite efforts to model antimicrobial resistance and prevention strategies, significant gaps in scope, geographical coverage, drug-pathogen combinations, and viral-bacterial dynamics persist, along with inadequate documentation, hindering model updates and consistent outcomes for policymakers. This review highlights the need for robust modelling practices to enable model refinement as new data becomes available. Particularly, new data for validating modelling outcomes should be a focal point in future modelling research.

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.

BackgroundA vaccine developed to prevent invasive extraintestinal pathogenic Escherichia coli disease (IED) is being evaluated in a phase 3 clinical trial (NCT04899336). However, historical performance of similar clinical trials has been challenged by inefficient endpoint catchment. Here we report the EXPECT-1 (NCT04087681) study findings on the capture techniques for IED and hospital admissions in a community-based setting.MethodsEXPECT-1 was a prospective, observational study conducted in networks of 8 hospitals with surrounding primary care centers in North America, Europe, and Asia. Participants were followed for 1 year to track hospital admissions and occurrence of IED as reported by the primary care physician (PCP) or the participant. In 151 US participants, a geofence technology was used to track admissions to hospital areas. Participants were eligible if aged ≥ 60 years and if they did not have severe chronic conditions. Data were collected from October 24, 2019 until January 28, 2021. Study outcomes included incidence of IED and the rate of hospital admission.ResultsIn total, 4470 participants were enrolled: 68% were female, 74.4% were white, median age was 70 years, and 59.4% had a urinary tract infection (UTI) in the past 10 years. Four IED events were captured with a cumulative incidence (95% CI) of 0.09% (0.024–0.229%) and an incidence rate of 98.6 cases (25.6–248.4) per 100,000 person-years. The incidence increased to 0.15% (0.041–0.385%) and 164.4 (43.8–420) per 100,000 person-years among participants with a history of UTI. Of the 4 IED events, 2 were participant self-reports, 1 PCP report, and 1 report via follow-up phone call. Of all hospital admissions, 56.6% were captured by PCPs and 48.7% by participants’ self-reports. The Kappa statistic varied from 0.31–0.65, indicating fair to moderate agreement between PCP reports and participant self-reports. Geofencing captured 99% of > 800 entries and exits from hospital areas.ConclusionThe findings suggest that older adults with a history of UTI in the past 10 years may be a good target population for an efficacy clinical investigation on IED. PCP reports, participant self-reports, and geofencing can be promoted to track study endpoints in a community-based clinical trial setting.DisclosuresJoachim Doua, MD, MPH, Janssen: Employee|Janssen: Stocks/Bonds Stephen Ruhmel, MPH, Janssen: Employee Oscar Go, PhD, Janssen: Employee of Janssen Research & Development LLC. Ranee Chatterjee, MD, MPH, Bristol Myers Squibb: Grant/Research Support|Epigenomics: Grant/Research Support|Verily: Grant/Research Support Michal Sarnecki, MD, Janssen: Employee|Janssen: Stocks/Bonds Jan Poolman, PhD, Janssen: Janssen Vaccines & Prevention B.V.|Janssen: Stocks/Bonds Marc Bonten, MD, PhD, Astra-Zeneca: Advisor/Consultant|Janssen: Advisor/Consultant|Merck: Advisor/Consultant|Novartis: Advisor/Consultant.

Abstract Background Invasive extraintestinal pathogenic Escherichia coli disease (IED) occurs more frequently with increasing age, and antimicrobial resistance (AMR) can complicate treatment. Yet IED is under-monitored by major disease surveillance systems. In addition, the diagnosis of IED can be challenging due to the diversity of clinical presentations. More research is warranted to better characterize IED. Here we report EXPECT-2 (NCT04117113) results describing the clinical profile of IED and AMR patterns of causative E. coli isolates. Methods EXPECT-2 was a prospective observational study conducted in patients aged ≥60 years with an IED and hospitalized at 8 sites in Europe, North America, and Asia. Data were collected from October 24, 2019 to January 28, 2021. IED was determined by clinical criteria of either systemic inflammatory response syndrome (SIRS) or Sequential Organ Failure Assessment (SOFA), and a positive E. coli culture either from blood (bacteremic IED), or other normally sterile body site samples and/or urine (non-bacteremic IED). Results Overall, 240 IED patients were enrolled (median age, 75 years; females: 51%); 80.4% of IED cases were bacteremic and 19.6% were non-bacteremic. IED was community-acquired in 50.4%, hospital-acquired in 20.0%, and health care–associated in 29.6% of patients. The most common source of IED was urinary tract (62.9%). Fever occurred in 51.5%, tachycardia in 58.6%, tachypnea in 24.3%, and altered mentation in 15.7% of patients. Laboratory markers of a systemic infection were observed in 86.3% of patients, including leukocytosis in 42.7% and leukopenia in 10.9% of patients. SIRS criteria (≥ 2) were met in 65.8% and SOFA criteria (≥ 2) in 60.4% of patients. According to the investigator, 76.5% of patients met criteria for sepsis and 10.6% for septic shock. At 28 days post diagnosis, 14.6% of patients were unrecovered; 12.9% had a complication of kidney dysfunction, and 4.6% had died. Of 238 patients whose E. coli isolates were tested, the AMR rates for ≥ 1 antibiotic were 62.6% in ≥ 1 drug class, 45.9% in ≥ 2 drug classes, and 35.0% in ≥ 3 drug classes. Conclusion In patients aged ≥ 60 years, IED manifested as a severe infection. AMR was frequently observed. The data suggest a need of preventive interventions for IED. Disclosures Joachim Doua, MD, MPH, Janssen: Employee|Janssen: Stocks/Bonds Jeroen Geurtsen, PhD, Janssen: Employee of Janssen Vaccines & Prevention BV Oscar Go, PhD, Janssen: Employee of Janssen Research & Development LLC. Michal Sarnecki, MD, Janssen: Employee|Janssen: Stocks/Bonds Bart Spiessens, PhD, Janssen: Employee Marc Bonten, MD, PhD, Astra-Zeneca: Advisor/Consultant|Janssen: Advisor/Consultant|Merck: Advisor/Consultant|Novartis: Advisor/Consultant Jan Poolman, PhD, Janssen: Janssen Vaccines & Prevention B.V.|Janssen: Stocks/Bonds.