Efficacy, safety, and immunogenicity of a 9-valent vaccine (ExPEC9V) for #prevention of invasive #Escherichia coli disease in older #adults: a phase 3, randomised, placebo-controlled trial (E.mbrace)

 

Summary

Background

Invasive Escherichia coli disease (IED) caused by extraintestinal pathogenic Escherichia coli (ExPEC) can lead to bacteraemia and sepsis. ExPEC9V is a conjugate vaccine targeting nine E coli O-serotypes that account for most E coli bloodstream infections. We aimed to evaluate ExPEC9V for safety, immunogenicity, and prevention of IED caused by ExPEC9V O-serotypes in adults aged 60 years and older.

Methods

In this randomised, double-blind, placebo-controlled, phase 3 study conducted at 332 clinical sites in 20 countries (E.mbrace), we enrolled participants aged 60 years and older in stable health and with a history of urinary tract infection (UTI) within the previous 2 years. Participants were randomly assigned (in blocks of no set size with the use of interactive web response system, stratified by age and presence or absence of risk factors for complicated UTI) 1:1 to receive a single dose of intramuscular ExPEC9V or placebo. Participants, study-site personnel, and investigators remained masked to group allocation throughout the study. The primary endpoint was first IED in blood or sterile sites caused by ExPEC9V O-serotypes in the per-protocol efficacy analysis set (all randomly assigned, vaccinated participants without major protocol deviations); secondary endpoints included immunogenicity assessment in a subset of participants. Safety endpoints included solicited (safety subset), unsolicited (full analysis set), and serious (full analysis set) adverse events. A prespecified futility analysis conducted when at least 40% of the expected 53 IED events had occurred indicated lack of efficacy, leading to early study termination. We present final study results (data up to the date of the futility announcement), when 17 701 of the planned 19 800 participants had been vaccinated. This trial is registered with ClinicalTrials.gov (NCT04899336).

Findings

Participants were enrolled between June 30, 2021, and Feb 13, 2025. Of 18 844 individuals assessed for eligibility, 17 701 were enrolled, randomly assigned, and vaccinated (8858 with ExPEC9V and 8843 with placebo). The per-protocol efficacy included 17 637 participants (8822 for ExPEC9V and 8815 for placebo). There were 24 IED cases (11 in vaccine and 13 in placebo groups) caused by ExPEC9V O-serotypes in blood or sterile sites, yielding a vaccine efficacy of 14·63% (95% CI −106·57 to 65·38), indicating no protective effect. ExPEC9V had an acceptable safety profile, with more frequent low-grade adverse events in the ExPEC9V versus placebo group, balanced serious adverse event distribution among both groups, and no vaccine-related deaths.

Interpretation

In this large phase 3 trial of older adults, ExPEC9V did not demonstrate efficacy in preventing first IED caused by ExPEC9V O-serotypes, despite generating robust and sustained antibody responses. Development of the ExPEC9V vaccine has been discontinued.

Funding

Johnson & Johnson and Sanofi.

Source: 

Link: https://doi.org/10.1016/S1473-3099(26)00469-X

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#Oya Virus in a Patient with Severe #Hepatitis, #Enteritis, and #Coagulopathy

 

Abstract

Oya virus, an orthobunyavirus, was identified in a 54-year-old woman who had sepsis-like symptoms, including leukocytosis, thrombocytopenia, elevated liver-function values, and disseminated intravascular coagulation.

Source: 

Link: https://doi.org/10.1056/NEJMc2602616

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#Bacterial #Infection in #Ebola Virus Disease, #Marburg Virus Disease, #CCHF, and #Lassa Fever

 

Abstract

Background

Concern for bacterial coinfection in patients with high consequence viral infections (HCVIs) has made empiric antibiotic administration the standard of care. However, the incidence, microbiology, and clinical significance of bacterial coinfection in HCVIs remain unclear.

Methods

We conducted a systematic review of case reports, cohort studies, and cross-sectional analyses describing bacterial coinfection in Ebola virus disease (EVD), Marburg virus disease (MVD), Crimean–Congo hemorrhagic fever (CCHF), and Lassa fever (LF). Data were extracted on study design, setting, diagnostic methods, pathogens, antibiotic use, and outcomes.

Results

Thirty publications met inclusion criteria. Bacteremia was most commonly reported among patients with CCHF (n = 46), followed by EVD (n = 16), MVD (n = 16), and LF (n = 2). Of 27 EVD patients treated outside Africa, 7 (26%) had bacterial coinfection. Across HCVIs, bacteremia was detected a median of 11 days after symptom onset (range 0–23) and was associated with features of sepsis. Pathogens included enteric flora, healthcare-associated organisms, opportunistic pathogens, and zoonotic bacteria—most notably Brucella spp. in CCHF. Ceftriaxone was the most common empiric antibiotic but is predicted to have activity against a minority of bloodstream isolates. Mortality among coinfected patients with EVD or MVD was similar to those without bacterial coinfection, whereas coinfected CCHF patients had higher mortality than those without coinfection (15.5%; 95% CI 8.0%–25.9% vs 5.7%; 95% CI 5.1%–6.4%).

Conclusions

Despite being a major concern driving empiric antibiotic use, bacterial coinfection in HCVIs remains poorly described, precluding determination of its incidence or clinical significance. Prospective studies with standardized protocols for bacterial diagnosis and characterization of antimicrobial resistance are needed to guide antimicrobial strategies.

Source: 

Link: https://academic.oup.com/ofid/article/13/8/ofag404/8741539

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#Pathogens #analysis and modeling of #mortality #risk in #sepsis patients with #COVID19 and without COVID-19

 

Abstract

This study compared isolate-level pathogen profiles, antimicrobial susceptibility, clinical characteristics, and mortality predictors between sepsis patients with and without coronavirus disease 2019 (COVID-19), and developed cohort-specific nomograms for in-hospital mortality. This retrospective intensive care unit (ICU) cohort included 608 adults with sepsis: 158 in group COVID-19 and 450 in group non–COVID-19. All patients were assessed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection status. Patient-level comparisons and mortality modeling used the full cohort, whereas microbiological analyses were restricted to 235 eligible bacterial or fungal isolates from baseline cultures after exclusion of colonizers, contaminants, clinically non-causative organisms, and duplicates. Candidate predictors were selected by least absolute shrinkage and selection operator (LASSO) regression and entered into multivariable logistic regression; coefficients were pooled using Rubin’s rules when multiple imputation was performed. External validation used MIMIC-IV with fixed internal coefficients. Gram-negative organisms predominated, mainly Acinetobacter baumannii and Klebsiella pneumoniae, with substantial antimicrobial resistance. The COVID-19 and non–COVID-19 models showed apparent internal area under the curve values of 0.938 and 0.871, conservative optimism-corrected values of 0.913 and 0.871, and external validation AUC values of 0.841 and 0.859, respectively. Cohort-specific nomograms may provide supplementary risk-stratification information in critically ill patients with sepsis.

Source: 

Link: https://www.nature.com/articles/s41598-026-58450-w

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Viral #sepsis: #diagnosis, clinical #features, #pathogenesis, and #clinical considerations

Abstract

Sepsis, characterized as life-threatening organ dysfunction resulting from dysregulated host responses to infection, remains a significant challenge in clinical practice. Despite advancements in understanding host-bacterial interactions, molecular responses, and therapeutic approaches, the mortality rate associated with sepsis has consistently ranged between 10 and 16%. This elevated mortality highlights critical gaps in our comprehension of sepsis etiology. Traditionally linked to bacterial and fungal pathogens, recent outbreaks of acute viral infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), among other regional epidemics, have underscored the role of viral pathogenesis in sepsis, particularly when critically ill patients exhibit classic symptoms indicative of sepsis. However, many cases of viral-induced sepsis are frequently underdiagnosed because standard evaluations typically exclude viral panels. Moreover, these viruses not only activate conventional pattern recognition receptors (PRRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) but also initiate primary antiviral pathways such as cyclic guanosine monophosphate adenosine monophosphate (GMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling and interferon response mechanisms. Such activations lead to cellular stress, metabolic disturbances, and extensive cell damage that exacerbate tissue injury while leading to a spectrum of clinical manifestations. This complexity poses substantial challenges for the clinical management of affected cases. In this review, we elucidate the definition and diagnosis criteria for viral sepsis while synthesizing current knowledge regarding its etiology, epidemiology, and pathophysiology, molecular mechanisms involved therein as well as their impact on immune-mediated organ damage. Additionally, we discuss clinical considerations related to both existing therapies and advanced treatment interventions, aiming to enhance the comprehensive understanding surrounding viral sepsis.

Source: Military Medical Research, https://mmrjournal.biomedcentral.com/articles/10.1186/s40779-024-00581-0 

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