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OBJECTIVES: Escherichia coli can cause infections in the urinary tract and in normally sterile body sites leading to invasive E. coli disease (IED), including bacteraemia and sepsis, with older populations at increased risk. We aimed to estimate the theoretical coverage rate by the ExPEC4V and 9V vaccine candidates. In addition, we aimed at better understanding the diversity of E. coli isolates, including their genetic and phenotypic antimicrobial resistance (AMR), sequence types (STs), O-serotypes and the bacterial population structure. METHODS: Blood and urine culture E. coli isolates (nâ=â304) were collected from hospitalized patients ≥60 years (n =â238) with IED during a multicentric, observational study across three continents. All isolates were tested for antimicrobial susceptibility, O-serotyped, whole-genome sequenced and bioinformatically analysed. RESULTS: A large diversity of STs and of O-serotypes were identified across all centres, with O25b-ST131, O6-ST73 and O1-ST95 being the most prevalent types. A total of 45.4% and 64.7% of all isolates were found to have an O-serotype covered by the ExPEC4V and ExPEC9V vaccine candidates, respectively. The overall frequency of MDR was 37.4% and ST131 was predominant among MDR isolates. Low in-patient genetic variability was observed in cases where multiple isolates were collected from the same patient. CONCLUSIONS: Our results highlight the predominance of MDR O25b-ST131 E. coli isolates across diverse geographic areas. These findings provide further baseline data on the theoretical coverage of novel vaccines targeting E. coli associated with IED in older adults and their associated AMR levels.
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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.
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Infecciones por Escherichia coli , Infecciones Urinarias , Humanos , Anciano , Estudios Prospectivos , Estudios de Factibilidad , Infecciones Urinarias/microbiología , Escherichia coli , Infecciones por Escherichia coli/microbiologíaRESUMEN
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.
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Antibacterianos , Farmacorresistencia Bacteriana , Infecciones por Escherichia coli , Escherichia coli , Humanos , Anciano , Estudios Prospectivos , Masculino , Femenino , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/epidemiología , Escherichia coli/efectos de los fármacos , Escherichia coli/aislamiento & purificación , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Anciano de 80 o más Años , Persona de Mediana Edad , Hospitalización/estadística & datos numéricosRESUMEN
BACKGROUND: Invasive Escherichia coli disease (IED), also known as invasive extraintestinal pathogenic E. coli disease, is a leading cause of sepsis and bacteremia in older adults that can result in hospitalization and sometimes death and is frequently associated with antimicrobial resistance. Moreover, certain patient characteristics may increase the risk of developing IED. This study aimed to validate a machine learning approach for the unbiased identification of potential risk factors that correlate with an increased risk for IED. METHODS: Using electronic health records from 6.5 million people, an XGBoost model was trained to predict IED from 663 distinct patient features, and the most predictive features were identified as potential risk factors. Using Shapley Additive predictive values, the specific relationships between features and the outcome of developing IED were characterized. RESULTS: The model independently predicted that older age, a known risk factor for IED, increased the chance of developing IED. The model also predicted that a history of ≥ 1 urinary tract infection, as well as more frequent and/or more recent urinary tract infections, and ≥ 1 emergency department or inpatient visit increased the risk for IED. Outcomes were used to calculate risk ratios in selected subpopulations, demonstrating the impact of individual or combinations of features on the incidence of IED. CONCLUSION: This study illustrates the viability and validity of using large electronic health records datasets and machine learning to identify correlating features and potential risk factors for infectious diseases, including IED. The next step is the independent validation of potential risk factors using conventional methods.
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Infecciones por Escherichia coli , Aprendizaje Automático , Humanos , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/microbiología , Factores de Riesgo , Anciano , Femenino , Masculino , Persona de Mediana Edad , Registros Electrónicos de Salud , Anciano de 80 o más Años , Escherichia coli/efectos de los fármacos , Escherichia coli/aislamiento & purificación , Escherichia coli/patogenicidad , Adulto , Infecciones Urinarias/microbiología , Infecciones Urinarias/epidemiología , Bacteriemia/microbiología , Bacteriemia/epidemiologíaRESUMEN
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.
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Bacteriemia , Infecciones por Escherichia coli , Escherichia coli Patógena Extraintestinal , Humanos , Anciano , Escherichia coli Patógena Extraintestinal/genética , Escherichia coli , Serogrupo , Estudios Retrospectivos , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/microbiología , Bacteriemia/epidemiología , Farmacorresistencia MicrobianaRESUMEN
Vaccines against Staphylococcus aureus have eluded researchers for >3 decades while the burden of staphylococcal diseases has increased. Early vaccine attempts mainly used rodents to characterize preclinical efficacy, and all subsequently failed in human clinical efficacy trials. More recently, leukocidin AB (LukAB) has gained interest as a vaccine antigen. We developed a minipig deep surgical wound infection model offering 3 independent efficacy readouts: bacterial load at the superficial and at the deep-seated surgical site, and dissemination of bacteria. Due to similarities with humans, minipigs are an attractive option to study novel vaccine candidates. With this model, we characterized the efficacy of a LukAB toxoid as vaccine candidate. Compared to control animals, a 3-log reduction of bacteria at the deep-seated surgical site was observed in LukAB-treated minipigs and dissemination of bacteria was dramatically reduced. Therefore, LukAB toxoids may be a useful addition to S. aureus vaccines and warrant further study.
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Infecciones Estafilocócicas , Vacunas Estafilocócicas , Animales , Carga Bacteriana , Proteínas Bacterianas , Leucocidinas , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus , Infección de la Herida Quirúrgica/prevención & control , Porcinos , Porcinos Enanos , VacunaciónRESUMEN
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.
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Antiinfecciosos , Bacteriemia , Infecciones por Escherichia coli , Escherichia coli Patógena Extraintestinal , Vacunas , Bacteriemia/epidemiología , Farmacorresistencia Microbiana , Escherichia coli , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/epidemiología , Escherichia coli Patógena Extraintestinal/genética , Humanos , Japón/epidemiología , Estudios Retrospectivos , Serogrupo , SerotipificaciónRESUMEN
BACKGROUND: Escherichia coli is the most common cause of bacteremia in high-income countries. To enable the development and implementation of effective prevention strategies, a better understanding of the current epidemiology of invasive E. coli infections is needed. METHODS: A systematic review of literature published between 1 January 2007 and 31 March 2018 on the burden and epidemiology of E. coli bacteremia in populations that include adults in high-income countries was conducted. Meta-analysis was performed for descriptive purposes. RESULTS: During the studied time interval, the estimated incidence rate of E. coli bacteremia was 48 per 100 000 person-years, but this increased considerably with age: rates per 100â 000 person-years wereâ >100 in 55-to-75-year-olds andâ >300 in 75-to-85-year-olds. Overall, E. coli accounted for 27% of documented bacteremia episodes: 18% if hospital acquired, 32% if community-onset healthcare associated, and 33% if community acquired. The estimated case fatality rate was 12%. Approximately 44% of episodes were community acquired, 27% community-onset healthcare associated, and 27% hospital acquired. Urinary tract infection (UTI) was the primary source for 53% of episodes. CONCLUSIONS: This systematic review confirms the substantial burden of E. coli bacteremia in older adults and justifies the implementation of community-level programs to prevent E. coli bacteremia and ideally UTI in this age group.
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Bacteriemia , Infecciones Comunitarias Adquiridas , Infecciones por Escherichia coli , Infecciones Urinarias , Anciano , Bacteriemia/epidemiología , Infecciones Comunitarias Adquiridas/epidemiología , Escherichia coli , Infecciones por Escherichia coli/epidemiología , Humanos , Infecciones Urinarias/epidemiologíaRESUMEN
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.
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Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/microbiología , Escherichia coli Patógena Extraintestinal/aislamiento & purificación , Biopsia Guiada por Imagen , Próstata/patología , Ultrasonido Enfocado Transrectal de Alta Intensidad/métodos , Anciano , Profilaxis Antibiótica , Humanos , Incidencia , Masculino , Pruebas de Sensibilidad Microbiana , Estudios Prospectivos , SerotipificaciónRESUMEN
Extraintestinal pathogenic Escherichia coli (ExPEC) is the most common gram-negative bacterial pathogen in humans. ExPEC causes the vast majority of urinary tract infections (UTIs), is a leading cause of adult bacteremia, and is the second most common cause of neonatal meningitis. Increasing multidrug resistance among ExPEC strains constitutes a major obstacle to treatment and is implicated in increasing numbers of hospitalizations and deaths and increasing healthcare costs associated with ExPEC infections. An effective vaccine against ExPEC infection is urgently needed. The O antigen, a component of the surface lipopolysaccharide, has been identified as a promising vaccine target. With the availability of a novel bioconjugation technology it is expected that multivalent O antigen conjugate vaccines can be produced at industrial scale. Clinical proof of concept of a 4-valent O antigen conjugate vaccine is ongoing. An ExPEC vaccine effective against strains that are associated with major diseases and resistant to multiple drugs could be routinely delivered to individuals at risk of developing severe E. coli infection, such as elderly people, individuals undergoing abdominal surgery and prostatic biopsy procedures, and persons at risk of recurrent and/or complicated UTI.
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Infecciones por Escherichia coli , Vacunas contra Escherichia coli , Escherichia coli , Farmacorresistencia Bacteriana , Humanos , Antígenos O , Infecciones UrinariasRESUMEN
Filamentous hemagglutinin (FHA) is an important adhesin of the whooping cough agent Bordetella pertussis and is contained in most acellular pertussis vaccines. Recently, FHA was proposed to exert an immunomodulatory activity through induction of tolerogenic IL-10 secretion from dendritic cells. We have re-evaluated the cytokine-inducing activity of FHA, placing specific emphasis on the role of the residual endotoxin contamination of FHA preparations. We show that endotoxin depletion did not affect the capacity of FHA to bind primary human monocyte-derived dendritic cells, while it abrogated the capacity of FHA to elicit TNF-α and IL-10 secretion and strongly reduced its capacity to trigger IL-6 production. The levels of cytokines induced by the different FHA preparations correlated with their residual contents of B. pertussis endotoxin. Moreover, FHA failed to trigger cytokine secretion in the presence of antibodies that block TLR2 and/or TLR4 signaling. The TLR2 signaling capacity appeared to be linked to the presence of endotoxin-associated components in FHA preparations and not to the FHA protein itself. These results show that the endotoxin-depleted FHA protein does not induce cytokine release from human dendritic cells.
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Adhesinas Bacterianas/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Interleucina-10/metabolismo , Factores de Virulencia de Bordetella/inmunología , Células Cultivadas , HumanosRESUMEN
The outer membrane of Gram-negative bacteria functions as a permeability barrier that protects these bacteria against harmful compounds in the environment. Most nutrients pass the outer membrane by passive diffusion via pore-forming proteins known as porins. However, diffusion can only satisfy the growth requirements if the extracellular concentration of the nutrients is high. In the vertebrate host, the sequestration of essential nutrient metals is an important defense mechanism that limits the growth of invading pathogens, a process known as "nutritional immunity." The acquisition of scarce nutrients from the environment is mediated by receptors in the outer membrane in an energy-requiring process. Most characterized receptors are involved in the acquisition of iron. In this study, we characterized a hitherto unknown receptor from Neisseria meningitidis, a causative agent of sepsis and meningitis. Expression of this receptor, designated CbpA, is induced when the bacteria are grown under zinc limitation. We demonstrate that CbpA functions as a receptor for calprotectin, a protein that is massively produced by neutrophils and other cells and that has been shown to limit bacterial growth by chelating Zn²âº and Mn²âº ions. Expression of CbpA enables N. meningitidis to survive and propagate in the presence of calprotectin and to use calprotectin as a zinc source. Besides CbpA, also the TonB protein, which couples energy of the proton gradient across the inner membrane to receptor-mediated transport across the outer membrane, is required for the process. CbpA was found to be expressed in all N. meningitidis strains examined, consistent with a vital role for the protein when the bacteria reside in the host. Together, our results demonstrate that N. meningitidis is able to subvert an important defense mechanism of the human host and to utilize calprotectin to promote its growth.
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Proteínas de la Membrana Bacteriana Externa/inmunología , Proteínas Bacterianas/inmunología , Evasión Inmune , Neisseria meningitidis/inmunología , Zinc/inmunología , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Humanos , Transporte Iónico/genética , Transporte Iónico/inmunología , Hierro/inmunología , Hierro/metabolismo , Complejo de Antígeno L1 de Leucocito/inmunología , Complejo de Antígeno L1 de Leucocito/metabolismo , Manganeso/inmunología , Manganeso/metabolismo , Neisseria meningitidis/genética , Neisseria meningitidis/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Zinc/metabolismoRESUMEN
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 .
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Neisseria meningitidis serogroup B (MenB) is a major cause of bacterial sepsis and meningitis, with the highest disease burden in young children. Available vaccines are based on outer membrane vesicles (OMVs) obtained from wild-type strains. However, particularly in toddlers and infants, they confer protection mostly against strains expressing the homologous protein PorA, a major and variable outer membrane protein. In the quest for alternative vaccine antigens able to provide broad MenB strain coverage in younger populations, but potentially also across all age groups, ZnuD, a protein expressed under zinc-limiting conditions, may be considered a promising candidate. Here, we have investigated the potential value of ZnuD and show that it is a conserved antigen expressed by all MenB strains tested except for some strains of clonal complex ST-8. In mice and guinea pigs immunized with ZnuD-expressing OMVs, antibodies were elicited that were able to trigger complement-mediated killing of all the MenB strains and serogroup A, C, and Y strains tested when grown under conditions of zinc limitation. ZnuD is also expressed during infection, since anti-ZnuD antibodies were detected in sera from patients. In conclusion, we confirm the potential of ZnuD-bearing OMVs as a component of an effective MenB vaccine.
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Proteínas Bacterianas/inmunología , Proteínas Bacterianas/metabolismo , Proteínas de Transporte de Catión/inmunología , Proteínas de Transporte de Catión/metabolismo , Infecciones Meningocócicas/prevención & control , Vacunas Meningococicas/inmunología , Neisseria meningitidis/metabolismo , Adolescente , Animales , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/química , Antígenos Bacterianos/genética , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas de Transporte de Catión/química , Proteínas de Transporte de Catión/genética , Niño , Preescolar , Femenino , Regulación Bacteriana de la Expresión Génica/fisiología , Cobayas , Humanos , Lactante , Ratones , Modelos Moleculares , Neisseria meningitidis/genética , Neisseria meningitidis/inmunología , Filogenia , Conformación Proteica , Determinación de Anticuerpos Séricos Bactericidas , Adulto Joven , Zinc/metabolismoRESUMEN
Pathogenic Neisseria meningitidis isolates contain a polysaccharide capsule that is the main virulence determinant for this bacterium. Thirteen capsular polysaccharides have been described, and nuclear magnetic resonance spectroscopy has enabled determination of the structure of capsular polysaccharides responsible for serogroup specificity. Molecular mechanisms involved in N. meningitidis capsule biosynthesis have also been identified, and genes involved in this process and in cell surface translocation are clustered at a single chromosomal locus termed cps. The use of multiple names for some of the genes involved in capsule synthesis, combined with the need for rapid diagnosis of serogroups commonly associated with invasive meningococcal disease, prompted a requirement for a consistent approach to the nomenclature of capsule genes. In this report, a comprehensive description of all N. meningitidis serogroups is provided, along with a proposed nomenclature, which was presented at the 2012 XVIIIth International Pathogenic Neisseria Conference.
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Cápsulas Bacterianas/genética , Cromosomas Bacterianos , Genes Bacterianos , Neisseria meningitidis/genética , Polisacáridos Bacterianos/genética , Cápsulas Bacterianas/metabolismo , Sitios Genéticos , Humanos , Espectroscopía de Resonancia Magnética , Infecciones Meningocócicas/microbiología , Familia de Multigenes , Neisseria meningitidis/clasificación , Neisseria meningitidis/aislamiento & purificación , Neisseria meningitidis/patogenicidad , Reacción en Cadena de la Polimerasa , Polisacáridos Bacterianos/biosíntesis , Polisacáridos Bacterianos/aislamiento & purificación , Serotipificación , Terminología como Asunto , VirulenciaRESUMEN
An exceptional gut-colonizing ability may underlie the dramatic epidemiological success of the multidrug-resistant H30R subclone of Escherichia coli sequence type 131 (O25b:K+:H4). In order to inform the development of colonization-preventing measures, we studied systemic immune correlates of H30R intestinal colonization. Human volunteers' fecal samples were screened for H30R by selective culture and PCR. Subjects were assessed by enzyme immunoassay for serum levels of anti-O25 IgG (representing H30R) and anti-O6 IgG (representing non-H30 E. coli generally), initially and for up to 14 months. Whole blood was tested for the antigen-stimulated release of IFNγ, TNFα, IL-4, IL-10, and IL-17 after incubation with E. coli strains JJ1886 (H30R; O25b:K+:H4) or CFT073 (non-H30; O6:K2:H1). Three main findings were obtained. First, H30R-colonized subjects had significantly higher anti-O25 IgG levels than controls, but similar anti-O6 IgG levels, suggesting an IgG response to H30R colonization. Second, anti-O25 and anti-O6 IgG levels were stable over time. Third, H30R-colonized subjects exhibited a lower TNFα and IL-10 release than controls in response to strain JJ1886 (H30R) relative to strain CFT073 (non-H30R), consistent with TNFα hypo-responsiveness to H30R possibly predisposing to H30R colonization. Thus, H30R-colonized hosts exhibit a sustained serum anti-O25 IgG response and an underlying deficit in TNFα responsiveness to H30R that could potentially be addressed for colonization prevention.
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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, 4-8â µg), ExPEC10V medium dose (4-16â µg), or ExPEC10V high dose (8-16â 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.
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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 ≥60â 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 >60â years were more likely to exhibit organ dysfunction than those ≤60â years; this trend was not observed for SIRS. The case-fatality rate (CFR) was 20.0% (60-75â years, 21.5%; ≥75â 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.