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Intro: Published data is limited in describing clinical features and disease burden of invasive Escherichia coli disease (IED). This study characterized bacteremic and non-bacteremic IED in relation to clinical features and multidrug resistance (MDR) of causative E. coli isolates. Methods: EXPECT-2 (NCT04117113) was a multinational, hospital-based, observational study that prospectively enrolled IED patients aged ≥60 years between October 2019 and January 2021. IED was defined by a positive E. coli culture from blood (bacteremic IED), a sterile body site or urine (non-bacteremic IED) in the presence of requisite criteria of Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), or quick SOFA (qSOFA). In-hospital mortality and IED-related medical encounters were assessed through 28 days following IED diagnosis. MDR was defined as acquired non-susceptibility to ≥1 antibiotic in ≥3 antimicrobial classes. Findings: The full analysis set included 193 bacteremic (80.4%) and 47 non- bacteremic (19.6%) patients. Patient demographics were balanced between bacteremic and non-bacteremic IED. The rates of patients with ≥2 SIRS criteria were comparable between bacteremic (64.8%) and non-bacteremic IED (70.2%). The rates of patients with the ≥2-point change in total SOFA score were comparable between bacteremic (62.2%) and non-bacteremic IED (53.2%). The rates of sepsis and septic shock were 75.0% and 11.4%, respectively, for bacteremic, and 83.3% and 7.1%, respectively, for non-bacteremic IED. The most common IED-related medical encounter was the emergency room both in patients with bacteremic (31.5%, [41/130]) and non-bacteremic IED (35.9%, [14/39]). Of 11 patients who died, 6 (54.5%) had bacteremic IED. Of 294 E. coli isolates with antimicrobial susceptibility testing collected from 238 patients, MDR rates were 34.7% (87/251) for bacteremic and 37.2% (16/43) for non-bacteremic isolates. Conclusion: IED manifested as severe infection, with approximately one-third of E. coli isolates displaying MDR. Bacteremic and non-bacteremic IED were characterized by similar clinical features and MDR phenotypes.

Intro: The safety, reactogenicity, and immunogenicity of VAC52416 (ExPEC10V), a vaccine candidate to prevent invasive Escherichia coli disease, was assessed in a phase 1/2a study (NCT03819049). Results from Cohort 1 have been presented. Here, we describe the immunogenicity profile of the high dose (selected as optimal in the primary analysis) from Cohort 1. Methods: The observer-blind, active-controlled design included a 28-day screening, vaccination, and follow-up through Day 366. Participants (60–85y) were randomized to a single dose (0.5 mL, intramuscular) of: ExPEC10V-high (n=104), -medium (n=102), or -low (n=104) dose; ExPEC4V (n=52); or pneumococcal 13-valent (PCV13; n=54). Immunogenicity (via electrochemiluminescent based immunoassay [ECL] and multiplex opsonophagocytic assay [MOPA]) was assessed on Days 15, 30, 181, and 366. Findings: The robust immunogenic response to ExPEC10V against all serotypes observed with ECL on Day 15 was maintained on Day 30 (N=310). Responses decreased on Day 181 and Year 1 but remained greater than PCV13. 68.0–99.0% of high-dose ExPEC10V participants exhibited ≥2-fold increase from baseline to Day 15 on the ECL across serotypes. Similarly, MOPA revealed high opsonophagocytic killing activity for all but serotype O8 on Day 15. Excluding O8, 38.0–98.0% of high-dose ExPEC10V participants exhibited ≥2-fold increase on the MOPA on Day 15. The highest response was observed for serotype O2 (Day 15, both assays) and the lowest for serotypes O75 (Day 15, ECL) and O8 (MOPA). ECL and MOPA responses to high-dose ExPEC10V were correlated (excluding O8, Pearson's coefficient range: Day 15=0.54–0.72; Day 30=0.45– 0.71, Day 181=0.44–0.77). Conclusion: These data informed the decision to remove serotype O8 and increase the polysaccharide content for serotype O75 of the vaccine composition to create a high-dose ExPEC9V. ExPEC9V is expected to be highly immunogenic, meriting further study as a vaccine candidate to prevent IED.

Aim: This phase 1 study (NCT04306302) evaluated the safety, reactogenicity, and immunogenicity of ExPEC10V (VAC52416) in healthy Japanese adults., Method: The randomized, double-blind, single-center study included 28-day screening, vaccination (Day 1), 30-day safety and immunogenicity follow-up and 181-day serious adverse events (SAEs) follow-up. Participants (60-85 years) were enrolled in dose-ascending approach and randomized to medium- and high-doses of ExPEC10V (n = 8 in each dose group) and placebo (n = 8). Incidence of adverse events: solicited AEs (until Day 15), unsolicited AEs (until Day 30), SAEs (until Day 181) and immunogenicity (electrochemiluminescent-based assay [ECL] and multiplex opsonophagocytic assay [MOPA]) were assessed on Day 15 and Day 30., Results: Total of 24 participants were included (median age, 66.5 years; 50.0 % female). Incidence of solicited AEs was 81.3 % (local) and 18.8 % (systemic) for pooled ExPEC10V group (medium-dose ExPEC10V: 75.0 % [local], 12.5 % [systemic]; high-dose ExPEC10V: 87.5 % [local], 25.0 % [systemic]). One SAE, not vaccine-related, was reported in high-dose ExPEC10V group after Day 30, which was resolved during study. The ECL demonstrated increase in binding antibody titers, which was maintained from Day 15 to Day 30. For all serotypes, the geometric mean fold increases from baseline on Day 15 ranged from 2.51 to 10.60 and 1.97-5.23 for medium- and high-dose groups, respectively. The MOPA demonstrated increase in functional antibody responses for all serotypes (except O8) at Day 15 which was maintained from Day 15 to Day 30., Conclusions: ExPEC10V medium- and high-doses were well tolerated with an acceptable safety profile without any significant safety issues in healthy Japanese participants., Competing Interests: Declaration of competing interest Miwa Haranaka has no conflicts of interest to disclose. Atsushi Momose, Yoshikazu Nakayama, and Yuki Saito are employees of Janssen Pharmaceutical K.K. Bart Spiessens, Todd A Davies, Germie van den Dobbelsteen, Jan Poolman, and Michal Sarnecki are employees of Janssen Pharmaceuticals., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest TM, HM, HO, KY, and MK participated as an investigator in this study. JG, EW, OG, BS, GvG, TvdH and JP are employees of Janssen Pharmaceuticals and are potential stockholders of Johnson & Johnson. NY and AM are employees and YH was an employee of Janssen Pharmaceutical K.K. All other authors report no conflicts of interest., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess immunogenicity, antibody persistence, immune memory, and reactogenicity of a novel heptavalent DTPw-HBV/Hib-MenAC (diphtheria, tetanus, whole cell pertussis-hepatitis B virus/Haemophilus influenzae type b-Neisseria meningitidis serogroups A and C) vaccine., Design: This was an open, randomized study in the Philippines, with DTPw-HBV/Hib-MenAC administered at 6, 10, and 14 weeks of age. Three different polysaccharide contents of the conjugate vaccine components were assessed with conjugated PRP (polyribosylribitol phosphate), MenA, and MenC polysaccharides at the following doses: 2.5 microg of each, 5 microg of each, or 2.5 microg of PRP and 5 microg each of MenA and MenC. Controls received licensed DTPw-HBV and Hib or DTPw-HBV/Hib and MenC conjugate vaccines separately. Immune memory was evaluated via plain polysaccharide challenge administered to half of the subjects at 10 months of age., Results: After primary vaccination, at least 97.7% of DTPw-HBV/Hib-MenAC recipients had serum bactericidal antibody (SBA)-MenA and SBA-MenC titers > or =1:8, and at least 99% had anti-PRP antibody concentrations > or =0.15 microg/ml. Immune responses to DTPw-HBV components were not impaired by the lowest dose of Hib-MenAC vaccine. Plain polysaccharide challenge induced marked increases in Hib, MenA, and MenC antibodies in primed subjects, indicative of immune memory. All of the experimental vaccines were well tolerated., Conclusion: The lowest dose of DTPw-HBV/Hib-MenAC polysaccharide conjugate vaccine was well tolerated, immunogenic, had good persistence of antibodies, and demonstrated immune memory, and consequently was selected for further development.

Background: Acute otitis media is one of the most commonly-diagnosed childhood infections. This study assessed the efficacy of a novel vaccine that contained polysaccharides from 11 different Streptococcus pneumoniae serotypes each conjugated to Haemophilus influenzae-derived protein D in prevention of acute otitis media., Methods: 4968 infants were randomly assigned to receive either pneumococcal protein D conjugate or hepatitis A vaccine at the ages of 3, 4, 5, and 12-15 months and were followed-up until the end of the second year of life. Middle-ear fluid was obtained for bacteriological culture and serotyping in children who presented with abnormal tympanic membrane or presence of middle-ear effusion, plus two predefined clinical symptoms. The primary endpoint was protective efficacy against the first episode of acute otitis media caused by vaccine pneumococcal serotypes. Analysis was per protocol., Findings: From 2 weeks after the third dose to 24-27 months of age, 333 clinical episodes of acute otitis media were recorded in the protein D conjugate group (n=2455) and 499 in the control group (n=2452), giving a significant (33.6% [95% CI 20.8-44.3]) reduction in the overall incidence of acute otitis media. Vaccine efficacy was shown for episodes of acute otitis media caused by pneumococcal vaccine serotypes (52.6% [35.0-65.5] for the first episode and 57.6% [41.4-69.3] for any episode). Efficacy was also shown against episodes of acute otitis media caused by non-typable H influenzae (35.3% [1.8-57.4]). The vaccine reduced frequency of infection from vaccine-related cross-reactive pneumococcal serotypes by 65.5%, but did not significantly change the number of episodes caused by other non-vaccine serotypes., Interpretation: These results confirm that using the H influenzae-derived protein D as a carrier protein for pneumococcal polysaccharides not only allowed protection against pneumococcal otitis, but also against acute otitis media due to non-typable H influenzae. Whether this approach would also allow improved protection against lower respiratory tract infections warrants further investigation.