Isabel Leroux-Roels

Improved CD4 + T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: A randomized trial

BACKGROUNDnThe Bacille Calmette-Guérin (BCG) tuberculosis (TB) vaccine provides incomplete protection, necessitating development of an effective vaccine against TB disease. The Mtb72F/AS02 candidate vaccine was previously shown to be clinically well tolerated and immunogenic in Purified Protein Derivative (PPD)-negative adults. To improve the stability of Mtb72F, a point mutation was introduced into a putative serine protease site to give the final M72 construct. AS01 is an Adjuvant System that can potentially improve both humoral and cellular immune responses compared to the AS02 Adjuvant System or unadjuvanted vaccine. This study evaluated the safety and immunogenicity in Mtb-naïve adults of vaccines containing 40 μg of the M72 antigen with AS02 or AS01 and compared the results with Mtb72F/AS02 vaccine (40 μg dose), M72 in saline (40 μg dose) and AS01 alone.nnnMETHODSnIn this Phase I/II observer-blind controlled trial, 110 participants were randomized (4:4:1:1:1) to receive M72/AS01, M72/AS02, Mtb72F/AS02, M72/saline or AS01, following a 0, 1-month schedule. Subjects receiving the adjuvanted M72 vaccines were followed up until 3 years post vaccination. Evaluation of the immune response and safety/reactogenicity was performed.nnnRESULTSnFor all vaccines, solicited adverse events (AEs) were predominantly mild to moderate and transient. No vaccine-related serious AEs occurred and no subject withdrew due to an AE. Immune responses induced by Mtb72F and M72 antigens combined with AS02 were similar. M72/AS01 and M72/AS02 induced robust polyfunctional M72-specific CD4(+) T cell and antibody responses persisting at 3 years, with the highest CD4(+) T cell responses found with M72/AS01.nnnCONCLUSIONnThis first clinical study with M72/AS01 and M72/AS02 showed that both vaccines were clinically well tolerated and induced high magnitude and persistent cell-mediated and humoral immune responses. The Mtb72F/AS02 and M72/AS02 vaccines were comparably immunogenic with significantly higher immune responses compared to the M72/saline control. Of the formulations tested, M72/AS01 demonstrated significantly higher vaccine specific Th1 CD4(+) T cell responses supporting its further clinical evaluation.

Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: a randomised controlled trial

PurposeThere is variability in the pharmacokinetics (PK) of antibiotics (AB) in critically ill patients. Therapeutic drug monitoring (TDM) could overcome this variability and increase PK target attainment. The objective of this study was to analyse the effect of a dose-adaption strategy based on daily TDM on target attainment.MethodsThis was a prospective, partially blinded, and randomised controlled trial in patients with normal kidney function treated with meropenem (MEM) or piperacillin/tazobactam (PTZ). The intervention group underwent daily TDM, with dose adjustment when necessary. The predefined PK/pharmacodynamic (PK/PD) target was 100xa0% fT>4MIC [percentage of time during a dosing interval that the free (f) drug concentration exceeded 4 times the MIC]. The control group received conventional treatment. The primary endpoint was the proportion of patients that reached 100xa0% fT>4MIC and 100xa0% fT>MIC at 72xa0h.ResultsForty-one patients (median age 56 years) were included in the study. Pneumonia was the primary infectious diagnosis. At baseline, 100xa0% fT>4MIC was achieved in 21xa0% of the PTZ patients and in none of the MEM patients; 100xa0% fT>MIC was achieved in 71xa0% of the PTZ patients and 46xa0% of the MEM patients. Of the patients in the intervention group, 76 % needed dose adaptation, and five required an additional increase. At 72xa0h, target attainment rates for 100xa0% fT>4MIC and 100xa0% fT>MIC were higher in the intervention group: 58 vs. 16xa0%, pxa0=xa00.007 and 95 vs. 68xa0%, pxa0=xa00.045, respectively.ConclusionsAmong critically ill patients with normal kidney function, a strategy of dose adaptation based on daily TDM led to an increase in PK/PD target attainment compared to conventional dosing.

Evaluation of the safety and immunogenicity of two antigen concentrations of the Mtb72F/AS02A candidate tuberculosis vaccine in purified protein derivative-negative adults.

ABSTRACT Tuberculosis (TB) remains a major cause of illness and death worldwide, making a new TB vaccine an urgent public health priority. Purified protein derivative (PPD)-negative adults (n = 50) were equally randomized to receive 3 doses at 1-month intervals (at 0, 1, and 2 months) of one of the following vaccines: Mtb72F/AS02A (10 or 40 μg antigen), Mtb72F/saline (10 or 40 μg antigen), or AS02A. Mtb72F/AS02A recipients received an additional dose 1 year after the first dose to evaluate if the elicited immune response could be boosted. Mtb72F/AS02A vaccines were locally reactogenic but clinically well tolerated, with transient adverse events (usually lasting between 1 and 4 days) that resolved without sequelae being observed. No vaccine-related serious adverse events were reported. Vaccination with Mtb72F/AS02A induced a strong Mtb72F-specific humoral response and a robust Mtb72F-specific CD4+ T-cell response, both of which persisted at 9 months after primary immunization and for 1 year after the booster immunization. There was no significant difference between the magnitude of the CD4+ T-cell response induced by the 10-μg and 40-μg Mtb72F/AS02A vaccines. The Mtb72F-specific CD4+ T cells predominantly expressed CD40L; CD40L and interleukin-2 (IL-2); CD40L and tumor necrosis factor alpha (TNF-α); CD40L, IL-2, and TNF-α; and CD40L, IL-2, TNF-α, and gamma interferon (IFN-γ). Serum IFN-γ, but not TNF-α, was detected 1 day after doses 2 and 3 for the Mtb72F/AS02A vaccine but did not persist. Vaccine-induced CD8+ T-cell responses were not detected, and no immune responses were elicited with AS02A alone. In conclusion, Mtb72F/AS02A is clinically well tolerated and is highly immunogenic in TB-naïve adults. The 10- and 40-μg Mtb72F/AS02A vaccines show comparable safety and immunogenicity profiles.

Adjuvant system AS02V enhances humoral and cellular immune responses to pneumococcal protein PhtD vaccine in healthy young and older adults: Randomised, controlled trials.

BACKGROUNDnThe protection elicited by polysaccharide pneumococcal vaccines against community-acquired pneumonia in older adults remains debatable. Alternative vaccine targets include well-conserved pneumococcal protein antigens, such as pneumococcal histidine triad protein D (PhtD).nnnOBJECTIVEnTo evaluate humoral and cellular immune responses and safety/reactogenicity following immunisation with PhtD vaccine with or without adjuvant (alum or AS02V) in older (≥65 years) and young (18-45 years) healthy adults.nnnMETHODSnTwo phase I/II, single-blind, parallel-group studies were conducted in 150 older and 147 young adults. Participants were randomised to receive 2 doses (months 0 and 2) of PhtD 30 μg, PhtD 10 μg plus alum, PhtD 30 μg plus alum, PhtD 10 μg plus AS02V or PhtD 30 μg plus AS02V, or the 23-valent polysaccharide pneumococcal vaccine (23PPV) at month 0 with placebo (saline solution) at month 2. Safety/reactogenicity was assessed. PhtD-specific antibody, T cell and memory B cell responses were evaluated.nnnRESULTSnSolicited adverse events were more common in young participants and with adjuvanted vaccines. No vaccine-related serious adverse events were reported. Although anti-PhtD geometric mean antibody concentrations (GMCs) were consistently lower in the older adult cohort than in young adults, GMCs in the older cohort following PhtD 30 μg plus AS02V were comparable to those induced by plain PhtD or PhtD 30 μg plus alum in the young cohort. Compared with alum adjuvant, AS02V adjuvant system was associated with an increased frequency of PhtD-specific CD4 cells in both cohorts and a significantly higher specific memory B cell response in the older cohort, similar to responses obtained in the young cohort.nnnCONCLUSIONnThe improved immune response to PhtD vaccine containing the AS02V adjuvant system in comparison to alum suggests that the reduced immune response to vaccines in older adults can be partially restored to the response level observed in young adults. ClinicalTrials.gov identifiers: NCT00307528/NCT01767402.

Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines: Randomized, double-blind study in malaria-naïve adults

This phase II, randomized, double-blind study evaluated the immunogenicity of RTS,S vaccines containing Adjuvant System AS01 or AS02 as compared with non-adjuvanted RTS,S in healthy, malaria-naïve adults (NCT00443131). Thirty-six subjects were randomized (1:1:1) to receive RTS,S/AS01, RTS,S/AS02, or RTS,S/saline at months 0, 1, and 2. Antibody responses to Plasmodium falciparum circumsporozoite (CS) and hepatitis B surface (HBs) antigens were assessed and cell-mediated immune responses evaluated by flow cytometry using intracellular cytokine staining on peripheral blood mononuclear cells. Anti-CS antibody avidity was also characterized. Safety and reactogenicity after each vaccine dose were monitored. One month after the third vaccine dose, RTS,S/AS01 (160.3 EU/mL [95%CI: 114.1–225.4]) and RTS,S/AS02 (77.4 EU/mL (95%CI: 47.3–126.7)) recipients had significantly higher anti-CS antibody geometric mean titers (GMTs) than recipients of RTS,S/saline (12.2 EU/mL (95%CI: 4.8–30.7); P < 0.0001 and P = 0.0011, respectively). The anti-CS antibody GMT was significantly higher with RTS,S/AS01 than with RTS,S/AS02 (P = 0.0135). Anti-CS antibody avidity was in the same range in all groups. CS- and HBs-specific CD4+ T cell responses were greater for both RTS,S/AS groups than for the RTS,S/saline group. Reactogenicity was in general higher for RTS,S/AS compared with RTS,S/saline. Most grade 3 solicited adverse events (AEs) were of short duration and grade 3 solicited general AEs were infrequent in the 3 groups. No serious adverse events were reported. In conclusion, in comparison with non-adjuvanted RTS,S, both RTS,S/AS vaccines exhibited better CS-specific immune responses. The anti-CS antibody response was significantly higher with RTS,S/AS01 than with RTS,S/AS02. The adjuvanted vaccines had acceptable safety profiles.

Validity analysis of a unique infection surveillance system in the intensive care unit by analysis of a data warehouse built through a workflow-integrated software application

BACKGROUNDnAn electronic decision support programme was developed within the intensive care unit (ICU) that provides an overview of all infection-related patient data, and allows ICU physicians to add clinical information during patient rounds, resulting in prospective compilation of a database.nnnAIMnTo assess the validity of computer-assisted surveillance (CAS) of ICU-acquired infection performed by analysis of this database.nnnMETHODSnCAS was compared with prospective paper-based surveillance (PBS) for ICU-acquired respiratory tract infection (RTI), bloodstream infection (BSI) and urinary tract infection (UTI) over four months at a 36-bed medical and surgical ICU. An independent panel reviewed the data in the case of discrepancy between CAS and PBS.nnnFINDINGSnPBS identified 89 ICU-acquired infections (13 BSI, 18 UTI, 58 RTI) and CAS identified 90 ICU-acquired infections (14 BSI, 17 UTI, 59 RTI) in 876 ICU admissions. There was agreement between CAS and PBS on 13 BSI (100 %), 14 UTI (77.8 %) and 42 RTI (72.4 %). Overall, there was agreement on 69 infections (77.5%), resulting in a kappa score of 0.74. Discrepancy between PBS and CAS was the result of capture error in 11 and 14 infections, respectively. Interobserver disagreement on probability (13 RTI) and focus (two RTI, one UTI) occurred for 16 episodes. The time required to collect information using CAS is less than 30% of the time required when using PBS.nnnCONCLUSIONnCAS for ICU-acquired infection by analysis of a database built through daily workflow is a feasible surveillance method and has good agreement with PBS. Discrepancy between CAS and PBS is largely due to interobserver variability.

Edwardsiella tarda sepsis in a live-stranded sperm whale (Physeter macrocephalus).

Whale strandings remain poorly understood, although bacterial infections have been suggested to contribute. We isolated Edwardsiella tarda from the blood of a stranded sperm whale. The pathogen was identified with MALDI-TOF MS, confirmed by 16S rRNA gene sequencing and quantified in blood by qPCR. We report the first case of sepsis in a sperm whale. The zoonotic potential of E. tarda and the possible role of bacterial infections in the enigmatic strandings of cetaceans are discussed.

Implementation of a multidisciplinary infectious diseases team in a tertiary hospital within an Antimicrobial Stewardship Program

Abstract Background: In January 2011, as part of an antimicrobial stewardship program the Antimicrobial Management Team (AMT) at the Ghent University Hospital initiated a multidisciplinary Infectious Diseases Team (MIT) consisting of infectious diseases physicians, clinical microbiologists, and clinical pharmacists. The aim of this study is to describe the type and acceptance rate of recommendations provided by the MIT. Method: Prospective, observational study in a tertiary care, university teaching hospital with 1062 beds in non-consecutive hospitalized adult patients, excluding intensive care units and paediatrics. Results: The MIT communicated 432 recommendations in 87 days observed. Of the 293 patients for whom a recommendation was made, the median age was 57 years (range: 16–91 years) and 169 (57·7%) were male. Skin or soft tissue infections (14%), respiratory tract infections (13%), infections without known focus (11%), abdominal infections (11%), and bone infections (8%) were most common. Recommendations were made to perform additional clinical investigation(s) [Nu200a=u200a137 (27%)], to adjust the dose of an antimicrobial drug [Nu200a=u200a42 (8%)], to stop an antimicrobial drug [Nu200a=u200a104 (21%)], to switch from a parenteral to an oral drug [Nu200a=u200a39 (8%)] or to initiate an antimicrobial drug [Nu200a=u200a178 (36%)], with an acceptance rate of 73·0%, 83·3%, 81·7%, 76·9%, and 84·0%, respectively. Conclusions: The MIT formulated about five recommendations a day primarily focusing on pharmacotherapy, but also on clinical investigations. In both fields, a high acceptance rate was observed.

Surveillance of Endoscopes: Comparison of Different Sampling Techniques

OBJECTIVE To compare different techniques of endoscope sampling to assess residual bacterial contamination. DESIGN Diagnostic study. SETTING The endoscopy unit of an 1,100-bed university hospital performing ~13,000 endoscopic procedures annually. METHODS In total, 4 sampling techniques, combining flushing fluid with or without a commercial endoscope brush, were compared in an endoscope model. Based on these results, sterile physiological saline flushing with or without PULL THRU brush was selected for evaluation on 40 flexible endoscopes by adenosine triphosphate (ATP) measurement and bacterial culture. Acceptance criteria from the French National guideline (<25 colony-forming units [CFU] per endoscope and absence of indicator microorganisms) were used as part of the evaluation. RESULTS On biofilm-coated PTFE tubes, physiological saline in combination with a PULL THRU brush generated higher mean ATP values (2,579 relative light units [RLU]) compared with saline alone (1,436 RLU; P=.047). In the endoscope samples, culture yield using saline plus the PULL THRU (mean, 43 CFU; range, 1–400 CFU) was significantly higher than that of saline alone (mean, 17 CFU; range, 0–500 CFU; P<.001). In samples obtained using the saline+PULL THRU brush method, ATP values of samples classified as unacceptable were significantly higher than those of samples classified as acceptable (P=.001). CONCLUSION Physiological saline flushing combined with PULL THRU brush to sample endoscopes generated higher ATP values and increased the yield of microbial surveillance culture. Consequently, the acceptance rate of endoscopes based on a defined CFU limit was significantly lower when the saline+PULL THRU method was used instead of saline alone. Infect Control Hosp Epidemiol 2017;38:1062–1069

Influenza vaccines: Where do we stand? Where do we go?. A bumpy but steady road upwards.

To set things straight, the best protection against an influenza irus is if we’ve previously been infected with that same influenza irus. And of all the other reasonable preventive flu measures availble, vaccination is the most effective one. But there is still ample oom for improvement. Indeed, broader, better and longer lastng protection would be very useful. In the meantime, the gap in accination coverage needs to be closed further.