Predicting the next pandemic: VACCELERATE ranking of the WorldHealth Organization's Blueprint forAction toPreventEpidemics.

INTRODUCTION: The World Health Organization (WHO)'s Research and Development (R&D) Blueprint for Action to Prevent Epidemics, a plan of action, highlighted several infectious diseases as crucial targets for prevention. These infections were selected based on a thorough assessment of factors such as transmissibility, infectivity, severity, and evolutionary potential. In line with this blueprint, the VACCELERATE Site Network approached infectious disease experts to rank the diseases listed in the WHO R&D Blueprint according to their perceived risk of triggering a pandemic. VACCELERATE is an EU-funded collaborative European network of clinical trial sites, established to respond to emerging pandemics and enhance vaccine development capabilities. METHODS: Between February and June 2023, a survey was conducted using an online form to collect data from members of the VACCELERATE Site Network and infectious disease experts worldwide. Participants were asked to rank various pathogens based on their perceived risk of causing a pandemic, including those listed in the WHO R&D Blueprint and additional pathogens. RESULTS: A total of 187 responses were obtained from infectious disease experts representing 57 countries, with Germany, Spain, and Italy providing the highest number of replies. Influenza viruses received the highest rankings among the pathogens, with 79 % of participants including them in their top rankings. Disease X, SARS-CoV-2, SARS-CoV, and Ebola virus were also ranked highly. Hantavirus, Lassa virus, Nipah virus, and henipavirus were among the bottom-ranked pathogens in terms of pandemic potential. CONCLUSION: Influenza, SARS-CoV, SARS-CoV-2, and Ebola virus were found to be the most concerning pathogens with pandemic potential, characterised by transmissibility through respiratory droplets and a reported history of epidemic or pandemic outbreaks.

Immunogenicity and reactogenicity of a first booster with BNT162b2 or full-dose mRNA-1273: A randomised VACCELERATE trial in adults ≥75 years (EU-COVAT-1).

BACKGROUND: Vaccination remains crucial for protection against severe SARS-CoV-2 infection, especially for people of advanced age, however, optimal dosing regimens are as yet lacking. METHODS: EU-COVAT-1-AGED Part A is a randomised controlled, adaptive, multicentre phase II trial evaluating safety and immunogenicity of a 3rd vaccination (1st booster) in individuals ≥75 years. Fifty-three participants were randomised to full-doses of either mRNA-1273 (Spikevax®, 100 µg) or BNT162b2 (Comirnaty®, 30 µg). The primary endpoint was the rate of 2-fold circulating antibody titre increase 14 days post-vaccination measured by quantitative electrochemiluminescence (ECL) immunoassay, targeting RBD region of Wuhan wild-type SARS-CoV-2. Secondary endpoints included the changes in neutralising capacity against wild-type and 25 variants of concern at 14 days and up to 12 months. Safety was assessed by monitoring of solicited adverse events (AEs) for seven days after on-study vaccination. Unsolicited AEs were collected until the end of follow-up at 12 months, SAEs were pursued for a further 30 days. RESULTS: Between 08th of November 2021 and 04th of January 2022, 53 participants ≥75 years received a COVID-19 vaccine as 1st booster. Fifty subjects (BNT162b2 n = 25/mRNA-1273 n = 25) were included in the analyses for immunogenicity at day 14. The primary endpoint of a 2-fold anti-RBD IgG titre increase 14 days after vaccination was reached for all subjects. A 3rd vaccination of full-dose mRNA-1273 provided higher anti-RBD IgG titres (Geometric mean titre) D14 mRNA-127310711 IU/mL (95 %-CI: 8003;14336) vs. BNT162b2: 7090 IU/mL (95 %-CI: 5688;8837). We detected a pattern showing higher neutralising capacity of full-dose mRNA-1273 against wild-type as well as for 23 out of 25 tested variants. INTERPRETATION: Third doses of either BNT162b2 or mRNA-1273 provide substantial circulating antibody increase 14 days after vaccination. Full-dose mRNA-1273 provides higher antibody levels with an overall similar safety profile for people ≥75 years. FUNDING: This trial was funded by the European Commission (Framework Program HORIZON 2020).

VACCELERATE Site Network: Real-time definition of clinical study capacity in Europe.

BACKGROUND: The inconsistent European vaccine trial landscape rendered the continent of limited interest for vaccine developers. The VACCELERATE consortium created a network of capable clinical trial sites throughout Europe. VACCELERATE identifies and provides access to state-of-the-art vaccine trial sites to accelerate clinical development of vaccines. METHODS: Login details for the VACCELERATE Site Network (vaccelerate.eu/site-network/) questionnaire can be obtained after sending an email to. Interested sites provide basic information, such as contact details, affiliation with infectious disease networks, main area of expertise, previous vaccine trial experience, site infrastructure and preferred vaccine trial settings. In addition, sites can recommend other clinical researchers for registration in the network. If directly requested by a sponsor or sponsor representative, the VACCELERATE Site Network pre-selects vaccine trial sites and shares basic study characteristics provided by the sponsor. Interested sites provide feedback with short surveys and feasibility questionnaires developed by VACCELERATE and are connected with the sponsor to initiate the site selection process. RESULTS: As of April 2023, 481 sites from 39 European countries have registered in the VACCELERATE Site Network. Of these, 137 (28.5 %) sites have previous experience conducting phase I trials, 259 (53.8 %) with phase II, 340 (70.7 %) with phase III, and 205 (42.6 %) with phase IV trials, respectively. Infectious diseases were reported as main area of expertise by 274 sites (57.0 %), followed by any kind of immunosuppression by 141 (29.3 %) sites. Numbers are super additive as sites may report clinical trial experience in several indications. Two hundred and thirty-one (47.0 %) sites have the expertise and capacity to enrol paediatric populations and 391 (79.6 %) adult populations. Since its launch in October 2020, the VACCELERATE Site Network has been used 21 times for academic and industry trials, mostly interventional studies, focusing on different pathogens such as fungi, monkeypox virus, Orthomyxoviridae/influenza viruses, SARS-CoV-2, or Streptococcus pneumoniae/pneumococcus. CONCLUSIONS: The VACCELERATE Site Network enables a constantly updated Europe-wide mapping of experienced clinical sites interested in executing vaccine trials. The network is already in use as a rapid-turnaround single contact point for the identification of vaccine trials sites in Europe.

A multinational, phase 2, randomised, adaptive protocol to evaluate immunogenicity and reactogenicity of different COVID-19 vaccines in adults ≥75 already vaccinated against SARS-CoV-2 (EU-COVAT-1-AGED): a trial conducted within the VACCELERATE network.

BACKGROUND: In the ongoing COVID-19 pandemic, advanced age is a risk factor for a severe clinical course of SARS-CoV-2 infection. Thus, older people may benefit in particular from booster doses with potent vaccines and research should focus on optimal vaccination schedules. In addition to each individual's medical history, immunosenescence warrants further research in this population. This study investigates vaccine-induced immune response over 1 year. METHODS/DESIGN: EU-COVAT-1-AGED is a randomised controlled, adaptive, multicentre phase II protocol evaluating different booster strategies in individuals aged ≥75 years (n=600) already vaccinated against SARS-CoV-2. The initial protocol foresaw a 3rd vaccination (1st booster) as study intervention. The present modified Part B of this trial foresees testing of mRNA-1273 (Spikevax®) vs. BNT162b2 (Comirnaty®) as 4th vaccination dose (2nd booster) for comparative assessment of their immunogenicity and safety against SARS-CoV-2 wild-type and variants. The primary endpoint of the trial is to assess the rate of 2-fold antibody titre increase 14 days after vaccination measured by quantitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wild-type virus. Secondary endpoints include the changes in neutralising antibody titres (Virus Neutralisation Assay) against wild-type as well as against Variants of Concern (VOC) at 14 days and up to 12 months. T cell response measured by qPCR will be performed in subgroups at 14 days as exploratory endpoint. Biobanking samples are being collected for neutralising antibody titres against potential future VOC. Furthermore, potential correlates between humoral immune response, T cell response and neutralising capacity will be assessed. The primary endpoint analysis will be triggered as soon as for all patients the primary endpoint (14 days after the 4th vaccination dose) has been observed. DISCUSSION: The EU-COVAT-1-AGED trial Part B compares immunogenicity and safety of mRNA-1273 (Spikevax®) and BNT162b2 (Comirnaty®) as 4th SARS-CoV-2 vaccine dose in adults ≥75 years of age. The findings of this trial have the potential to optimise the COVID-19 vaccination strategy for this at-risk population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05160766 . Registered on 16 December 2021. PROTOCOL VERSION: V06_0: 27 July 2022.

EQUAL Trichosporon Score 2022: an ECMM score to measure QUALity of the clinical management of invasive Trichosporon infections.

BACKGROUND: Invasive infections due to Trichosporon spp. are life-threatening opportunistic fungal infections that require complex clinical management. Guidelines assist clinicians but can be challenging to comply with. OBJECTIVES: To develop a scoring tool to facilitate and quantify adherence to current guideline recommendations for invasive trichosporonosis. METHODS: We reviewed the current guideline for managing rare yeast infections (ECMM, ISHAM and ASM). The most important recommendations for diagnosis, treatment and follow-up were assembled and weighted according to their strength of recommendation and level of evidence. Additional items considered highly relevant for clinical management were also included. RESULTS: The resulting EQUAL Trichosporon Score 2022 comprises 18 items, with a maximum score of 39 points. For diagnostics, seven or eight items, depending on whether organ involvement is present or not, apply, resulting in a maximum of 18 or 21 points. Recommendations on diagnostics include imaging, infectious diseases expert consultation, culture, microscopy, molecular techniques, histopathology, and susceptibility testing. For treatment, six recommendations with a maximum of ten points were identified, with two additional points for organ involvement and one point for second-line treatment in uncontrolled disease. Treatment recommendations include immediate initiation, source control, pharmacological treatment, therapeutic drug monitoring, treatment duration and surgical intervention. Follow-up comprises two items with five points maximum, covering follow-up blood cultures and imaging. CONCLUSIONS: The EQUAL Trichosporon Score weighs and aggregates factors recommended for optimal management of Trichosporon infections. It provides a tool for antifungal stewardship as well as for measuring guideline adherence, but remains to be correlated with patient outcomes.

Mobile PCR-based surveillance for SARS-CoV-2 to reduce visiting restrictions in nursing homes during the COVID-19 pandemic: a pilot study.

PURPOSE: Residents in nursing homes for the elderly (NH) are at high risk for death from COVID-19. We investigated whether repeated non-mandatory RT-PCR SARS-CoV-2 surveillance of NH staff and visitors reduces COVID-19 incidence rates in NH residents and allows to reduce visiting restrictions. METHODS: This pilot study at the beginning of the COVID-19 pandemic compared a surveillance approach of regular, twice-weekly voluntary PCR testing of health-care workers (HCW) and visitors in interventional NH (INH) with a setting without regular testing in control NH (CNH). Residents were not tested routinely within this study. Testing was performed in a mobile testing site with same-day result reporting. SARS-CoV-2 incidence among residents in both INH and CNH was the primary endpoint; secondary endpoints being SARS-CoV-2 infection among visitors and HCW in INH. RESULTS: Two INH and two CNH participated between October and December, 2020. At INH1, 787 tests of HCW and 350 tests of visitors were performed, accounting for 18.1% (n = 1930) of visits. At INH2, 78 tests of HCW and 372 tests of visitors were done, i.e., 30.5% (n = 1220) of visits. At the two INH 23 HCW and three visitors tested positive for SARS-CoV-2. COVID-19 outbreaks occurred among residents in INH1 (identified through study testing) and in CNH1. Utilization of voluntary testing was low. CONCLUSION: In a real-world setting without available rapid testing, voluntary RT-PCR SARS-CoV-2 testing of HCW and visitors does not prevent COVID-19 outbreaks in NH. Complete, non-selective testing for these groups should be instituted before visiting restrictions can be reduced. TRIAL REGISTRATION: The study has been registered at ClinicalTrials.gov with the identifier: NCT04933981.

[The inhibitor of integrins Cilengitide: a new active drug in neuro-oncology]. / L'inhibiteur d'intégrines Cilengitide : un nouveau principe actif en neuro-oncologie.

Last years saw the development of anti-angiogenic strategies in the treatment of cancers. Cilengitide (EMD121974; Merck KGaA, Darmstadt, Germany) is a new drug targeting αvß3 and αvß5 integrins thanks to a specific peptide called RGD sequence. Cilengitide acts in correlations between endothelial cells, tumor cells and extracellular matrix. The promising results obtained with Cilengitide in vitro, used alone or in combination with cytotoxic chemotherapy or ionizing radiations, could give many hopes especially for the treatment of cerebral tumors. Clinical trials are nowadays ongoing in this indication. The aim of this review is to take stock of the situation on the mechanisms of action of the integrin inhibitor Cilengitide (EMD121974; Merck KGaA, Darmstadt, Germany) with a focus on the first pre-clinical and clinical results.

Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial.

BACKGROUND: Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. METHODS: This parallel-group study reports the trial's final data for progression-free survival for a protocol unspecified interim time-point, while overall survival is still being monitored. 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone (182 in perioperative chemotherapy group vs 182 in surgery group). Patients were centrally randomised by minimisation, adjusting for centre and risk score. The primary objective was to detect a hazard ratio (HR) of 0.71 or less for progression-free survival. Primary analysis was by intention to treat. Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152). This trial is registered with ClinicalTrials.gov, number NCT00006479. FINDINGS: In the perioperative chemotherapy group, 151 (83%) patients were resected after a median of six (range 1-6) preoperative cycles and 115 (63%) patients received a median six (1-8) postoperative cycles. 152 (84%) patients were resected in the surgery group. The absolute increase in rate of progression-free survival at 3 years was 7.3% (from 28.1% [95.66% CI 21.3-35.5] to 35.4% [28.1-42.7]; HR 0.79 [0.62-1.02]; p=0.058) in randomised patients; 8.1% (from 28.1% [21.2-36.6] to 36.2% [28.7-43.8]; HR 0.77 [0.60-1.00]; p=0.041) in eligible patients; and 9.2% (from 33.2% [25.3-41.2] to 42.4% [34.0-50.5]; HR 0.73 [0.55-0.97]; p=0.025) in patients undergoing resection. 139 patients died (64 in perioperative chemotherapy group vs 75 in surgery group). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 [25%] vs 27/170 [16%]; p=0.04). After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group. INTERPRETATION: Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients.

Risk factors for breakthrough invasive fungal infection during secondary prophylaxis.

BACKGROUND: Intensive chemotherapy with severe neutropenia is associated with invasive fungal infections (IFIs) leading to high mortality rates. During leukaemia induction chemotherapy, IFI often prohibited further curative treatment, thus predisposing for leukaemia relapse. Continuing myelosuppressive chemotherapy after diagnosis of IFI has become feasible with the now expanding arsenal of safe and effective antifungals. Secondary prophylaxis of IFI is widely administered, but reliable data on outcome and risk factors for recurrent IFI during subsequent chemotherapy are not available. This study determines risk factors for recurrent IFI in leukaemia patients. METHODS: From 25 European cancer centres, 166 consecutive patients with acute myelogenous leukaemia (AML) and a recent history of proven or probable pulmonary IFI were included. Patients were followed for recurrence or breakthrough IFI during the subsequent chemotherapy cycle. RESULTS: Of the 166 patients included, 69 (41.6%) were female, the median age was 53 years (range 2-81) the and 3 (1.8%) were <16 years. Recurrent IFI occurred in 26 patients (15.7%). Multiple logistic regressions yielded predisposing factors: duration of neutropenia [per additional day; odds ratio (OR) 1.043, confidence interval (CI) 1.008-1.078], high-dose cytarabine (OR 3.920, CI 1.120-12.706), number of antibiotics (per antibiotic; OR 1.504, CI 1.089-2.086), partial response as outcome of prior IFI (OR 4.037, CI 1.301-12.524) and newly diagnosed AML (OR 3.823, CI 0.953-15.340). Usage of high efficiency particulate air filter appeared protective (OR 0.198, CI 0.036-1.089). CONCLUSIONS: Duration of neutropenia, high-dose cytarabine, prior antibiotic therapy and a partial response to the first IFI therapy were risk factors for recurrent IFI and should be considered in AML patients with prior pulmonary IFI undergoing further chemotherapy.

Weekly infusional high-dose fluorouracil (HD-FU), HD-FU plus folinic acid (HD-FU/FA), or HD-FU/FA plus biweekly cisplatin in advanced gastric cancer: randomized phase II trial 40953 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group and the Arbeitsgemeinschaft Internistische Onkologie.

PURPOSE: This multicentric, randomized, two-stage phase II trial evaluated three simplified weekly infusional regimens of fluorouracil (FU) or FU plus folinic acid (FA) and cisplatin (Cis) with the aim to select a regimen for future phase III trials. PATIENTS AND METHODS: A total of 145 patients with advanced gastric cancer where randomly assigned to weekly FU 3,000 mg/m2/24 hours (HD-FU), FU 2,600 mg/m2/24 hours plus dl-FA 500 mg/m2 or l-FA 250 mg/m2 (HD-FU/FA), or FU 2000 mg/m2/24 hours plus FA plus biweekly Cis 50 mg/m2, each administered for 6 weeks with a 1-week rest. The primary end point was the response rate. RESULTS: Confirmed responses were observed in 6.1% (two of 33) of the eligible patients treated with HD-FU, in 25% (12 of 48, including one complete remission [CR]) with HD-FU/FA, and in 45.7% (21 of 46, including four CRs) with HD-FU/FA/Cis. The HD-FU arm was closed after stage 1 because the required minimum number of responses was not met. The median progression-free survival of all patients in the HD-FU, HD-FU/FA, and HD-FU/FA/Cis arm was 1.9, 4.0, and 6.1 months, respectively. The median overall survival was 7.1, 8.9, and 9.7 months, and the survival rate at 1 year was 24.3%, 30.3%, and 45.3%, respectively. Grade 4 toxicities were rare. The most relevant grade 3/4 toxicities were neutropenia in 1.9%, 5.4%, and 19.6%, and diarrhea in 2.7%, 1.9%, and 3.9% of the cycles in the HD-FU, HD-FU/FA, and HD-/FU/Cis arms, respectively. CONCLUSION: Weekly infusional FU/FA plus biweekly Cis is effective and safe in patients with gastric cancer.

Once-daily oral levofloxacin monotherapy versus piperacillin/tazobactam three times a day: a randomized controlled multicenter trial in patients with febrile neutropenia.

A prospective, randomized, controlled multicenter trial was performed to evaluate the efficacy and safety of once-daily oral monotherapy with 500 mg levofloxacin in comparison with 4.5 g piperacillin/tazobactam 3 times a day in patients with low-risk febrile neutropenia. Low risk was defined by oral temperature > or = 38.5 degrees C on one occasion or > or = 38.0 degrees C twice within 24 hours and granulocytopenia < or = 500/microL for less than 10 days. The primary end point was defined as defervescence after 72 hours followed by at least 7 afebrile days. Secondary end points were overall response, time to defervescence, survival on day 30, and toxicity. Thirty-four episodes were included. Fever of unknown origin accounted for 26 (76.5%) of the episodes, microbiologically defined infection for 5 (14.7%) of the episodes, and clinically defined infection for 3 (8.8%) of the episodes. On an intent-to-treat basis, all episodes were evaluable for the primary end point. Levofloxacin and piperacillin/tazobactam were successful after 72 hours of treatment in 76.5% and 88.3% of the episodes. Overall response was achieved in 94.1% and 100% of the episodes, respectively. One inpatient in the oral treatment group died of septic shock without identification of a causative pathogen. A larger phase III trial is warranted to further evaluate the lack of inferiority of the oral monotherapy regimen versus standard intravenous therapy.

Outcomes of nosocomial bloodstream infections in adult neutropenic patients: a prospective cohort and matched case-control study.

OBJECTIVE: To examine the clinical and epidemiologic features, excess length of stay, extra costs, and mortality attributable to bloodstream infection (BSI) in neutropenic patients with hematologic malignancies. DESIGN: Prospective cohort and matched case-control study. PATIENTS: All adult neutropenic patients with hematologic malignancies admitted to Cologne University Hospital between May 1, 1997, and April 30, 1998, were prospectively observed. Case-patients were defined as patients with nosocomial BSI; control-patients were selected among patients without BSI. RESULTS: During the study period, the BSI rate in neutropenic patients was 14.3 per 100 neutropenic episodes. Eighty-four case-patients were included. Matching was successful for 96% of the cohort; 81 matched pairs were studied. The mean total length of stay was significantly longer for patients with BSI than for control-patients (37 vs 29 days; P = .002). Extra costs attributable to the infection averaged 3,200 dollars (U.S.) per patient. The crude mortality rates of case-patients and control-patients were 16% and 4%, respectively (P = .013), with an attributable mortality of 12% (odds ratio, 11). Eighty-seven percent of patients met the criteria for sepsis according to the American College of Chest Physicians/Society of Critical Care Medicine. Severe sepsis or septic shock occurred in 13% of patients and was correlated with mortality (55% vs 10% in patients without severe sepsis or septic shock; P = .01). CONCLUSIONS: Nosocomial BSI in neutropenic patients is significantly associated with an excess length of hospital stay, extra costs, and excess mortality. Severe sepsis and septic shock are closely correlated with an adverse outcome.

Treatment for hepatitis C virus in human immunodeficiency virus-infected patients: clinical benefits and cost-effectiveness.

BACKGROUND: Hepatitis C virus (HCV) is an important cause of liver disease in human immunodeficiency virus (HIV)-infected patients. OBJECTIVE: To assess the cost-effectiveness of alternative management strategies for chronic HCV in co-infected patients with moderate hepatitis. METHODS: A state-transition model was used to simulate a cohort of HIV-infected patients with a mean CD4 cell count of 350 cells/ micro L and moderate chronic hepatitis C stratified by genotype. Strategies included interferon alfa (48 weeks), pegylated interferon alfa (48 weeks), interferon alfa and ribavirin (24 and 48 weeks), pegylated interferon alfa and ribavirin (48 weeks), and no treatment. Outcomes included life expectancy, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. RESULTS: Treatment for moderate chronic HCV with combination therapy using an interferon-based regimen reduced the incidence of cirrhosis and provided gains in quality-adjusted life expectancy ranging from 6.2 to 13.9 months, depending on genotype. Regardless of genotype, the cost-effectiveness of interferon alfa and ribavirin for patients with moderate hepatitis was lower than $50 000 per QALY vs the next best strategy. With genotype 1, pegylated interferon alfa (vs interferon alfa) and ribavirin therapy provided an additional 1.6 quality-adjusted life-months for $40 000 per QALY. Because treatment is more effective with non-1 genotypes, pegylated interferon (vs interferon alfa) and ribavirin provided only 3 additional quality-adjusted life-months for $105 300 per QALY. For patients who were intolerant of ribavirin, monotherapy with pegylated interferon was always the most cost-effective option. CONCLUSIONS: Combination therapy for moderate hepatitis in coinfected patients will increase quality-adjusted life expectancy and have a cost-effectiveness ratio comparable to that of other well-accepted clinical interventions.