BackgroundT-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults.MethodsWe conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18–46 years and 24 subjects aged 50 years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18 months.FindingsBoth vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold-increase and peak immune responses after a single MVA-NP + M1 vaccination was significantly higher compared to ChAdOx1 NP + M1. In a mixed regression model, T-cell responses over 18 months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP + M1.InterpretationA two dose heterologous vaccination regimen of MVA/ChAdOx1 NP + M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A.Funding SourceMedical Research Council UK, NIHR BMRC Oxford.

Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases.

NCT02044198.

Background. The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector.Method. Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara–vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls.Results. No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected.Conclusions. The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types.Clinical Trials Registration. NCT01883609.

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g; Public Health England South-East Regional Microbiology Services, Southampton, United Kingdom h Results from 3,263 QuantiFERON-TB Gold in-tube (QFT-GIT) assays were analyzed to determine the impact of age on test performance. The proportion of indeterminate results was significantly higher in pediatric and elderly (9.1% and 7.4%, respectively) than in adult (2.6%; chi-square test, P < 0.0001) patients. A detailed analysis of indeterminate QFT-GIT assay results is presented.

IntroductionAccelerating progress in reducing child deaths is needed in order to achieve the Sustainable Development Goal child mortality target. This will require a focus on vulnerable children–including young children, those who are undernourished or with acute illnesses requiring hospitalization. Improving adherence to inpatient guidelines may be an important strategy to reduce child mortality, including among the most vulnerable. The aim of our assessment of nine sub-Saharan African and South Asian hospitals was to determine adherence to pediatric inpatient care recommendations, in addition to capacity for and barriers to implementation of guideline-adherent care prior to commencing the Childhood Acute Illness and Nutrition (CHAIN) Cohort study. The CHAIN Cohort study aims to identify modifiable risk factors for poor inpatient and post discharge outcomes above and beyond implementation of guidelines.MethodsHospital infrastructure, staffing, durable equipment, and consumable supplies such as medicines and laboratory reagents, were evaluated through observation and key informant interviews. Inpatient medical records of 2–23 month old children were assessed for adherence to national and international guidelines. The records of children with severe acute malnutrition (SAM) were oversampled to reflect the CHAIN study population. Seven core adherence indicators were examined: oximetry and oxygen therapy, fluids, anemia diagnosis and transfusion, antibiotics, malaria testing and antimalarials, nutritional assessment and management, and HIV testing.ResultsAll sites had facilities and equipment necessary to implement care consistent with World Health Organization and national guidelines. However, stockouts of essential medicines and laboratory reagents were reported to be common at some sites, even though they were mostly present during the assessment visits. Doctor and nurse to patient ratios varied widely. We reviewed the notes of 261 children with admission diagnoses of sepsis (17), malaria (47), pneumonia (70), diarrhea (106), and SAM (119); 115 had multiple diagnoses. Adherence to oxygen therapy, antimalarial, and malnutrition refeeding guidelines was >75%. Appropriate antimicrobials were prescribed for 75% of antibiotic-indicative conditions. However, 20/23 (87%) diarrhea and 20/27 (74%) malaria cases without a documented indication were prescribed antibiotics. Only 23/122 (19%) with hemoglobin levels meeting anemia criteria had recorded anemia diagnoses. HIV test results were infrequently documented even at hospitals with universal screening policies (66/173, 38%). Informants at all sites attributed inconsistent guideline implementation to inadequate staffing.ConclusionAssessed hospitals had the infrastructure and equipment to implement guideline-consistent care. While fluids, appropriate antimalarials and antibiotics, and malnutrition refeeding adherence was comparable to published estimates from low- and high-resource settings, there were inconsistencies in implementation of some other recommendations. Stockou...

Declared competing interests of authors: Saul N Faust was UK chief investigator and University Hospital Southampton NHS Foundation Trust principal investigator for a Cubist-sponsored clinical trial of daptomycin against standard of care antibiotic therapy in paediatric osteomyelitis. All funds were paid into accounts within the NHS trust or university and not paid as personal fees. He reports consultancy fees for advisory board participation paid into accounts within the NHS trust or university (not personal fees) from vaccine manufacturers and antimicrobial agent manufacturers, including AstraZeneca, Cubist, Merck, GlaxoSmithKline (GSK) and Pfizer, outside the submitted work. He acts as principal investigator for clinical trials and other studies conducted on behalf of University Hospital Southampton NHS Foundation Trust/ University of Southampton that are sponsored by vaccine manufacturers and antimicrobial agents, and has participated in advisory boards for vaccine manufacturers. Adam Finn reports grants and personal fees from Sanofi Pasteur MSD Ltd (SPMSD), and grants and personal fees from GSK, outside the submitted work. In addition, prior to October 2014, the University of Bristol and University Hospitals Bristol NHS Foundation Trust received funding for research conducted by Adam Finn and for consultancy and lectures from Pfizer, GSK, SPMSD and Novartis, who manufacture licensed and developmental meningococcal vaccines. Stuart C Clarke acts as principal investigator for clinical trials and other studies conducted on behalf of University Hospital Southampton NHS Foundation Trust/University of Southampton that are sponsored by vaccine manufacturers but receive no personal payments from them. He has participated in advisory boards for vaccine manufacturers and has received financial assistance from vaccine manufacturers to attend conferences, but receives no personal payments for this work. All grants and honoraria are paid into accounts within the respective NHS trusts or universities. Jethro Herberg reports that he was an investigator for a Cubist-sponsored clinical trial of daptomycin against standard of care antibiotic therapy in paediatric osteomyelitis; he received no personal payments. Andrew Riordan reports that the trust, but not he, has received funding for research sponsored by vaccine manufacturers and antimicrobial agents. He was lead editor for an e-learning package on meningitis produced by the Royal College of Paediatric and Child Health, funded by an unrestricted grant from Novartis Vaccines. Marieke Emonts was Newcastle upon Tyne Hospitals Foundation Trust's principal investigator for a Cubist-sponsored clinical trial of daptomycin against standard of care antibiotic therapy in paediatric osteomyelitis. All grants and honoraria are paid into accounts within the NHS trust or university; she received no personal payment of any kind. Marieke Emonts reports acting as site principle investigator on behalf of the Newcastle upon Tyne Hospitals Foundation Trust/Newcastle University for clinical tr...