Pseudomonas aeruginosa is a major cause of nosocomial infections. This organism shows a remarkable capacity to resist antibiotics, either intrinsically (because of constitutive expression of beta-lactamases and efflux pumps, combined with low permeability of the outer-membrane) or following acquisition of resistance genes (e.g., genes for beta-lactamases, or enzymes inactivating aminoglycosides or modifying their target), over-expression of efflux pumps, decreased expression of porins, or mutations in quinolone targets. Worryingly, these mechanisms are often present simultaneously, thereby conferring multiresistant phenotypes. Susceptibility testing is therefore crucial in clinical practice. Empirical treatment usually involves combination therapy, selected on the basis of known local epidemiology (usually a beta-lactam plus an aminoglycoside or a fluoroquinolone). However, therapy should be simplified as soon as possible, based on susceptibility data and the patient's clinical evolution. Alternative drugs (e.g., colistin) have proven useful against multiresistant strains, but innovative therapeutic options for the future remain scarce, while attempts to develop vaccines have been unsuccessful to date. Among broad-spectrum antibiotics in development, ceftobiprole, sitafloxacin and doripenem show interesting in-vitro activity, although the first two molecules have been evaluated in clinics only against Gram-positive organisms. Doripenem has received a fast track designation from the US Food and Drug Administration for the treatment of nosocomial pneumonia. Pump inhibitors are undergoing phase I trials in cystic fibrosis patients. Therefore, selecting appropriate antibiotics and optimising their use on the basis of pharmacodynamic concepts currently remains the best way of coping with pseudomonal infections.
Background
The aim was to investigate safety and immunogenicity of vaccine formulations against respiratory syncytial virus (RSV) containing the stabilized prefusion conformation of RSV fusion protein (RSVPreF3).
Methods
This phase I/II, randomized, controlled, observer-blind study enrolled 48 young adults (YA; 18–40 years) and 1005 older adults (OA; 60–80 years) between January and August 2019. Participants were randomized into equally sized groups to receive two doses of unadjuvanted (YA and OA) or AS01-adjuvanted (OA) vaccine or placebo two months apart. Vaccine safety and immunogenicity were assessed until one (YA) or 12 months (OA) after second vaccination.
Results
The RSVPreF3 vaccines boosted humoral (RSVPreF3-specific IgG and RSV-A neutralizing antibody) responses, which increased in an antigen-concentration-dependent manner and were highest post-dose one. Compared to pre-vaccination, the geometric mean frequencies of polyfunctional CD4+ T-cells increased after each dose and were significantly higher in adjuvanted than unadjuvanted vaccinees. Post-vaccination immune responses persisted until end of follow-up. Solicited adverse events (AEs) were mostly mild-to-moderate and transient. Despite a higher observed reactogenicity of AS01-containing vaccines, no safety concerns were identified for any assessed formulation.
Conclusions
Based on safety and immunogenicity profiles, the AS01E-adjuvanted vaccine containing 120 μg of RSVPreF3 was selected for further clinical development.
Trial registration
ClinicalTrials.gov NCT03814590; URL: https://clinicaltrials.gov/ct2/show/NCT03814590
Pseudomonas aeruginosa causes severe nosocomial pneumonia in IntensiveCare Unit (ICU) patients, with an increased prevalence of multiresistant strains. We examined the impact of the use of antipseudomonal antibiotic(s) on the susceptibility of P. aeruginosa isolated from ICU patients with clinically suspected hospital-acquired pneumonia collected in five teaching hospitals
HibMenCY-TT induced noninferior Hib and MenC responses compared with monovalent Hib and MenC conjugates with a comparable safety profile. Bactericidal antibodies against MenC/Y were induced after 2 doses of HibMenCY-TT.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.