Staphylococcus aureus is a leading pathogen in surgical site, intensive care unit, and skin infections, as well as healthcare-associated pneumonias. These infections are associated with an enormous burden of morbidity, mortality, and increase of hospital length of stay and patient cost. S. aureus is impressively fast in acquiring antibiotic resistance, and multidrug-resistant strains are a serious threat to human health. Due to resistance or insufficient effectiveness, antibiotics and bundle measures leave a tremendous unmet medical need worldwide. There are no licensed vaccines on the market despite the significant efforts done by public and private initiatives. Indeed, vaccines tested in clinical trials in the last two decades have failed to show efficacy. However, they targeted single antigens and contained no adjuvants and efficacy trials were performed in severely ill subjects. Herein, we provide a comprehensive evaluation of potential target populations for efficacy trials taking into account key factors such as population size, incidence of S. aureus infection, disease outcome, primary endpoints, as well as practical advantages and disadvantages. We describe the whole-blood assay as a potential surrogate of protection, and we show the link between phase III clinical trial data of failed vaccines with their preclinical observations. Finally, we give our perspective on how new vaccine formulations and clinical development approaches may lead to successful S. aureus vaccines.

Background Staphylococcus aureus skin and soft tissue infections (SA-SSTI) are common in healthcare and community settings, and recurrences occur at variable frequency even after successful initial treatment. Knowing their exact burden and timing of recurrent disease are critical to plan and evaluate interventions to prevent recurrent SSTI. Methods In this retrospective study, SSTI cases in patients ≥18 years of age at three US medical centers between 2006–2016 were analyzed according to a biennial cohort design. Index SSTIs (with or without key comorbidities), either microbiologically confirmed to be SA-SSTI or not tested microbiologically (NMT-SSTI), were recorded within one calendar year (evaluable cohort) and followed-up for 12 months for recurrent infections. The number of index cases, proportion of index cases with ≥1 recurrence(s), time-to-first recurrence, and number of recurrences were collected for both SA-SSTI and NMT-SSTI events. Results In the most recent cohorts, 4,755 SSTI cases were reported at Columbia, 2,873 at Chicago, and 6,433 at Vanderbilt. Of these, 452, 153, and 354 cases were confirmed to be due to S. aureus. Most cases were reported in patients without key comorbidities. Across centers, 16.4–19.0% (SA-SSTI) and 11.0–19.2% (NMT-SSTI) of index cases had ≥1 recurrence(s). In patients without key comorbidities, more than 60% of index SSTIs with recurrences had only one recurrence, half of which occurred in the first three months following primary infection. Conclusion SA-SSTI recurrences are common among healthy adults and occur in at least 1 in 6 individuals during the one year following the primary event.

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This study showed long-term persistence of anti-TBEV NT antibodies for up to 10 years after the first booster dose of TBEvac in all age groups, regardless of the primary vaccination schedule.

Despite high vaccination coverage worldwide, pertussis has re-emerged in many countries. This randomized, controlled, observer-blind phase I study and extension study in Belgium (March 2012–June 2015) assessed safety and immunogenicity of investigational acellular pertussis vaccines containing genetically detoxified pertussis toxin (PT) (NCT01529645; NCT02382913).420 healthy adults (average age: 26.8 ± 5.5 years, 60% female) were randomized to 1 of 10 vaccine groups: 3 investigational aP vaccines (containing pertussis antigens PT, filamentous hemagglutinin [FHA] and pertactin [PRN] at different dosages), 6 investigational TdaP (additionally containing tetanus toxoid [TT] and diphtheria toxoid [DT]), and 1 TdaP comparator containing chemically inactivated PT. Antibody responses were evaluated on days 1, 8, 30, 180, 365, and approximately 3 years post-booster vaccination. Cell-mediated immune responses and PT neutralization were evaluated in a subset of participants in pre-selected groups. Local and systemic adverse events (AEs), and unsolicited AEs were collected through day 7 and 30, respectively; serious AEs and AEs leading to study withdrawal were collected through day 365 post-vaccination.Antibody responses against pertussis antigens peaked at day 30 post-vaccination and then declined but remained above baseline level at approximately 3 years post-vaccination. Responses to FHA and PRN were correlated to antigen dose. Antibody responses specific to PT, toxin neutralization activity and persistence induced by investigational formulations were similar or significantly higher than the licensed vaccine, despite lower PT doses. Of 15 serious AEs, none were considered vaccination-related; 1 led to study withdrawal (premature labor, day 364; aP4 group).This study confirmed the potential benefits of genetically detoxified PT antigen. All investigational study formulations were well tolerated.