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In 2014, the European Medicines Agency (EMA) set out requirements for an enhanced safety surveillance for seasonal influenza vaccines. This paper presents data from the yearly Enhanced Passive Safety Surveillance (EPSS) implemented for Influvac® since season 2014/15 and continued for Influvac® Tetra from season 2018/19 onwards.In seven consecutive seasons, an EPSS, aiming for at least 1,000 vaccinees (additional target of 100 vaccinees per five predefined age groups), was conducted in Germany, where market characteristics were expected to allow for a quick generation of representative data. Reactogenicity data in terms of reporting rates, severity and duration of pre-specified local and systemic adverse events of interest (AEI) were collected using response cards, which were completed by vaccinees and returned seven days after vaccination via regular mail. In addition, response cards contained a call center number to enhance reporting of other than pre-specified adverse events.The primary target of at least 1,000 vaccinees was surpassed in all seasons, as was the additional target of 100 adults and elderly. Reactogenicity data were in line with known safety profile of Influvac® and Influvac® Tetra. In children, the target was mostly met in seasons when the EPSS was conducted for Influvac®, but not in seasons when it was conducted for Influvac® Tetra. Although the data for Influvac® Tetra are based on a low number of paediatric vaccinees, they do not indicate a different reactogenicity profile of Influvac® Tetra compared with Influvac®. No signals were identified.The EPSS set up for Influvac® and Influvac® Tetra proved a robust and effective methodology to comply with the objectives of EMÁ's guidance on enhanced safety surveillance of seasonal influenza vaccines. Safety data from seven consecutive seasons confirmed the favourable safety profile of both vaccines.

Children are an important target group for influenza vaccination, but few studies have prospectively evaluated influenza vaccine efficacy (VE) in children under 3 years of age. This was a randomized Phase III trial to assess the efficacy, immunogenicity, and safety of an inactivated quadrivalent influenza vaccine (QIV) in young children (EudraCT: 2016-004904-74).Influenza-naïve children aged 6-35 months were randomized during three influenza seasons to receive vaccination with QIV or a non-influenza control vaccine. One group of participants was revaccinated with QIV in the subsequent influenza season. The primary efficacy endpoint was the absolute VE of QIV against influenza caused by any circulating strain. Key secondary efficacy endpoints included the absolute VE of QIV against influenza due to antigenically matching strains and immunogenicity. Safety and reactogenicity were also evaluated.In total, 1005 children received QIV and 995 received control vaccine. Influenza A/B infection due to any circulating influenza strain occurred less frequently in children who received QIV versus children receiving a control vaccine. The absolute VE of QIV against any circulating influenza strain was 54% (95% confidence interval [CI]: 37%, 66%). The absolute VE of QIV against antigenically matching influenza strains was 68% (95% CI: 45%, 81%). Mean hemagglutination inhibition titers for all influenza strains in the QIV group increased post-vaccination, whereas increases were minimal in the control vaccine group; results from virus neutralization and neuraminidase-inhibition assays were generally consistent with the hemagglutination inhibition assay findings. Approximately 12 months after primary vaccination with QIV, antibody titers remained higher than pre-vaccination titers for most strains. In participants who were revaccinated, QIV elicited strong antibody responses. The overall safety profile and reactogenicity of QIV was comparable with control vaccine.Primary vaccination with QIV was well tolerated and effective in protecting children aged 6-35 months against influenza.

Objective: A meta-analysis was performed to explore the relative effects of clarithromycin and amoxicillin (with or without clavulanate potassium) in the treatment of acute maxillary sinusitis. Methods: Six studies were identified in the peer-reviewed literature. All were randomized single-blind (investigator-blind) or open-label trials in outpatients diagnosed with acute maxillary sinusitis. A total of 1580 patients were enrolled, of whom 1194 were clinically evaluable. The total daily dose of clarithromycin was 1000 mg; the total daily dose of amoxicillin (with or without clavulanate potassium) was either 1500 or 2000 mg. The duration of study drug treatment varied from 8 to 14 days. Endpoints comprised clinical and radiological success within 48 h of the end of study drug treatment plus bacteriologic cure and eradication. Success and cure rate differences were analyzed using fixed- and random-effect models. The absence of between-study heterogeneity was tested using Cochran’s Q-test. Results: Clinical success rates varied between 85.8% and 97.9% for clarithromycin and between 84.2% and 96.8% for amoxicillin. The combined rate difference in clinical success rates between clarithromycin and amoxicillin was +1.9% (P=0.14). Radiological success rates (four studies) varied from 78.2% to 94.0% for clarithromycin and 79.7% to 95.0% for amoxicillin, with a combined rate difference of zero (P=1.00). Bacteriologic cure rates (four studies) were 87.1–94.6% for clarithromycin, compared with 89.8–98.1% for amoxicillin, with a combined difference in cure rates of –3.2% (P=0.16). Overall bacterial eradication rates were comparable between the two treatments (clarithromycin, 89.3%; amoxicillin, 92.1%). Conclusion: These data, with their limitations properly acknowledged, identify clarithromycin as a valid and viable alternative to amoxicillin for the treatment of acute maxillary sinusitis in adults.

International audience; Introduction: Fighting pandemics requires an established infrastructure for pandemic preparedness, with existing, sustainable platforms ready to be activated. This includes platforms for disease surveillance, virus circulation, and vaccine performance monitoring based on Real-World data, to complement clinical trial evidence.Areas covered: Because of its complexity, this can best be done by combining efforts between public and private sectors, developing a multi-stakeholder approach. Public-Private-Partnerships increasingly play a critical role in combating infectious diseases but are still looked at with hesitancy. The Development of Robust and Innovative Vaccine Effectiveness (DRIVE) project, which established a platform for measuring brand-specific influenza vaccine effectiveness in Europe, exemplifies how to build a collaborative platform with transparent governance, state-of-the-art methodology, and a large network of participating sites. Lessons learned from DRIVE have been cardinal to set up COVIDRIVE, a platform for brand-specific COVID-19 vaccine effectiveness monitoring.Expert opinion: The DRIVE partners propose that a debate on the benefits of Public-Private-Partnership-generated real-world evidence for vaccine effectiveness monitoring should be pursued to clarify roles and responsibilities, set up expectations, and decide the future environment for vaccine monitoring in Europe. In parallel, the driving factors behind PPP hesitancy should be studied.

Introduction Among the bacterial upper respiratory tract infections (UTRIs), the most medically significant is pharyngitis due to Group A beta-hemolytic Streptococci (GABHS). A 2012 meta-review and a 2016 Cochrane systematic review reported favorably on the comparative efficacy and safety of clarithromycin in pediatric patients with URTIs and in adults with GABHS pharyngitis. In this paper, the evidence base for clarithromycin in patients with URTIs is augmented by a meta-analysis of comparative studies in GABHS pharyngitis. Methods A series of five outpatient trials of clarithromycin for the treatment of streptococcal pharyngitis from an internal database were subjected to meta-analysis. Active comparators comprised penicillin VK and erythromycin. Results Rates of clinical cure or improvement were very similar in all treatment assignments, but the rates of bacteriological cure were numerically higher with clarithromycin than with comparator antibiotics. Adverse events data indicated that clarithromycin was generally well tolerated in these studies, with a relatively low incidence of adverse events and few severe incidents. Discussion Though currently not advised as a first-line therapy for URTI in most guidelines, the results of the meta-analysis indicate that clarithromycin is nevertheless a valid, effective and largely well-tolerated treatment option for GABHS pharyngitis patients who cannot benefit from other agents.

To analyse the immunogenicity and safety of inactivated subunit quadrivalent influenza vaccine (QIV) versus trivalent influenza vaccine (TIV) in children and adolescents 3-17 years of age.In this phase III, multicentre, double-blind study, 1200 subjects were randomized to receive QIV (n=402), TIV with the B-strain of the Victoria lineage (n=404), or TIV with the B-strain of the Yamagata lineage (n=394). The primary objective was to demonstrate non-inferiority of QIV to TIV for immunogenicity against shared influenza strains, based on post-vaccination hemagglutinin inhibition (HI) titres. Secondary objectives were to show superiority of QIV to TIV for immunogenicity against alternate-lineage B-strains, and to further characterize the immune response by analysing virus neutralization and neuraminidase inhibition titres. Reactogenicity and safety were also compared post-vaccination.QIV elicited a non-inferior response for shared strains (upper limits of the 95% confidence intervals for the HI geometric mean ratios (GMRs) of TIV/QIV1.5) and a superior response for alternate-lineage B-strains (HI GMRs of TIV/QIV1.0; p0.0001) versus TIV. Reporting rates of local and systemic adverse reactions were similar between vaccine arms.QIV had comparable immunogenicity to TIV for shared strains and superior immunogenicity to the alternate-lineage B-strains in TIV. Safety and tolerability profiles were comparable.

BACKGROUND Trivalent influenza vaccines (TIVs) offer substantial protection against matching B-strains, however, protection against alternate-lineage B-strains may be enhanced by adding a second B-strain in quadrivalent influenza vaccines (QIVs). In this Phase III, double-blind, multicentre, randomised study, the immunogenicity and safety of subunit inactivated QIV versus TIV was assessed in adult (aged ≥18 to ≤60 years) and elderly (aged ≥61 years) subjects by analysing a combination of haemagglutinin inhibition (HI) and virus neutralisation (VN). METHODS Subjects (n = 1980) were recruited off season (2015/2016) from 20 centres in five European countries and randomised to receive either QIV (n = 1538), TIV with B-strain of the Victoria lineage (n = 221) or TIV with B-strain of the Yamagata lineage (n = 221). The primary aim was to demonstrate non-inferiority of QIV to TIV for immunogenicity against matched influenza strains based on post-vaccination HI titres. Secondary aims were to show superiority of QIV to TIV for immunogenicity against alternate-lineage B-strains and to characterise the immune response by reverse cumulative distribution (RCD) curves of antibody titres and derived serological parameters for HI and VN. Reactogenicity and occurrence of adverse events were assessed post-vaccination. RESULTS QIV elicited a non-inferior immune response for matched strains (upper limit of 95% CI for HI geometric mean ratios [GMRs]

To assess the efficacy of fenofibrate and statin dual therapy versus a double or equivalent dose of statin monotherapy.A systematic literature search and meta-analysis was performed for publications before 1 January 2014 in MEDLINE, Embase, and BIOSIS Previews, among others.The difference in percentage change from baseline was in favor of dual therapy versus a double dose of statin monotherapy for triglycerides (difference -20%; standard error [SE] 2.6%) and HDL-C (8.7%; SE 1.2%), but not for LDL-C (8.4%; SE 1.5%), non-HDL-C (2.8%; SE 1.1%), total cholesterol (4.5%; SE 1.0%) and apolipoprotein B (2.6%; SE 1.1%). For high intensity statins, the difference in percentage change from baseline was in favor of dual therapy versus equivalent statin monotherapy for triglycerides (-17%; SE 2.6%) and for HDL-C (8.7%; SE 1.9%). The difference in percentage change from baseline for LDL-C was 6% (SE 1.7%), implying a greater reduction in LDL-C with statin monotherapy. For moderate intensity statins, the difference in percentage change from baseline was in favor of dual therapy versus equivalent statin monotherapy for triglycerides (-24.2%; SE 1.2%) and HDL-C (8.2%; SE 0.9%). LDL-C decreased 2.2% (SE 1.4%) more with dual therapy.When aiming to change HDL-C or triglycerides, dual therapy is to be preferred to doubling the statin dose; conversely, doubling the statin dose is to be preferred when aiming to reduce LDL-C. If the aim is both to change HDL-C or triglycerides and to reduce LDL-C, the importance of the three outcomes may need to be weighed depending on the intensity of the statin. Combining high intensity statin therapy with fenofibrate improves the effect on HDL-C and triglycerides, but lowers the effect on LDL-C. Combining a moderate intensity statin with fenofibrate improves the effect on HDL-C and triglycerides without reducing the effect on LDL-C. There is a need for long-term randomized clinical trials to compare dual therapy versus doubling the statin dose to assess the importance of improvement in HDL-C and triglycerides versus improvement in LDL-C in terms of cardiovascular outcomes. Further, the addition of ezetimibe to statin/fenofibrate therapy may be of interest.

This subanalysis compared the efficacy of betahistine plus piracetam dual therapy versus betahistine monotherapy using data from OSVaLD, a 3 month, open-label, observational study conducted in 2272 patients with peripheral vestibular vertigo. Of the 1898 patients included in the original efficacy population, 1076 were from countries where betahistine plus piracetam dual therapy was prescribed to1 patient; 114 of these 1076 patients (11%) received the dual therapy and 567 (53%) were treated with betahistine monotherapy; these patients were selected for analysis.Efficacy was assessed using the Dizziness Handicap Inventory (DHI) total and subscale scores. Propensity-score matching was used to correct potential differences in patient baseline characteristics between treatment groups. In addition, a subgroup analysis evaluated 103 patients treated with betahistine because of insufficient efficacy with their existing treatment.In the propensity-score matched, total-population evaluation, improvements in the DHI total and subscale scores were numerically greater in the betahistine plus piracetam group (n = 88) versus the betahistine group (n = 89) (DHI total, -42.9 vs. -37.6, respectively; DHI physical, -12.1 vs. -10.4; DHI emotional, -13.5 vs. -13.2) and statistically significant for the DHI functional score (-17.3 vs. -14.0, respectively, p = 0.01). The percentage of patients with no impairment at final visit was 27% with betahistine and 47% with betahistine plus piracetam; odds ratio: 2.3, 95% confidence interval: 1.3-2.4 (p = 0.007). Similar results were obtained in the subgroup analyses for patients whose current vertigo treatment was insufficient. The overall incidence of adverse events was low and similar in both groups, and there were no discontinuations due to drug-related adverse events.By using propensity-score matching, which controls for potential heterogeneity in patient baseline characteristics and small patient numbers, the results of this analysis suggest that combined betahistine and piracetam may be more effective than betahistine alone in patients with peripheral vestibular vertigo.

Background/objectives Between 1982 and 2011, 84 clinical studies were performed by the manufacturers of Influvac®, including the annual update studies required for licensing in Europe. This paper presents data from a 30-year evaluation of clinical experience with Influvac®. Subjects and methods In all, 8776 subjects were vaccinated with Influvac®, including healthy adults, healthy elderly subjects, adult and elderly at-risk subjects, and healthy and at-risk children. All subjects received the trivalent inactivated subunit influenza vaccine Influvac® (Abbott, Weesp, The Netherlands). Subjects recorded solicited local and systemic reactions for 3–7 days after vaccination. Inconvenience was scored in some studies. Unsolicited reports of adverse events were collected up to 21 days after vaccination. Haemagglutination inhibition (HI) antibody titres were determined before and up to 45 weeks after vaccination with Influvac®. The immunogenicity of Influvac® was assessed using the criteria of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency. Post marketing surveillance data were also analyzed. Results Treatment-emergent adverse events up to 21 days after vaccination were reported by 583 of 4746 subjects (12.3%), most commonly headache. Overall, 2318 of 6825 subjects (34.0%) recorded local reactions (most commonly tenderness and pain on slightest pressure) and 1229 of 6825 subjects (18.2%) recorded systemic reactions (most commonly headache and fatigue). All local and systemic reactions were mild or moderate and resolved in 1–2 days. Most subjects in each population group reported inconvenience as none-to-mild. Post marketing surveillance data collected from 1982 to 2012 indicated an overall reporting rate of 24.5 events/million doses. The age-specific CHMP serological criteria for immunogenicity were generally met in all the adult and elderly populations and the HI antibody titres and derived serological parameters in children were similar to those in adults. The CHMP requirement for immunogenicity for annual re-licensing for both healthy adults and elderly subjects was consistently met over the 30-year period. One study in elderly subjects demonstrated that HI antibody titres were maintained at relatively high levels for at least 6 months, providing coverage throughout the influenza season, but by 1 year after vaccination antibody titres had declined to low enough levels to necessitate revaccination. Conclusions This review of the 30-year clinical experience with Influvac® found that the overall benefit-to-risk ratio is positive for all age groups from 6 months upwards. The currently available evidence from the many clinical trials that have been performed confirms that Influvac® remains an effective and safe vaccine for preventing seasonal influenza.

The burden of influenza is well known in the elderly and at-risk patients, but also in children. Especially in those under 5 years old, influenza may cause severe morbidity and mortality. Influenza infections and complications can be reduced by vaccination. In a randomized, endpoint-blinded, parallel group trial the immunogenicity and safety was studied of two trivalent inactivated surface antigen (subunit) influenza vaccines Influvac ® and Agrippal ® in healthy children as well as in adults and the elderly. An open safety part in 30 children aged 3–12 years and 30 adults aged 18–60 years vaccinated with Influvac ® was followed by an endpoint-blind, parallel group part in 300 healthy children aged 3–12 years, 300 healthy adults aged 18–59 years, and 240 healthy elderly persons aged 60 years or over, in which subjects were randomized 2:1 to vaccination with either Influvac ® or Agrippal ® . The primary immunogenicity endpoint was the geometric mean titer (GMT) 4 weeks after vaccination. Both Influvac ® and Agrippal ® induced high anti-hemagglutinin antibody titers in the children and in the adult and elderly subjects. Seroprotection rates were >85% and seroconversion rates >70% for both vaccines in all three age groups for all three-virus strains. The GMT ratios after vaccination indicated that the immunogenicity of Influvac ® was at least comparable with that of Agrippal ® in all three age groups. Both vaccines were well tolerated and safe. In this trial, Influvac ® and Agrippal ® were immunogenic, safe and well tolerated in healthy children as well as in adults and elderly people.

Background. The incidence of distant metastases in head and neck cancer patients is rising because of greater locoregional control of the disease. Methods. The relative risks for having distant metastases as first site of failure relative to the regional lymph node involvement were determined. Results. The overall incidence was 10.7%, with a clear relationship between the number of involved lymph nodes and extranodal spread on one hand, and distant spread on the other hand. The group with histopathologic presence of disease in the neck had twice as much distant metastases as did those with histopathologic absence (13.6% versus 6.9%). Patients with more than three histologically positive lymph nodes were most at risk for having distant metastases (46.8%). The presence of extranodal spread meant a threefold increase in the incidence of distant metastases, compared with patients without this feature (19.1% versus 6.7%). Conclusions. Patients with three or more positive nodes and with extranodal spread may benefit from adjuvant systemic therapy.

Several inactivated influenza vaccine formulations for systemic administration in man are currently available for annual (seasonal) immunization: split virus and subunit (either plain-aqueous, or virosomal, or adjuvanted by MF59). From a literature search covering the period 1978-2009,33 articles could be identified, which described randomized clinical trials comparing at least two of the four vaccine formulations with respect to serum hemagglutination inhibition (HI) antibody response, local and systemic vaccine reactions and serious adverse events after vaccination, and employing seasonal vaccine components and doses. In total, 9121 vaccinees of all ages, either healthy or with underlying diseases, were involved. Most vaccinees were primed or had been vaccinated in previous years. For immunogenicity, homologous post-vaccination geometric mean HI titers (GMTs) were analyzed by a random effects model for continuous data. Unreported standard deviations (SD) were addressed by imputing assumed SD-values. Age and health state of the vaccinees appeared to have little influence on the outcome. The immunogenicity of split, aqueous and virosomal subunit formulations were similar, with geometric mean ratio values (GMR, quotient of paired GMT-values) varying around one (0.93-1.24). The MF59-adjuvanted subunit vaccine induced, on average, larger antibody titers than the non-adjuvanted vaccine formulations, but the absolute increase was small (GMR-values varying between 1.25 and 1.40). Vaccine reactions were analyzed using a random effects model for binary data. Local and systemic reactogenicity was similar among non-adjuvanted formulations. The adjuvanted subunit formulation was more frequently associated with local reactions than the non-adjuvanted formulations (rate ratio: 2.12, significant). Systemic reactions were similar among all vaccine formulations. The original articles emphasized the mild and transient character of the vaccine reactions and the absence of serious vaccine-related adverse events. This adequate amount of evidence led to the conclusion that all the currently available inactivated influenza vaccine formulations are safe, well tolerated and similarly effective to control seasonal influenza outbreaks across primed populations and age ranges. (C) 2011 Published by Elsevier Ltd.

In a randomized, observer-blind, three-arm, parallel group, multi-centre trial including 386 elderly subjects in four countries, the immunogenicity and safety was studied of three different trivalent inactivated surface antigen (subunit) influenza vaccine types: a conventional subunit influenza vaccine (SIV, brand: Influvac and two newer vaccines: a MF59-adjuvanted subunit influenza vaccine (adSIV, brand: Fluad and a virosomal subunit influenza vaccine (vSIV, brand: Invivac. All vaccines were trivalent containing 15 microg hemagglutinin of each virus strain as recommended by the World Health Organization for the 2004-2005 season. The study was designed to demonstrate the serological non-inferiority of vSIV to both adSIV and SIV in elderly persons. The secondary objective was to investigate whether vSIV is superior to adSIV with respect to local reactogenicity. For all three vaccine strains, the post-vaccination geometric mean titres were comparable between SIV and adSIV and between vSIV and SIV. Seroprotection rates (i.e. percentages of subjects with a post-vaccination titre >or=40) varied between 84.1-100% indicating that the three vaccines all induced a strong antibody response. Local and systemic reactions were more frequently associated with adSIV (46 and 32%, respectively) than with vSIV or SIV ( approximately 20%). Vaccinations caused only little inconvenience as measured by questionnaire. In general, all vaccines were safe and well tolerated. In this trial, virosomal vaccine had similar immunogenicity to MF59-adjuvanted and conventional subunit vaccine and was considerably less reactogenic than the MF59-adjuvanted vaccine in the elderly.