Influvac Tetra: clinical experience on safety, efficacy, and immunogenicity.

INTRODUCTION: This paper summarizes the safety and immunogenicity data of Influvac Tetra across all age groups starting from 6 months of age, obtained during its clinical development program. AREAS COVERED: The article covers the clinical development program of Influvac Tetra based on five registration studies that included different age groups, different comparators, and participants from Europe and Asia. Safety and immunogenicity were assessed in all studies and in one study, the efficacy of Influvac Tetra was assessed. EXPERT OPINION: Seasonal influenza is a vaccine-preventable disease that can cause serious complications. Several types of influenza vaccines are available, including egg-based (standard dose, high dose, and adjuvanted), cell-based, and recombinant. The COVID-19 pandemic has stimulated innovation in the development such as mRNA vaccines. However, these vaccines are still in development and the true value still has to be proven. Regardless of the type of vaccine, it is also important to increase overall vaccination coverage. ECDC recommends that EU Member States implement action plans and policies aimed at reaching 75% coverage in at-risk groups and healthcare workers. Even so, vaccine coverage is still far from recommended.

Enhanced passive safety surveillance of Influvac® and Influvac® Tetra: Results from seven consecutive seasons.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Investigating confounding in network-based test-negative design influenza vaccine effectiveness studies-Experience from the DRIVE project.

BACKGROUND: Establishing a large study network to conduct influenza vaccine effectiveness (IVE) studies while collecting appropriate variables to account for potential bias is important; the most relevant variables should be prioritized. We explored the impact of potential confounders on IVE in the DRIVE multi-country network of sites conducting test-negative design (TND) studies. METHODS: We constructed a directed acyclic graph (DAG) to map the relationship between influenza vaccination, medically attended influenza infection, confounders, and other variables. Additionally, we used the Development of Robust and Innovative Vaccines Effectiveness (DRIVE) data from the 2018/2019 and 2019/2020 seasons to explore the effect of covariate adjustment on IVE estimates. The reference model was adjusted for age, sex, calendar time, and season. The covariates studied were presence of at least one, two, or three chronic diseases; presence of six specific chronic diseases; and prior healthcare use. Analyses were conducted by site and subsequently pooled. RESULTS: The following variables were included in the DAG: age, sex, time within influenza season and year, health status and comorbidities, study site, health-care-seeking behavior, contact patterns and social precautionary behavior, socioeconomic status, and pre-existing immunity. Across all age groups and settings, only adjustment for lung disease in older adults in the primary care setting resulted in a relative change of the IVE point estimate >10%. CONCLUSION: Our study supports a parsimonious approach to confounder adjustment in TND studies, limited to adjusting for age, sex, and calendar time. Practical implications are that necessitating fewer variables lowers the threshold for enrollment of sites in IVE studies and simplifies the pooling of data from different IVE studies or study networks.

The value of public-private collaborative real-world evidence platforms to monitor vaccine performance post authorization: DRIVE - a European initiative.

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.

Efficacy and safety of a quadrivalent influenza vaccine in children aged 6-35 months: A global, multiseasonal, controlled, randomized Phase III study.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: Primary vaccination with QIV was well tolerated and effective in protecting children aged 6-35 months against influenza.

Immunogenicity and safety of quadrivalent versus trivalent inactivated subunit influenza vaccine in children and adolescents: A phase III randomized study.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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/QIV<1.5) and a superior response for alternate-lineage B-strains (HI GMRs of TIV/QIV<1.0; p<0.0001) versus TIV. Reporting rates of local and systemic adverse reactions were similar between vaccine arms. CONCLUSIONS: 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.

Clinical And Bacteriological Impact Of Clarithromycin In Streptococcal Pharyngitis: Findings From A Meta-Analysis Of Clinical Trials.

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.

A Phase III randomised trial of the immunogenicity and safety of quadrivalent versus trivalent inactivated subunit influenza vaccine in adult and elderly subjects, assessing both anti-haemagglutinin and virus neutralisation antibody responses.

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] <1.5) and a superior response for alternate-lineage B-strains (HI GMRs < 1; p < 0.0001) versus TIV. RCD curves demonstrated that post-vaccination HI and VN titres were higher for QIV versus TIV for both alternate-lineage B-strains. Seroconversion rates and geometric mean fold increases of the VN assay were consistent with the HI assay for all strains in QIV. Reporting rates of local and systemic reactions were similar in both vaccine groups. CONCLUSIONS: QIV was non-inferior in immunogenicity to TIV for matched strains and superior to the alternate-lineage B-strains in TIV. Safety and tolerability profiles of QIV and TIV were comparable.

Systematic literature review and meta-analysis of dual therapy with fenofibrate or fenofibric acid and a statin versus a double or equivalent dose of statin monotherapy.

OBJECTIVE: To assess the efficacy of fenofibrate and statin dual therapy versus a double or equivalent dose of statin monotherapy. METHODS: A systematic literature search and meta-analysis was performed for publications before 1 January 2014 in MEDLINE, Embase, and BIOSIS Previews, among others. RESULTS: 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. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: 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.

Betahistine plus piracetam dual therapy versus betahistine monotherapy for peripheral vestibular vertigo: a confounder-corrected subanalysis of the OSVaLD study.

INTRODUCTION: 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 to >1 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Safety and immunogenicity of two subunit influenza vaccines in healthy children, adults and the elderly: a randomized controlled trial in China.

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.

Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly.

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.