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.

Immunogenicity, reactogenicity and safety of an inactivated quadrivalent influenza vaccine in children and adolescents 6 months through 17 years of age in India.

Efficacy and safety data on quadrivalent influenza vaccines (QIVs) for immunization of Indian children are scarce. This phase 3, registration study evaluated the immunogenicity, safety, and tolerability of a QIV in Indian children aged 6-35 months (Group 1) and 3-17 y (Group 2). Subjects received one or two doses (0.5 mL each) of the study vaccine based on their priming status. Immunogenicity (post-vaccination geometric mean fold increase in hemagglutination inhibition [HI] titers and proportion of patients with seroprotection and seroconversion against the four influenza strains), unsolicited adverse events (AEs), and tolerability were analyzed. Among 118 subjects enrolled in each group, the geometric mean(standard deviation) fold increase in HI titers against A(H3N2), A(H1N1), B(Victoria), and B(Yamagata) strains were 31.7(5.33), 10.5(6.06), 4.1(5.70), and 8.6(5.34) in Group 1 and 14.0(4.37), 9.2(4.26), 14.3(6.73), and 14.4(5.41) in Group 2, respectively. Seroprotection was achieved by 91.2%, 83.3%, 41.2%, and 68.4% subjects in Group 1 and 100%, 95.8%, 73.7%, and 89.8% subjects in Group 2, respectively. Seroconversion was achieved by 87.7%, 66.7%, 41.2%, and 64.9% subjects in Group 1 and 89.0%, 78.8%, 69.5%, and 75.4% subjects in Group 2, respectively. Vaccination site pain and fever were the most common local and systemic reactions, respectively. Systemic reactions were more frequent in Group 1 (16.9% vs 7.6%). Most subjects (>90%) did not experience inconvenience within 7 d of vaccination; <10% in both groups reported unsolicited AEs. Thus, the QIV had a positive benefit/risk profile in Indian children/adolescents aged 6 months to 17 y.CTRI Registry No: CTRI/2018/05/014191Registry Name: Clinical Trials Registry - IndiaDate of Trial Registration: May 29, 2018Study Dates: August 03, 2018 (first subject first visit) to January 31, 2019 (last subject last visit)Drugs Controller General of India [DCGI] permission letter number: CT-03/2018.

Validation of a Harmonized Enzyme-Linked-Lectin-Assay (ELLA-NI) Based Neuraminidase Inhibition Assay Standard Operating Procedure (SOP) for Quantification of N1 Influenza Antibodies and the Use of a Calibrator to Improve the Reproducibility of the ELLA-NI With Reverse Genetics Viral and Recombinant Neuraminidase Antigens: A FLUCOP Collaborative Study.

Current vaccination strategies against influenza focus on generating an antibody response against the viral haemagglutination surface protein, however there is increasing interest in neuraminidase (NA) as a target for vaccine development. A critical tool for development of vaccines that target NA or include an NA component is available validated serology assays for quantifying anti-NA antibodies. Additionally serology assays have a critical role in defining correlates of protection in vaccine development and licensure. Standardisation of these assays is important for consistent and accurate results. In this study we first validated a harmonized enzyme-linked lectin assay (ELLA)- Neuraminidase Inhibition (NI) SOP for N1 influenza antigen and demonstrated the assay was precise, linear, specific and robust within classical acceptance criteria for neutralization assays for vaccine testing. Secondly we tested this SOP with NA from influenza B viruses and showed the assay performed consistently with both influenza A and B antigens. Third, we demonstrated that recombinant NA (rNA) could be used as a source of antigen in ELLA-NI. In addition to validating a harmonized SOP we finally demonstrated a clear improvement in inter-laboratory agreement across several studies by using a calibrator. Importantly we showed that the use of a calibrator significantly improved agreement when using different sources of antigen in ELLA-NI, namely reverse genetics viruses and recombinant NA. We provide a freely available and detailed harmonized SOP for ELLA-NI. Our results add to the growing body of evidence in support of developing biological standards for influenza serology.

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 two quadrivalent influenza vaccines in healthy adult and elderly participants in India - A phase III, active-controlled, randomized clinical study.

BACKGROUND: This study was conducted to compare the immunogenicity and safety profile of two quadrivalent influenza vaccines (QIVs) in healthy adults (18-60 years) and elderly (>61 years) participants. METHOD: This phase III study was conducted from March 2018 to April 2018 across 12 sites in India. In this randomized, observer-blind, active-controlled study, 480 participants were randomized to receive a single dose of test vaccine (subunit, inactivated influenza vaccine; Influvac® Tetra, Abbott) (n = 240) or reference vaccine (split virion, inactivated influenza vaccine; VaxiFlu-4, Zydus Cadilla Healthcare) (n = 240). The primary objective was to describe and compare the immunogenicity of each vaccination group based on hemagglutination inhibition (HI) assay seroprotection and seroconversion rates, and geometric mean fold increase (GMFI) against four vaccine strains in two age groups. Safety and reactogenicity were also compared for the vaccines in both the age groups. RESULTS: The pre- and post-vaccination HI titers for both the vaccines were comparable. The GMFI varied from 4.3 - 22.7 in the test and 3.7-21.6 in the reference vaccine group. The seroprotection rates were >90% for the A-strains and ranged between >43% and <60% for B-strains for both the vaccines. Seroconversion rates varied between 41.4% and 78.8%. Overall, the reported adverse events (AEs) for both the vaccines were <1% and comparable. Reported local and systemic reactions were comparable. CONCLUSION: Influvac® Tetra elicited an adequate immune response with a favorable safety profile which was comparable with the reference vaccine. (Clinical trial registry number: CTRI/2018/02/012222).

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.

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.

Temporal stability of the Unified Dyskinesia Rating Scale.

BACKGROUND: The objective of this study was to establish temporal stability characteristics for objective components of the Unified Dyskinesia Rating Scale (UDysRS). The UDysRS has strong internal consistency and a reliable factor structure, but the important issue of temporal stability has not been established. METHODS: Using intraclass correlation coefficient (ICC) analyses, we examined UDysRS temporal stability for the objective scale components (Part III and IV) over an 8-hour observation period. We assessed ICCs for the single centralized rater, the on-site raters, and the agreement between the single centralized rater and the on-site raters. Kappa statistic assessed agreement between the single centralized and on-site raters for clinical state (ON vs OFF). RESULTS: For both the single centralized rater and the on-site raters, there was high temporal stability of the UDysRS Part III, Part IV, and Total Objective UDysRS in both ON and OFF states, with ICCs ranging from 0.822 (P < .0005) to 0.513 (P < .013). The agreement between the 2 rating techniques (centralized vs on-site) was significant for ON and OFF ratings of Part III, Part IV, and Total Objective UDysRS, ranging from 0.821 (P < .0005) to 0.703 (P < .0005). CONCLUSIONS: The UDysRS is highly stable for ON and OFF. Our data suggest that a single UDysRS evaluation for ON and for OFF states is highly representative of that state regardless of time. Likewise, if appropriate protocols need to assess dyskinesia in a field or community setting, the UDysRS can be filmed without an on-site rater and rated centrally with retained validity.

Pardoprunox in early Parkinson's disease: results from 2 large, randomized double-blind trials.

This report presents the results of 2 randomized trials-Rembrandt and Vermeer-on the efficacy and safety of pardoprunox in patients with early Parkinson's disease. Patients with Parkinson's disease with a Unified Parkinson's Disease Rating Scale-Motor score ≥ 10 and modified Hoehn and Yahr stage ≤ 3 were randomized to pardoprunox (fixed doses of 6 mg/day [n = 115] or 12 mg/day [n = 118] or a flexible-dose range of 12-42 mg/day [n = 116]) or placebo (n = 119) in Rembrandt and pardoprunox 12-42 mg/day (n = 108), pramipexole 1.5-4.5 mg/day (n = 116), or placebo (n = 110) in Vermeer. Pardoprunox showed a significant benefit over placebo in the primary efficacy variable, least-square mean change from baseline in Unified Parkinson's Disease Rating Scale-Motor score: Rembrandt-fixed doses of 6 and 12 mg/day, -6.0 and -4.7 points, respectively; flexible-dose 12-42 mg/day, -5.5 points; placebo, -2.9 points; Vermeer-flexible-dose 12-42 mg/day, -4.9 points; placebo, -2.5 points; pramipexole, -5.7 points. No minimum effective dose was established. Secondary efficacy parameters supported the results of the primary efficacy variable. Pardoprunox tolerability was dose related: flexible-dose 12-42 mg/day showed the highest dropout rate due to treatment-emergent adverse events (Rembrandt, 56.0%; Vermeer, 46.3%) and overall incidence of treatment-emergent adverse events (Rembrandt, 97.4%; Vermeer, 92.6%), primarily due to nausea, somnolence, and dizziness. Because pardoprunox showed similar efficacy across all dose groups, these observations suggest that the 12-42 mg/day dose range was higher than therapeutically required. Furthermore, the early onset of treatment-emergent adverse events and dropouts observed for pardoprunox suggest that titration was too rapid. Pardoprunox significantly improved motor symptoms in patients with early Parkinson's disease, but further investigation into the dose and titration schedule is required to improve tolerability.

Double-blind study of pardoprunox, a new partial dopamine agonist, in early Parkinson's disease.

This study examined the efficacy and safety of the partial dopamine agonist, pardoprunox (SLV308), in the treatment of patients with early Parkinson's disease (PD). Patients were randomized to receive pardoprunox (n = 69) or placebo (n = 70). Pardoprunox was titrated to each patient's optimal dose (9-45 mg/d) over 2 to 6 weeks and then maintained at this dose for a further 3 weeks. Concomitant anti-Parkinson treatment was not permitted. In the primary analysis, Unified PD Rating Scale (UPDRS)-Motor score was improved in pardoprunox-treated patients (overall mean dose 23.8 mg/d; -7.3 points), as compared with placebo (-3.0 points; P = 0.0001), from baseline to end point. At end point, there were more responders (> or = 30% reduction in UPDRS-Motor score) in the pardoprunox group (50.7%) than in the placebo group (15.7%; P < 0.0001). In other secondary analyses, UPDRS-activities of daily living (ADL) and -ADL+Motor scores were also significantly more improved in the pardoprunox group. Nausea was reported by 32 of 68 (47.1%) pardoprunox-treated patients (vs. 3/70, 4.3%, placebo-treated patients), with dizziness, somnolence, headache, and asthenia also reported by > or = 10 patients. In this exploratory proof-of-concept study, pardoprunox significantly improved motor function in patients with early PD. The efficacy and safety profile of pardoprunox justifies its further investigation in PD.

Dynorphin displaces binding at the glycine site of the NMDA receptor in the rat striatum.

Binding of dynorphin A (1-17 and 2-17) to NMDA receptors in the rat striatum was studied by displacing radioactive ligands for the receptor's polyamine ([3H]-Ifenprodil), glutamate ([3H]-CGP-39653), dizocilpine ([3H]-MK-801) and glycine ([3H]-MDL105,519) sites with the neuropeptide. Dynorphin A selectively displaced [3H]-MDL105,519 and none of the other ligands. Opioid antagonists did not affect displacement. Thus, in the striatum dynorphin may regulate NMDA receptor function via the glycineB site through non-opioid mechanisms. This may contribute to the long-term changes in behavioral responsiveness seen after dopamine depletion and treatment with dopaminomimetics which are associated with substantial changes in striatal dynorphin metabolism.

MK-801 alters the effects of priming with L-DOPA on dopamine D1 receptor-induced changes in neuropeptide mRNA levels in the rat striatal output neurons.

In a previous study, we have shown in unilaterally dopamine-depleted rats that increased behavioral responsiveness to the dopamine D1-receptor agonist SKF-38393, which was induced by pretreatment with L-DOPA, is paralleled by specific alterations in striatal neuropeptide mRNA levels. The behavioral 'priming' effect of L-DOPA is prevented if L-DOPA is preceded by the NMDA-receptor antagonist MK-801. In the present study, the question is addressed whether blockade of the increased behavioral responsiveness with MK-801 also prevents the observed changes in striatal neuropeptide mRNA levels. After a challenge with SKF-38393 (3 mg/kg, s.c.), the striatal levels of preprodynorphin, preprotachykinin, and preproenkephalin mRNA were compared between unilaterally dopamine-depleted rats that were either primed with a single administration of L-DOPA (50 mg/kg, i.p.) or with L-DOPA preceded by MK-801 (0.1 mg/kg, i.p.). Priming with L-DOPA enhanced the increase in dynorphin mRNA levels in the dorsolateral part of the dopamine-depleted striatum that occurred after SKF-38393. On the other hand, it had no significant effect on substance P or enkephalin mRNA levels. MK-801 prior to L-DOPA prevented the increased responsiveness of dynorphin regulation. However, it induced a decreased response to dopamine D1-receptor stimulation in the substance P mRNA levels in dorsal regions of the dopamine-depleted striatum. The levels of enkephalin mRNA after challenge with SKF-38393 were not affected by the MK-801 administration. These results demonstrate that the increased behavioral responsiveness to the D1-receptor agonist SKF-38393 after priming with L-DOPA is primarily related to the upregulation of dynorphin mRNA levels in the dopamine-depleted striatum.