A Reduced Dose Whole Virion Aluminum Adjuvanted Seasonal Influenza Vaccine Is Immunogenic, Safe, and Well Tolerated in Pediatric Patients.

BACKGROUND: Data suggest that pediatric patients might react differently to influenza vaccination, both in terms of immunity and side effects. We have recently shown that using a whole virion vaccine with aluminum phosphate adjuvants, reduced dose vaccines containing 6 µg of viral hemagglutinin (HA) per strain are immunogenic, and well tolerated in adult and elderly patients. Here we show the results of a multicenter clinical trial of pediatric patients, using reduced doses of a new, whole virion, aluminum phosphate adjuvanted vaccine (FluArt, Budapest, Hungary). METHODS: A total of 120 healthy volunteers were included in two age groups (3-11 years, receiving 3 µg of HA per strain, and 12-18 years, receiving 6 µg of HA per strain). We used hemagglutination inhibition testing to assess immunogenicity, based on EMA and FDA licensing criteria, including post/pre-vaccination geometric mean titer ratios, seroconversion and seropositivity rates. Safety and tolerability were assessed using CHMP guidelines. RESULTS: All subjects entered the study and were vaccinated (ITT population). All 120 subjects attended the control visit on Day 21 (PP population). All immunogenicity licensing criteria were met in both age groups for all three vaccine virus strains. No serious adverse events were detected and the vaccine was well tolerated by both age groups. DISCUSSION: Using a whole virion vaccine and aluminum phosphate adjuvants, a reduction in the amount of the viral hemmaglutinin is possible while maintaining immunogenicity, safety and tolerability in pediatric and adolescent patients.

Licensing the first reduced, 6 µg dose whole virion, aluminum adjuvanted seasonal influenza vaccine - A randomized-controlled multicenter trial.

INTRODUCTION: Shortages of vaccine supplies repeatedly occur, limiting our abilities to prevent influenza. Therefore, increasing production volume remains a priority. The presently licensed seasonal influenza vaccines contain 15 µg of viral hemagglutinin per strain in adult, and up to 60 µg in elderly patients. Decreasing the amount of viral parts while maintaining efficacy is one way of increasing production capacity. METHODS: This was multicenter, stratified (18-60 years and >60 years of age), prospective, randomized, double-blind, active-controlled, parallel-arm, non-inferiority clinical trial, conducted in the European Union, involving 1206 patients. We used hemagglutination inhibition assay to assess the immunogenicity of a newly developed, whole virion, seasonal trivalent influenza vaccine, containing 6 µg hemagglutinin per strain (FluArt, Hungary) and to assess whether it is non-inferior to the presently licensed vaccine containing 15 µg hemagglutinin per strain. Safety and tolerability of both vaccines were assessed based on EMEA guidelines. RESULTS: The reduced dose vaccine containing 6 µg of hemagglutinin per strain was safe and non-inferior to the currently licensed 15 µg vaccine, not only in adult, but also in elderly patients, according to the immunogenicity criteria by the FDA and EMEA (seroconversion, seroprotection and post/pre vaccination GMT ratios), and it fulfilled all applicable licensing requirements for both age groups. CONCLUSIONS: Based on the results, the reduced dose vaccine was licensed in the EU member state Hungary and safely administered in over 1.5 million cases so far. The amount of viral hemagglutinin needed can be reduced by using a whole virion vaccine with aluminum phosphate adjuvants. REGISTRATION: This study was registered by the European Clinical Trials Database, EudraCT, number: 2011-003314-16.

[Safety data of the new, reduced-dose influenza vaccine FluArt after its first season on the market]. / Az új, csökkentett dózisú, hazai gyártású influenzavakcina (FluArt) forgalomba hozatalát követo elso szezonjának biztonságossági vizsgálata.

INTRODUCTION: The currently licensed seasonal influenza vaccines contain split, subunit or whole virions, typically in amounts of 15 µg hemagglutinin per virus strain for adult and up to 60 µg in elderly patients. AIM: The present study reports safety data of the newly licensed, reduced dose vaccine with 6 µg of hemagglutinin per strain produced by Fluart (Hungary) after its first season on the market. The main objective of enhanced safety surveillance was to detect a potential increase in reactogenicity and allergic events that is intrinsic to the product in near real-time in the earliest vaccinated cohorts. METHOD: The study methods were based on the Interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU by the European Medicines Agency. STATISTICS: We used the Fisher exact test with 95% confidence intervals. RESULTS: We studied 587 patients and detected a total 24 adverse events, all of which have already been known during the licensing studies of the present vaccine. The frequencies of the adverse events were not different from what had been seen with the previously licensed 15 µg vaccine. CONCLUSIONS: Based on the results, the authors conclude that the new, reduced dose vaccine FluArt is safe and tolerable. Orv Hetil. 2017; 158(49): 1953-1959.

Dose sparing and the lack of a dose-response relationship with an influenza vaccine in adult and elderly patients - a randomized, double-blind clinical trial.

AIMS: The currently licensed seasonal trivalent influenza vaccines contain 15 µg haemagglutinin per strain for adult, and up to 60 µg for elderly patients. However, due to recent shortages, dose sparing to increase production capacity would be highly desirable. In the present study, we attempted to find a dose-response relationship for immunogenicity and, thus, the optimal dose for seasonal influenza vaccines in adult and elderly patients. METHODS: A total of 256 subjects, including adult (aged 18-60 years) and elderly (aged over 60 years) individuals, were enrolled. Subjects were randomly assigned in a 1:1:1:1 ratio to receive a whole-virion, aluminium-adjuvanted trivalent influenza vaccine containing 3.5, 6, 9 or 15 µg haemagglutinin of seasonal A/H1N1, A/H3N2 and B influenza antigens manufactured by Omninvest Ltd., Hungary. Serum antibody titres against the vaccine virus strains were measured by haemagglutination inhibition. RESULT: All vaccines were well tolerated. All four vaccines fulfilled all three immunogenicity licensing criteria, as determined by the European Committee for Proprietary Medicinal Products (CPMP)/Biotechnology Working Party (BWP)/214/96 guideline for all three virus strains and both age groups. The 3.5 µg vaccine showed 28% less seroconversion compared to the 15 µg dose in terms of influenza AH3N2 in the adult group (95% confidence interval -51, -3; P < 0.05). All other doses showed no significant difference in immunogenicity compared with the licensed vaccine containing 15 µg haemagglutinin. CONCLUSIONS: Our data suggested that significant dose sparing is possible with the use of whole-virion vaccines and aluminium adjuvants, without compromising safety. This could have significant economic and public health impacts.