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.

Influenza A (H5N1) pandemic prototype vaccine Fluval.

The timely development of safe and effective vaccines is likely to be the single most important public-health tool for decreasing the morbidity, mortality and economic effects of the influenza pandemic. The objective of this article is to provide a detailed description of the chemistry and immunogenicity of one of the better studied inactivated whole-virion aluminum phosphate-adjuvanted vaccines, Fluval (Omninvest, Hungary), while we discuss safety data of all clinical trials published on H5N1 vaccines to date. Fluval was chosen for detailed discussion owing to its immunogenicity after only one dose, the fact that it was one of the very first H5N1 vaccines that demonstrated the potential for dose sparing and, unlike all mainstream oil-in-water adjuvanted reverse genetics-derived H5N1 vaccines, it is whole virion based.

Cross-reactive immunity to clade 2 strains of influenza virus A subtype H5N1 induced in adults and elderly patients by Fluval, a prototype pandemic influenza virus vaccine derived by reverse genetics, formulated with a phosphate adjuvant, and directed to clade 1 strains.

High fatality rates and multiple cases of transmission of avian H5N1 influenza viruses to humans illustrate the urgent need for an efficacious, cross-protective vaccine against H5N1 strains. Extensive genetic characterization of H5N1 strains has elucidated the natural evolutionary relationship of these strains, linking groups known as clades to a common ancestor. Although the clades and subclades probably differ sufficiently in their antigenic structure to warrant the preparation of different vaccines, there is some evidence that cross-reactive immunity can be afforded. We aimed to assess the immunogenicity of a clade 1 H5N1 (NIBRG-14) whole-virus vaccine with an aluminum phosphate adjuvant and to determine whether it can induce cross-reactive immunity against antigenically drifted clade 2 H5N1 strains, both those derived by reverse genetics and wild-type isolates. A total of 88 (44 adult and 44 elderly) subjects, who received one dose (6 microg) of the vaccine, were studied. As judged by U.S. and European licensing criteria based on hemagglutination inhibition, the subjects developed cross-reactive immunity against all studied H5N1 strains belonging to a clade different from that of the strain utilized to produce the vaccine. Our findings highlight the importance of stockpiling, since cross-immune reactions induced by prepandemic vaccines will likely reduce morbidity and mortality in case of a pandemic.

Yearly licensing studies from 1997 to 2007 of the inactivated whole virus seasonal influenza vaccine fluval--a useful approach to pandemic vaccine development even in less well developed countries?

OBJECTIVE: Seasonal vaccination has been consistently shown to significantly reduce morbidity and mortality because of influenza epidemics, even in healthy, working adults. Here we report the results of the yearly licensing studies of the past 11 influenza seasons (1997-2007) with a trivalent, inactivated whole virus vaccine with an aluminum phosphate adjuvant system. METHODS: Sixty healthy volunteers per age group (18-60 years and 60 years and older) were enrolled to receive vaccination each year, thus, a total of 1080 subjects were studied. Serum antibody titers were measured by hemagglutination inhibition (HI). RESULTS: The vaccine met the criteria for licensing each year, meaning seroprotection (achievement of an HI titer of >1:40 in >70% of subjects); seroconversion, i.e. a >4-fold increase in HI antibody titer, or reaching a titer of >1:40, in >40% of subjects; and an increase in geometric mean titers by >2.5-fold. Side effects were rare and mild. The same method was used to produce a pre-pandemic vaccine against influenza A (H5N1), which has been shown to be safe and immunogenic in humans. CONCLUSIONS: We conclude that the method presented is safe, effective and may serve as a useful approach to seasonal and pandemic vaccine production even in less well-developed countries by means of technological transfer.