Abstract
Influenza is a major cause of respiratory disease leading to hospitalization in young children. However, seasonal trivalent influenza vaccines (TIVs) have been shown to be ineffective and poorly immunogenic in this population. The development of live-attenuated influenza vaccines and adjuvanted vaccines are important advances in the prevention of influenza in young children. The oil-in-water emulsions MF59 and adjuvant systems 03 (AS03) have been used as adjuvants in both seasonal adjuvanted trivalent influenza vaccines (ATIVs) and pandemic monovalent influenza vaccines. Compared with non-adjuvanted vaccine responses, these vaccines induce a more robust and persistent antibody response for both homologous and heterologous influenza strains in infants and young children. Evidence of a significant improvement in vaccine efficacy with these adjuvanted vaccines resulted in the use of the monovalent (A/H1N1) AS03-adjuvanted vaccine in children in the 2009 influenza pandemic and the licensure of the seasonal MF59 ATIV for children aged 6 months to 2 years in Canada. The mechanism of action of MF59 and AS03 remains unclear. Adjuvants such as MF59 induce proinflammatory cytokines and chemokines, including CXCL10, but independently of type-1 interferon. This proinflammatory response is associated with improved recruitment, activation and maturation of antigen presenting cells at the injection site. In young children MF59 ATIV produced more homogenous and robust transcriptional responses, more similar to adult-like patterns, than did TIV. Early gene signatures characteristic of the innate immune response, which correlated with antibody titers were also identified. Differences were detected when comparing child and adult responses including opposite trends in gene set enrichment at day 3 postvaccination and, unlike adult data, a lack of correlation between magnitude of plasmablast response at day 7 and antibody titers at day 28 in children. These insights show the utility of novel approaches in understanding new adjuvants and their importance for developing improved influenza vaccines for children.
Highlights
MF59 and adjuvant systems 03 (AS03) have proven to be immunogenic in young children, provide cross protection against mismatched influenza virus strains and allow for antigen sparing which is important in the setting of pandemics where the global demand is high
MF59 adjuvanted trivalent influenza vaccines (ATIVs) is efficacious in children leading to its licensure in Canada in children; further studies investigating the effectiveness of MF59 seasonal vaccines would potentially improve the likelihood of licensure in young children in other countries and more widespread use of this vaccine in children
A variety of bacteria-derived adjuvants which take advantage of the ability of bacterial components to activate the innate immune system have been incorporated in seasonal trivalent influenza vaccines, with some moving to phase III clinical trials
Summary
MF59 is an oil-in-water emulsion composed of squalene and two surfactants, Tween 80 and Span 85. The MF59-adjuavanted inactive trivalent influenza vaccine (TIV) [Fluad®, MF59-adjuvanted trivalent influenza vaccine (ATIV), Novartis Vaccines] contains 15 μg of each influenza strain surface antigen and the MF59 adjuvant and is administered as a 0.5 ml dose. It is licensed for adults aged 65 years and over. Two MF59-adjuvanted monovalent A/H1N1 pandemic influenza vaccines (Focetria® and Celtura®, Novartis Vaccines) were licensed for children during the H1N1 influenza pandemic in 2009. The AS03 adjuvant is an oil-in-water emulsion composed of squalene, polysorbate 80 and α-tocopherol (vitamin E). Two AS03 formulations with differing amounts of tocopherol, AS03A (11.86 mg tocopherol) and AS03B (5.93 mg tocopherol), were used in the full dose and half dose
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