AS03- and MF59-Adjuvanted Influenza Vaccines in Children

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.

Liposomes used as a vaccine adjuvant-delivery system: From basics to clinical immunization

“…Further, this situation may be exacerbated by the notice that the licensed vaccines based on a VADS are functioning to elicit immunity against pathogens without loading Ags to carriers via encapsulation or adsorption. And they are manufactured mostly through admixing Ags with liposomes, or other NPs, even just before immunization, as exemplified by Shingrix® vaccines which are supplied with separated packages of Ag and VADS [126].…”

“…VADSs based on other micro−/nanoparticles, such as metal (gold, silver, iron) NPs, inorganic (silica) NPs and polymeric NPs, though have also showed a few advantages over conventional formulations in fulfilling functions of delivery and adjuvant, are mostly in early development [134]. An emulsion-based VADS, MF59, approved to Novartis for delivery of influenza vaccines, is a defined formulation consisting of o/w emulsion of squalene/Span85 /Tween80/water [162], which was later reformulated by GSK as an emulsion of squalene/α-tocopherol/ Tween 80/water, known as AS03 [126]. However, unlike liposomes, emulsions are in fact a very fragile carrier having a limited capacity to allow surface modification with functional materials, such as targeting molecules, to form a diverse VADS for delivering subunit vaccines.…”

Oil-in-water emulsion adjuvants for pediatric influenza vaccines: a systematic review and meta-analysis

“…Similarly, AS03 facilities a stronger antibody response by inducing a local cytokine and chemokine response at the injection site to enhance antigen uptake 43 . Studies in young children also showed that MF59-adjuvanted influenza vaccines produced a stronger and more homogeneous innate transcription response like that of adults, thus resulting in significantly higher HI titers than those elicited by non-adjuvanted vaccines 22 .…”

“…MF59-adjuvanted seasonal influenza vaccines were first licensed for the elderly in 1997 21 . AS03, another oil-in-water formulation of squalene, polysorbate 80, and α-tocopherol, allowed the mass production of pandemic influenza vaccines using reduced antigen dose during the 2009 global A(H1N1) pandemic 22 .…”

Influenza – Krankheitslast und Impfprävention bei Kindern und Jugendlichen

“…Adjuvantierte Grippeimpfstoffe sind ein Weg, die bei manchen Per sonengruppen verminderte Immunogenität zu verbessern. Auch für junger Kinder konnten adjuvantierte IIVs entwickelt und er folgreich in klinischen Studien eingesetzt werden [17]. Insbeson dere bei Kindern, die noch keinen Kontakt mit Grippewild oder Impfviren hatten, ist dieser Ansatz vielversprechend.…”