title: Evaluation of the bioactivity of influenza vaccine strains in vitro suggests that the introduction of new strains in the 2010 Southern Hemisphere trivalent influenza vaccine is associated with adverse events.
abstract: In Australia, during the 2010 Southern Hemisphere (SH) influenza season, there was an unexpected increase in post-marketing adverse event reports of febrile seizures (FS) in children under 5 years of age shortly after vaccination with the CSL trivalent influenza vaccine (CSL 2010 SH TIV) compared to previous CSL TIVs and other licensed 2010 SH TIVs. The present study describes the outcomes of a series of in vitro experiments directed at elucidating the root cause. The scientific investigations found that a subset of paediatric donors displayed elevated cytokine/chemokine responses to the CSL 2010 SH TIV but not to previous CSL TIVs nor other 2010 SH TIVs. The induction of elevated cytokines/chemokines in paediatric whole blood correlated with elevated NF-κB activation in a HEK293 cell reporter assay. The data indicate that the introduction of the B/Brisbane/60/2008 strain within the CSL manufacturing process (such as occurred in the preceding 2009/10 NH season) appears to have raised the pyrogenic potential of the CSL 2009/10 NH TIV but that this was insufficient to elicit FS in children <5 years. The 2010 SH season coincided with the first introduction of the H1N1 A/California/07/2009 in combination with the B/Brisbane/60/2008 strain. Our data demonstrates that the introduction of the H1N1 A/California/07/2009 (and to a much lesser degree, H3N2 A/Wisconsin/15/2009) in combination with B/Brisbane/60/2008 (as expressed through the CSL method of manufacture) combined and likely compounded the bioactivity of the CSL 2010 SH TIV. This was associated with stronger immune responses, which in a proportion of children <5 years were associated with FS. The assays and systems developed during these investigations should greatly assist in determining the bioactivity of new influenza strains, and thus aid with the manufacture of CSL TIVs indicated for use in the paediatric population.
authors.affiliation: bioCSL, Parkville 3052, Victoria, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Rockman
authors.affiliation: CSL Limited, Parkville 3052, Victoria, Australia.
authors.forename: Allison
authors.initials: A
authors.lastname: Dyson
authors.affiliation: CSL Limited, Parkville 3052, Victoria, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Koernig
authors.affiliation: CSL Limited, Parkville 3052, Victoria, Australia.
authors.forename: Dorit
authors.initials: D
authors.lastname: Becher
authors.affiliation: CSL Limited, Parkville 3052, Victoria, Australia.
authors.forename: Milica
authors.initials: M
authors.lastname: Ng
authors.affiliation: CSL Limited, Parkville 3052, Victoria, Australia.
authors.forename: Adriana Baz
authors.initials: AB
authors.lastname: Morelli
authors.affiliation: CSL Limited, Parkville 3052, Victoria, Australia.
authors.forename: Megan
authors.initials: M
authors.lastname: Barnden
authors.affiliation: Royal Children's Hospital, Parkville 3052, Australia; Murdoch Children's Research Institute, Melbourne, Australia; University of Melbourne, Australia.
authors.forename: Mimi L K
authors.initials: ML
authors.lastname: Tang
authors.affiliation: CSL Limited, Parkville 3052, Victoria, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Pearse
authors.affiliation: CSL Limited, Parkville 3052, Victoria, Australia. Electronic address: eugene.maraskovsky@csl.com.au.
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
mesh_terms: D001315:Australia / Q000453:epidemiology; D018925:Chemokines / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D053118:Influenza A Virus, H1N1 Subtype; D053122:Influenza A Virus, H3N2 Subtype; D009981:Influenza B virus; D007252:Influenza Vaccines / Q000009:adverse effects* / Q000276:immunology; D007251:Influenza, Human / Q000517:prevention & control*; D016328:NF-kappa B / Q000378:metabolism; D011358:Product Surveillance, Postmarketing; D003294:Seizures, Febrile / Q000139:chemically induced*
chemical_list: D018925:Chemokines; D016207:Cytokines; D007252:Influenza Vaccines; D016328:NF-kappa B
keywords: Adverse events; Chemokines; Cytokines; Febrile reactions; Immune response; NF-kappaB; Paediatric; Seasonal trivalent influenza vaccine