title: Role of viral RNA and lipid in the adverse events associated with the 2010 Southern Hemisphere trivalent influenza vaccine.
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 2010 SH trivalent influenza vaccine (CSL 2010 SH TIV) compared to previous CSL TIVs and other licensed 2010 SH TIVs. In an accompanying study, we described the contribution to these adverse events of the 2010 SH influenza strains as expressed in the CSL 2010 SH TIV using in vitro cytokine/chemokine secretion from whole blood cells and induction of NF-κB activation in HEK293 reporter cells. The aim of the present study was to identify the root cause components that elicited the elevated cytokine/chemokine and NF-κB signature. Our studies demonstrated that the pyrogenic signal was associated with a heat-labile, viral-derived component(s) in the CSL 2010 SH TIV. Further, it was found that viral lipid-mediated delivery of short, fragmented viral RNA was the key trigger for the increased cytokine/chemokine secretion and NF-κB activation. It is likely that the FS reported in children <5 years were due to a combination of the new influenza strains included in the 2010 SH TIV and the CSL standard method of manufacture preserving strain-specific viral components of the new influenza strains (particularly B/Brisbane/60/2008 and to a lesser extent H1N1 A/California/07/2009). These combined to heighten immune activation of innate immune cells, which in a small proportion of children <5 years of age is associated with the occurrence of FS. The data also demonstrates that CSL TIVs formulated with increased levels of splitting agent (TDOC) for the B/Brisbane/60/2008 strain can attenuate the pro-inflammatory signals in vitro, identifying a potential path forward for generating a CSL TIV indicated for use in children <5 years.
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: Dorit
authors.initials: D
authors.lastname: Becher
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: 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: bioCSL, Parkville 3052, Victoria, Australia.
authors.forename: Sarina
authors.initials: S
authors.lastname: Camuglia
authors.affiliation: CSL Limited, Parkville 3052, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Soupourmas
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; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology; D004337:Drug Carriers / Q000008:administration & dosage; D057809:HEK293 Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D009981:Influenza B virus; D007252:Influenza Vaccines / Q000009:adverse effects*; D007251:Influenza, Human / Q000517:prevention & control; D008055:Lipids / Q000008:administration & dosage*; D016328:NF-kappa B / Q000378:metabolism; D011358:Product Surveillance, Postmarketing; D012367:RNA, Viral / Q000008:administration & dosage*; D003294:Seizures, Febrile / Q000139:chemically induced*
chemical_list: D018925:Chemokines; D016207:Cytokines; D004337:Drug Carriers; D007252:Influenza Vaccines; D008055:Lipids; C086724:Lipofectamine; D016328:NF-kappa B; D012367:RNA, Viral
keywords: Adverse events; Cytokines; Febrile reactions; Lipid; NF-kapaB; RNA; Seasonal trivalent influenza vaccine; Split viral complexes