Non-clinical safety and biodistribution of AS03-adjuvanted inactivated pandemic influenza vaccines.
Pandemic-influenza vaccines containing split-inactivated-virus antigen have been formulated with the immunostimulatory Adjuvant System AS03 to enhance the antigen immunogenicity and reduce antigen content per dose. AS03 is an oil-in-water emulsion containing α-tocopherol, squalene and polysorbate 80. To support the clinical development of AS03-adjuvanted pandemic-influenza vaccines, the local and systemic toxicity of test articles containing split-influenza A(H5N1) and/or AS03 were evaluated after 3-4 intramuscular (i.m.) injections in rabbits. Treatment-related effects were restricted to mild inflammatory responses and were induced primarily by the test articles containing AS03. The injection-site inflammation was mild at 3 days, and minimal at 4 weeks after the last injection; and was reflected by signs of activation in the draining lymph nodes and by systemic effects in the blood including a transient increase of neutrophils. In addition, a study in mice explored the biodistribution of A(H5N1) vaccines or AS03 through radiolabelling the antigen or constituents of AS03 prior to injection. In this evaluation, 57-73% of AS03's principal constituents had cleared from the injection site 3 days after injection, and their different clearance kinetics were suggestive of AS03's dissociation. All these AS03 constituents entered into the draining lymph nodes within 30 min after injection. In conclusion, the administration of repeated doses of the H5N1/AS03 vaccine was well tolerated in the rabbit, and was primarily associated with transient mild inflammation at the injection site and draining lymph nodes. The biodistribution kinetics of AS03 constituents in the mouse were consistent with AS03 inducing this pattern of inflammation.
GSK Vaccines, Rue de l'Institut 89, 1330, Rixensart, Belgium.
Lawrence
L
Segal
GSK Vaccines, Rue de l'Institut 89, 1330, Rixensart, Belgium.
Sandrine
S
Wouters
GSK Vaccines, Rue de l'Institut 89, 1330, Rixensart, Belgium.
Danielle
D
Morelle
Chelatec SAS, 1 rue Aronnax, 44821, Saint-Herblain Cedex, France.
Gaëlle
G
Gautier
Chelatec SAS, 1 rue Aronnax, 44821, Saint-Herblain Cedex, France.
Julien
J
Le Gal
Covance Laboratories Ltd., Otley Road, Harrogate, HG3 1PY, England.
Thomas
T
Martin
TNO, Utrechtseweg 48, NL-3700, AJ, Zeist, The Netherlands.
Frieke
F
Kuper
GSK Vaccines, Rue de l'Institut 89, 1330, Rixensart, Belgium.
Eric
E
Destexhe
GSK Vaccines, Rue de l'Institut 89, 1330, Rixensart, Belgium.
Arnaud M
AM
Didierlaurent
GSK Vaccines, Rue de l'Institut 89, 1330, Rixensart, Belgium.
Nathalie
N
Garçon
D000818:Animals; D002250:Carbon Radioisotopes; D004196:Disease Outbreaks / Q000517:prevention & control; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity; D007273:Injections, Intramuscular; D008297:Male; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control*; D011136:Polysorbates / Q000633:toxicity; D011817:Rabbits; D013185:Squalene / Q000276:immunology / Q000633:toxicity; D014018:Tissue Distribution; D014316:Tritium; D024502:alpha-Tocopherol / Q000276:immunology / Q000633:toxicity
D002250:Carbon Radioisotopes; D004338:Drug Combinations; D007252:Influenza Vaccines; D011136:Polysorbates; D014316:Tritium; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol
adjuvant system; inflammation; influenza; pandemic; split-influenza antigen; vaccine