AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity.
Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-kappaB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4(+) T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.
Didierlaurent
Arnaud M
AM
GlaxoSmithKline Biologicals, Rixensart, Belgium. arnaud.didierlaurent@gskbio.com
Morel
Sandra
S
Lockman
Laurence
L
Giannini
Sandra L
SL
Bisteau
Michel
M
Carlsen
Harald
H
Kielland
Anders
A
Vosters
Olivier
O
Vanderheyde
Nathalie
N
Schiavetti
Francesca
F
Larocque
Daniel
D
Van Mechelen
Marcelle
M
Garçon
Nathalie
N
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000536:Aluminum Hydroxide / Q000494:pharmacology*; D000818:Animals; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D052161:Human papillomavirus 18 / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology* / Q000821:virology; D053918:Papillomavirus Vaccines / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology; D014162:Transfection
C532963:ASO4 mixture; D000276:Adjuvants, Immunologic; D051940:B7-2 Antigen; D019013:CD40 Antigens; D016207:Cytokines; D008050:Lipid A; D016328:NF-kappa B; D053918:Papillomavirus Vaccines; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C510352:human papillomavirus vaccine, L1 type 16, 18; D000536:Aluminum Hydroxide; D010047:Ovalbumin; C048436:monophosphoryl lipid A