AS04, an Aluminum Salt- and TLR4 Agonist-Based Adjuvant System, Induces a Transient Localized Innate Immune Response Leading to Enhanced Adaptive Immunity

GlaxoSmithKline Biologicals, Rixensart, Belgium.
The Journal of Immunology (Impact Factor: 4.92). 11/2009; 183(10):6186-97. DOI: 10.4049/jimmunol.0901474
Source: PubMed


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.

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    • "MPL is a component of the AS04 Adjuvant System used in the human papillomavirus-16/18 AS04-adjuvanted vaccine (Cervarix®; GSK, Rixensart, Belgium). A previous study assessing the contribution of MPL in response to AS04, demonstrated a localized and transient effect of MPL after intramuscular immunization with no evidence of systemic effects (Didierlaurent et al., 2009). Transient activation of an innate response at the injection site was also observed after administration of the AS01 Adjuvant System, containing MPL and QS-21 (Didierlaurent et al., 2014). "
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    • "In the current study, Montanide ISA61 administered by the subcutaneous route induced primarily IgG with stimulation of only moderate levels of IgA. Studies have shown that MPL which activates toll-like receptor 4 (TLR4), contributes to the activation of the innate immune response (Didierlaurent et al., 2009). However, when added to Montanide ISA61, MPL did not further enhance antibody responses to GT2. "
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    • "AF03 is also a squalene-based emulsion adjuvant that is present in the adjuvanted pandemic influenza vaccine, Humenza™ [83]. AS04 was also developed by GSK and used as the adjuvant for viral vaccines including hepatitis B (Fendrix ® ), and HPV (Cervarix ® ) [111]. AS04 is comprised of traditional alum with a Toll-like receptor (TLR) agonist. "
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