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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901474v1 183/10/6186    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Didierlaurent, A. M. Articles by Garçon, N. PubMed PubMed Citation Articles by Didierlaurent, A. M. Articles by Garçon, N.

AS04, an Aluminum Salt- and TLR4 Agonist-Based Adjuvant System, Induces a Transient Localized Innate Immune Response Leading to Enhanced Adaptive Immunity¹

Arnaud M. Didierlaurent,^23* Sandra Morel,^2* Laurence Lockman,^* Sandra L. Giannini,^* Michel Bisteau,^* Harald Carlsen, Anders Kielland, Olivier Vosters,⁴ Nathalie Vanderheyde,^* Francesca Schiavetti,^5* Daniel Larocque, Marcelle Van Mechelen,^* and Nathalie Garçon^*

^*GlaxoSmithKline Biologicals, Rixensart, Belgium; Cgene, Oslo, Norway; Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium; and GlaxoSmithKline Biologicals, Laval, Canada

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-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by GlaxoSmithKline Biologicals (to H.C. and A.K.).

² A.D. and S.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Arnaud Didierlaurent, GlaxoSmithKline Biologicals, Rue de l’Institut 98, 1330 Rixensart, Belgium. E-mail address: arnaud.didierlaurent{at}gskbio.com

⁴ Current address: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium.

⁵ Current address: Novartis Vaccines, Sienna, Italy.

⁶ Abbreviations used in this paper: AS04, Adjuvant System 04; VLP, virus-like particle; HPV, human papillomavirus; DC, dendritic cell; BMDC, bone marrow DC; Fluo-OVA, Alexa Fluor 647-labeled OVA; HEK, human embryonic kidney; CBA, cytokine bead array.

⁷ The online version of this article contains supplemental material.