Article

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: 5.36). 11/2009; 183(10):6186-97. DOI: 10.4049/jimmunol.0901474
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
234 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Formulation science is an unappreciated and often overlooked aspect in the field of vaccinology. In this review we highlight key attributes necessary to generate well characterized adjuvant formulations. The relationship between the adjuvant and the antigen impacts the immune responses generated by these complex biopharmaceutical formulations. We will use 5 well established vaccine adjuvant platforms; alum, emulsions, liposomes, PLG, and particulate systems such as ISCOMS in addition to immune stimulatory molecules such as MPL to illustrate that a vaccine formulation is more than a simple mixture of component A and component B. This review identifies the challenges and opportunities of these adjuvant platforms. As antigen and adjuvant formulations increase in complexity having a well characterized robust formulation will be critical to ensuring robust and reproducible results throughout preclinical and clinical studies.
    Seminars in Immunology 07/2013; 25(2). DOI:10.1016/j.smim.2013.05.007 · 6.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adjuvants are used in many vaccines, but their mechanisms of action are not fully understood. Studies from the past decade on adjuvant mechanisms are slowly revealing the secrets of adjuvant activity. In this review, we have summarized the recent progress in our understanding of the mechanisms of action of adjuvants. Adjuvants may act by a combination of various mechanisms including formation of depot, induction of cytokines and chemokines, recruitment of immune cells, enhancement of antigen uptake and presentation, and promoting antigen transport to draining lymph nodes. It appears that adjuvants activate innate immune responses to create a local immuno-competent environment at the injection site. Depending on the type of innate responses activated, adjuvants can alter the quality and quantity of adaptive immune responses. Understanding the mechanisms of action of adjuvants will provide critical information on how innate immunity influences the development of adaptive immunity, help in rational design of vaccines against various diseases, and can inform on adjuvant safety.
    Frontiers in Immunology 05/2013; 4:114. DOI:10.3389/fimmu.2013.00114
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A patient presented at our clinic with severe subacromial bursitis, which persisted for several months following a third booster injection with Cervarix™. Chronic subacromial bursitis manifested itself in this patient after what appeared to be the misinjection of vaccine in close proximity to the acromion. This bursitis was resistant to conventional physiotherapy and to corticosteroid therapy, but was responsive to arthroscopic surgery. Since such patients may present to an arthroscopic surgeon only months after receiving a vaccine injection, this etiological link may not be fully appreciated by treating clinicians. Further, the accuracy of injection in the deltoid region also appears under appreciated, and this report highlights the importance of accurate injection to the deltoid region or in certain cases, the value of simply changing the injection site to another larger muscle.
    Vaccine 10/2012; 31(1). DOI:10.1016/j.vaccine.2012.10.075 · 3.49 Impact Factor