Aluminum Hydroxide Adjuvant Differentially Activates the Three Complement Pathways with Major Involvement of the Alternative Pathway

Introduction

Immunological adjuvants are compounds which initiate and boost immune responses, leading to stronger and faster adaptive immune responses without having any antigenic effect by themselves [1], [2]. Many different compounds of both organic and inorganic origin have been observed to stimulate a vigorous immune response and therefore have adjuvant properties; these include mineral oils and different metal salts, notably aluminum compounds (e.g. aluminium hydroxide (Al(OH)3), the hydrated form of aluminium oxide (Al2O3) [2]-[6]. Also, the pathogen-associated molecular patterns (PAMPs) are a big group of naturally occurring compounds with adjuvant properties. They include CpG DNA, ssDNA, dsRNA and bacterial cell wall components [7], [8].

The first adjuvant effect of an aluminum compound was described by Glenny et al. [9] and the effect has been used in vaccines since the first half of the 20th century (from around 1930). Among the few approved adjuvants for human vaccines the aluminum compounds are often preferred and have been used extensively for diphtheria vaccines, tetanus vaccines, pertussis vaccines, hepatitis vaccines and polio vaccines [10]-[12].

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The modes of action of aluminum adjuvants are still a subject of research but several mechanisms have been suggested. Glenny et al. initially described the adjuvant effect of aluminium adjuvants to be due to the ability of these to form a depot and to control the release of antigen [13]; this has later been questioned [14]. Other non-exclusive modes of action have also been suggested, including enhancement of antigen uptake and presentation, innate immune system activation and enhancement of cytokine production and release [1]-[4], [15]-[18]. Recently, aluminum hydroxide has been observed to bind lipid moieties on dendritic cells and promote lipid sorting in the plasma membrane, leading to signal transduction and immune response initiation [19] and increase antigen uptake and enhance antigen presentation on dendritic cells [20], [21] and directly affect B lymphocytes [22]. Aluminum hydroxide has also been described to be able to activate the complement system. Already in 1975, Polley and Nachman observed that aluminum hydroxide could remove 40-60% of the haemolytic complement activity in a serum sample [23]. This was later confirmed by Ramanathan et al., who found that aluminum and zirconium compounds could activate the complement system and it was suggested that the complement activation occurred through the lectin pathway [24]. However, findings by Arvidsson et al., suggested that an aluminum surface binds C3 through the classical complement pathway [25]. On the contrary, Tengvall et al., found no evidence that complement deposition on aluminium hydroxide occurred as a result of complement activation [26] (the three major complement pathways are described in Fig. 1).

Here, we confirm that Al(OH)3 activates the complement system and show that aluminum hydroxide adjuvant activates the three complement pathways with major involvement of the alternative complement pathway, thus providing a rationale for its efficient adjuvant properties.

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