vivax patients [42]. 2.2. Emulsions Adjuvants composed of emulsions include oil in water (o/w) and water in oil (w/o) systems. There are two formulations approved for human use in Europe, MF59 and AS03. There is also another

compound, Montanide, under phase III stage trials. MF59, a squalene-based o/w emulsion is licensed for influenza vaccine (Fluad). Vaccines with MF59 are safe and have demonstrated a better immunogenicity than nonadjuvanted ones, even in the elderly [44] and childhood [45]. Evaluation of safety data of 64 clinical trials involving MF59 revealed that MF59 adjuvanted subjects had lower risks than nonadjuvanted ones of undergoing unsolicited Inhibitors,research,lifescience,medical adverse events. On the other hand, MF59 adjuvanted subjects had a higher risk of expected local (mild or moderate pain, injection-site warmth induration, and erythema) or systemic reactions (myalgia, headache, fatigue, and malaise) [46]. The effects of Inhibitors,research,lifescience,medical the exposure to MF59 during pregnancy have also been evaluated. Tsai et al. analysed the clinical trial database of Novartis Vaccine studies from 1991 to 2009 and found that distribution of pregnancy outcomes (normal, abnormal, or ending in the therapeutic abortion) was similar Inhibitors,research,lifescience,medical in subjects exposed to MF59 compared to non exposed ones at any time of pregnancy,

specifically in early pregnancy [47]. Although these data are few to draw definitive conclusions, available observations, so far, indicate no signal of risk. Despite the wide use of MF59, its mechanism of action is not well understood. Immunofluorescence analysis showed that MF59 promoted antigen uptake by DCs after intramuscular injection Inhibitors,research,lifescience,medical [48], which suggest that its adjuvancity is not mediated by a depot effect. A study comparing the adjuvant effect of MF59, alum and CpG, characterized the changes in the expression of genes after intramuscular injection in mice. MF59 was the Inhibitors,research,lifescience,medical stronger inducer of cytokines, cytokine receptors, adhesion TPCA-1 nmr molecules involved in leukocyte migration, and antigen presentation genes [49]. In this study, it was hypothesised

that MF59 combines the antigen delivery function with strong immunostimulating activity. Moreover, it may also promote a sustained antigen-presentation triggering the recruitment of CD11b+ monocytes, which might differentiate in functional inflammatory DCs, expressing high levels of MHC class II, as previously Advanced Drug Delivery Reviews described for alum [33]. AS03 is a tocopherol o/w emulsion-based adjuvant used in Pandemrix, an influenza pandemic vaccine. Clinical trials have demonstrated that AS03 adjuvanted vaccines are able to trigger an immune response comparable to that obtained with nonadjuvanted ones using a fourfold lower dose [50]. In addition, the vaccine is well tolerated, and solicited adverse events are transient and mainly mild to moderate in intensity.