The Adjuvants Aluminum Hydroxide and MF59 Induce Monocyte and Granulocyte Chemoattractants and Enhance Monocyte Differentiation toward Dendritic Cells

Abstract

Aluminum hydroxide (alum) and the oil-in-water emulsion MF59 are widely used, safe and effective adjuvants, yet their mechanism of action is poorly understood. We assessed the effects of alum and MF59 on human immune cells and found that both induce secretion of chemokines, such as CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β), and CXCL8 (IL-8), all involved in cell recruitment from blood into peripheral tissue. Alum appears to act mainly on macrophages and monocytes, whereas MF59 additionally targets granulocytes. Accordingly, monocytes and granulocytes migrate toward MF59-conditioned culture supernatants. In monocytes, both adjuvants lead to increased endocytosis, enhanced surface expression of MHC class II and CD86, and down-regulation of the monocyte marker CD14, which are all phenotypic changes consistent with a differentiation toward dendritic cells (DCs). When monocyte differentiation into DCs is induced by addition of cytokines, these adjuvants enhanced the acquisition of a mature DC phenotype and lead to an earlier and higher expression of MHC class II and CD86. In addition, MF59 induces further up-regulation of the maturation marker CD83 and the lymph node-homing receptor CCR7 on differentiating monocytes. Alum induces a similar but not identical pattern that clearly differs from the response to LPS. This model suggests a common adjuvant mechanism that is distinct from that mediated by danger signals. We conclude that during vaccination, adjuvants such as MF59 may increase recruitment of immune cells into the injection site, accelerate and enhance monocyte differentiation into DCs, augment Ag uptake, and facilitate migration of DCs into tissue-draining lymph nodes to prime adaptive immune responses.

Head-to-Head Comparison of Poxvirus NYVAC and ALVAC Vectors Expressing Identical HIV-1 Clade C Immunogens in Prime-Boost Combination with Env Protein in Nonhuman Primates

“…It should be pointed out that after priming, immunization with NYVAC-C and ALVAC-C gave better antibody responses to clade B gp140 than the immunization with clade B immunogens (A2AP2 [B/E, AIDSVAX]). This could be due to the nature of the adjuvant, even though both adjuvants (MF59 and alum) potentially augment the immune response through a common mechanism, inducing a similar pattern of phenotypical and chemokine responses in monocytes (49). Furthermore, immunization with A2AP2 (B/E, AIDSVAX) also induced good cross-clade antibody responses against clade C HIV-1 gp140 and gp120 antigens.…”

Effects of MF59 Adjuvant on Induction of Isotype-Switched IgG Antibodies and Protection after Immunization with T-Dependent Influenza Virus Vaccine in the Absence of CD4 + T Cells

“…MF59 was shown to create an immunocompetent microenvironment at the injection site by inducing chemokines and cytokines as well as recruiting neutrophils, eosinophils, and, later, DCs and macrophages (7). Previous studies on MF59 suggest that an immunocompetent microenvironment with activated innate immune cells and APCs leads to the induction of effector CD4 ϩ T cells, eventually helping B cells to differentiate IgG antibody-secreting plasma cells (17,(33)(34)(35). By using microarray and immunofluorescence analyses, MF59 was determined to be a strong inducer of cytokines, cytokine receptors, adhesion molecules, and antigen-presenting genes FIG 6 MF59 induces acute production of cytokines and chemokines at higher levels than does alum.…”

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

“…It is believed to act through a depot effect and direct stimulation of cytokine and chemokine production by monocytes, macrophages, and granulocytes [206]. Like alum, MF59 does not induce increased CD4+ Th1 immune responses, but because of its ability to increase the levels of functional haemagglutination-inhibiting antibodies and CD8+ T-cell responses, it has the potential for use in pandemic influenza vaccines [207,208].…”