Cells of the innate immune system, principally the dendritic cell (DC), are amongst the first cells to encounter antigen. Receptors of the Toll-like receptor family are particularly useful in facilitating the targeting and transport of vaccine cargos to DCs. Toll-like receptor 2 (TLR-2) is an endocytic, plasma membrane receptor which upon ligation triggers uptake of ligand into the cell. Pam2Cys is a powerful ligand and agonist for TLR-2 which initiates signal transduction pathways in the DC via MyD88 and NFkB. This leads to DC activation and maturation followed by migration of the DC to the draining lymph node. If Pam2Cys is associated with a vaccine cargo it can efficiently present processed antigen to T cells and trigger a potent immune response.

The low immunogenicity exhibited by most soluble antigens is in general due to the absence of molecular signatures that are recognized by the immune system as dangerous. We have shown that binding of a charged lipopeptide to an oppositely charged protein results in formation of stable complexes at physiological pH and salt concentrations. These complexes elicit very high titers of antigen-specific antibody while vaccination with similarly charged antigen and lipopeptide results in significant but lower antibody titers of antibody. Strong cell-mediated responses are also induced which are dependent on binding of lipopeptide to antigen. Induction of a CD8⁺ T cell response correlates with the ability of lipopeptide to facilitate antigen uptake by DCs followed by trafficking of antigen-bearing cells into draining lymph nodes.

This system of adjuvanting soluble protein antigens is simple and robust and has been demonstrated to work for a variety of antigens including those from influenza, M. tuberculosis and the heat stable toxin of enterotoxigenic E. coli.