Vaccine adjuvants: current challenges and future approaches

Abstract

For humans, companion animals, and food producing animals, vaccination has been touted as the most successful medical intervention for the prevention of disease in the twentieth century. However, vaccination is not without problems. With the development of new and less reactogenic vaccine antigens, which take advantage of molecular recombinant technologies, also comes the need for more effective adjuvants that will facilitate the induction of adaptive immune responses. Furthermore, current vaccine adjuvants are successful at generating humoral or antibody mediated protection but many diseases currently plaguing humans and animals, such as tuberculosis and malaria, require cell mediated immunity for adequate protection. A comprehensive discussion is presented of current vaccine adjuvants, their effects on the induction of immune responses, and vaccine adjuvants that have shown promise in recent literature.

Figure 1.

Exogenous and endogenous antigen presentation. (a) Following engulfment, a pathogen or immunogenic protein is contained within a phagosome or endosome. Fusion of the phagosome with the lysosome creates a phagolysosome bringing together the engulfed antigens and degradative enzymes and MHC II molecules. Following proteolytic cleavage, MHC II chaperone protein (CLIP) is displaced by the peptide (9–13 amino acids), which binds within the MHC II cleft. The vesicle containing the peptide-MHC II complex (pMHC II) traffics through the cytosol, eventually fusing with the cell membrane and the pMHC II is now displayed on the cell surface. (b) For antigens gaining access to the cytosol of the cell (self-antigens, viruses, or cytosolic bacteria) proteins are degraded by cytosolic proteosomes or immune proteosomes. Degraded peptides are guided to TAP (transporter protein associated with antigen processing) and enter the endoplasmic reticulum. Subsequently, the peptides are loaded into MHC I molecules and following intracellular trafficking, are presented on the surface of the cell.

Figure 2.

Signals from DCs can influence the differentiation of naïve T cells. Stimulated, mature DCs present not only antigen in the context of MHC but also costimulatory surface molecules necessary for T cell activation. Furthermore, the type and quantity of cytokines secreted by DCs in conjunction with these costimulatory molecules can direct the naïve T cell into different effectors phenotypes. IL-12 secretion from the DC initiates a Th1 type response characterized by secretion of IFNγ. IL-4 secretion from the DC results in a Th2 type response characterized by the secretion of IL-4, IL-5, and IL-10. The cytokines secreted by DCs are induced following ligation of cellular receptors (PRRs or TLRs) and signals from the surrounding tissues (i.e., IL-8). New evidence is emerging regarding the role of DCs in activating Th17 and Treg cells.

Figure 3.

Recognition of antigen and PRR ligand by immature DC. An adjuvant may act as a depot, releasing both vaccine antigen and stimulatory PRR ligand over time (a) as in many a.u. or mineral oil formulations containing MDP, MPLA, or CpG. Conversely, the adjuvant may be directly recognized by the PRR (such as mannose receptor or TLRs) (b), as may be used in whole cell, killed bacterin vaccines or some polymer adjuvants.