Most current vaccines confer protection primarily through humoral immunity (Plotkin, 2010
). Responses are elicited by a variety of vaccine platforms that include live attenuated, recombinant protein, toxoids, or polysaccharide-protein conjugates. Antibody responses to many current vaccines are long-lived and require infrequent or no additional boosting to sustain protection (Amanna et al., 2007
). Despite the impressive success of such vaccines, there are substantial groups of people for which current vaccines, even those using alum adjuvant, do not achieve adequate seroconversion rates or protective antibody titers. Moreover, responses to vaccines begin to decline in healthy adults after 40–50 years of age (Chen et al., 2009
) and as a result of health conditions such as chronic kidney disease (Beran, 2008
). The addition of an adjuvant to an existing vaccine, as has been done for influenza (Podda, 2001
), or a switch from alum to a more effective adjuvant, as for hepatitis B virus (HBV) (Beran, 2008
; Halperin et al., 2006
), represents a substantial benefit for these groups.
For polarization of helper T cell, there are striking differences in the type of response preferentially stimulated by different adjuvants. Adjuvants such as MF59 and ISCOMs (), as well as Toll-like receptor 2 (TLR2) and TLR5 ligands, enhance T cell and antibody responses without altering their Th1/Th2 cell balance of the specific antigens. In contrast, more polarized Th1 cell responses are elicited by adjuvants that incorporate agonists of TLR3, TLR4, TLR7-TLR8, and TLR9. Complete Freund’s adjuvant (CFA) and CAF01 induce mixed Th1 and Th17 cell responses. Thus, selection of an appropriate adjuvant is influenced by the type of CD4+ T cell response required for protection.
A more daunting challenge is developing adjuvants that will generate protective CD8+ T cell responses to soluble proteins. Here, the type of vaccine is dictated by the particular processing pathway of MHC class I presentation. Vaccines that lead to direct infection of cells, such as viral vectors or DNA, induce CD8+ T cell immunity through the endogenous class I presentation pathway; however, exogenous protein vaccines require cross-presentation. To promote differentiation of functional CD8+ T cells, a successful adjuvant must be given with a protein formulated in a manner that facilitates entry into the MHC class I processing pathway, trigger dendritic cell (DC) activation, and induce type-I interferon (IFN) production.
The difficulty in generating potent and durable T cell immunity with current vaccines and adjuvants has profound clinical implications for a variety of diseases. There are still no fully effective vaccines against many widespread infectious diseases, including HIV-AIDS, malaria, and tuberculosis. Although humoral immunity has a clear role in preventing infection by HIV (Mascola et al., 2000
) and can influence certain stages of malaria infection (Moorthy and Ballou, 2009
), there is compelling evidence that Th1 cells, CD8+
T cells, or both also have a critical role in preventing or controlling these infections. More challenging still is the task of developing adjuvants for therapeutic treatment of cancers and chronic viral infections, where it will be necessary to generate potent and perhaps multifunctional T cell responses in patients who respond poorly to the relevant tumor or viral antigens as a result of multiple layers of immune regulation (Gale and Foy, 2005
; Rosenberg et al., 2004
). For such vaccines, the major hurdles for an adjuvant will be to stimulate CD8+
T cells and to circumvent the regulatory mechanisms that limit the host response to the tumor or pathogen. Together, these examples underscore the critical need to develop vaccines capable of inducing potent and durable T cell immunity in man.