Immunostimulatory combinations: designing the next generation of vaccine adjuvants

Agents that activate dendritic cells are essential components for vaccines and can be conceptualized as molecular adjuvants. Other molecular adjuvants affect downstream factors that shape the resulting immune response. This review provides a compendium of recently studied molecular adjuvants, focusing on CD8+ T cell responses, which have important roles in HIV vaccines. Reference is also made to CD8+ T cell antitumor responses, where parallel studies of molecular adjuvants are being pursued. Molecular adjuvants can be considered in the following groups: TNF superfamily molecules such as CD40 ligand; agonists for TLRs; agonists for NAIP, CIITA, HET‐E, TP‐1‐leucine‐rich repeat pathway receptors, such as nucleotide‐binding and oligomerization domain (NOD)1, NOD2, and cryopyrin; chemokines; ILs; CSFs; IFNs; alarmins; and purinergic P2X7 receptor agonists. Complementing these positively acting agents are strategies to reduce the immunosuppressive effects of CD4+CD25+ regulatory T cells and negatively acting factors such as TGF‐β, IL‐10, suppressor of cytokine signaling 1, and programmed cell death‐1 using neutralizing antibodies, antisense, and small interfering RNA. Especially effective are combinations of molecular adjuvants, which can elicit a massive expansion of antigen‐specific CD8+ T cells and show unprecedented efficacy in vaccine and tumor models. Taken together, these new approaches provide significant incremental progress in the development of vaccines to elicit cell‐mediated immunity against HIV and other pathogens.