Vaccine adjuvants: putting innate immunity to work

Abstract

Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms. In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response. The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects. We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens. Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines. However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens.

Figure 1. PRR Ligands Shape Adaptive T Cell Immunity through Direct and Indirect Effects on Dendritic Cells

(A) Expression of PRRs in human antigen-presenting and nonhematopoietic cells. The ability of the corresponding PRR ligands to produce cytokines and induce Th1 cell and cross-presentation from such cells is depicted below. MPL-based adjuvants (ASO1, ASO2, ASO4) activate monocyte and myeloid DCs, whereas TLR7 (Imiquimod) and TLR9 (CpG) ligands activate pDCs. Such adjuvants induce Th1 cell and low-level CD8⁺ T cell responses. In humans, it is not clear whether these cells contribute to cross-priming in vivo. (B) The influence of direct innate activation and antigen presentation, bystander innate immunity on antigen presentation, or both together are shown. The relative potency of Th1 cell and CD8⁺ T cell immunity from these respective pathways are derived from in vivo mouse studies. Optimal Th1 cell and CD8⁺ T cell immunity is elicited by direct activation of antigen-presenting cells and bystander production of type I IFN. This can be achieved by using Poly IC and TLR7-TLR8 ligands as adjuvants, with the source of type I IFN derived from nonhematopoetic and pDCs, respectively.