Modes of Action for Mucosal Vaccine Adjuvants

Abstract

Vaccine adjuvants induce innate immune responses and the addition of adjuvants to the vaccine helps to induce protective immunity in the host. Vaccines utilizing live attenuated or killed whole pathogens usually contain endogenous adjuvants, such as bacterial cell wall products and their genomic nucleic acids, which act as pathogen-associated molecular patterns and are sufficient to induce adaptive immune responses. However, purified protein- or antigen-based vaccines, including component or recombinant vaccines, usually lose these endogenous innate immune stimulators, so the addition of an exogenous adjuvant is essential for the success of these vaccine types. Although this adjuvant requirement is mostly the same for parental and mucosal vaccines, the development of mucosal vaccine adjuvants requires the specialized consideration of adapting the adjuvants to characteristic mucosal conditions. This review provides a brief overview of mucosa-associated immune response induction processes, such as antigen uptake and dendritic cell subset-dependent antigen presentation. It also highlights several mucosal vaccine adjuvants from recent reports, particularly focusing on their modes of action.

Keywords: adjuvant; dendritic cells; mucosal adjuvant; vaccine.

FIG. 1.

Adjuvant classification chart based on the mode of action. The adjuvant can be divided into two types based on the presence or absence of in vitro innate immune stimulating activities. “Innate immune receptor agonists” are mostly pathogen- or microbe-derived substances, and work as PAMPs. “Others” mainly consist of nonpathogen-derived substances. “Others” are further divided into “DAMP inducer” and “Delivery system.” Both PAMP and DAMP adjuvants activate innate immune receptors and resulted in cytokine responses and dendritic cell maturation/migration. “Delivery system” promotes vaccine uptake and enhances antigen presentation by dendritic cells. ALR, AIM2-like receptor; bCD, hydroxypropyl-β-cyclodextrin; cCHP, cationic cholesteryl group-bearing pullulan; C-CPE, a C-terminal fragment of Clostridium perfringens enterotoxin; CLR, C-type lectin receptor; DAMP, damage-associated molecular pattern; NLR, Nod-like receptor; PAMP, pathogen-associated molecular pattern; RLR, RIG-I like receptor, TLR, Toll-like receptor.

FIG. 2.

Antigen transport across the mucosal barrier and DC subset-dependent immune responses. Antigen and adjuvant can cross the mucosal barrier through the following pathways: (1) paracellular pathway, (2) transepithelial pathway, (3) goblet pathway, (4) TED pathway, (5) M-cell pathway, (6) IED pathway, and (7) epithelial cell damage pathway. The translocated antigens and adjuvants are subsequently taken up by several different mucosal tissue DCs. These antigen-carrying DCs migrate to the draining lymph nodes for antigen presentation to T cells, where they induce characteristic T cell differentiation dependent on their specialized function and associated immune context. IED, intraepithelial dendritic cell; TED, transepithelial dendrite.