Toward Establishing an Ideal Adjuvant for Non-Inflammatory Immune Enhancement

The vertebrate immune system functions to eliminate invading foreign nucleic acids and foreign proteins from infectious diseases and malignant tumors. Because pathogens and cancer cells have unique amino acid sequences and motifs (e.g., microbe-associated molecular patterns, MAMPs) that are recognized as "non-self" to the host, immune enhancement is one strategy to eliminate invading cells. MAMPs contain nucleic acids specific or characteristic of the microbe and are potential candidates for immunostimulants or adjuvants. Adjuvants are included in many vaccines and are a way to boost immunity by deliberately administering them along with antigens. Although adjuvants are an important component of vaccines, it is difficult to evaluate their efficacy ex vivo and in vivo on their own (without antigens). In addition, inflammation induced by currently candidate adjuvants may cause adverse events, which is a hurdle to their approval as drugs. In addition, the lack of guidelines for evaluating the safety and efficacy of adjuvants in drug discovery research also makes regulatory approval difficult. Viral double-stranded (ds) RNA mimics have been reported as potent adjuvants, but the safety barrier remains unresolved. Here we present ARNAX, a noninflammatory nucleic acid adjuvant that selectively targets Toll-like receptor 3 (TLR3) in antigen-presenting dendritic cells (APCs) to safely induce antigen cross-presentation and subsequently induce an acquired immune response independent of inflammation. This review discusses the challenges faced in the clinical development of novel adjuvants.