Hydroxypropyl-b-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen

Cyclodextrins are commonly used as a safe excipient to enhance the solubility and bioavailability of hydrophobic pharmaceutical agents. Their efficacies and mechanisms as drug-delivery systems have been investigated for decades, but their immunological properties have not been examined. In this study, we reprofiled hydroxypropyl-b-cyclodextrin (HP-b-CD) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. HP-b-CD triggered the innate immune response at the injection site, was trapped by MARCO + macrophages, increased Ag uptake by dendritic cells, and facilitated the generation of T follicular helper cells in the draining lymph nodes. It significantly enhanced Ag-specific Th2 and IgG Ab responses as potently as did the conventional adjuvant, aluminum salt (alum), whereas its ability to induce Ag-specific IgE was less than that of alum. At the injection site, HP-b-CD induced the temporary release of host dsDNA, a damage-associated molecular pattern. DNase-treated mice, MyD88-deficient mice, and TBK1-deficient mice showed significantly reduced Ab responses after immunization with this adjuvant. Finally, we demonstrated that HP-b-CD–adjuvanted influenza hemagglutinin split vaccine protected against a lethal challenge with a clinically isolated pandemic H1N1 influenza virus, and the adjuvant effect of HP-b-CD was demonstrated in cynomolgus macaques. Our results suggest that HP-b-CD acts as a potent MyD88-and TBK1-dependent T follicular helper cell adjuvant and is readily applicable to various vaccines. T he term " adjuvant " has its origin in the Latin " adjuvare " meaning " to help, " because adjuvants enhance the effects of vaccines. Many substances can act as adjuvants, and their modes of action vary widely (1, 2). Recent studies showed that conventional adjuvants, such as alum, act via the " Ag-depot " mechanism, as well as induce multiple innate immune pathways, including the activation of inflammasomes, the production of PGE 2 , and the release of damage-associated molecular patterns (DAMPs), such as DNA (3–5). In addition to enhancing the im-munogenicity of vaccines, adjuvants can be responsible for their adverse effects, including local swelling, systemic fever, and a theoretical risk for autoimmunity (6). Even alum and MF59, widely used adjuvants for human vaccines, induce local and systemic adverse effects (6–8). Therefore, the high safety profile of an designed and performed the murine influenza infectious model research and analyzed the data. The online version of this article contains supplemental material. adjuvant, based on scientific evidence, must be demonstrated before its application to clinical practice. One approach to identifying ideal adjuvants …