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

Abstract

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-β-cyclodextrin (HP-β-CD) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. HP-β-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-β-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-β-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-β-CD was demonstrated in cynomolgus macaques. Our results suggest that HP-β-CD acts as a potent MyD88- and TBK1-dependent T follicular helper cell adjuvant and is readily applicable to various vaccines.

Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines

“…Six hours after administration of 1 mg Advax, the spleen, lung, kidney, lymph node and liver were removed ( n  = 3), and total RNAs were extracted as described previously (Onishi et al, 2015). After total RNA preparation, the gene expression profiles were obtained using 3′ IVT Express Kit and GeneChip Mouse Genome 430 2.0 Array (Affymetrix, 900496).…”

COVID-19: A Recommendation to Examine the Effect of Mouthrinses with β-Cyclodextrin Combined with Citrox in Preventing Infection and Progression

“…For example, it has been established that methylated beta-cyclodextrin can reduce influenza A virus and coronavirus infectivity by sequestering cholesterol from viral particles or depleting it from the host cell membranes [51]. Hydroxypropyl-β-cyclodextrin was used as a vaccine adjuvant providing protection against the H1N1 influenza virus in the cynomolgus monkey model [52,53]. One point to emphasize is that for natural CDs, the intramolecular hydrogen bond with the CD molecule decreases their hydrogen bond formation with the surrounding water molecules [54].…”

Cyclodextrins: Emerging Medicines of the New Millennium

“…HPβCD, already approved as an excipient for various oral medicines and a few injectable ones, was chosen for its excellent tolerability. The synergic effect of HPβCD with immunoglobulins was proven by several previous in vivo studies with mice and macaques, which demonstrated that HPβCD brings a 30% increase in the production of antibodies and that it further induces the production of a subclass of immune cells responsible for long-term immune 'memory'; that is, long-term immunization against the virus [44,45]. It was also demonstrated that the effect of immunization occurs not only at the nasal mucosa, the site of administration, but that it is systemic, spreading throughout the entire body to convey strong immunity to the virus [46].…”