Cutting Edge: The Mucosal Adjuvant Cholera Toxin Redirects Vaccine Proteins into Olfactory Tissues

TLDR

The study examined whether intranasal cholera toxin could target olfactory nerves/epithelium and bulbs in addition to nasal lymphoreticular tissues. Intranasal cholera toxin and its B subunit entered olfactory nerves and bulbs via GM1‑dependent uptake, persisted for six days, and enabled tetanus toxoid to reach the olfactory epithelium but not the bulbs, demonstrating that GM1‑binding adjuvants can retrogradely transport vaccine proteins into neuronal tissues and raising safety concerns.

Abstract

Abstract We tested the notion that the mucosal adjuvant cholera toxin (CT) could target, in addition to nasal-associated lymphoreticular tissues, the olfactory nerves/epithelium (ON/E) and olfactory bulbs (OBs) when given intranasally. Radiolabeled CT (125I-CT) or CT-B subunit (125I-CT-B), when given intranasally to mice, entered the ON/E and OB and persisted for 6 days; however, neither molecule was present in nasal-associated lymphoreticular tissues beyond 24 h. This uptake into olfactory regions was monosialoganglioside (GM1) dependent. Intranasal vaccination with 125I-tetanus toxoid together with unlabeled CT as adjuvant resulted in uptake into the ON/E but not the OB, whereas 125I-tetanus toxoid alone did not penetrate into the CNS. We conclude that GM1-binding molecules like CT target the ON/E and are retrograde transported to the OB and may promote uptake of vaccine proteins into olfactory neurons. This raises concerns about the role of GM1-binding molecules that target neuronal tissues in mucosal immunity.