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

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.

Mutants of Type II Heat-Labile Enterotoxin LT-IIa with Altered Ganglioside-Binding Activities and Diminished Toxicity Are Potent Mucosal Adjuvants

“…The use of HLT as mucosal adjuvants in human vaccines has been restricted by their intrinsic toxicity and by their propensity to traffic to the brain via the olfactory bulb (55,56). A variety of methods have been used to reduce or eliminate the toxic activities of the type II HLT in order to facilitate their use in human vaccines.…”

CTA1-DD-Immune Stimulating Complexes: a Novel, Rationally Designed Combined Mucosal Vaccine Adjuvant Effective with Nanogram Doses of Antigen

“…Therefore, several groups have developed nontoxic mutants of CT or lymphotoxin, most of which have mutations in the CTA1-subunit that result in complete or partial disruption of the enzymatic activity. However, all of these mutant holotoxins retain their promiscuous binding to the GM1-ganglioside receptor, leaving a potential ability to bind to all nucleated cells and so gain access to unwanted tissues such as the CNS (7).…”

Oral immunization of rhesus macaques with adenoviral HIV vaccines using enteric-coated capsules

“…We also attempted to address one important issue related to safety of using the cholera toxin mutant as mucosal adjuvant by the immunohistochemical analyses of brain tissue, specifically the olfactory bulb because antigens/adjuvants delivered by the intranasal route can be retrograde transported into the brain potentially causing complicaitons such as Bell's palsy [43]. Based on literature reports on similar studies, we determined the expression of the nerve growth factor beta 1 (NGF-β1) as a sarrogate for toxicity in terms of retrograde transport to olfactory bulb [42].…”

“…Based on literature reports on similar studies, we determined the expression of the nerve growth factor beta 1 (NGF-β1) as a sarrogate for toxicity in terms of retrograde transport to olfactory bulb [42]. As a control we used the tissue similarly obtained from another monkey (H341) from a different study where the monkey was dosed with the native form of the cholera toxin (nCT) that is known to casue retrograde transport to the brain and activation of NGF-b1 in the olfactory bulb [43]. The side-by-side immunohistochemial analyses revealed NGF-β1 expression only in the tissues of the monkey immunized using the nCT but not those where CT2* was used as adjuvant (Fig.…”