Transcutaneous Immunization with Bacterial ADP-Ribosylating Exotoxins as Antigens and Adjuvants

Abstract

Transcutaneous immunization (TCI) is a new technique that uses the application of vaccine antigens in a solution on the skin to induce potent antibody responses without systemic or local toxicity. We have previously shown that cholera toxin (CT), a potent adjuvant for oral and nasal immunization, can induce both serum and mucosal immunoglobulin G (IgG) and IgA and protect against toxin-mediated mucosal disease when administered by the transcutaneous route. Additionally, CT acts as an adjuvant for coadministered antigens such as tetanus and diphtheria toxoids when applied to the skin. CT, a member of the bacterial ADP-ribosylating exotoxin (bARE) family, is most potent as an adjuvant when the A-B subunits are present and functional. We now show that TCI induces secondary antibody responses to coadministered antigens as well as to CT in response to boosting immunizations. IgG antibodies to coadministered antigens were also found in the stools and lung washes of immunized mice, suggesting that TCI may target mucosal pathogens. Mice immunized by the transcutaneous route with tetanus fragment C and CT developed anti-tetanus toxoid antibodies and were protected against systemic tetanus toxin challenge. We also show that bAREs, similarly organized as A-B subunits, as well as the B subunit of CT alone, induced antibody responses to themselves when given via TCI. Thus, TCI appears to induce potent, protective immune responses to both systemic and mucosal challenge and offers significant potential practical advantages for vaccine delivery.

Transcutaneous delivery and thermostability of a dry trivalent inactivated influenza vaccine patch

“…Moreover, an augmentation in the antibody levels was obtained when the LT adjuvant was also used in the patch administration, which is consistent with our previous findings. 3,4,7,8,11 With respect to the dry adjuvanted TIV patch, a more robust immune response was obtained than with the standard i.m. injected TIV vaccine.…”

“…[2][3][4][5][6] We, and others, showed that a potent and robust immune response to TCI immunization can be obtained by delivering the vaccine antigen with an adjuvant. [7][8][9] Adjuvants are immunostimulating compounds that are often used to amplify the immune response to the vaccine antigens. TCI studies have shown that a potent adjuvant, such as heat-labile enterotoxin from Escherichia coli (LT), when administered in conjunction with vaccine antigens, induces functional antibodies to higher levels than the antigens alone.…”

“…The wet patch has been used to establish proof-of-principle that a specific vaccine antigen co-administered with an adjuvant can be delivered to the skin to induce a robust immune response. 6,7 Our success in eliciting immune responses transcutaneously has prompted us to formulate a stabilized dry patch for vaccine delivery. A dry patch is appealing in terms of its ease of use in a clinical setting (i.e.…”

Adjuvants in Veterinary Vaccines: Modes of Action and Adverse Effects

“…10,11,15 They appear to induce strong humoral responses as well as CTLs. 11,17 For mucosal use, both LT and cholera toxins must be mutated to less toxic forms, but Glenn et al 48 have discovered that the virulent native toxins are effective adjuvants for transcutaneous immunization. When intact cholera toxin was applied to the skin of mice, immune responses were induced to coadministered antigens with no major adverse effects.…”

Comparative study of liposomes, transfersomes, ethosomes and cubosomes for transcutaneous immunisation: characterisation and in vitro skin penetration

“…Adjuvants play a critical role in TCI [21] as they improve the immune response to subunit antigens, such as peptides, that are either poorly immunogenic or non-immunogenic when administered by themselves, and may lead to a decrease in the dose of antigen required to stimulate protective immunity. [22] In this study the adjuvants Quil A and monophosphoryl lipid A (MPL) were co-encapsulated into colloidal lipid particles.…”