Trivalent Vaccine against Botulinum Toxin Serotypes A, B, and E That Can Be Administered by the Mucosal Route

Abstract

Most reports dealing with vaccines against botulinum toxin have focused on the injection route of administration. This is unfortunate, because a mucosal vaccine is likely to be more efficacious for patients and pose fewer risks to health care workers and to the environment. Therefore, efforts were made to generate a mucosal vaccine that provides protection against the botulinum serotypes that typically cause human illness (serotypes A, B, and E). This work demonstrated that carboxy-terminal peptides derived from each of the three serotypes were able to bind to and penetrate human epithelial barriers in vitro, and there was no cross inhibition of membrane binding and transcytosis. The three polypeptides were then tested in vivo as a trivalent vaccine that could be administered to mice by the intranasal route. The results indicated that the mucosal vaccine evoked high secretory titers of immunoglobulin A (IgA), as well as high circulating titers of IgG and IgA, and it also evoked a high level of resistance to challenge with toxin. The immunoglobulin responses and the levels of resistance to challenge were increased by coadministration of adjuvants, such as chitosan and vitamin E. At least three mechanisms were identified to account for the antibody-induced resistance: (i) blockade of toxin absorption across epithelial cells, (ii) enhanced clearance of toxin from the circulation, and (iii) blockade of toxin action at the neuromuscular junction. These results are a compelling demonstration that a mucosal vaccine against multiple serotypes of botulinum toxin has been identified.

In Vivo Molecular Imaging Analysis of a Nasal Vaccine That Induces Protective Immunity against Botulism in Nonhuman Primates

“…Although BoHc/A degraded gradually on the surface of the nasal epithelium and/or within the nasal cavity beginning 6 h after administration (Fig. 3B) by contact with proteolytic enzymes (26,27), intact BoHc/A can bind and penetrate the mucosal epithelial cells by a transcytosis mechanism mediated by an as yet unknown receptor (28). Therefore, we propose that some of the BoHc/A taken up by and released from the nasal epithelium might stimulate the airway immune system and lead to the induction of Ag-specific immune responses.…”

Enhancing the Protective Immune Response against Botulism

“…Antibody-mediated protection to BoNTs works by three mechanisms: (i) IgA antibodies generated at mucosal surfaces prevent transcytosis across gut epithelia and block entry into circulation, (ii) IgA and IgG bind BoNTs in circulation and mark toxins for clearance by phagocytic immune cells, and (iii) specific antibodies bind in the vicinity of the receptor binding sites and block neuronal receptor interaction (termed a neutralizing antibody) (51)(52)(53). In addition, neutralizing antibodies that target the light chain of BoNT/A through another mechanism, potentially by preventing translocation of the LC but not endocytosis of the holotoxin, have been found (54)(55)(56).…”

Balancing the benefits and risks of a botulinum toxin vaccine

“…A trivalent vaccine (serotypes A, B and E) that is active by the inhalation route has already been described [16]. The authors of this study are now engaged in efforts to develop an oral formulation.…”

“…The various mechanisms by which antibodies against this polypeptide produce neutralization have been described [16]. The first of the several mechanisms occurs in the lumen of the gut or airway, where the antibodies associate with the toxin and prevent its binding to epithelial cells.…”

“…The underlying motive is to ensure that any candidate vaccine is capable of evoking as many layers of protection as possible. To date, there are three major layers of protection that have been characterized when the carboxyterminal portion of the heavy chain is administered as a mucosal antigen [16].…”