Subunit vaccine against the seven serotypes of botulism.
Botulinum neurotoxins (BoNTs) are the most toxic proteins for humans and are classified as category A toxins. There are seven serotypes of BoNTs defined by the lack of cross-serotype toxin neutralization. Thus, an effective vaccine must neutralize each BoNT serotype. BoNTs are organized as dichain A-B toxins, where the N-terminal domain (light chain) is a zinc metalloprotease targeting soluble NSF attachment receptor proteins that is linked to the C-terminal domain (heavy chain [HC]) by a disulfide bond. The HC comprises a translocation domain and a C-terminal receptor binding domain (HCR). HCRs of the seven serotypes of BoNTs (hepta-HCR) were engineered for expression in Escherichia coli, and each HCR was purified from E. coli lysates. Immunization of mice with the E. coli-derived hepta-serotype HCR vaccine elicited an antibody response to each of the seven BoNT HCRs and neutralized challenge by 10,000 50% lethal doses of each of the seven BoNT serotypes. A solid-phase assay showed that the anti-hepta-serotype HCR sera inhibited the binding of HCR serotypes A and B to the ganglioside GT1b, the first step in BoNT intoxication of neurons. This is the first E. coli-derived vaccine that effectively neutralizes each of the seven BoNT serotypes.
Baldwin
Michael R
MR
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Tepp
William H
WH
Przedpelski
Amanda
A
Pier
Christina L
CL
Bradshaw
Marite
M
Johnson
Eric A
EA
Barbieri
Joseph T
JT
D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000992:Antitoxins / Q000097:blood; D001905:Botulinum Toxins / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D001906:Botulism / Q000276:immunology / Q000517:prevention & control*; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009500:Neutralization Tests; D022223:Vaccines, Subunit / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology
D000907:Antibodies, Bacterial; D000992:Antitoxins; D005732:Gangliosides; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; C016481:trisialoganglioside GT1; D001905:Botulinum Toxins