BIOMAT Database Logo BIOMAT Database Logo

Enhancing toxin-based vaccines against botulism. 2018

Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
Medical College of Wisconsin, 8701 W Watertown Plank Rd., Microbiology and Immunology, Milwaukee, WI 53226, United States.

Botulinum neurotoxins (BoNT) are the most toxic proteins for humans. BoNTs are single chain proteins with an N-terminal light chain (LC) and a C-terminal heavy chain (HC). HC comprises a translocation domain (HCN) and a receptor binding domain (HCC). Currently, there are no approved vaccines against botulism. This study tests a recombinant, full-length BoNT/A1 versus LCHCN/A1 and HCC/A1 as vaccine candidates against botulism. Recombinant, full-length BoNT/A1 was detoxified by engineering 3-amino acid mutations (E224A/R363A/Y366F) (M-BoNT/A1) into the LC to eliminate catalytic activity, which reduced toxicity in a mouse model of botulism by >106-fold relative to native BoNT/A1. As a second step to improve vaccine safety, an additional mutation (W1266A) was engineered in the ganglioside binding pocket, resulting in reduced receptor binding, to produce M-BoNT/A1W. M-BoNT/A1W vaccination protected against challenge by 106 LD50 Units of native BoNT/A1, while M-BoNT/A1 or M-BoNT/A1W vaccination equally protected against challenge by native BoNT/A2, a BoNT subtype. Mice vaccinated with M-BoNT/A1W surviving BoNT challenge had dominant antibody responses to the LCHCN domain, but varied antibody responses to HCC. Sera from mice vaccinated with M-BoNT/A1W also neutralized BoNT/A1 action on cultured neuronal cells. The cell- and mouse-based assays measured different BoNT-neutralizing antibodies, where M-BoNT/A1W elicited a strong neutralizing response in both assays. Overall, M-BoNT/A1W, with defects in multiple toxin functions, elicits a potent immune response to BoNT/A challenge as a vaccine strategy against botulism and other toxin-mediated diseases.

UI MeSH Term Description Entries
D007114 Immunization Deliberate stimulation of the host's immune response. ACTIVE IMMUNIZATION involves administration of ANTIGENS or IMMUNOLOGIC ADJUVANTS. PASSIVE IMMUNIZATION involves administration of IMMUNE SERA or LYMPHOCYTES or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). Immunologic Stimulation,Immunostimulation,Sensitization, Immunologic,Variolation,Immunologic Sensitization,Immunological Stimulation,Sensitization, Immunological,Stimulation, Immunologic,Immunizations,Immunological Sensitization,Immunological Sensitizations,Immunological Stimulations,Sensitizations, Immunological,Stimulation, Immunological,Stimulations, Immunological,Variolations
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D011994 Recombinant Proteins Proteins prepared by recombinant DNA technology. Biosynthetic Protein,Biosynthetic Proteins,DNA Recombinant Proteins,Recombinant Protein,Proteins, Biosynthetic,Proteins, Recombinant DNA,DNA Proteins, Recombinant,Protein, Biosynthetic,Protein, Recombinant,Proteins, DNA Recombinant,Proteins, Recombinant,Recombinant DNA Proteins,Recombinant Proteins, DNA
D001905 Botulinum Toxins Toxic proteins produced from the species CLOSTRIDIUM BOTULINUM. The toxins are synthesized as a single peptide chain which is processed into a mature protein consisting of a heavy chain and light chain joined via a disulfide bond. The botulinum toxin light chain is a zinc-dependent protease which is released from the heavy chain upon ENDOCYTOSIS into PRESYNAPTIC NERVE ENDINGS. Once inside the cell the botulinum toxin light chain cleaves specific SNARE proteins which are essential for secretion of ACETYLCHOLINE by SYNAPTIC VESICLES. This inhibition of acetylcholine release results in muscular PARALYSIS. Botulin,Botulinum Neurotoxin,Botulinum Neurotoxins,Clostridium botulinum Toxins,Botulinum Toxin,Neurotoxin, Botulinum,Neurotoxins, Botulinum,Toxin, Botulinum,Toxins, Botulinum,Toxins, Clostridium botulinum
D001906 Botulism A disease caused by potent protein NEUROTOXINS produced by CLOSTRIDIUM BOTULINUM which interfere with the presynaptic release of ACETYLCHOLINE at the NEUROMUSCULAR JUNCTION. Clinical features include abdominal pain, vomiting, acute PARALYSIS (including respiratory paralysis), blurred vision, and DIPLOPIA. Botulism may be classified into several subtypes (e.g., food-borne, infant, wound, and others). (From Adams et al., Principles of Neurology, 6th ed, p1208) Botulism, Infantile,Botulism, Toxico-Infectious,Clostridium botulinum Infection,Foodborne Botulism,Infant Botulism,Toxico-Infectious Botulism,Wound Botulism,Botulism, Foodborne,Botulism, Infant,Botulism, Toxico Infectious,Botulism, Wound,Clostridium botulinum Infections,Foodborne Botulisms,Infant Botulisms,Infantile Botulism,Infection, Clostridium botulinum,Toxico Infectious Botulism,Wound Botulisms
D003014 Clostridium botulinum A species of anaerobic, gram-positive, rod-shaped bacteria in the family Clostridiaceae that produces proteins with characteristic neurotoxicity. It is the etiologic agent of BOTULISM in humans, wild fowl, HORSES; and CATTLE. Seven subtypes (sometimes called antigenic types, or strains) exist, each producing a different botulinum toxin (BOTULINUM TOXINS). The organism and its spores are widely distributed in nature.
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004797 Enzyme-Linked Immunosorbent Assay An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. ELISA,Assay, Enzyme-Linked Immunosorbent,Assays, Enzyme-Linked Immunosorbent,Enzyme Linked Immunosorbent Assay,Enzyme-Linked Immunosorbent Assays,Immunosorbent Assay, Enzyme-Linked,Immunosorbent Assays, Enzyme-Linked
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
Vaccines against Botulism.
September 2017, Toxins,
Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
Vaccines against botulism.
June 2012, Current opinion in microbiology,
Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
Vaccines against Clostridium perfringens alpha-toxin.
January 2013, Current pharmaceutical biotechnology,
Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
[Botulism toxin, bioterrorist weapon].
March 2003, Presse medicale (Paris, France : 1983),
Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
[Botulism toxin in practice].
July 2003, Annales de readaptation et de medecine physique : revue scientifique de la Societe francaise de reeducation fonctionnelle de readaptation et de medecine physique,
Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
Botulism and vaccines for its prevention.
November 2009, Vaccine,
Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
Decoy toxin harnessed to fight botulism.
January 2021, Science (New York, N.Y.),
Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
BOTULISM: THE DISEASE AND THE TOXIN.
March 1965, The American journal of the medical sciences,
Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
Are DNA-based vaccines useful for protection against secreted bacterial toxins? Tetanus toxin test case.
January 1998, Vaccine,
Amanda Przedpelski, and William H Tepp, and Madison Zuverink, and Eric A Johnson, and Sabine Pellet, and Joseph T Barbieri
Plant-based vaccines against viruses.
December 2014, Virology journal,
Copied contents to your clipboard!