title: Thermostable ricin vaccine protects rhesus macaques against aerosolized ricin: Epitope-specific neutralizing antibodies correlate with protection.
abstract: Ricin toxin (RT) is the second most lethal toxin known; it has been designated by the CDC as a select agent. RT is made by the castor bean plant; an estimated 50,000 tons of RT are produced annually as a by-product of castor oil. RT has two subunits, a ribotoxic A chain (RTA) and galactose-binding B chain (RTB). RT binds to all mammalian cells and once internalized, a single RTA catalytically inactivates all of the ribosomes in a cell. Administered as an aerosol, RT causes rapid lung damage and fibrosis followed by death. There are no Food and Drug Administration-approved vaccines and treatments are only effective in the first few hours after exposure. We have developed a recombinant RTA vaccine that has two mutations V76M/Y80A (RiVax). The protein is expressed in Escherichia coli and is nontoxic and immunogenic in mice, rabbits, and humans. When vaccinated mice are challenged with injected, aerosolized, or orally administered (gavaged) RT, they are completely protected. We have now developed a thermostable, aluminum-adjuvant-containing formulation of RiVax and tested it in rhesus macaques. After three injections, the animals developed antibodies that completely protected them from a lethal dose of aerosolized RT. These antibodies neutralized RT and competed to varying degrees with a panel of neutralizing and nonneutralizing mouse monoclonal antibodies known to recognize specific epitopes on native RTA. The resulting antibody competition profile could represent an immunologic signature of protection. Importantly, the same signature was observed using sera from RiVax-immunized humans.
authors.affiliation: Department of Microbiology and Immunology, Tulane School of Medicine, New Orleans, LA 70112; Divisions of Microbiology, Comparative Pathology, and Veterinary Medicine, Tulane National Primate Research Center, Covington, LA 70433;
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Roy
authors.affiliation: Soligenix, Inc., Princeton, NJ 08540; ellen.vitetta@utsouthwestern.edu.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Brey
authors.affiliation: Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, NY 12208; Department of Biomedical Sciences, University of Albany School of Public Health, Albany, NY 12201; and.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Mantis
authors.affiliation: Department of Immunology and.
authors.forename: Kelly
authors.initials: K
authors.lastname: Mapes
authors.affiliation: Department of Immunology and.
authors.forename: Iliodora V
authors.initials: IV
authors.lastname: Pop
authors.affiliation: Department of Immunology and.
authors.forename: Laurentiu M
authors.initials: LM
authors.lastname: Pop
authors.affiliation: Department of Immunology and.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ruback
authors.affiliation: Divisions of Microbiology, Comparative Pathology, and Veterinary Medicine, Tulane National Primate Research Center, Covington, LA 70433;
authors.forename: Stephanie Z
authors.initials: SZ
authors.lastname: Killeen
authors.affiliation: Divisions of Microbiology, Comparative Pathology, and Veterinary Medicine, Tulane National Primate Research Center, Covington, LA 70433;
authors.forename: Lara
authors.initials: L
authors.lastname: Doyle-Meyers
authors.affiliation: Divisions of Microbiology, Comparative Pathology, and Veterinary Medicine, Tulane National Primate Research Center, Covington, LA 70433;
authors.forename: Heather S
authors.initials: HS
authors.lastname: Vinet-Oliphant
authors.affiliation: Divisions of Microbiology, Comparative Pathology, and Veterinary Medicine, Tulane National Primate Research Center, Covington, LA 70433;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Didier
authors.affiliation: Department of Immunology and Department of Microbiology, the University of Texas Southwestern Medical Center, Dallas, TX 75390 ellen.vitetta@utsouthwestern.edu.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Vitetta
mesh_terms: D000336:Aerosols; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D057134:Antibodies, Neutralizing / Q000737:chemistry*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D008168:Lung / Q000473:pathology; D008253:Macaca mulatta; D051379:Mice; D008968:Molecular Conformation; D012276:Ricin / Q000737:chemistry*; D013696:Temperature; D014612:Vaccines / Q000737:chemistry*
chemical_list: D000336:Aerosols; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D007074:Immunoglobulin G; C509236:RiVax; D014612:Vaccines; D012276:Ricin
keywords: immunoprofiling; monoclonal antibody; rhesus macaques; ricin; vaccine