Thermostable ricin vaccine protects rhesus macaques against aerosolized ricin: Epitope-specific neutralizing antibodies correlate with protection

Author:

Roy Chad J.,Brey Robert N.,Mantis Nicholas J.,Mapes Kelly,Pop Iliodora V.,Pop Laurentiu M.,Ruback Stephen,Killeen Stephanie Z.,Doyle-Meyers Lara,Vinet-Oliphant Heather S.,Didier Peter J.,Vitetta Ellen S.

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.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Reference31 articles.

1. Franz DR Jaax NK (1997) Ricin toxin. Textbook of Military Medicine, eds Sidell FR Takafuji ET Franz DR (Office of the Surgeon General, Department of the Army, Washington, DC), pp 631–642

2. The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes. The site and the characteristics of the modification in 28 S ribosomal RNA caused by the toxins;Endo;J Biol Chem,1987

3. RNA N-glycosidase activity of ricin A-chain. Mechanism of action of the toxic lectin ricin on eukaryotic ribosomes;Endo;J Biol Chem,1987

4. The three-dimensional structure of ricin at 2.8 A;Montfort;J Biol Chem,1987

5. Pathology of Lethal and Sublethal Doses of Aerosolized Ricin in Rhesus Macaques

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