期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：12
页码：3782-3787
DOI：10.1073/pnas.1502585112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceRicin toxin (RT) is a CDC-designated select agent that can be dispersed as an aerosol. In mammals, aerosolized RT causes rapid and irreversible necrosis of the lung epithelium, multifocal hemorrhagic edema, and death within 24-36 h. A safe and effective recombinant subunit vaccine (RiVax) has been developed and formulated as a thermostable, lyophilized, adjuvant-containing "powder." This formulation of RiVax elicited neutralizing antibodies against RT, which protected macaques from the lethality of aerosolized RT. The epitope-specific antibody responses in macaques revealed a distinctive profile that was also observed in vaccinated humans. This profile might represent a signature of protection in both species. 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.
