RiVax® is Soligenix’s proprietary vaccine developed to protect against exposure to ricin toxin and is the most advanced vaccine product in the company’s portfolio. With RiVax®, Soligenix is a world leader in ricin toxin vaccine research. The immunogen in RiVax® induces a protective immune response in animal models of ricin exposure and functionally active antibodies in humans. The immunogen consists of a genetically inactivated subunit ricin A chain that is enzymatically inactive and lacks residual toxicity of the holotoxin.
The development of RiVax® has been sponsored through a series of overlapping challenge grants (UC1) and cooperative grants (U01) from the NIH, as well as a grant from the Food and Drug Administration (FDA) Orphan Products Division, granted to Soligenix and to the University of Texas Southwestern Medical Center (UTSW) where the vaccine originated. Soligenix and UTSW have collectively received approximately $22 million in grant funding from the NIH and FDA for RiVax®. Results from a Phase 1A clinical trial conducted with a formulation of RiVax® that did not contain an adjuvant, revealed dose dependent seroconversion as well as lack of toxicity of the molecule when administered intramuscularly to human volunteers. This adjuvant-free formulation of RiVax® induced toxin neutralizing antibodies that lasted up to 127 days after the third vaccination in several individuals. The outcome of the study was published in the Proceedings of the National Academy of Sciences (Vitetta et al., 2006, PNAS, 105:2268-2273). To increase the longevity and magnitude of toxin neutralizing antibodies, RiVax® was formulated with an adjuvant of aluminum salts (known colloquially as Alum) for a Phase 1B clinical trial. Alum is an adjuvant that is used in many human vaccines, including most vaccines used in infants. Results of the Phase 1B study indicated that Alum adjuvanted RiVax® was safe and well tolerated, and induced greater ricin neutralizing antibody levels in humans than adjuvant-free RiVax®. The outcomes of this second study were published in the Clinical and Vaccine Immunology (Vitetta et al., 2012, Recombinant Ricin Vaccine Phase 1B Clinical Trial, Clin. Vaccine Immunol. 10:1697-9).
In addition to the government, Soligenix has also collaborated with other academic and industrial, and not-for profit institutions for different facets of RiVax® development. The subunit component of the RiVax® vaccine originally required cold shipment and storage and was extremely unstable at room temperature. By utilizing its ThermoVax technology, Soligenix was able to demonstrate at least 1 year stability at elevated temperatures (40 degrees Celsius for up to one year). Soligenix has adapted the original manufacturing process for the immunogen contained in RiVax® for large scale manufacturing and is further establishing correlates of the human immune response in non-human primates.
RiVax® has been granted Orphan Drug Designation by the Office of Orphan Products Development of the FDA for the prevention of ricin intoxication.
Ricin as a Biological Weapon
The Centers for Disease Control (CDC) has classified ricin as a Category B biological agent. Currently, there is neither a therapeutic nor a vaccine that can be used to protect against ricin exposure or reverse the effects once exposed. The potential use of ricin toxin as a biological weapon of mass destruction has been highlighted in a FBI Bioterror report released in November 2007 entitled Terrorism 2002-2005, which states that “Ricin and the bacterial agent anthrax are emerging as the most prevalent agents involved in WMD investigations”.
Ricin has a long history of use in espionage and warfare. Recent economic surveys have shown that there are over 1 million tons of castor beans produced in the world annually. The global commercial production has the potential to yield approximately 50,000 tons of pure ricin. The fate of much of this ricin in countries outside of the US is unknown. Ricin toxin can constitute up to 5 percent of the total protein of the bean. Ricin is highly stable at room temperature and difficult to inactivate by conventional methods. Because of the high content of ricin in castor beans, ricin toxin can be extracted from the mash produced as a by-product of castor oil production by several simple enrichment steps, and therefore easy to stockpile. While ricin is second in toxicity only to botulinum toxin, it is far easier to obtain, prepare, and use. Before the 1990 war, the Iraqi military had attempted to devise ways to disseminate ricin as an explosive bomb, attempts which were forestalled by the war and ensuing events. Ricin has also been detected in a powder form sent in a letter addressed to Senator Bill Frist in 2004, and several other similar but less publicized incidents. More recently, there have been sporadic reports of ricin stockpiles and attempted use of ricin in the US and Europe.
Once exposed to lethal doses of ricin, the effects are essentially irreversible and symptoms appear more rapidly than symptoms of botulinum intoxication (in a dose-dependent manner). Since its lethality is irreversible after four hours and takes three to five days to kill an individual, immunization after ricin exposure is impractical on a large scale. Since ricin is cleared rapidly from the blood and the symptoms of ricin intoxication mimic the symptoms of other diseases, it is not practical to carry out post-exposure immunization via infusion of neutralizing antibodies in a reliable manner. The current expectation that drives vaccine development is that ricin is most likely to be distributed as an aerosol form, since it is highly lethal by this route.