A combination ricin/anthrax vaccine shows promise

About Ricin toxin
Ricin toxin is a plant toxin thought to be a bioterror threat because of its stability and high potency as well as the large worldwide reservoir created as a by-product of castor oil production. Ricin comes in many forms like powder, mist, pill, or pellet. Ricin can also be dissolved in water and other liquids. As a poison, Ricin is so potent that the U.S. Centers for Disease Control (CDC) estimates the lethal dose in humans is about the size of a grain of salt. Exposure to ricin results in local tissue necrosis and general organ failure leading to death within several days of exposure and is especially toxic when inhaled.

Ricin is a ribosome inactivating protein (RIP) and a potent member of the AB family of toxins. The enzymatic ricin toxin A subunit (RTA) is an RNA-N-glycosidase which cleaves a specific adenine residue with eukaryotic 28S ribosomal RNA, leading to protein synthesis arrest and cell death.

About RiVax
RiVax is Soligenix’s proprietary vaccine candidate being developed to protect against exposure to ricin toxin, and if approved would be the first ricin vaccine. RiVax has demonstrated statistically significant (p < 0.002) preclinical survival results in a lethal aerosol exposure non-human primate model, and has also been shown to be well tolerated and immunogenic in two Phase 1 clinical trials in healthy volunteers. A Phase 1A clinical trial was conducted with a formulation of RiVax that did not contain an adjuvant. This trial revealed dose dependent seroconversion as well as lack of toxicity of the molecule when administered intramuscularly to human volunteers. The adjuvant-free formulation of RiVax induced toxin neutralizing antibodies that lasted up to 127 days after the third vaccination in several individuals. 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. The 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. In preclinical animal studies, the Alum formulation of RiVax also induced higher titers and longer lasting antibodies than the adjuvant-free vaccine.

The development of RiVax has been sponsored through a series of overlapping grants from both NIAID and the US Food and Drug Administration (FDA), which were granted to Soligenix and to Dr. Ellen Vitetta and colleagues at the University of Texas Southwestern (UTSW) where the vaccine originated. Most recently, Soligenix was awarded a contract valued at up to $24.7 million by the U.S. Department of Health and Human Service’s National Institutes of Health (NIH) (specifically funded by the National Institute of Allergy and Infectious Diseases or NIAID) to advance the development of Soligenix’s thermostabilization technology, ThermoVax, combined with the company’s ricin toxin vaccine, Rivax as a medical countermeasure (MCM) to prevent the effects of ricin exposure.

RiVax has been granted orphan drug designation by the FDA for the prevention of ricin intoxication.

About Anthrax
Anthrax is an acute infectious disease that is easily transmitted to humans by environmentally durable spores that are produced by gram positive bacterium Bacillus anthracis. Because the spores are robust and contagious, anthrax is considered a Category A bioterror threat. Anthrax infection can occur in three forms: cutaneous (skin), inhalation, and gastrointestinal. Inhaled spores can cause a rapidly progressing form of anthrax since the spores are transported to lymph nodes near the lungs where they germinate, releasing vegetative bacteria into the bloodstream. After infection in the bloodstream, the bacteria secrete a complex series of toxin components that make up anthrax toxin, resulting in overwhelming toxemia that causes shock and organ failure. The toxin component that binds to the surface of cells is Protective Antigen (PA). Antibodies targeting PA can neutralize the secreted toxins, and recombinant PA (rPA) and its derivatives are targets for development of highly purified next generation anthrax vaccines. PA is the major antigen in the currently licensed anthrax vaccine adsorbed (AVA, Biothrax).

Treatment of anthrax involves long-term antibiotic therapy, since ungerminated spores can lie dormant in the lungs for up to sixty days. Only a few inhaled spores can cause inhalational anthrax. Once the toxin has entered the bloodstream, antibiotics are ineffective, and only toxin-specific therapy is effective. Passively transferred antibodies can neutralize anthrax toxins and can be used post-exposure in conjunction with antibiotics. Because of the long residence time of spores in the lung, it is possible to vaccinate post-exposure, but the onset of neutralizing antibodies must occur during the period of antibiotic therapy.

About VeloThrax
VeloThrax is Soligenix’s proprietary vaccine to prevent exposure to anthrax. VeloThrax consists of a hyperimmunogenic derivative, termed DNI (Dominant Negative Inhibitor), of rPA (recombinant protective antigen) that is formulated with adjuvants to induce rapid protective immunity in fewer vaccinations than the currently licensed anthrax vaccine. The DNI vaccine antigen is an analog of rPA containing two mutations that prevent translocation of the anthrax holotoxin into cells, resulting in higher immune responses. It has been shown that animals vaccinated with the DNI antigen induced higher levels of antibodies to toxin and maintained high levels of protective antibody titers for up to one year without booster injections of antigen. The DNI vaccine was originally developed in the laboratory of Dr. John Collier and colleagues at Harvard University and has been developed as a post exposure therapeutic for exposure to anthrax.

Soligenix has obtained an exclusive license with Harvard for the development of DNI as a pre- and post-exposure vaccine for anthrax. When combined with ThermoVax technology, the DNI vaccine has also shown stability at temperatures as high as 70 degrees Celsius (158 degrees Fahrenheit). The development of VeloThrax using the DNI antigen has been sponsored through a NIAID cooperative grant to Soligenix and is a candidate for a next generation anthrax vaccine.

About ThermoVax
ThermoVax is a technology that is designed to eliminate the standard cold chain production, distribution and storage logistics required for most vaccines. Cold chain requirements add considerable cost to the production and storage of current conventional vaccines. According to the Biopharma Cold Chain Sourcebook of 2010, 98 percent of all vaccines (with a total value of $20.6 billion) require shipment through cold chain. Elimination of the cold chain would also enhance the utility of these vaccines for emerging markets and for other applications requiring but lacking reliable cold chain capabilities. Further, the World Health Organization (WHO) reports that 50 percent of all global vaccine doses are wasted because they are not kept within required temperature ranges. NIAID has also highlighted the priority of technologies for biodefense vaccines that focus on broad spectrum approaches including vaccine adjuvants and temperature stabilization for long shelf life, rapid onset of immunity, and surge capacity for production. For vaccines that are intended for long-term stockpiling, such as for use in biodefense or in pandemic situations, the utilization of ThermoVax has the potential to facilitate easier storage and distribution of strategic national stockpile vaccines in emergency situations.

The technology utilizes precise lyophilization of protein immunogens with conventional aluminum adjuvants in combination with secondary adjuvants for rapid onset of protective immunity with the fewest number of vaccinations. RiVax and VeloThrax are extremely labile in their liquid form requiring careful management under refrigerated conditions at 4 degrees Celsius (39 degrees Fahrenheit). By employing ThermoVax during their final formulation, it is possible to produce stable and potent vaccines that are capable of withstanding temperatures at least as high as 40 degrees Celsius (104 degrees Fahrenheit) for up to one year.

The underlying technology has been developed by Drs. John Carpenter and Theodore Randolph at the University of Colorado. The vaccine technology has been developed to date in collaboration with SRI International, the University of Kansas, the Wadsworth Center of the New York State Department of Health, and the Tulane National Primate Research Center under the sponsorship of a cooperative grant from NIAID.

— Read more in David J. Vance et al., “Combination of two candidate subunit vaccine antigens elicits protective immunity to ricin and anthrax toxin in mice,” Vaccine 33, no. 3 (9 January 2015): 417-21 (doi:10.1016/j.vaccine.2014.11.036); see also “Combo Ricin-Anthrax Vaccine Shows Protective Immunity,” Global Biodefense (29 December 2014)