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New compound could provide rapid treatment and long-term protection in a single injection
The immune response generated in rats by the new agent protects against lethal toxin exposure after only one injection, and is faster and stronger than any currently available vaccine.
The new study, led by Scripps Research scientists Anette Schneemann and Marianne Manchester, and Salk Institute Professor John A.T. Young, was published in the October 5 issue of the journal PLoS Pathogens (Volume 3, Issue 10).
"The new anti-anthrax agent that we developed is an important and potentially critical development for anyone who works with the bacterium or those who might be exposed to it in a bioterrorism attack," Schneemann said. "While other strategies are being pursued to develop improved anthrax vaccines, none of these offer the distinct advantage of combining the function of a vaccine with a potent antitoxin."
Concerns about anthrax-a potentially fatal disease caused by the spore-forming, gram-positive bacterium Bacillus anthracis-as a weapon of bioterrorism has prompted increased efforts to develop better antitoxins and vaccines. The current vaccine, which was developed in the 1950s, is safe and effective, but requires multiple injections followed by annual boosters. Current anthrax treatment involves antibiotics such as ciprofloxacin and doxycycline that attack the bacteria but provide no protection against the dangerous toxins secreted by the bacteria.
The new study introduces a highly effective dual-action compound that leapfrogs current efforts to develop a second-generation anthrax vaccine. In the research, the scientists created a "multivalent display," with several sites of attachment for recombinant protective antigen protein (PA), the primary component of the current anthrax vaccine, rather than only one. Virus-like particles coated with PA were found to produce a potent toxin-neutralizing antibody response that protected rats from the lethal anthrax toxin after only a single immunization.
The antitoxin strategy arose from the discovery of the anthrax toxin receptor, ANTXR2, in the Young lab. "The new anti-anthrax agent is based on a multivalent display of ANTXR2 on the surface of an insect virus," explains Schneemann. "Our approach was based on the assumption that a multivalent display of recombinant protective antigen protein would induce a far more potent immune response. That turned out to be correct."
Specifically, the new vaccine-antitoxin combination is based on the multivalent display (180 copies) of the PA-binding von Willebrand A (VWA) domain of the ANTXR2 cellular receptor on the Flock House virus. The chimeric virus-like particle platform, which produces protective immunity and has been shown to be safe, inhibited lethal toxin action in in vitro and in vivo models of anthrax infection.
In fact, rats survived exposure to the toxin four weeks after a single injection of the new double-acting agent. This result suggests an extremely rapid production of neutralizing antibodies without the use of an adjuvant, a secondary agent that helps stimulate the immune system and is often used to increase the vaccine response-key goals for the development of third-generation anthrax vaccines.
In addition to its use against anthrax, Schneemann notes that creating a multivalent platform may also have the potential to work against other infectious agents.
"One important reason for the success of this project is that it arose from the multidisciplinary and highly collaborative efforts of our team of microbiologists, structural biologists, and immunologists," said Manchester, who headed a National Institutes of Health (NIH)-funded program project grant that supported the work.
Other authors of the study, "A Viral Nanoparticle with Dual Function as an Anthrax Antitoxin and Vaccine," are Darly J. Manayani, Vijay Reddy, Michael E. Pique, Marc E. Siladi, Diane Thomas, Kelly A. Dryden, and Marianne Manchester of The Scripps Research Institute; John M. Marlett, G. Jonah A. Rainey, Heather M. Scobie, and John A.T.Young of The Salk Institute for Biological Studies; and Mark Yeager of The Scripps Research Institute and the Scripps Clinic.
About Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.
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