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ShareOct. 16, 2001 — COLUMBUS, Ohio - Researchers here have shown that mice injected with fragments of DNA from anthrax bacteria can be immunized against the disease. In traditional vaccine approaches, researchers have used live, weakened or dead pathogens - or proteins produced by the organisms - to produce an immune response.
This new approach represents a new -- and perhaps, safer -- way to produce vaccines against highly contagious diseases.
This latest study, published in a recent issue of the journal Infection and Immunity, improves on earlier work that suggested that DNA-based vaccines might be effective. By using combinations of two gene products produced by the bacteria responsible for causing anthrax -Bacillus anthracis - the researchers were able to successfully immunize mice against the disease.
The work was headed by Darrell Galloway, associate professor of microbiology at Ohio State University, and colleagues at the National Institute of Dental and Craniofacial Research and the Biological Defense Research Directorate program at the Naval Medical Research Center in Silver Spring, MD.
Anthrax is a lethal disease if not detected shortly after exposure to bacterial spores. Antibiotics are effective in halting it if given soon after exposure before any symptoms develop. It is one of the leading potential agents discussed for use in biological terrorist attacks.
Once anthrax spores are inhaled, they are pulled deep into the lungs where they usually are consumed by macrophages - white cells that scavenge the body for pathogens and other components that may lead to disease.
"Unfortunately," Galloway says, "the macrophages seem to be uniquely sensitive to this bacteria and are essentially targeted." Once inside the macrophages, the spores germinate producing bacterial cells that multiply until their numbers literally burst the cells, spreading infection. The bacterial cells produce and release toxin components that specifically attack additional macrophages, ultimately leading to death. This, in turn, releases massive amounts of cytokines - critical chemical components of the immune response that cause physiologic effects throughout the system.
"Ultimately, the destruction of the macrophages, and the dumping into the bloodstream of the large amounts of cytokines produced by these cells, causes the patient to go into shock which ultimately kills him," Galloway says.
His team focused on using the genes responsible for producing the bacterial toxin. These genes normally secrete three gene products - protective antigen (PA), lethal factor (LF) and edema factor (EF). The protective antigen combines with the lethal factor to form a molecule known as lethal toxin, which can invade the cell and claim credit for the fatal potential of anthrax.
"Without PA," Galloway said, "neither of the remaining two toxin components would be effective."
To construct their vaccine, the researchers assembled groups of mice and injected them three times at two-week intervals with plasmids - circular DNA molecules that are widely used for the cloning and expression of genes and their products - containing fragments of PA and LF.
Some mice received PA plasmids only, some LF plasmids only and some received a combination of both. A control group received plasmids lacking PA or LF genes. Two weeks after the last injection, researchers measured the groups' antibody response to both gene products. Mice receiving gene-laden plasmids developed strong immune responses to the gene product they were exposed to.
"Significantly," the researchers wrote, "titers (measures) of antibody to the LF antigen appeared to be about twice those of antibody to the PA. This suggests that the LF antigen induces a greater response."
The researchers also found that mice that had received both PA and LF had nearly twice the immune response of mice receiving either agent alone. This is extremely important for researchers striving to produce the most effective vaccine.
The groups of mice were then injected with five times the lethal dose of the anthrax bacterial toxin. All mice that had received the plasmid injections were immune while all animals in the control group died within several hours.
Galloway says that the results are important enough to suggest that an effective vaccine might be possible that focuses on using additional Bacillus anthracis antigens, including a mutated form of the lethal factor antigen. This point is important since earlier vaccine studies were focused on using the PA antigen alone.
"The LF antigen appears to be much more immunogenic and produces an immune response lasting much longer than the response to the PA antigen," he said.
The researchers believe their current work is a strong argument for the feasibility of using a "DNA-based immunization strategy against anthrax" and that any future vaccines should incorporate a mutated version of the LF antigen.
In a recent, as-yet unpublished study, the Ohio State University research team, in collaboration with scientists from Battelle, has demonstrated that the vaccine can protect against a significant aerosol challenge more than a year following the last inoculation.
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