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PUTTING ANTHRAX TO WORK

By Sean Henahan, Access Excellence


BOSTON (NOV. 4, 1996)- Harvard researchers have developed an experimental vaccine utilizing anthrax (Bacillus anthracis) one of the most toxic microorganisms known to man.

Photo: Purple chains of anthrax bacilli © C. James Webb, 1994

The researchers developed a vaccine exploiting a potent toxin produced by the anthrax organism to transport molecules into cells. In early studies, the vaccine was found to protect mice against infection by that pathogen,

Though still in early stages, the vaccine may lead to an entirely new class of human vaccines against most viruses, certain bacteria, and parasites. Moreover, the approach may be useful in developing cancer vaccines and therapies, says Michael Starnbach, assistant professor of microbiology and molecular genetics.

The study is the first successful attempt to engineer a protein-based vaccine that works by priming the immune system's killer T cells to respond against infection and to generate a specific immunological memory for future protection. Most current protein-based vaccines, such as the one commonly used against tetanus, stimulate B cells, which then churn out antibodies. The trouble is, B cells can detect invading pathogens only as long as they are outside of cells. Once the pathogen has snuck past this line of defense and slipped inside cells of the body-a strategy most viruses employ-they become invisible to all cells of the immune system, except killer T cells.

Harnessing the killer T cells' power for vaccination has been difficult, says Starnbach, because they require that the antigens against which they act be displayed to them from inside infected cells. And delivering a vaccine into cells is much more complex than simply injecting it into a person's bloodstream. Another approach to solving this problem, using so-called naked DNA, harbors the danger of introducing foreign genetic material that could possibly insert itself into the human's own DNA.

"The safety of protein-based vaccines is one of their main attractions," says Starnbach. Starnbach collaborated with John Collier, professor of microbiology and molecular genetics at Harvard Medical School, an expert in the area of how anthrax toxin transports proteins across the cell membrane and into the cytoplasm. Collier had already developed a technique to manipulate some of the toxin's components so they became innocuous but could in theory transport any protein-a drug or vaccine-into cells.

Armed with this technology, the researchers genetically fused a harmless section of the anthrax toxin to a section of their model pathogen required to stimulate T cells but unable to cause full-blown disease. Then they mixed this construct with the transporter component of the anthrax toxin and injected it into mice. When they infected vaccinated and unvaccinated animals with the model pathogen-bacteria causing food poisoning-they found that the killer T cells in the vaccinated mice were geared up specifically in response to this bacterium, and that the vaccinated mice contained 25-fold fewer bacteria than did the control mice.

The work is still in the early stages, the researchers caution. For starters, they need to test if their vaccine can protect against death, not just reduce bacterial load, and whether it can do so in diverse strains of mice, not only the inbred strain that was studied. These are necessary steps toward testing a vaccine in humans.

Next they need to apply their method to more medically important pathogens than the bacteria used in this study. First candidates could be the cytomegalovirus that causes retinitis in people with AIDS, and the bacterium that causes dysentery, says Starnbach.

Anthrax is fatal to livestock and humans. Louis Pasteur developed the first vaccine based on an attenuated or weakened form of the organism. Pasteur demonstrated the principle of immunity in a public demonstration in which half a flock of sheep were given live anthrax and the other half an attenuated form. All of the vaccinated sheep survived while all of the unvaccinated were dead in a week. Anthrax is also the basis for a crude but powerful biological weapon.

The research appears in the October 29, 1996 issue of Proceedings of the National Academy of Sciences.


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