A biological weapon of an entirely different sort is what Harvard Medical School researchers are trying to build from the potent toxin of Bacillus anthracis. Exploiting the toxin's ability to transport molecules into cells, the researchers have used it to develop an experimental vaccine directed against a model pathogen. What's more, the vaccine was found to protect mice against infection by that pathogen, the researchers report in the October 29 Proceedings of the National Academy of Sciences.
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 senior author Michael Starnbach, assistant professor of microbiology and molecular genetics. "This study provides the proof of principle that this strategy works," he says.
It also represents 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 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.
A current 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.
To engineer an intracellular vaccine, Starnbach collaborated with John
Collier, professor of microbiology and molecular genetics at Harvard Medical
School, who had, for years, studied the way in which the anthrax toxin managed
to do exactly what Starnbach needed: ferry 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 Armed with this technology, the researchers genetically fused a harmless
snippet of the anthrax toxin to a snippet 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 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.
It may seem ironic to us that we should allow any part of Bacillus
anthracis into our bodies to protect us from disease. But it is also oddly
fitting that this organism opens the door to solving a knotty problem in vaccine
development, because it was one of the first pathogens against which a vaccine
was successfully made