In experiments with mice, scientists including Eyal Raz, M.D., Sandip Datta, M.D., and Joshua Fierer, M.D., of the University of California, San Diego, School of Medicine demonstrated that a vaccine made from irradiated Listeria monocytogenes bacteria, unlike a vaccine made from heat-killed bacteria, provides protection against challenge with live Listeria. The irradiated bacteria also stimulated a protective response from immune system cells called T cells. Previously, only vaccines made from live, weakened Listeria bacteria were believed capable of eliciting a T-cell response.
"This advance is potentially of great importance in meeting the challenge of creating vaccines that are safe, effective and simple to manufacture and transport," says NIH Director Elias A. Zerhouni, M.D.
Ideally, vaccines should stimulate a strong response not only from both arms of the adaptive immune system (antibodies and T cells), but also the body's innate immune system. However, traditional ways of making vaccines--either by killing disease-causing agents with heat, chemicals or by weakening (attenuating) live pathogens--have characteristic shortcomings. For example, heat- and chemical-killed vaccines, while safe and relatively easy to produce, generally produce a less broad immune response than live, attenuated vaccines. Conversely, it can be difficult to create live, attenuated vaccines that safely preserve the pathogen's abi lity to trigger strong innate and adaptive immune responses.
"By showing that whole, irradiated bacteria can form the basis of a vaccine that elicits a strong response from both arms of the adaptive immune system, Dr. Raz and his colleagues have opened the possibility of making a variety of bacterial vaccines that combine the best features of both killed-agent and live, attenuated vaccines," says NIAID Director Anthony S. Fauci, M.D.
Earlier research in Dr. Raz's laboratory had shown that irradiated probiotics (bacteria that are beneficial to health) retain the ability to trigger innate immune system responses via proteins called toll-like-receptors. Based on that observation, says Dr. Raz, "we hypothesized that a vaccine made from whole, irradiated bacteria would retain the properties needed to evoke a broad immune response and result in a superior vaccine compared with other methods of killing the pathogen."
The investigators inactivated Listeria with lethal doses of gamma radiation and then vaccinated a group of 10 mice twice with the irradiated bacteria. Another group of 10 mice received two inoculations with heat-killed Listeria, while a third group of 10 received no vaccine. Twenty-eight days after the first vaccinations, all the mice were infected with a large dose of live Listeria (four times the amount required to kill 50 percent of infected unvaccinated animals). All the unvaccinated mice and all the mice vaccinated with heat-killed Listeria died, but 80 percent of the mice vaccinated with the irradiated bacteria survived. Further experiments showed that protection conferred by irradiated Listeria bacteria lasted for at least 12 months, indicating that the vaccine promoted the development of a "memory" T cell response.
Consistent with their earlier experiments with irradiated probiotics, Dr. Raz and his colleagues also found that irradiated Listeria retained the ability to stimulate innate immune responses via tol l-like-receptor proteins. "Although completely inactivated by the radiation, and thus unable to cause illness, irradiated bacterial pathogens evidently retain characteristics that prompt the immune system to mount a full-fledged defense," says Dr. Datta, the study's lead author. "In this respect, irradiated pathogens more closely mimic the body's response to a live, attenuated vaccine."
Finally, the scientists found that mice could be protected by vaccination with irradiated Listeria that had been freeze-dried into a powder. This point is potentially of great practical importance, notes Dr. Raz. A serious drawback of live, attenuated vaccines is that they must be kept refrigerated at all times: if the "cold chain" is broken, the vaccine is liable to spoil and become useless. In countries with reliable electricity, maintaining the cold chain is rarely a problem. The same is not true in less developed countries. Vaccines made from whole, irradiated bacteria, freeze-dried into an easy-to-transport powder, could be reconstituted just before use, explains Dr. Raz, thereby eliminating the cold chain requirement.
It is also possible that a strategy based on irradiation-inactivated whole pathogens could rapidly yield vaccines against such bacterial diseases as typhoid, cholera, tuberculosis and other diseases of public health concern, such as intestinal parasites. This strategy might also be deployed in the event of epidemic outbreaks or against bioterrorist attacks, says Dr. Raz.