|Radiation-Killed Bacteria Vaccine Induces Broad Immune Response
Vaccines made with bacteria killed by gamma irradiation, rather than by standard
methods of heat or chemical inactivation, may be more effective, say researchers
supported by the National Institute of Allergy and Infectious Diseases (NIAID),
part of the National Institutes of Health (NIH). Vaccines made from gamma-irradiated
bacteria also may not need to be kept cold; an advantage in settings where refrigerating
vaccines is impractical or impossible. A report on the research appears in the
current issue of the journal Immunity.
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 ability 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 toll-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
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.
News releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.
NIAID is a component of the National Institutes of Health. NIAID supports
basic and applied research to prevent, diagnose and treat infectious diseases
such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also supports
research on basic immunology, transplantation and immune-related disorders,
including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.