Mouse Model Mimics Real-World Plague Infection

The new report, authored by lead researcher and RML plague expert B. Joseph Hinnebusch, Ph.D., appears in the April edition of Infection and Immunity, now available online. Collaborators included Clayton O. Jarrett, M.S., and Florent Sebbane, Ph.D., of RML in Hamilton, MT; and Jeffrey J. Adamovicz, Ph.D., and Gerard P. Andrews, Ph.D., of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), where the recombinant plague vaccine tested in the model was made.

"Replicating the natural transmission of plague from flea to host in this model is tedious and unusual work," notes NIAID Director Anthony S. Fauci, M.D. "This creative approach, however, brings researchers much closer to answers to real-life questions."

In their study, the RML scientists first infected fleas by letting them feed on blood containing a virulent strain of Yersinia pestis, the bacterial agent of plague. The infected fleas then fed on 15 mice that had been inoculated with the experimental vaccine containing an adjuvant (an immune booster). For comparison, the researchers let infected fleas also feed on a second group of 15 mice that had received only the adjuvant.

Although all 15 vaccinated mice remained symptom-free even after multiple feedings by the fleas, plague occurred in 14 of the 15 mice that had received the adjuvant alone.

"This research shows that the vaccine worked in a real-world context," Dr. Hinnebusch says. "The vaccine had prior successes in rodents and non-human primates, but in those experiments, the animals received laboratory-grown plague bacteria and were artificially exposed to it by needle and syringe."

Despite these earlier successes, says Dr. Hinnebusch, "It wasn't a given that this vaccine would work in a natural setting." With natural flea transmission, he explains, the bacteria exist in a special form and are deposited along with flea saliva into the skin of the animal in a way that cannot be duplicated artificially. During a natural infection, the digestive system of some fleas becomes blocked with a highly infectious bacterial mass. When these "blocked" fleas continue to feed, the host blood hits the mass, becomes tainted with concentrated plague bacteria, and is regurgitated back into the host.

In their experiment, the RML scientists made certain that numerous blocked fleas--in some cases as many as 13--fed repeatedly on the vaccinated mice to ensure that the rodents could withstand multiple bites by infected fleas.

"It's difficult to do a natural challenge for an arthropod-transmitted disease, particularly with plague," Dr. Hinnebusch says, explaining why this method is uncommon. "You have to have flea colonies. You have to be able to infect them safely. You need medical entomology, microbiology and biosafety expertise. It's much easier to infect a host artificially with a needle and syringe."

Dr. Hinnebusch and his colleagues will use the natural challenge model to test other plague vaccines in development. They also will try to learn how plague bacteria spreads through a host after being transmitted by a flea, with hopes of developing new treatments to counteract the spread of plague in an infected person.

A plague vaccine available until the mid-1990s is no longer being made, Dr. Hinnebusch says, because of its short-term effectiveness and many side effects.

The experimental plague vaccine invented at USAMRIID is a fusion of protective proteins referred to as F1-V. The F1-V vaccine has been shown to protect mice, black-footed ferrets and monkeys against injected plague. Furthermore, USAMRIID has shown the vaccine protects both mice and monkeys against the highly lethal form of inhaled plague.

"Two factors--the threat of antibiotic-resistant plague and the possible use of plague by bioterrorists--have the public health system scrambling to come up with an effective vaccine and alternative treatments," Dr. Hinnebusch says. "Plague has been used as a bioweapon before and it could be again."

Bubonic plague killed millions of people in Europe in the Middle Ages. The World Health Organization now reports some 2,500 new cases of plague annually, including about 180 annual deaths; 75 percent of the new cases and deaths are in Africa. The United States experiences 10 to 15 cases annually, according to the Centers for Disease Control and Prevention. The most common source of infection is bites from infected fleas carried by wild rodents.

Bubonic plague is characterized by painful, swollen lymph nodes called buboes that are often hot to the touch. Symptoms usually include fever, extreme exhaustion and headaches. Onset of bubonic plague generally occurs 2 to 6 days after exposure. If untreated in humans, the disease spreads rapidly, and the bacteria can invade the bloodstream (leading to plague septicemia) and the lungs (leading to pneumonic plague).

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USAMRIID, located at Fort Detrick in Frederick, MD, is the lead medical research laboratory for the U.S. Biological Defense Research Program and plays a key role in national defense and in infectious disease research.

NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. 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 transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.

Reference: C Jarrett et al. Flea-borne transmission model to evaluate vaccine efficacy against naturally acquired bubonic plague. Infection and Immunity 72:2052-56 (2004). DOI: 10.1128/IAI.72.4.2052-2056.2004.

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