An experimental plague vaccine proved 100 per cent effective when tested in a new mouse model for plague infection developed by scientists at Rocky Mountain Laboratories (RML), part of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health.

The scientists developed their model to mimic the natural transmission route of bubonic plague through the bites of infected fleas. The flea-to-mouse model provides a more realistic test setting than previously used methods, enabling a better assessment of a vaccine's ability to protect against a real-world challenge.

The new report, authored by lead researcher and RML plague expert B. Joseph Hinnebusch, appears in the April edition of "Infection and Immunity", now available online. Collaborators included Clayton O. Jarrett, M.S., and Florent Sebbane, of RML in Hamilton, MT; and Jeffrey J. Adamovicz, and Gerard P. Andrews, 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.

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.