Travelers call it "la turista" or "Montezuma's revenge." Doctors call itshigellosis, a serious, sometimes fatal, gut infection, which causesdiarrhea, dysentery, cramps and fever. A Japanese bacteriologist, KiyoshiShiga, discovered the vicious bacillus, which now bears his name, in 1897.

This coming January, a group of healthy adult volunteers in Baltimore willgulp down an oral vaccine designed to immunize them against virulentwild-type Shigella flexneri. An attenuated, genetically engineered strain ofthe organism was developed by gastroenterologist Myron Levine, whoheads the University of Maryland's Baltimore-based Center for VaccineDevelopment (CVD).

Levine and Thomas Monath, vice president of research and developmentat OraVax Inc. of Cambridge, Mass., will co-manage the Phase I clinicaltrial of the oral shigella vaccine.

OraVax announced today that it has entered into a five-year, $3.5-millionpartnership with CVD to develop the mutated strain not only to preventshigellosis, but as a live-organism cloning vector to express other bacterialvaccine epitopes.

Among these are the pathogens Clostridium difficile and Helicobacterpylori. The latter was recently indicted as a likely cause of peptic ulcers.OraVax's vice-president of business development, marketing and sales,Robert Rombauer, told BioWorld that his company will soon announce ajust-concluded pact with Vanderbilt University to license its patent-pendingH. pylori gene and gene product.

OraVax's agreement with Maryland's CVD comprises both a five-yearresearch collaboration and patent licensure. "We have made a licensepayment to the university," Rombauer told BioWorld, "and we have aroyalty arrangement." OraVax is picking up the tab for all clinical trials, heexplained, "because the work on this vaccine up to this point has beendone entirely in Levine's lab."

"The vaccine that's going into clinical trials in January is a strain of Shigellflexneri that has been genetically engineered so that its two virulencegenes are deletetion-mutated," OraVax's Monath told BioWorld. "Thus,there is no possibility that they can revert to wild type." One of thesegenes, he explained, controls rate of replication and growth; the other, theability of the bacterium to spread from one intestinal epithelial cell to itsneighbor.

One of these genes, Monath noted, is protected by a patent application.He added that the bacterium's lipopolysaccharide, a critically protectiveantigen, is fully expressed and generates antibodies.

Animal trials in guinea pigs, mice and monkeys confirm that the largelyattenuated double-mutant microorganism retains enough immunogenicityand replication ability to generate an immune response in a vaccinatedhost. "But these don't answer the critical question," Monath emphasizes."You've got to go into people. They are the only truly acceptable host indysentery."

The Phase I trial next January will be a placebo-controlled, double-blindedstudy. Subjects will get two different doses of the live bacteria. Then, if itproves sufficiently immunogenic and free of side effects, the volunteers willbe brought back and challenged with virulent, wild-type S. flexneri. "Theprotocol is in the university's institutional review board right now forapproval," Monath said.

Follow-on clinical trials will take place near Santiago, Chile, where theincidence of shigellosis runs as high as 15 percent to 20 percent. "Theywill be a test-bed for Phase III studies when we're ready to do them,"Monath said.

Part of OraVax's $3.5-million payment to CVD will go to re-establish anepidemiological surveillance unit in Chile PP unfunded for the past twoyears PP where Levine had long conducted research on enteric bacterialdiarrheal diseases.

Shigellosis afflicts at least 200 million people worldwide, Monath said, andkills 600,000 to 700,000 of them every year. "It's a very important cause ofinfant diarrhea in the developing world," he added.

In the U.S., cases average 15,000 to 20,000 annually, but this numberoften doubles or triples in epidemic years. The infection is transmitted byfecally contaminated food or water, and is often spread by house-flies.Infant day-care centers are particularly vulnerable, as are military troopsdeployed to high-incidence countries.

Such a global market for the oral vaccine can only be tackled by the WorldHealth Organization, Rombauer said. "We will price it appropriately, alongthe lines of WHO vaccines." But he reserves the U.S. market for separatepricing.

"As few as 10 ingested Shigella microorganisms -- maybe less -- cantrigger the disease in a human large intestine, " Monath observed. An oralvaccine will work, he explained, because the bacteria are quite resistant tothe gastric-acid barrier.

Another unique advantage that makes Shigella a promising candidatevector for foreign genes is that the bacterium gains access to the humanbody by way of the specialized "M" cells in the Peyer's patches of theintestinal mucosa. The antigens are trapped by these target cells, and theimmune response initiated.

The first such foreign gene, which OraVax has just begun to clone in itsmutated S. flexneri vector, comes from Clostridium diffile. This largeintestinal pathogen causes antibiotic-associated diarrhea, "a very commonproblem among elderly and hospitalized patient populations in the U.S.,"Monath said. "Anybody getting antibiotics for another indication is at risk ofthis disease."

OraVax is going ahead with this project, Monath said, before determining"that the strain we're going to test in January is the ultimate vaccine. It willtake us a year of research to get to the point where we've got the systemworked out, by which time we'll have a lot of clinical data."

Helicobacter pylori, the presumed ulcer bug, is next up. The agreementRombauer concluded last month with Martin Blaser and Vanderbilt givesthe company exclusive rights to the cagA gene and gene product of H.pylori's cell membrane. "The license we have acquired," Rombauer said,"is for diagnostic, therapeutic and vaccine uses of this material. FromBlaser's early work with clinical samples, this gene product is alwayspresent in peptic ulcers."

Blaser, who directs Vanderbilt's division of infectious diseases, has joinedOraVax's scientific advisory board.

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.