By Lisa Seachrist

Washington Editor

WASHINGTON -- OraVax Inc. has entered into a collaboration with Pasteur Merieux Connaught (PMC) to develop a vaccine to prevent dengue fever.

Cambridge, Mass.-based OraVax's ChimeriVax technology serves as the basis of the agreement, which could be worth up to $23.5 million, plus royalties.

Lance Gordon, OraVax's CEO and president, called ChimeriVax "very promising."

Under the terms of the agreement, Paris-based PMC will make an up-front payment to OraVax of $1 million. Over the next year, PMC will pay $6 million to fund research and development of the vaccine through the first clinical trials. Additional milestone payments to OraVax could be worth up to $16.5 million.

ChimeriVax exploits the peculiar structure of flaviviruses to create a host of live, attenuated viruses against diseases such as dengue fever, yellow fever, tick-borne encephalitis, Japanese encephalitis and hepatitis C.

Flaviviruses are single-stranded RNA viruses that express their exterior antigenic proteins in a contiguous two-kilobase region on their genomes. OraVax is taking advantage of the existing yellow-fever 17D vaccine, which has been given to 300 million people worldwide. ChimeriVax uses the yellow-fever vaccine and replaces the DNA coding for the exterior protein with those of other flaviviruses.

"The yellow fever 17D virus is a live, attenuated virus that is 100 percent effective with a single dose -- often considered the world's most effective vaccine," Gordon said. "If you think of the chimera, which had the body of a goat, the head of a lion and the tail of the serpent, you can see that the vaccine we create using ChimeriVax is very similar: The vaccine has the replication and attenuation of the yellow-fever vaccine, but the surface of a different flavivirus."

At Risk: 2.5 Billion Tropical Residents And Visitors

Dengue fever is a mosquito-borne disease caused by four related flaviviruses. It affects more than 100 million people each year, primarily in tropical countries. About 2.5 billion people living in those regions and the 10 million people traveling to the tropics are at risk for dengue fever. Symptoms include high fever, severe headache, rash, bone pain and muscle pain.

Infection with dengue viruses can lead to dengue hemorrhagic fever, a severe form of the disease characterized by hemorrhage, shock and death in up to 15 percent of cases.

Creating a dengue fever vaccine will require several steps. First, the company must make vaccines against all four strains of the dengue virus. Then, it will have to combine those vaccines to create a polyvalent vaccine that effectively protects against all four strains.

Varying Viral Replication Rates Create Hurdle

Gordon said one of the stumbling blocks for creating a dengue fever vaccine has been the fact that different strains of the virus replicate at different rates, causing the immune system to respond to the faster-replicating viruses, thus leaving a person unprotected from the slower ones. OraVax hopes to overcome that problem with ChimeriVax, which replicates at a set rate.

In addition to the dengue-fever project, PMC has an option to negotiate a separate agreement to license OraVax's Japanese encephalitis vaccine, which also uses ChimeriVax technology. In exchange for the option, PMC will fund the development and clinical testing of the JE vaccine through completion of a Phase I trial.

Gordon said the company intends to file an investigational new drug application for the JE vaccine in the first half of 1999, and an IND for the monovalent dengue fever vaccine by the end of 1999. The hepatitis C effort is still in the early preclinical stage.

Last month, OraVax disclosed it would merge with Cambridge, U.K.-based Peptide Therapeutics Group plc. (See BioWorld Today, Nov. 12, 1998, p. 1.)

OraVax's stock (OTC BB:ORVX) closed at $0.45 per share, unchanged. *