West Nile virus vaccine heads into clinical trials

Agent derived from live strain of yellow fever virus

By Terry Murray

SAN DIEGO – Phase I trials are expected to begin early next year of a live, attenuated vaccine against West Nile virus (WNV).
   Data showing the vaccine to be safe and immunogenic in several animal models were presented in a late-breaker session of the Interscience Conference on Antimicrobial Agents and Chemotherapy here last month.
   The vaccine, developed by Acambis Inc. with funding from the U.S. National Institutes of Health (NIH), uses a chimeric virus made by replacing the envelope genes of yellow fever vaccine with those of WNV.
   It was derived from the live, attenuated 17D strain of the yellow fever virus, which is the basis of existing yellow fever vaccines, said Dr. Juan Arroyo (PhD), senior scientist at Acambis in Cambridge, Mass., and project leader for the West Nile vaccine.
   The genes that encode the two structural proteins in the yellow fever 17D virus are known to contain the critical antigens that confer immunity against yellow fever, Dr. Arroyo said. For the vaccine, a chimeric virus was created by replacing those yellow fever genes with the corresponding WNV genes.
   The resulting vaccine has a similar safety and immunogenicity profile as the yellow fever vaccine, but directed against West Nile. The same approach has been used by Acambis to make vaccines against yellow fever/ Japanese encephalitis and dengue (all of which are flaviviruses), which are currently in clinical trials.
   Mice given a single dose of the new vaccine did not develop encephalitis, in contrast to those who were given the parent wild type WNV strain.
   The vaccine was less neurovirulent than the commercial yellow fever vaccine, but three sites in the amino acid sequence of the yellow fever/West Nile virus envelope proteins were selected for point mutations to further attenuate the chimeric virus.
   Mice given a single inoculation of the triple mutant vaccine developed high levels of neutralizing antibodies and were protected against challenge with the wild type WNV.
   Other studies in hamsters and rhesus monkeys also showed the vaccine to be safe and immunogenic.
   "We believe that a virus with three point mutations is safer," Dr. Arroyo told a news conference at the meeting.
   "It has enough attenuation so in case there's going to be a reversion, you still have two other attenuated mutations that will maintain the safety of the vaccine.
   "However, adding point mutations also reduces viral replication so antibody responses are lower than if you have a virus with no mutations. But the antibody response is still high enough to be protective."
   In an additional study, Culex and Aedes mosquitoes were fed the yellow fever/WN virus, but showed no viral replication.
   Mosquitoes will not be able to transmit the attenuated virus, thus reducing the risk of uncontrolled spread, Dr. Arroyo said.
   The company was given a $3-million U.S. grant by the NIH in August 2000 to develop the vaccine, which is expected to cover the costs of research and development up to the point of clinical trials, according to an Acambis statement.
   Phase I trials are expected to start in the first quarter of 2003, Dr. Arroyo said.
   "We will continue to work with relevant government agencies like the NIH, the Centres for Disease Control and Prevention, and the Food and Drug Administration," he added.
   "We understand the need and urgency for a vaccine and will continue to respond accordingly."