Ebola, Marburg vaccines work in monkeys

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Jun 7, 2005 (CIDRAP News) – A pair of vaccines created by a Canadian-based international team of researchers protected monkeys against the lethal Ebola and Marburg viruses, according to a new report in Nature Medicine.

The vaccines were made by splicing a gene from either the Ebola or the Marburg virus into a weakened version of the vesicular stomatitis virus, which causes mouth inflammation in livestock. Small groups of monkeys that received one of the two vaccines stayed completely healthy after they were exposed to a heavy dose of the corresponding virus.

Publication of the findings comes as public health workers in Angola continue to battle the largest Marburg hemorrhagic fever outbreak on record. The outbreak had reached 423 cases, with 357 deaths, by May 27, according to the World Health Organization. There is no vaccine or effective treatment for either Marburg or Ebola, which are fatal in most cases.

The first two authors of the study, Steven M. Jones and Heinz Feldmann, have been helping to diagnose cases in Angola, according to a news release from the Public Health Agency of Canada.

"When you see the tragedies these viruses cause, it's very frustrating that we can't do more to help people," Feldmann said in the news release. "It'll be some time before we can use these vaccines in the field, but it's satisfying to know that we're getting closer."

Jones and Feldmann work at Canada's National Microbiology Laboratory in Winnipeg, Man. They collaborated with researchers from the US Army Medical Research Institute of Infectious Diseases, the US National Institute of Allergy and Infectious Diseases, and laboratories in Germany and France.

The team previously created a live but weakened recombinant form of vesicular stomatitis virus (rVSV) and inserted a glycoprotein, or surface protein, gene from the Ebola virus into it. Later they followed the same procedure with rVSV and the glycoprotein gene from the Marburg virus.

The researchers injected six cynomolgous macaques with the Ebola vaccine and another six with the Marburg vaccine. None of the animals were made ill by the vaccine. Four weeks after vaccination, four Ebola-immunized monkeys were injected with a high dose of Ebola virus, and four Marburg-immunized monkeys were injected with Marburg virus. The researchers used two Marburg-immunized monkeys and two Ebola-immunized monkeys as controls by exposing them to the noncorresponding virus.

The eight monkeys that were exposed to the same virus they had been vaccinated against all stayed healthy. No signs of either virus were found in the animals' blood, nor did they shed any virus. But the four monkeys that were exposed to the noncorresponding virus all died within 9 days after exposure.

The team found evidence of both humoral (antibody) and cellular immune responses in the Ebola-immunized monkeys after they were exposed to the virus. Both kinds of responses also were seen in the Marburg-immunized monkeys after vaccination, but there was no evidence of a cellular immune response after exposure to the virus.

Months after the initial experiment, the eight surviving monkeys were exposed to a different strain of Ebola or Marburg virus. When the four Ebola-immunized monkeys were inoculated with a different Ebola strain 234 days after the first test, three of them died within a week, while one survived. The four Marburg-immunized animals all stayed healthy when they were exposed to a different Marburg strain 113 days after the initial challenge.

The authors say these contrasting results were not unexpected, because the two Ebola virus strains differed by 37% to 41% at the DNA level, while the two Marburg strains were 94% the same.

The report says other researchers previously created an Ebola virus vaccine by inserting two of the virus's genes into human adenoviruses. That vaccine protected monkeys, but because many people are immune to adenoviruses, such a vaccine might have limited utility in humans, the authors say.

Researchers also have had some success using an engineered form of alphavirus to make a Marburg virus vaccine, according to the report. However, attempts to use alphavirus as a "platform" for an Ebola vaccine failed.

The two new vaccines improve on these previous attempts, the researchers write. "This current study is the first to show that nonhuman primates can be protected with a single-dose immunization using a vector expressing solely the ZEBOV [Zaire Ebola virus] glycoprotein. In addition, this is the first vaccine platform to show the ability to protect nonhuman primates against EBOV and MARV [Ebola virus and Marburg virus], which is an important first step toward developing a vaccine that will be effective against all filoviruses."

In the news release, Dr. Thomas Geisbert of USAMRIID added that the vaccines target dendritic cells, the same cells targeted by Ebola and Marburg. "These cells are also important in generating an immune response. So the vaccine goes exactly where we want it to go," he said.

Jones SM, Feldmann H, Stroher U, et al. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat Med 2005 Jun 5 (advance online publication) [Abstract]

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