Ebola mutations could make some drugs ineffective

Small mutations to the Ebola virus could create big problems for some experimental treatment drugs.

In the year since Ebola began spreading across West Africa, the virus has mutated in more than 600 ways that change it slightly from versions studied in labs and used to develop treatments, according to researchers at Fort Detrick. And 10 of the mutations could make some drugs used to treat the virus ineffective, they wrote in research published Tuesday.

The "genomic drift," as the scientists called it, could make agents similar to the experimental drug ZMapp unable to bind to the virus anymore.

While the changes affect only a tiny fraction of Ebola's genome, they offer new lessons about the virus that might not have been learned because of the wide scope of the outbreak, larger than all others combined.

The mutations do not threaten the many vaccines in development that are designed to limit the spread of the virus and prevent future outbreaks, scientists said. While Ebola is a type of virus that is prone to genetic variation, it is unlike the flu virus, which is hitting harder in the United States this year because mutations have made the flu vaccine less effective.

But the research could inform efforts to test and develop drugs used to treat Ebola, said Gustavo F. Palacios, director of the Center for Genomic Sciences at the U.S. Army Research Institute of Infectious Diseases at Fort Detrick.

"It could work that even these changes might not have an effect on the way the drug does its job, or it could be that there is a difference in the efficiency of the drug with the mutated strain," said Palacios, a senior author of the study, published in the journal mBio.

The scientists used recent research on the outbreak to map mutations to the virus' genome, made up of 19,000 pairs of genetic building blocks.

The virus changes slightly as it is transmitted from human to human because each time it replicates, it is prone to genetic errors, said Alan Schmaljohn, a professor of microbiology and immunology at the University of Maryland School of Medicine who was not involved in the research. Mutations are common in viruses such as Ebola, which replicate using RNA rather than DNA to code their genetic makeup, and typically gain a foothold or fade away through Darwinian survival of the fittest, he said.

In this case, the virus is believed to have emerged in Guinea after being transmitted from an animal, likely a fruit bat. More mutations are expected in the virus when it jumps from one species to another, Schmaljohn said.

As a result, the virus circulating in West Africa is slightly different from those in previous outbreaks, he said.

While it is considered to be a strain of virus known as Ebola Zaire, it has been given its own name — Ebola Makona. It has slight differences from strains that emerged in Africa in 1976 and 1995 and formed the basis of much of what had been previously known about the virus. It has sickened nearly 22,000 people and killed more than 8,600 of them in West Africa since December 2013.

The differences between the viruses are small, but could create big problems for researchers developing drugs. Those like ZMapp work by binding to specific sections of the virus and preventing it from replicating. But the mutations could alter those key sections of the virus, making the drugs ineffective.

ZMapp is being developed by Mapp Pharmaceutical in San Diego, which could not be reached for comment. Other drugmakers are developing similar treatments.

While ZMapp was given to a handful of Ebola patients, it is not clear whether the drug played a role in the outcomes of their cases.

Such drugs require precision to be effective.

"A very small mismatch at the level of nucleic acids will defeat it," said John Eldridge, chief scientific officer of Profectus BioSciences, a Baltimore biotechnology company that is helping to develop and manufacture an Ebola vaccine.

Vaccines, on the other hand, are not expected to be hampered by the mutations because they produce an immune response based on the body's recognition of Ebola's larger external structure, Eldridge said. Many vaccine candidates, including one developed by the National Institutes of Health and GlaxoSmithKline and being tested on humans in Baltimore, works by tricking the immune system into thinking a harmless cold-like virus is Ebola because it is engineered to contain an Ebola protein.

"If one particular site mutates, you might have defeated a portion of the response engendered by the vaccine, but the remainder is still in place," Eldridge said.

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