Today, a highly controversial study in which researchers synthesized a smallpox relative from scratch is finally seeing the light of day. The paper, in PLOS ONE, spells out how virologist David Evans at the University of Alberta in Canada, and his research associate Ryan Noyce ordered bits of horsepox DNA from the internet, painstakingly assembled them, then showed that the resulting virus was able to infect cells and reproduce.
The study stirred alarm when Science first reported it in July 2017 because it might give would-be terrorists a recipe to construct smallpox virus, a major human scourge vanquished in 1980. And now that it's out, many scientists say the paper doesn’t answer the most pressing question: Why did they do it?
The team claims its work, funded by Tonix, a pharmaceutical company headquartered in New York City, could lead to a safer, more effective vaccine against smallpox. But safe smallpox vaccines already exist, and there appears to be no market for a horsepox-based replacement, says virologist Stephan Becker of the University of Marburg in Germany. “It simply does not add up,” Becker says. Given the apparent lack of benefits, publishing the paper was “a serious mistake,” says Thomas Inglesby, director of the Center for Health Security at the Johns Hopkins University Bloomberg School of Public Health in Baltimore, Maryland. “The world is now more vulnerable to smallpox.”
A spokesperson for the journal’s publisher, PLOS, wrote in an email that a committee on “dual use research of concern” at the journal unanimously agreed that the benefits of publication, including “the potential improvements in vaccine development” outweighed the risks. But Inglesby says that given its implications, national and global health authorities should have approved the work; currently, there is no requirement for such a review. “This ought to be a wake-up call for science agencies and governments,” Inglesby says.
If anyone wants to recreate another poxvirus, they now have the instructions to do that in one place.
Vaccination against smallpox ended worldwide in the 1980s, and most people have no immunity. Experts worry that the virus that causes it, variola, could be used in an act of bioterror or biological warfare. The last samples of variola are kept under tight security in Russia and the United States. But the paper could provide another route for terrorists or other bad actors.
World Health Organization recommendations ban the synthesis of variola’s full genome, and ordering its DNA might be difficult because some synthesis companies screen their orders. “This is not something that can be done tomorrow in any lab,” says Gregory Koblentz, a biodefense expert at George Mason University in Arlington, Virginia. The horsepox virus itself, thought to have gone extinct in nature, is not known to cause human disease.
But over time, other labs will adopt the technique used to make it and gain the ability to recreate smallpox as well, Koblentz says, “and that just creates a huge vulnerability.” “If anyone wants to recreate another poxvirus, they now have the instructions to do that in one place,” says Andreas Nitsche of the Robert Koch Institute in Berlin.
The work arose in part from Tonix CEO Seth Lederman's fascination with Edward Jenner, the English physician who invented the first smallpox vaccine in 1796. Lederman, who says he’s “obsessed” with Jenner and has been working on a biography of the scientist for 20 years, is convinced that Jenner’s original vaccine, now named vaccinia, was derived from a virus circulating in horses, not cows, as folklore has it. “Jenner essentially says that” in his famous paper “Inquiry into the Causes and Effects of the Variolae Vaccine,” Lederman says. A genetic analysis published in October 2017 strengthened his case, he says.
In a conversation about one of Evan’s earlier vaccinia papers, Lederman told Evans that he’d love to know whether horsepox still works as a vaccine, but that he had had trouble getting hold of the virus. The only known samples are stored at the U.S. Centers for Disease Control and Prevention, which would not give permission for them to be used commercially, Lederman says.
“I think if you’re really interested in that, I know how to make it,” Evans says he responded. Tonix provided about $100,000 for the project, and Lederman became a co-author on the paper.
Vaccinia can cause a serious rash and inflammation of the brain and the heart muscle; it's especially dangerous for immunocompromised people. It has been estimated to kill between 1.4 and 8.4 people per million recipients, depending on the strain. Lederman believes that may be because the horsepox virus used by Jenner evolved during the almost 180 years it was used, racking up mutations that made it better at replicating in humans, which led to more serious side effects. A virus closer to Jenner’s vaccine might be safer and more effective, he argues.
But safer vaccines are already on the market. Bavarian Nordic, a German-Danish company, produces a weakened vaccinia strain called Modified Vaccinia Ankara (MVA) that doesn’t replicate in humans. It was originally developed by the Bavarian government and given to 150,000 German children in the 1970s; it has proved safe in more recent trials on HIV-positive people and stem-cell transplant patients. The European Union and Canada have licensed MVA, and U.S. regulators are expected to follow suit this year. The U.S. government has already stockpiled 28 million doses and signed an option for 13 million additional doses last September. U.S. government agencies “have been signaling for many years that we are not going to invest in a whole new smallpox vaccine,” Koblents says.
In the paper, Evans and his co-authors don't discuss MVA, or a similar vaccine developed in Japan named LC16m8, which “makes no sense to me,” Becker says. But Lederman argues that MVA’s efficacy was never properly tested because it was developed when smallpox was already very rare. Using it in a real outbreak would be “taking a huge uneducated guess with the health of an entire country’s population,” he says. “We believe there is more historical evidence supporting the efficacy of horsepox or horsepoxlike vaccine.” Tonix has already shown that horsepox can protect mice from an otherwise lethal dose of vaccinia, he says, and is investing in production of the virus under the strict conditions that would allow human trials.
Whether the world really needs another smallpox vaccine is a crucial question, says Diane DiEuliis, a biosecurity consultant at the National Defense University in Washington, D.C. “I would have liked to see an open debate about that at the outset of these experiments.”
Evans, for his part, says he "was far more interested in advancing the technology” than in developing a vaccine. Creating poxviruses from scratch could help answer basic questions about their biology, for instance about the role of so-called hairpin structures at the end of the genome, Evans says. Besides, “It's a very powerful technology and I do see there being lots of applications for it,” he says, for instance in the design of cancer-fighting viruses.
Lederman and Evans disagree that the publication makes the world less secure. The work could aid preparedness by showing that synthetic smallpox, long a theoretical concern, is a real possibility, they say. On that point, at least, Nitsche agrees. “For that reason alone, it’s good someone has finally done this.”