Dangerous Proposal for “Gain of Function” Modification of Smallpox Virus Must Never be Approved



(23 to 28 May 2016, Geneva)
Dangerous Proposal for "Gain of Function" Modification of Smallpox Virus Must Never be Approved

In 2014-15, the World Health Organization’s scientific committee overseeing smallpox virus research, the ACVVR,(1)  turned down three projects proposed by United States scientists to use live smallpox (variola) virus.  The report of the ACVVR (WHO/OHE/PED/2016.1) does not describe what these proposals were.

It has come to light in a documentary film(2) released by the New York Times on 18 May, however, that at least one of those projects was a proposal to create a new and very dangerous form of smallpox virus that is adapted to monkeys, through a technique called "serial passaging".

The smallpox serial passaging proposal fits within a controversial class of studies called "gain of function" experiments, that is, research in which a pathogen is deliberately induced to acquire dangerous new characteristics, such as enhanced virulence or – as is the case here – an expanded host range.

It is extremely important that WHO Member States at the 69th World Health Assembly draw attention to the fact that the ACVVR acted correctly to deny this proposal, and to emphasize in plenary and other discussions that all gain of function research with smallpox is prohibited, whether it is based on serial passaging, biotechnological, or other techniques.

Why is the US proposal to create a novel monkey-adapted smallpox so dangerous?

1.         Creation of an Animal Reservoir

Under natural circumstances, smallpox only infects humans.  This was a key factor aiding the success of the WHO Smallpox Eradication Program, making smallpox the only disease to date that has been successfully eradicated in the wild. Because smallpox virus does not naturally infect other animals, once smallpox was eliminated from the human population, outbreaks ceased to occur. People were no longer exposed to sources of the virus in the environment, unlike what happens with many other dangerous viruses such as Ebola (monkeys), MERS (camels), SARS (bats), and Zika (monkeys).

Monkeys can only be induced to develop smallpox disease under unnatural laboratory conditions – by extraordinarily high doses injected intravenously, sometimes in combination with aerosol exposure.

In order to create a new smallpox virus that is adapted to monkeys by serial passaging, scientists would infect one monkey with a massive dose of human smallpox, and then take the virus from that monkey and inject it in another, and so on, over multiple generations, until the virus strain changed in ways such that it more readily infected monkeys. Quite possibly, such a virus could be casually transmitted between monkeys and could have novel characteristics in other mammals, including humans.

The US scientist proposing the research rationalizes that a novel serially passed monkey smallpox is a good idea for development of vaccines and drugs, but sufficient vaccines and drugs already exist, and have or are on-track for regulatory approval without need for such a virus.
If a monkey-adapted smallpox virus were to escape laboratory containment, by an accident or deliberate act, the result could be the creation of a smallpox natural reservoir where none presently exists.  If a natural reservoir of smallpox virus existed decades ago, the WHO Eradication Programme might never have succeeded.

2.         Unpredictable Results for Human Disease

How would a monkey-adapted smallpox strain behave in humans? The answer cannot be known without infecting humans, something that, of course, is an ethical impossibility.  So creation of monkey-adapted smallpox will exacerbate one of the key problems WHA has encountered trying to reach consensus on destruction of smallpox virus stocks – the dog-chasing-its-own-tail phenomenon in smallpox virus research.

New research projects like this proposal breed new man-made "what ifs?" prompted by the research itself, and although the public health needs for smallpox virus identified by WHA are satisfied and WHO public health experts have concluded the virus should be destroyed, this sort of experiment prompts arguments from a small group of smallpox researchers for more research.  Arguing that monkey-adapted smallpox is distinct from other strains, they might say the monkey-adapted strains create the need for a new round of research in and of themselves.

But as DA Henderson, who led the WHO Smallpox Eradication Programme, has remarked, the less that is done with smallpox virus today, the better off humanity is – particularly considering the several licensed, effective vaccines, rapid and accurate diagnostics, and antiviral drugs that already exist.  Indeed, it would be supremely ironic if experiments to create a novel monkey smallpox were used to mount campaigns to do more vaccine and antiviral research targeted at the "threat" of this or other novel man-made strains.  The dog chases its own tail – but in this case, the dog might bite us all.

3.          Tinkering Where We Should Not

Serial passaging gain of function experiments with potentially pandemic influenza viruses have been hugely controversial in the scientific community, and even the US government has placed a moratorium on funding them, due to concern over the dangers they pose.

While the controversial arguments in favor of taking viruses like H7N9 influenza and making them more transmissible in mammal models of humans are debated, proponents of such risky research can say that H7N9 exists in nature and might naturally change its host range or virulence. (However, it is a separate question if changes done in a laboratory would be sufficiently predictive of those that occur in nature, and hence useful for public health.)

But a disease like smallpox – eradicated in the wild for almost 40 years – has no existing reservoir and no existing victims, human or animal (except in laboratory experiments).  So the argument that a changed smallpox virus could emerge from nature does not exist.

Arguably one would have to be insane to deliberately adapt Zika virus to be hosted by household pets, or Ebola to readily infect pigs or other farm animals. The dangers of such an approach are especially clear due to recent alarming outbreaks.  What if it got out?  What could justify such a terrible risk of creating new natural hosts for the human disease?

Yet this approach is what the US has proposed for smallpox. The argument for doing gain of function research in the case of smallpox is even weaker than that for other diseases, yet because smallpox has not been seen in humans in decades, the implications of serially passaging it to adapt to a new species may not seem as clear as they are for, say, Zika.

The bottom line is that deliberately adapting / expanding the host range of any pathogen that has human pandemic potential – be it influenza, Ebola, Zika, MERS, SARS, or others – is extremely scientifically and ethically controversial and due to extraordinary public health risks this is something that should not be done.

If the WHO and the WHA were to approve gain of function experiments with smallpox, WHO’s endorsement could trigger a horrible panoply of gain of function experiments with other pandemic viruses, creating and amplifying public health risks from dangerous research the world over.

Action at the WHA

The US government scientist proposing smallpox gain of function research is disgruntled at the ACVVR’s rejection of his proposal and has pledged to keep trying to gain approval for such experiments. The scientist still believes his idea to perform gain of function studies on smallpox is "brilliant", despite WHO’s rejection:

"I actually came up with the idea, I still think this is a brilliant idea," said Peter Jahrling, a US government biodefense scientist, "Let’s take virus from an infected monkey and use it as the inoculum for another round of monkeys. I proposed this to the World Health Organization."

Jahrling then described WHO’s reaction to his proposal, in a tone arguably mocking the Organization, saying that WHO answered "’Oh no, you can’t do that, you’re modifying the virus, that’s forbidden … that’s a no-no, and you’re adapting it to another host … The reason the virus was eradicated from the planet was that it’s uniquely adapted to humans, and now you want to adapt it to monkeys? You can’t do that."

Does Jahrling accept WHO’s judgment? He defiantly told filmmaker Errol Morris, "I’ll stop when it’s a success, and I can feel that my career was a success, but I don’t feel I’ve succeeded yet.(3)   

Therefore WHO Member States at the 69th WHA need to make very clear in plenary that the ACVVR acted correctly to reject the proposal to serially passage smallpox in monkeys, and that any gain of function experiment with smallpox virus, i.e. one that could lead to changes in the viruses host range or an increase in infectivity or virulence, will not be approved under the WHA-authorized research program.

Indeed, the Advisory Group of Independent Experts to review the smallpox research programme (AGIES) has concluded that there is no public health need for any research utilizing smallpox virus to continue, much less the especially dangerous new experiments that have been proposed.

Thus, fixing a destruction date for smallpox virus remains an urgent priority. The sooner the WHA acts on the conclusion of the AGIES that no public health reason remains to retain the viruses and that the WHA-authorized research program has reached its conclusion, the less chance there is for future risky experiments that threaten the world.

For more information please contact:
Edward Hammond (
1.  The ACVVR is the WHO Advisory Committee on Variola Virus Research
2.  Morris E 2016. The Demon in the Freezer. New York Times. 19 May. (A documentary film "video editorial") URL: http://www.nytimes.com/video/opinion/100000004412128/)
3.  ibid.Peter Jahrling interviewed by Errol Morris.  Jahrling’s admission of career interest is striking. For a number of years, Third World Network has argued that demands for continued smallpox research have become unacceptably intertwined with the personal aspirations of a small number of virologists specializing in orthopoxviruses, a link that Jahrling acknowledges.

Dangerous Proposal for “Gain of Function” Modification of Smallpox Virus Must Never be Approved

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