The problem of horsepox synthesis: new approaches needed for oversight and publication review for research posing population-level risks

By Tom Inglesby

In summer 2017, a team of Canadian scientists revealed that they had synthesized the horsepox virus in a lab at the University of Alberta, and planned to publish their research. I and others expressed strong concern about the work at that time, and we have opposed its publication. 

Today, the science journal PLOS ONE published this research online, so it is now globally available. The horsepox researchers acknowledged that this work may lower the bar for other scientists interested in synthesizing smallpox. Before its eradication from nature in 1980, smallpox was humanity’s greatest infectious disease killer. Almost none of the global population in 2018 has effective immunity, and smallpox vaccine supplies are available only to protect a small fraction of the world. There are only two declared smallpox repositories, one in the United States and one in Russia. Any research that reduces the challenges of synthesizing smallpox de novo outside these repositories—as this work does—should be off limits unless, perhaps, there were to be extraordinary benefits that make the risks worth taking.

This work does not carry such extraordinary benefits. As Greg Koblenz has articulated in his paper on this issue, there is not a compelling case that governments will need or use this virus to develop a new and improved smallpox vaccine. Another justification made by the horsepox researchers was that it is important to demonstrate the feasibility of synthesizing smallpox de novo. But creating a new extraordinary risk (i.e., instructions for how to simplify smallpox synthesis) to show that the risk is legitimate is a dangerous path. In any event, relevant members of the science community have widely agreed that smallpox synthesis has been technically feasible for many years now. What this new research does is show the global scientific community how to synthesize orthopox viruses in an efficient way, to overcome technical challenges, and to employ techniques developed by one of the leading orthopox labs in the world.

Now, with this research published and accessible to the world, those of us who are deeply concerned about it should consider what is needed to prevent future events with such potential harmful impact. This horsepox synthesis research work has exposed serious flaws in how governments oversee research that has profound potential population-level adverse consequences. The University of Alberta research team admitted that regulatory authorities “may not have fully appreciated the significance of, or potential need for, regulation or approval of” their work. Clearly, fundamental changes need to be made. 

The most important locus of control should be whether specific research is approved and funded in the first place. When scientists are considering the pursuit of research that has the potential to increase highly consequential national population-level risks, national authorities and leading technical experts on those issues should be part of the approval process. When there are highly consequential international population-level implications, international public health leaders should also be involved. When researchers put forth claims about potential benefits of this work to justify extraordinary risks, those claims ought not be accepted without discussion; those claims should instead be examined by disinterested experts with the expertise to validate or refute them.

If research posing potential population-level risks does get performed without such high level national or international scrutiny, or without a disinterested examination of the benefits, publishers should have clear guidance from governments and a process for engaging with governments in the decision-making process regarding publication. That kind of system is not in place in the United States or elsewhere. Journals are now often on their own, in some cases with the help of a dual-use research committee that is comprised of individual scientists who may or may not have full understanding of the potential risks or the claims of benefits of the underlying research being published.   

We need to turn what we’ve learned from this damaging situation into actionable policies aimed at strengthening preparedness and global health security. The first step is changing the oversight and approval process for experiments that have potential to create highly consequential population-level risks. We also need a coinciding publication review system for such research with the scientific and government input necessary to avoid publishing research that increases risks to global populations.   

Honoring Vaccine Heroes

From: LEGO Ideas

From: LEGO Ideas

Over the next year, we have the opportunity to recognize some of the greatest public health achievements in history.  In 1796, Edward Jenner introduced to the world the smallpox vaccine (and the term “vaccination”), inoculating an eight-year-old boy with cowpox (vaccinia virus) and later showing the vaccination to be successful when the boy showed immunity to variola virus.  In addition to numerous other contributions to biology, Louis Pasteur administered an inactivated rabies virus to a boy bitten by a rabid dog in 1885 and demonstrated the efficacy of such a vaccine, pioneering the way for countless future immunization efforts.  In the face of a global polio pandemic, Jonas Salk followed in Pasteur’s footsteps and developed an inactivated polio vaccine, and efforts began almost immediately to quell the epidemic (and hopefully eradicate the disease).  In 1980, the WHO under the leadership of D.A. Henderson completed what Jenner began and declared smallpox eradicated, accomplishing what is arguably the single greatest feat in human history.

Little did these giants of public health, upon whose shoulders we stand today, know that they would one day be nominated for one of the highest honors to which man can be bestowed.  They have the opportunity to stand beside countless other legends in the echelon of recognition reserved for only the most influential of figures.  In the annals of history, the names Jenner, Pasteur, Salk and Henderson could be found right alongside the likes of Michelangelo; Cinderella; Admiral Ackbar; and Tank Top with Surfer Silhouette, Red Short Legs, Reddish Brown Ponytail and Swept Sideways Fringe Female Hair…immortalized as LEGO men.

Vaccine Heroes, a recent submission on the LEGO Ideas website, seeks to acknowledge the historical efforts of these public health pioneers in a series of LEGO vignettes.  Jenner is portrayed alongside a fair-skinned milkmaid; Pasteur is in his laboratory, ready to vaccinate rabies case Joseph Meister; and Salk stands at his transmission electron microscope, working diligently on his poliovirus vaccine.  The series culminates with a panorama of D.A. Henderson’s efforts leading the WHO Smallpox Eradication Program, complete with African scenery, animals and grateful natives.  Keep your fingers crossed that LEGO is willing to produce a historically accurate bifurcated needle to complete the set!

The submission needs 10,000 votes over the next year to be eligible for production.  You do have to create an account to vote, but just like a shot, the pain is minimal.

With the development of Ebola vaccines and the recent reemergence of vaccine-preventable diseases like pertussis and measles in the United States, now seems like an ideal time to promote the success of historical vaccination programs and pioneers.  If produced, this LEGO set will provide disease nerds and children of all ages with inspiration to investigate and celebrate these public health success stories!

D.A. and the WHO may have been counting down to zero, but we’re all counting up to 10,000!  Let’s get this project going viral!

Smallpox’s State of Affairs

While it may seem odd to write about and take note of popular culture references to infectious diseases, I believe it is an important activity because these references serve as bellwethers for the general public’s view of these issues. During the recent Ebola outbreak, for example, it seemed clear that the public was reacting not just to the facts, but was also influenced by the frightening plots of the movies Outbreak and World War Z. Understanding how the public views certain infectious diseases pre-event is key to crafting effective risk communication strategies as well as anticipating issues that may arise

The latest episode of NBC’s CIA drama State of Affairs portrayed a smallpox outbreak in Panama sparked when vials of the virus at an old US research facility are broken during an earthquake. This is detected when a Department of Defense sniffer plane detects the virus during a fly over and sparks a robust US response. Many individuals are exposed and a vaccination plan is implemented.

Notwithstanding the reality of the sniffer plane component of the story, any case of smallpox anywhere in the world represents a grave public health emergency, as this is a disease that no longer circulates naturally. Therefore any case would have to be the result of an accident or a deliberate act of biowarfare.

Smallpox was eradicated from the planet—thanks, in part, to the bifurcated needle—decades ago and shortly thereafter samples of the virus were to be destroyed or consolidated at one of two laboratories: the CDC in Atlanta and Vector in Russia. However, given the discoveries at the NIH earlier this year, we know that samples existed outside of those two laboratories. Incidents such as occurred at the NIH and are fictionally depicted in State of Affairs reinforce the importance of threat reduction via ensuring that the appropriate biosafety measures are meticulously followed when storing and working with deadly pathogens such as smallpox.

Another aspect of smallpox, which made it eradicable, is that the vaccine can be effective as post-exposure prophylaxis if administered while the virus is incubating. Such vaccination, while not as effective as pre-event vaccination, can help staunch a burgeoning outbreak.

Overall, State of Affairs got the major issues of smallpox right during the episode—hopefully reflecting more than a modicum of understanding by the public of this naturally extinct virus.