As the SARS-CoV-2 pandemic enters a third calendar year, the Department of Health and Human Services is poised to make key decisions about future access to the pathogen. This moment in history may prove to be an important inflection point in the regulation of emergent pandemic pathogens and is an occasion for careful reconsideration of the decision-making process. While regulation plays an important role in securing against accidental or intentional release of biological threats, missteps resulting in overregulation could stymie scientific progress, leading to deficiencies in public health preparedness and security infrastructure in the long term.
Today’s list of the most dangerous biological agents, which is key to regulating their possession, use, and transfer, first took form in 1996 as a list of “select infectious agents” proposed by the Working Group on Civilian Biodefense. Throughout its history, the list has served as a mechanism for bolstering the biosecurity of the United States by preventing unauthorized access, theft, loss, or release of dangerous pathogens and toxins. This is orchestrated by the Federal Select Agents Program (FSAP), which rigorously reviews individual and laboratory requests to possess and work with restricted agents. In addition, the regulations guide regular inspections of laboratory facilities and protocols, review of import and transfer requests, and penalties in the case of failure to meet standards (see box below). Over time, the type and number of agents included have changed, and today’s list contains 67 pathogens and toxins. The addition of a new agent is relatively unusual; however, it is reasonable to assume that additions of the future are likely to be emergent diseases with significant risks to global health security.
Picking and choosing
At first blush, SARS-CoV-2 may seem to fall squarely into this category. If added to the select agents list, it would be the first novel pandemic pathogen added since its close relative SARS-CoV-1 was included in 2012. But the decision isn’t as simple as it may appear. Not every dangerous pathogen that emerges makes the list—for example, another deadly coronavirus, Middle Eastern Respiratory Syndrome-related coronavirus (MERS-CoV), was discovered in 2012 but has not been added. And pathogens including HIV and the bacterium causing tuberculosis, two diseases that represent a considerable proportion of the global infectious disease burden annually, have not made the cut, either.
Clearly, criteria beyond novelty, pandemic potential, and total fatalities factor into whether an agent is “select.” But these factors are not as clearly defined as one might think. Four general criteria were determined by the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, which considers the virulence or toxicity of an agent, its mode of transmission, and the availability of treatments. But from a critical analysis of agents on the list, it’s apparent that further, unwritten factors are routinely considered, which confuses an already obfuscated process. In 2010, the National Research Council more carefully described the actual criteria that appear to be used, based on the agents on the list currently, and this analysis expanded the considerations to include the ability to produce and disseminate the agent at scale, the public’s perception of the microorganism or toxin, and previous reports of bioweapons research on the agent. The Department of Health and Human Services (HHS) has not clarified its official criteria in response.
There is a reason for this lack of transparency: it is the general stance of the US government that the exact deliberations behind an agent’s inclusion or exclusion is information that, if public, would pose a risk to national security. But obfuscation of how agents become select and a dearth of clear guidelines and metrics for evaluating the effectiveness of the attendant regulations has frustrated many in the scientific community. Some see the list as an obstacle to biosecurity advancements that ultimately leads to negative effects, such as the destruction of invaluable microbial collections and the shuttering of important research programs. These effects have stemmed from a variety of restrictions, most notably burdensome transport logistics, reporting rules, and the massive security and safety installation costs necessary to make a laboratory compliant for work with a select agent.
Chimeras, criteria, and coronavirus
As a first step in addressing whether SARS-CoV-2 deserves select agent status, HHS has presented an interim rule in the Federal Register that seeks to add chimeras combining features of SARS-CoV-1 and SARS-CoV-2 to the select agents list. This is in line with the stance of the government to carefully review and often limit dual-use research of concern, and in particular, gain of function research. However, in our estimation, such chimeric viruses are already regulated by the Code of Federal Regulations, which restricts access to “HHS select agents and toxins . . . that have been genetically modified.” This newly proposed regulation is therefore duplicative and unnecessary.
The natural next question is: Should SARS-CoV-2 be added to the select agents list? Such a decision seems premature, at best. It is worth noting that the addition of SARS-CoV-1 took nearly a decade, and was a contentious choice even then. At the very least, more time is warranted to determine whether SARS-CoV-2 meets the full range of criteria for selection, particularly in regard to whether it could be a desirable candidate for bioweapon development by nefarious actors. Further, the situation begs for the government’s reconsideration of the criteria themselves, both stated and presumed. How dynamic do the criteria allow the security community to be in the face of emergent, novel pathogens, which may represent the clearest examples of the select agents of the future? What improvements can be made in the clarity and stringency of such criteria to enhance scientific progress on protective measures without risking national security? And to similar ends, should we establish clearer and more transparent guidelines for future addition and removal of listed agents?
Our position is that regulation of an emergent pathogen is not in the best interest of public health during an ongoing pandemic, and we argue against regulation of any material that may play a role in development and promulgation of necessary biological technologies for preparedness and mitigation efforts. To support this position, we have evaluated SARS-CoV-2 using the National Research Council criteria, and from this analysis, can come to some general conclusions, presented in the table below.
Fit of the National Research Council's agent selection criteria to SARS-CoV-2
Virulence, pathogenicity, or toxicity of the organism; its potential to cause death or serious disease
Clearly met and is likely to remain a risk for a significant period of time
Availability of treatments such as vaccines or drugs to control the consequences of a release or epidemic
Will clearly present lower risk in the near future as a result of mass vaccination campaigns, concomitant protection from vaccination and natural infection, other emerging therapeutic approaches, and general public health precautions like isolation and quarantine
Transmissibility of the organism; its potential to cause an uncontrolled epidemic
Ease of preparing the organism in sufficient quantity and stability for use as a bioterrorism agent; for example, the ability to prepare large quantities of stable microbial spores
Relate more specifically to bioterrorism concerns that are difficult to assess currently. It is still too early to determine the possibility of preparing SARS-CoV-2 at scale, and while ease of dissemination would appear to be high due to natural transmission dynamics, considerations that exclude criteria 2 and 3 will similarly temper this as a risk factor
Ease of disseminating the organism in a bioterrorism event to cause mass casualties; for example, by aerosolization
Public perception of the organism; its potential to cause societal disruption by mass panic
Remains a risk factor, but this is likely to wane precipitously in the near term as infections become less severe and common
Known research and development efforts on the organism by national bioweapons programs
While some have claimed that SARS-CoV-2 originated in a laboratory, until data is presented to support these claims, we determine this risk to be inapplicable
SARS-CoV-2 appears to soundly fit only one of these seven criteria, and it is too early to determine whether ongoing biomedical research and public health efforts will successfully alleviate the concerns put forth in three others. While there is not a defined threshold for how many criteria an agent must meet to be selected, there are other pathogens that better fit these criteria which are not on the list. As an example, HIV meets criteria 1, 2 (partial), 3, and 7 more than 35 years after its discovery and has still not been designated a select agent. This illustrates that even these expanded criteria fail to encompass all of the factors that go into government decision-making, in large part because they are undisclosed.
Regulations, refinements, and ramifications
Ultimately, the decision about whether SARS-CoV-2 is named a select agent has broad implications for the scientific and policy communities. Regulation in this manner would severely restrict access to clinical and field samples, and would result in a mass destruction and consolidation campaign the likes of which may rival the one ongoing for polio, which, though not a select agent, is the subject of an $5.1B eradication effort that includes destroying most samples of the virus and restricting others to certain well-secured labs. Such a campaign for SARS-CoV-2 would have economic ramifications that, while perhaps not debilitating for individual laboratories, are clearly burdensome. But more importantly, these burdens would translate to unavoidable losses in research productivity, which may ultimately harm public health security both in the US and globally. In particular, the development of therapeutics and the acquisition of fundamental knowledge about coronavirus biology could be hobbled.
These concerns are echoes of the past; the scientific community has voiced them before, when SARS-CoV-1 was under consideration for addition to the select agents list. As a biosecurity community, we must seriously consider whether the decision to make SARS-CoV-1 a select agent was connected to, and partly responsible for, the world’s vulnerability to SARS-CoV-2. If we are honest with ourselves about the likelihood that it was, we should take pause at the prospect of similar, rippling regulatory ramifications this time around.
A brief overview of requirements for laboratory research on select agents