The grand challenge of pandemic preparedness is how to develop and maintain a proactive stance against a foe whose current identity and timeframe of attack is unspecified. The sea of microorganisms that can inflict harm on humans is vast and every changing. It reminds of the problem faced in the world of The Three Body Problem: preparing for the unspecified alien threat that is coming at sometime in the future.
However, amongst the plethora of microorganisms that have the capacity to pose pandemic level threats to the human species in the modern era, several characteristics are prerequisites. Disease X, the conceptual tool being used to foster proactive pandemic preparedness, should be informed by the fact that a pathogen’s ability to constitute a pandemic threat will be constrained and grounded by its biological attributes. As previously outlined and argued for in a project I led that aimed to derive pandemic preparedness first principles, the essential attributes of such a pathogen will include:
1. A viral etiology
2. Predominant and efficient respiratory/airborne mechanism of transmission
In the absence of these two factors, pathogens may rise to epidemic status and be regionally disruptive but will fall short of the pandemic threshold.
Historically, pandemic potential status was reserved — almost exclusively — for influenza viruses. Pandemic preparedness was considered to be synonymous with influenza preparedness. This equivalence was not without basis as the only occurring pandemics for almost a century (spanning from at least 1918 to 2009) were all caused by influenza A viruses. However, this solo focus on influenza constituted an unwarranted freezing of the concept of pandemic pathogen in the mind. The advent of SARS—CoV-1 in 2003, MERS-CoV in 2012, and, most recently and obviously, SARS-CoV-2 in 2019-2020 highlighted, in dramatic fashion, how a non-influenza virus could not only pose a pandemic threat but foment one.
An alternative approach is to focus pandemic preparedness on pathogens that possess the requisite traits by mapping those traits onto the known viral families. Of approximately 2 dozen viral families that are known to infect humans, there are 6 that warrant special attention. These families are:
1. Orthomyxoviridae (the influenza virus family)
2. Coronaviridae
6. Adenoviridae
These viral families all include members that have the capacity for efficient human-to-human spread via the respiratory route, seasonal endemic members, and zoonotic analogues.
Honing pandemic preparedness activities to focus on these 6 viral families serves as a razor or an operative principle to simplify the task by focusing efforts on areas with the highest yield. As such, it is akin to a lens or conceptual tool with which to survey the microbial world. As such, this lens will, by necessity, include certain viral families (some of which such as the adenoviridae that have been completely discounted as pandemic threats) and exclude others.
In the wake of the rise of the coronaviridae as a pandemic threat, several groups have adopted the term “prototype pathogen” as a mechanism to facilitate work in viral families on a specific member that could serve as the basis for further accelerated work if a pandemic was incited by a member of that family. This approach is correct however its full impact is diluted as there is a tendency to focus — not just on the 6 respiratory viral families — but on all the 24-25 extant human infecting viral families, conflating outbreak, epidemic, pandemic, and as Osterholm has identified, pathogens of critical regional importance.
Moreover, even while better approaches have supplanted prior thinking and created an improved paradigm that recognizes preparedness should be focused on viral families in addition to specific agents, it must be protected from the tendency to slip into the familiar mode of making lists of pathogens that are members of the high consequence viral families.
Specifically, it is not necessarily the case that a pandemic pathogen will be a known human pathogen in a viral family. For instance, it is unlikely that parainfluenza virus 1 will develop pandemic potential in the future. What is more likely to be the case is that a fellow member of the viral family that includes parainfluenza virus 1, one that is infecting animals and not currently causing documented infections in humans, could acquire the capacity to cause a pandemic in humans. Similarly, Nipah virus has been infecting humans with some regularity yet not risen to pandemic level. This phenomenon suggests that it is not Nipah, but perhaps a Nipah-adjacent henipavirus that is the true pandemic threat. The epidemiological history of the sarbecovirus coronaviruses SARS-CoV-1 and MERS-CoV juxtaposed to their relationship to the pandemic causing sarbecovirus SARS-CoV-2 is a concretization of this point.
As such, a pandemic threat will be most likely to emerge from a zoonotic member of those respiratory viral families whose other members are well-characterized and/or ubiquitous human pathogens.
This means that working on list of known human pathogens in these viral families too narrowly focuses the scope of pandemic preparedness. It is undoubtedly critical to work on Nipah, for example, but not only because it is a threat in itself but also because a related virus that may be exclusively in bats today may emerge. If a Nipah vaccine becomes available, it will not necessarily remove the threat of a Nipah-like virus (although it would lessen it if there were cross protection and provide critical information for targeted vaccine development). It is necessary to delve into the full breadth of the family, particularly its zoonotic potential members, and work to develop a pathophysiological understating of the family (including immune system targets, organ tropism, etc.) and to develop countermeasures that have impact on one or more family members.
An optimized viral family approach to pandemic preparedness recognizes that well-characterized human-infecting members of respiratory viral families are the most likely pandemic threat. While it is a truism that a pandemic viral family will hail from the 25 viral families that have the capacity to infect humans. Once this prerequisite is met, however, it will be higher yield to pare the task down using the razor of respiratory viral families. The great conceptual value of this approach is that it is a means of systematically approaching pandemic preparedness.