The Ultimate Resource

  “The main fuel to speed the world’s progress is our stock of knowledge, and the brake is our lack of imagination.” — Julian Simon

“Man cannot survive except through his mind. He comes on earth unarmed. His brain is his only weapon.” — Ayn Rand

“All men by nature desire to know” — Aristotle

 All of us have heard that 99% of the species that have ever existed on Earth are now extinct. Extinction events occur for myriad reasons, one of which could be an outbreak of an infectious disease. While there are countless portrayals of end of day scenarios in Hollywood movies and television programs, many of their post-apocalyptic worlds bear little resemblance to what could really occur with a large infectious disease outbreak amongst humans (as opposed to Christmas Island rats).

 The most famous extinction event is, of course, that of the dinosaurs 66 million years ago. Though we tend to associate it exclusively with dinosaurs, the truth is that three quarters of animal and plant species perished during this period, formally known as the Cretaceous-Paleogene extinction event. The leading hypothesis, which has amassed enough supportive evidence to reach the level of a theory, points to an asteroid impact. Still, it is important to note that the impact alone, rather than cause mass extinctions, would have created changes in planetary conditions that made life impossible for those species unable to adapt to a markedly different habitat.

 Such a cataclysmic result is not surprising, since many species had not developed resiliency mechanisms to cope with a major habitat change. Natural selection would not have produced superfluous traits (in the absence of an asteroid strike) on a large scale. The Cretaceous-Paleogene extinction event was a great culling, the survivors of whom had, by chance mutations, the characteristics that allowed them to survive.

 An interesting footnote to this event is the idea (theory) that drastic reductions of sunlight killed those plants that relied on photosynthesis for life, resulting in the proliferation of non-photosynthetic organisms such as fungi. If, like me, you try to find an infectious cause in every event, you may wonder if the increase of fungi led to widespread fungal infections, magnifying the devastation posed by the loss of nutritious vegetation relied upon by most species. Today, fungal infections annihilate species of reptiles and amphibians.

Whatever the mechanics, the Cretaceous-Paleogene extinction event is the most widely known of its kind. For many species – unequipped by evolution for changes in habitat, predator-prey relationship variations, and myriad other factors – micro-extinction events occur continuously.

As I have tried to sketch out throughout the book, there is a lot of reasons to be wary of infectious disease outbreaks but many reasons to believe that nothing fathomable could spell the end of our species—not Ebola, not bird flu, not HIV, and not COVID-19. While there is much we do not know about the microbial world and countless possibilities, one thing stays true: human beings are a resilient species, the most resilient.

In recent years the emergency preparedness community, of which I am a part, has made resiliency a buzzword that has crossed into the vernacular of the public. Resiliency refers to the ability to recover from some sort of shock whether it is a hurricane, a pandemic, or even the loss of your job. Resiliency, on a larger scale such as that of a city, speaks to the ability to get back to normal life after some major alteration in daily life and the same can be said of a species. Humans showed resiliency to the Black Death, to the HIV pandemic, and The Great Influenza; we are showing resiliency to COVID-19.

But what enables resiliency? Is resiliency just duct tape, batteries, and flashlights. Why is it that humans are the species that can cultivate resiliency as opposed to relying on instinct and genetic programming like other organisms do?

Humans have the ultimate resource: their conceptual consciousness, which is capable of abstract thought, long-range planning, and principled action. All those aspects make possible the foresight to buy duct tape and batteries. It is the human mind that makes possible all our technological marvels that allow real resiliency to inhere in the species. Vaccines, antibiotics, and even hospitals are components of the human species resiliency mechanism. In a manner of speaking, all this technology obviates the need of a biblical arc to protect us from doom and in another sense, we already exist in an arc-like environment.

 The other aspect of resiliency that is common to all organisms is our genetic makeup. Evolution is not a process that occurs arbitrarily, natural selection directs it. Natural selection is an exacting process that magnifies, over time, even the miniscule advantage one trait possessor has over another. Humans emerged from the battles of natural selection and possess certain attributes, such as the powerfully adaptive immune system, that suits them well for life on this planet. As Darwin’s grandfather Erasmus eloquently said, “All nature exists in a state of perpetual improvement.”

 Though, as I emphasized, we live on a planet—and have a body populated by— microbes, our evolution occurred in this context, and we have the means to flourish in such an environment. We not only flourish but we have evolved to enjoy a symbiotic relationship with bacteria in our bodies and in our environment. While I often emphasize the pre-industrial world human life as short and fraught with disease, humans survived in those times and their population grew even before Jenner’s development of vaccines and the antibiotic revolution.

 Part of our evolutionary heritage is our immune system, one of the most complex on the planet, even without the benefit of vaccines or the helping hand of antimicrobial drugs. This system, when viewed at a species level, has the ability to respond to almost any enemy imaginable with its adaptability. The immune system’s response capacity coupled to genetic variations amongst humans (such as genetic resistance to HIV and malaria) almost ensures that any infectious disease onslaught will leave a substantial proportion of the population alive to rebuild, in contrast to the fictional Hollywood versions.

 Natural selection favors traits that confer survival advantage. Humans, their immune systems, and their unique conceptual and volitional consciousness emerged out of an environment with myriad potentially lethal infectious disease-inducing microbes. While the immune system’s role can never be understated, an even more powerful protector is the faculty of consciousness. Humans are not the most prolific, quickly evolving, or strongest organisms on the planet, but as Aristotle identified, humans are the rational animals—and it is this fundamental distinguishing characteristic that allows humans to form abstractions, think in principles, and plan long-range. These capacities, in turn, allow humans to modify, alter, and improve themselves and their environments. Consciousness equips us, at an individual and a species level, to make nature safe for the species through such technological marvels as antibiotics, antivirals, vaccines, and sanitation. When humans began to focus their minds on the problems posed by infectious disease, human life ceased being nasty, brutish, and short. In many ways, human consciousness became infectious diseases’ worthiest adversary.

On my first trip to the Galapagos Islands, the area of the world that provided much of the data that Darwin induced the idea of evolution from, I spent hours in conversations with naturalist guides. In one such conversation, centering on Zika virus, he endorsed the view – with which I disagree –that humans should not seek to modify their lives in a way that interferes with natural selection. Not only do I disagree with this statement morally – I take human life as my standard of value – but the statement ignores the fact that our consciousness — a biological faculty that evolved with us — is a faculty that has the capacity to use nature to create city sanitation systems, vaccines, antibiotics, microscopes, and genetically modified mosquitoes. It is striking to need to emphasize that humans possess this remarkable form of consciousness as the very result of the natural selection the guide was saying humans should not interfere with. Exercising our consciousness is what has allowed humans to rise to the heights we have on this planet. So, allowing natural selection to work is just what is happening when we make vaccines, antivirals, and the like to promote our species’ well-being. So, when I, as an infectious disease physician, intervene on an illness I am not preventing natural selection from occurring I am exemplifying it.

While I have tried to defuse the fears surrounding certain diseases and direct attention to other threats, it is important to remember all the hypothetical caveats that are in place. While it is extremely intellectually stimulating to contemplate space microbes, dark matter attacks, and the like our chief infectious disease threats throughout time have come from the “known” categories. Even surprise infections like SARS and COVID come from a known viral family whose ability to cause a pandemic the former dean at an institution I am affiliated with presciently predicted decades earlier. There has not been a true unknown unknown outbreak and most of our dark matter infections and mysterious illnesses reflect our technological diagnostic limitations which the advent of a whole host of modern technologies are now increasingly illuminating. What was once mysterious will become routine, especially with the revolutionary advances in synthetic biology, nanotechnology, and systems biology.

 The above is not meant to allay all fears for to totally adopt a Panglossian viewpoint would be foolish—and dangerous. We do face countless infectious disease threats and if not handled appropriately severe calamity could, and will, ensue. From the rise of antibiotic-resistant bacteria to the explosive nature of widespread foodborne outbreaks to the looming threat of pandemic influenza to the return of the primitive exemplified by the anti-vaccine and anti-pasteurization movements, humanity has more than its hands full in this realm.

 The Ebola outbreak in West Africa concretized for many in industrialized nations just what could happen if an outbreak burned out of control and teetered a society towards failure, but it need not be that way in Africa or anywhere on the planet.

 Just 6 years later, a novel coronavirus swept the world in a fashion not seen since 1918. Disruption, death, and divisiveness were what it wrought. However, pathbreaking vaccines were in arms in less than a year accompanied by monoclonal antibodies, home diagnostics, antivirals, and an explosion of knowledge about the novel virus’ epidemiology, clinical course, and treatment.

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We stand today on the shoulders of giants who have developed so many of the tools that enable the human species to flourish each year better than the last. We also live today amongst scientists and physicians developing the next generation of these tools that will stretch our ability even further. This never-ending quest to understand reality, which stretches all the way back to Thales, is the ultimate safeguard to any existential threat we might face. Paraphrasing a great philosopher, to save the world [from infectious disease] is simple, all one has to do is think.

Preparing for Disease X Proactively

Another chapter from my book project

Based upon what I have written in prior chapters, a focused approach to preparedness — even if nothing rises to an existential threat —is critical for to minimize the disruption and mortality that will occur with the inevitable infectious disease threats we face.

As I have argued preparation for pandemic — as opposed to outbreak or epidemic — by governments, non-governmental agencies, and other organizations threats should focus on those viral families most likely to cause a pandemic, as outlined in the prior chapter. Preparation translates into 2 major categories: surveillance/diagnosis and therapeutic/preventative medical countermeasures.

Biological Dark Matter

As we try to prepare for the next infectious disease emergency and decide how best to invest limited resources in early warning systems for detection of future viral threats, it is critical to prioritize surveillance activities that: (1) are most likely to uncover actual, rather than hypothetical, threats and (2) are practical and add value every day to preparedness, even between outbreaks.

Too often, our limited surveillance dollars are funding overly broad surveillance and basic analysis that includes a vast collection of animal samples with the goal of finding potential infectious diseases emanating from animals in spillover, or zoonotic events. Given the history of viruses such as SARS-CoV2, Nipah, Ebola, and HIV, zoonotic spillover events is a suitable priority. However, focusing our surveillance efforts on the constant sampling of animals can be like looking for a needle in a never-ending haystack. While this type of surveillance can play a part in early warning systems and it helps us to improve our understanding of disease in animal species, we should be careful not to place an overemphasis on viral cataloging efforts. These are, indeed, essential virological and scientific tasks but none should construe them to be synonymous with early warning or a substitute for pandemic preparedness activities.

We should complement the broad sampling of animal species with a more targeted type of surveillance focused on sampling of viruses present in patients in clinical environments. A microbe most likely to cause a pandemic or a disruptive outbreak is one that can infect humans now (even if only to a diminished extent). These are infections that are occurring in humans by pathogens that could do so now. Such a microbe may go unnoticed, mistaken for other causes, or occur in populations where diagnostic technology is not available. The pathogen may spread via the respiratory route and cause a respiratory infection such as pneumonia. It may also have characteristics that can cause a brain or central nervous system infection like meningitis. And, critically, it is likely to result in sepsis or septic shock as the final common pathway to severe disease and death.

These types of syndromes occur all over the world every day, even in the US. In some cases, we discover that the cause was a known pathogen such as pneumococcus, influenza, or the like. But most of these cases go without identification of the virus and without a specific diagnosis. The empiric treatment either works or it does not. This is something I commonly see in the hospitals in which I round in the Pittsburgh area--it is much more common internationally.

This passive status quo of our surveillance systems makes us much more vulnerable to infectious disease threats. This vulnerability derives from the fact that we lack full situational awareness of the microbial threats that we are facing now and will face in the future. Testing people already sick to aggressively pursue a specific microbiologic diagnosis is not only practical, but high yield as it aims at uncovering, not theoretical threats that have not yet materialized, but ones already present.

As I wrote earlier, I liken the undiagnosed syndromes to biological dark matter which holds key information about what is making people sick — some deathly — today, right now, everywhere. The first COVID-19 cases in Wuhan camouflaged in with influenza and, because the two syndromes are clinically indistinguishable, clinicians missed them. This caused weeks delay in digging into more about this emerging novel virus. Imagine having even a few weeks head start on this pandemic: it would have translated to even faster scientific understanding, faster medical countermeasures, less economic disruption. A few weeks would have saved lives. The first U.S. cases of the novel influenza H1N1 virus that sparked the last flu pandemic in 2009 became known only because the young children the virus infected happened to go to a medical facility that was part of a U.S. Navy study that strived to figure out what viruses were making people sick, even mildly sick.

In many international locations infectious disease diagnosis is based on a generic syndrome such as pneumonia and clinicians prescribe first line medications without a specific microbial diagnosis -- the organism responsible -- but arrived at by local epidemiology (what is common) and clinical presentation. While this is valuable and astute clinicians are extremely valuable it is not enough. For example, during the 2013-2014 West African Ebola outbreak it was often emphasized that West Africa had not seen Ebola before (save one isolated case in the Ivory Coast) but by analyzing blood samples of those thought to have another viral hemorrhagic fever, Lassa Fever, revealed Ebola had been present for over a decade mixed in with Lassa. Imagine how useful that information would have been when health authorities in Guinea took 3 months to realize it was Ebola they were dealing with and not some virulent form of cholera. Lives saved, epidemic curves bent, and spill into other countries prevented by an early warning followed by prompt containment strategies deployed successfully in every prior Ebola outbreak.

Whether what is lurking in the biological dark matter is the first human foray for an emerging pathogen, a change in behavior of a known pathogen, or an ordinary infection that went undiagnosed it is valuable information. We need to commit and spend more time diving deep to understand this dark matter. It is a no regret investment because it is most likely to uncover actual, rather than hypothetical, threats and it is practical adding value every day to preparedness, even between outbreaks.

This focus finds synergies with home testing for infectious diseases. Building on the momentum of COVID home testing, I have a vision of the future that includes a device in many people’s homes that allow them to swab their nose of throat and figure out if the symptoms that they have are due to COVID, influenza, RSV, strep throat, and other causes. This will improve antibiotic overuse issues, minimize contagion, and enhance surveillance, and provide vital intelligence. Imagine an outbreak of a respiratory pathogen in a city in which some proportions of people can test themselves for a variety of pathogens and it all comes back negative — that would be a signal that public health practitioners should pursue further investigation. It is much more precise than watching sales of cough and cold medicine at drug stores.

I also want to emphasize that to make these diagnostic capabilities routine does not require sophisticated futuristic machines. The technology and tools exist today, and clinicians are using them in healthcare facilities every day. In the past several years, technology has improved to such a degree that sophisticated molecular detection techniques such as PCR or the equivalent, that an untrained person can perform them at home. Diagnostic panels that check for a multitude of organisms all at once are not only available in an ordinary hospital lab, but even at the point-of-care. These machines exist now for routine use in many hospitals and medical facilities around the globe. Some of them are point-of-care requiring little training. As such, they will not need constructions of fancy labs but could be as simple as just augmenting diagnostics laboratories that already exist. The ability to improve routine infectious disease care will, as I have argued, naturally, also have major implications for early detection of all infectious disease hazards. The interconnection and dependency of U.S. domestic infectious disease response on international detection and characterization of COVID-19 variants such as Omicron, achieved through ordinary sampling of people ill with COVID-19, concretizes this fact.

Proactivity

In the past, much of medical countermeasure development for biosecurity and emerging infectious disease has been reactive. For instance, after the anthrax attacks of 2001, it became clear that medical countermeasures against biothreat agents were sorely deficient. The U.S. government put forth a concerted effort to remedy this problem. Bioshield, the name for this program, has been an unequivocal success. However, the model that this program used was based on a list of threat agents weaponized by the Soviet Union—it was reactive. For     emerging infectious diseases, there exists no definitive list of potential pathogens. Therefore, we cannot rely on this approach. If we want resiliency, we must push for more. In the prior chapters, I have sketched out what a proactive pandemic approach would amount to in a research and development agenda that is not exclusive to a particular virus, but to viral families.

It is also important to include medical countermeasures against common immune system pathways that trigger in people post-infection. These host-directed approaches aimed at the immune system have seen remarkable success with COVID-19. Potential threat agents also will also trigger these and similar pathways. Having medical countermeasures that focus on changing the aberrant dysregulated immune responses that various viruses set off  could provide early means of ameliorating some of the negative consequences of infection before more specific medications are available. The success of medications like dexamethasone and tocilizumab in the treatment of COVID-19 illustrates the value of these types of treatments.

At the policy level, this type of programmatic shift would primarily involve a transition in the categories of disease for which organizations provide funding. Instead of funding R&D specific diseases, grants would target whole categories of disease, thereby facilitating a broader approach to the program than in the past. Additionally, this new program would involve educating policymakers about the importance of proactively and sustainably funding not just what is in headlines but also what will be in headlines. Situations such as waiting for Congress to distribute specific funding for Zika because it was not a virus pre-specified in prior funding cycles would never occur. The programs would be pathogen agnostic but still recognize that focus on pathogens with pandemic-requisite traits merit prioritization.

Following COVID-19, it has become clear that we, as a species, cannot tolerate what has happened ever again because of our own willful inaction. For decades many in my field have advocated proactive preparation for both natural and intentional infectious disease threats. However, while earlier attempts to dislodge the reactive, boom-boost, panic-neglect cycle that typifies how society has dealt with these threats, an opportunity now exists to reconfigure our thinking and our methods. We must not squander this chance.

9 years without D.A. Henderson and what does he have to do with a Sherman Tank?

It’s been 9 years since D.A. Henderson — who I call the commander-in-chief of infectious disease — died. As I do each year to mark his passing, I have assembled some questions I would love to ask him. I used to have the privilege of walking down to his office and posing these questions to him regularly and then rushing back to my office to look up things he said, historical examples he drew on, and make new integrations his thoughts prompted. In the last few weeks, amongst the mountain of infectious disease books I am always trying to get through — I am always reading an infectious disease book — I came across this quote from Jonathan Quick’s The End of Epidemics.

 “Sherman tank of a human being—he simply rolled over bureaucrats who got in his way.”

What a simple and accurate  way to concretize how D.A. Approached the field and the confidence in his own expertise. How needed this attitude is today. Imagine D.A. in the COVID-19 response — that would make for awesome fan fiction (to see how bureaucracy and politicians destroyed the chance for an appropriate response see Deborah Birx’s Silent Invasion). Another fun aspect of the quote was that upon reading it, I sent it to two friends/colleagues who also got to work with D.A. I asked them who it was describing and within seconds the correct reply came, illustrating just how unmistakeable D.A.’s modus operandi was.

On to the questions I — and the world — desperately needs D.A.’s answers to:

1.        How would you handle the H5N1 outbreak in dairy cattle? What would you do to get more cattle testing performed on farms and of farm workers? How would you deal with the conflicts between USDA, FDA, CDC, state health departments, and state agriculture departments? (I think it would involve the Sherman tank mode) What would your threshold be for deploying vaccine to farm workers? Do you think clade 2.3.4.4B is constrained in some way from causing severe disease?  

2.        Is the solution to Mpox — including clade Ib — aggressive vaccine in endemic countries? Or is there more to it? Would you use the ring vaccination of contacts of cases plus high-risk individuals or universal immunization? I know you would be happy to see LC16m8 (you used to just call it “LC” like it was your friend’s initials) — the next generation Japanese smallpox vaccine you advocated for and told stories about — finding a use.

3.        What do you think the outcome of the polio eradication effort will be? I ask this every year. I recently had to discuss this topic and I said “everything D.A. predicted would occur, has occurred.” Not only has the virus — wild or vaccine-derived — defied efforts, but a new vaccine also (nOPV2) deployed has caused the same problem of vaccine-derived cases (albeit at a lower rate). I still think what you said is the most reasonable approach — focus on wild poliovirus only if eradication is the goal.  

4.        How would you optimize wastewater monitoring in the US? Currently it is being used, variably, for SARS-CoV-2, mpox, antibiotic resistance genes, influenza, and polio? What else would be good? How about the airport wastewater monitoring? Should airports be just sequenced for everything in the hope of early detection of something novel or worrisome? How do you use that information for public health intervention ?  

5.        What do you think of the CDC director becoming a senate-confirmed position? Will it cement the idea of Republican CDC directors and Democrat CDC directors? Will presidents and HHS secretaries look for CDC directors that are able to be confirmed and politically savvy vs. competence in epidemiology and infectious disease?

Those are my top questions right now but there are so many controversies and conundrums that’s D.A.’s mind, expertise and wisdom would cut through like a razor — a razor that is so desperately needed in this field.

What do The Ghostbusters, Men in Black, and demonic possession have to do with Pandemic Preparedness?

Building on what I’ve written in prior chapters, this very short chapter serves to concretize an important principle of infectious diseases: solving the puzzle of what is making someone sick.

In the early days of a burgeoning pandemic, epidemic, or outbreak the key task is to identify the inciting pathogen. What type of pathogen is it? A virus, fungi, bacteria, prion, parasite, etc.? What species is it? What does it resemble? All these questions are aiming to understand the identity of the pathogen. While this might sound very obvious and simple, knowing the identity of a pathogen gives humans a very powerful tool. It illuminates what I call “biological dark matter” — all the unidentified pathogens that lurk behind infectious syndromes of all severities that are not completely identified (more on this in a later chapter).

Every sniffle, every UTI, every sore throat, every pneumonia, every gastroenteritis, every ear infection starts out as biological dark matter that may or may not yield a final specific diagnosis (often because diagnostic tests might not be deemed necessary).

However, when one grasps the entity’s identity and is able to categorize it, a whole host of related knowledge one has accumulated can then be applied to it. For example, if one knows that some clinical syndrome is due to an infecting bacterial species that will lead to general treatment and diagnostic principles such as the use of certain types of antibiotics, certain types of culture media, and anticipating certain types of transmission. Similarly, if something is known to be caused by a virus it will lead to unique considerations specific to viruses.

This reasoning can be extended, for example, to knowing a virus is of a specific viral family or if a bacterial species is of a certain type (e.g., gram stain positive or gram negative). What comes along with each iterative step of identification is a whole slew of information that can be applied to the problem based on what has been learned in the past regarding entities of this type. If the unidentified pathogen is subsumed by an already known concept, all that prior knowledge can now be applied to the new instance of it.

Knowing, to any degree of specificity, what kind of thing the culprit organism is conveys explanatory power which can then be wielded for therapeutic, prognostic, or other purposes.

A little digression

I am someone who shamelessly loves the Ghostbusters and am always at the ready to equate infectious disease physicians to the Ghostbusters or the Men in Black (”We're your first, last and only line of defense against the worst scum of the universe”;  “'Cause we see things that you need not see and we be places that you need not be”).

But I sometimes think a better analogy is to a science-based “exorcist”. After all, infection is a type of possession or infestation in which the host’s normal physiology can be severely altered by the invader It then becomes the infectious disease physician’s task to identify the invader and develop a plan to remove its influence on the host by killing it with medications and modulating the host’s immune response to it.

Maybe I’m making too much of this and it’s just the indelible 9 years of Catholic school I attended as an atheist child who was intrigued by the mythology of the dark side.

But, an aspect of all the exorcist demonic possession movies I have watched is the power that the exorcist (infectious disease physician) gains by learning the demon’s name (the identity of the pathogen).

In the movie The Rite, it is explained that:

“It is the job of an exorcist...
...to determine the number of
possessing demons and their names...
...something the demons protect
with great ferocity.
And when the exorcist has a name...
...he can then begin to
assert control over the entity...”

Like the German fairytale character Rumpilztilksen, the evildoer hides its name lest it lose the power it possesses. Once the name is known, it seems like child’s play to rid the person of the demon. Quoting again from the movie, The Rite, when the priest discovers the demon’s name he states:

“I know you, Ba'al.
And I command you, retire therefore.
Depart from this place. Leave!
Surrender now.”

To complete the analogy: in the case of, for example, severe septic shock, once the inciting cause is discovered the clinician can start a specific treatment plan and gain some control back (“Well I guess we're gonna have to take control”). While this may or may not be ultimately successful in rescuing the patient by ridding them of the infection, at a minimum, explanatory power is obtained.

***

Having the capacity to determine the etiology of the unknown unknown making someone, a city, a country, or the world sick is a critical aspect of pandemic preparedness and response. You have to know the demon’s name. However, to be able to do this adeptly in an emergency situation requires aiming for specific microbiologic diagnoses (and not ceasing investigation at the level of, for example, “pneumonia” or “viral syndrome”) to be the norm during day-to-day medical care, the topic for the next chapter.

Towards a Unified Theory of Pandemic Pathogens

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

3.    Paramyxoviridae

4.    Picornavirdae

5.    Pneumoviridae

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.