Chapter 2 The nature of the microbial world and infectious diseases

It’s a Microbial World After All

The realm of infectious disease is so ripe and attractive as a backdrop for contemplating the catastrophic decimation of populations of species because of its very nature of the microbial world.

We live on a planet dominated—in terms of species biomass—by microbes. This ubiquity is not accidental but the result of the causal forces responsible for the nature of life. The earth was formed 4.6 billion years ago, and life began 1 billion years later. For the majority of that time, life on earth was exclusively microbial species. Mammals represent only a sliver of that nearly 4-billion-year epoch, with humans representing just a sliver of a sliver.

 What that microbial multi-billion-year advantage has done is allow microbes time to evolve and diversify to inhabit every niche of this planet, including areas inhospitable to any other form of life. Such environs including radiation-laden environments and undersea heat vents, which are home to extremophile bacteria that are “extreme” in a manner very different than human extreme sports participants.

 Viewing the planet in this context, you can see how foolish it is to try and over sterilize one’s life with antibacterial hand sanitizer, respect the 5-second rule for food dropped on the floor, and memorize articles cataloging the density of “germs” in various public locations. Everything is germy and always will be.

 Even the human body, soon after birth, becomes virtually melded to its microbial colonizers. These constitute the human microbiota or human microbiome. This patina of microbes has become so essential for life that disruption or alteration of the microbiome has been linked with adverse health outcomes such as Clostridium difficile infection, gastro-esophageal reflux disease (GERD) and possibly will help unravel the mysteries of autism.

 We are really unable to live without bacteria. The symbiotic relationship we have with bacteria provides essential physiological support for our life. From synthesizing the vitamin K needed for adequate blood clotting to fending off potential nefarious bacteria by leaving them no space to set up shop, our microbiome is our protector. A disrupted microbiome is not conducive to good health.

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Bacteria, though mere single-celled organisms, are not simple in any sense. They possess many sophisticated genetic and metabolic components. For example, certain bacteria can flip a genetic switch when they sense enough others of their species are present to constitute a quorum. Such quorum sensing provides a massive survival advantage to bacteria that possess the faculty, which, in effect, allows a bacterial colony to operate like a super-organism reminiscent of the societal structure advocated in Plato’s Republic. These bacterial super-organisms can take the form of a biofilm, an impregnable slime layer, that in the certain setting such as the infection of a prosthetic hip, can stymie the power of antibiotics to the great detriment of the patient.

In fact, if looked at from the perspective of an alien race, as I frequently say, the Earth could be described as a planet of bacteria with a spattering of other species that, as Eula Biss puts it in her excellent book, bacteria use to travel about. Of course, this is hyperbole, because bacteria, though ubiquitous, cannot be thought to dominate the planet in the manner in which humans do but it is a perspective that is based on significant and under-appreciated facts.

 A similar analysis could be applied to other major members of the microbial world such as fungi and protozoa. It is more complicated with viruses, of which a quadrillion quadrillion exist on earth, because viruses exist on the chasm between animate and inanimate. As such, they do not have the a “life” cycle akin to bacteria or fungi. In fact, some hypotheses have been put forward postulating that viruses are devolved bacteria that have given up some of the trappings of life and the related energy upkeep costs in favor of a simpler existence. In fact, there exist some viruses which are endogenously present in our DNA and are literally part of us, along for the ride of life.

Standing on the Shoulders of Darwin

The veracity of Darwin’s observations and inductions, which coalesced from hypothesis into the theory of evolution by natural selection, are — in the modern context — apparent to anyone who just looks with an active mind. However, there is no better setting in which to witness evolution unravel real time than in the microbial world where the equivalent of world wars and a struggle for existence are occurring continuously.

Any microbe has to fight for its life, competing for sources of food in order to survive, reproduce, and flourish. Some environments are luscious resource-replete locales in which life is relatively easy with little effort required to meet needs. However, situations can be temporary and drastically change for any number of reasons, including cleaning out the fridge some bacteria call home.

 Because of the sheer number of bacteria and their ability to reproduce rapidly, mutations will occur routinely. Some mutations may not be beneficial, some will have no effect, and some will be advantageous. Advantageous mutations could allow a microbe to utilize a new food source, withstand extremes of temperature, expand an ecological niche, or develop a weapon to use against competitors.

 All of this dynamism of evolution is occurring all the time in the microbial world, irrespective of humans. Remember, humans have only existed for a brief segment of the time that microbes have flourished on this planet. It is only when humans and other organisms appeared that this evolution had implications for health.

 For instance, the weapons some bacteria evolve to use against each other and other microbes, sometimes take the form of what we know as antibiotics. Antibiotics are the missiles microbes use against each other to keep outsiders away from their niche and its treasures. In response to these weapons, some bacteria develop anti-weapons systems or antimicrobial resistance mechanisms—naturally, in order to survive.

 Antibiotic resistance is often framed as a novel threat because of the role of injudicious antibiotic prescribing (which is a real issue). However, antibiotic resistance is truly almost as old as the planet itself. It has been detected in bacteria that reside within caves in which no human has set foot and also in tribes of remote peoples who have never received an antibiotic prescription. Following this line of reasoning, it becomes clear that our tit-for-tat war with microbes is doomed to end in failure if an antibiotic arms race is our chosen tactic, for the microbes can evolve much faster than we can develop new antibiotics, which ultimately are often derived from them. We are playing on their field using tools they themselves developed.

 It is important to recognize that evolutionary pressures do not always select for more virulent or dangerous microbes and, in some cases, may select for less virulence. It all depends on the context. For example, the bacterium that causes the diarrheal illness cholera might be very deadly in one setting but in another much milder. For instance, it has been hypothesized that the level of sanitation has an influence on the volume of the diarrhea produced by Vibrio cholerae, which is spread via the fecal-oral route. In certain situations, voluminous diarrhea gives it the best chance to pass from person-to-person where in others just a little diarrhea can go a long way.

 The forces of evolution are manifest in the microbial world and, because of the magnitude of reproduction achievable by microbes (compare the 20-minute doubling time of an E.coli cell vs. that of a human) have real-time consequences for disease and health. Accordingly, these forces play a major role in how we think about and respond to these threats. Conversely, even though we are also indisputable products of evolution, our reproductive time leaves us woefully without an ability to rapidly develop an intrinsic species level adaption, though over centuries, we do fairly well—and better than the Christmas Island rat—as I will discuss at several later points in the book.

 There are three touchstone infectious disease emergencies in our species’ past (and present) that highlight important threads that I will draw out and integrate throughout the book. A context-setting thumbnail sketch of each follows.

The Black Death and the Power to Reshape Society

 The Black Death, which occurred in the 14th century, is arguably the most important infectious disease outbreak in history. Not only did it shake medical foundations to their core, but it also literally reshaped societal structure in medieval Europe by culling a large swath (1/3rd!) of the population.

 The Black Death was an outbreak of plague, a disease caused by infection with the flea-associated bacteria Yersina pestis. This bacteria spreads from fleas to humans and then between humans when it reaches the lungs. It has always been well recognized in its bubonic form in which the lymph nodes in the groin and armpit become markedly swollen.

 There have been countless books written about the Black Death as well as extemporaneous accounts such as Boccaccio’s The Decameron and I don’t seek to recapitulate the intricate details. For our purposes, it is important to realize that The Black Death, by killing 1/3 of Europe’s population, is a touchstone in understanding how infectious diseases impact history, world events, geopolitics, and national security. No war or weapon (save biological ones) could ever deliver such a blow as this tiny bacterium did.

 With one-third of Europe’s population dead, labor shortages abounded and because of the demand for labor and its reduced supply, it is thought that peasant laborers were able to change the terms of employment via The Peasant’s Revolt—an event that dramatically changed the structural relationship between landlords and their tenants who worked the land. The other element of The Black Death worth emphasizing is the deadly anti-Semitism that sought to blame European Jews for the outbreak. Jews were repeatedly accused of having poisoned wells and were consequently killed in large numbers using horrific means. Societal disruption during such an existential crisis, how The Black Death clearly must have been viewed by those experiencing it, is a major factor in infectious disease outbreaks. You might think that humans have jettisoned something as prejudicial and arbitrary as blaming certain members of society for a disease outbreak, but in large part they haven’t. Just recall HIV/AIDS, Ebola, and even the 2009 H1N1 influenza pandemic, in which North Americans faced stigma.

Malaria: This Leaves a Mark

 If something killed half of all humans that ever lived, it is safe to say it is something that would leave its mark on history both literally and figuratively on the human genome. Such is the “achievement” of malaria.

 This mosquito-borne scourge of mankind, caused by the Plasmodium species of parasites, still kills at an amazing clip of 1 million humans per year. Though most of the industrial world is now free of malaria—thanks in part to DDT—the planet on the whole is still malarious. In areas in which malaria is endemic, it exacts an enormous toll on the people, robbing parents of their children, confining productive people to their beds, and diverting precious resources to beat back what could’ve been just a problem of the past, as it is in many parts of the world.

 Because of the incredible ability of malaria to cull the population of humans, it can be thought of as a Darwinian selection pressure on the population. In other words, because of the myriad, often subtle, genetic differences (i.e., mutations) that exist between humans there may be some that, for whatever reason, are advantageous to those who are infected with malaria. Such an advantage may be that the possessor of the mutation is unable to be infected by the malaria parasite or has only a mild case if infected. Over time those that are resistant to dying from malaria would have more of a chance to reproduce and pass on the protective genes to their offspring. As more and more time passes, a proportion of the population who descended from these “mutants” would exist and be able to flourish in an area that other humans would find inhospitable.

 The above is a brief explanation for why such mutations as the one that causes sickle cell anemia was preserved by natural selection. In this case, if one possesses just one of two mutant genes and is only a carrier, they are resistant to malaria and not affected by sickle cell anemia (whereas those with both genes mutated suffer the effects of sickle cell anemia). The offspring of carriers, who would have at least a 50% chance of inheriting the gene from one of its parents, would be evolutionarily privileged in malarious areas where those not so preferred would have a higher chance of succumbing to malaria. Similar mechanics underlie the propagation of other malaria-resistant genetic diseases such as glucose-6-phosphate deficiency (G6PD), thalassemia, hereditary spherocytosis, hereditary elliptocytosis, and the Duffy blood group. To indelibly concretize the point, one just has to superimpose maps of where malaria has been present on the planet and where these genetic mutations are highly prevalent and see the perfect overlap.

 The lesson I draw from such a prolific killing machine as malaria is that even when it appears bleak—a 50% kill rate of the human population can’t be described, even if you’re a glass half-full type, as anything but bleak—there is inherent resiliency in humans derived from their genomes.

1918: The Great Influenza

 For most of human history, globalization was not fathomable as people tended to locate in one geographic area and not move far from it because of the cost, difficulty, and danger incurred when leaving one’s enclave. That all changed with Christopher Columbus’ path-breaking, heroic, and pioneering voyage of 1492. Indeed, I believe our modern perspective of “a small world”, when viewed in terms of fundamentals, can be traced back to that pregnant voyage that changed so many things.

 Fast-forward 400 or so years in the future to the early 20th century and we find ourselves in the midst of the world’s first global conflict in which nations, literally separated by oceans, are engaged in an unprecedented war with each other.

 Inserted into the melee was the influenza virus.

 This small virus, which hadn’t even been discovered, embarked on a killing spree that dwarfed war casualties. It charted up to 50 to 100 million deaths in its deadly yearlong circumnavigation of the globe, aided by mass global troop movements.  By comparison HIV is estimated to have killed 39 million people in its decades of existence.

 While debate exists to the original origin of this virus—Kansas vs. China vs. somewhere else—this pandemic concretized for many the ability of an infectious disease, in the modern era, to literally wreak havoc.

 There are many books that have been written about this incident detailing the utter calamity the human race was in during the pandemic with shortages, curfews, closures, masks, casket piles, mass graves, and the like becoming a normal part of life. With “just” an estimated 1-2.5% fatality rate with infection, the sheer scope of the respiratory virus’s infectiousness exacted a staggering toll killing about 5% of the extant population of 1 billion humans on Earth in what is really just a blink of time.

 Though fictional portrayals of a post-apocalyptic world inhabited by zombies, monsters, and mystery abound in popular culture, one need not delve into the world of science-fiction fantasy to understand pandemics and infectious disease emergencies. One can simply study the course of The Black Death, malaria, and the 1918 influenza pandemic to see worst case scenarios.

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 From the above it should, hopefully, be apparent that the human race has been through major infectious disease emergencies that took a horrendous toll on the species who, not knowing the power that laid within their genes, must have thought the end of the universe was at hand (and for those who succumbed indeed it was the end). However, the human race persisted—even in an era before widespread availability of effective supportive medical care, not to mention vaccines, antibiotics, and antivirals. These were not even close to existential or “x-risks” even though they were the biggest foes our ancestors faced from the microbial world.

 With these basic facts and a little bit of history at hand, we can now turn to unraveling the alchemy of a pandemic pathogen — the first lens for how I evaluate every infectious disease outbreak.

Chapter 1: When to Worry

This is the first installment of what was a book project of mine. It is written for a general scientifically interested audience and the style reflects that. Feedback on my ideas is always welcome.

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“You’ll tell us when you’re worried, right?” This was a question I was frequently asked by reporters, colleagues, and even my barista during the height of the 2014 West African Ebola outbreak — the deadliest in history — when, drawing on my work in infectious diseases and pandemic preparedness, I was called upon to serve as a media expert.

Throughout the hysteria and the 24-hour news cycle, I repeated one statement: “Ebola is a deadly scary disease, but it is not that contagious and will not find the United States (or other industrialized nations) to be a hospitable environment.” In the end, this was borne out, increasing my credibility with those who had heard my predictions.

But my predictions were not based on some overly rosy outlook on the landscape of infectious disease. How could I have a rosy outlook on infectious disease with serial killers such as HIV, malaria, and tuberculosis presently threatening the human race, and diseases such as MERS and SARS emerging as deadly threats? We had just experienced a pandemic of a novel influenza virus that took the world by storm and surprise. Meanwhile, its highly lethal avian cousins, including to this day, seem to be waiting for the right opportunity to pounce. In 2014, abetted by the primal scream of the anti-vaccine movement, the US had a record number of measles cases (in the post-vaccine era) and just 4 years later the Americas lost their measles elimination status and the US broke measles records. Perpetually lurking in the background of all these explosive outbreaks, antibiotic resistant bacteria threatened to collapse the entire structure of modern medicine.

 In short, I know just how deadly and disruptive infectious diseases have been, both historically and presently, as well as what it takes for an infectious disease to be included in the pantheon of pandemic causing pathogens.

Despite almost no chance of contracting Ebola, ordinary people in industrialized nations took extreme, unwarranted measures – such as buying spacesuit-like apparatuses for what they believed was the coming apocalypse – that would not make them any safer from the disease. Though many people truly feared the world was poised to become a dead zone inhabited by Ebola-stricken zombies, their fears have not come true.

 Indeed, in the midst of the unprecedented Zika outbreak in 2016, I echoed a similar message to dampen fear. Drawing on historical examples such as rubella – which caused similar devastating fetal anomalies – I tried to explain that Zika, notwithstanding its considerable public health impact, doesn’t measure up to a widespread pandemic threat.

 What some actually fear, with each outbreak of emerging infectious disease, is the arrival of an extinction event. Hypothetically, such an event would cause such a large proportion of the human race to succumb to infection, leaving few or no survivors, that the population would cross a critical threshold, beyond which the species cannot be sustained. The extinction event concept activates the human imagination like nothing else: our minds fill with dinosaur images, science fiction narratives, and post-apocalyptic scenarios.

This focus on extinction or existential level infectious disease threats may be intellectually stimulating, has synergy with ordinary pandemic preparedness, catches the eye of prominent philanthropists such as those involved in the Effective Altruism movement, but is often hyperbolic and distracts away from actual infectious disease and public health tasks that are tractable and merit attention. As we have learned through COVID-19, hyperbolic pronouncements sow mistrust between public health authorities and the public and often create false alternatives for policymakers.

 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. It is important to note that the impact alone, rather than cause mass extinctions in itself, created changes in planetary conditions that made life impossible for those species unable to adapt and ill-equipped to a markedly different habitat.

 Such a cataclysmic result is not surprising, since many species would not have 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. In essence, the Cretaceous-Paleogene extinction event was a great culling, the survivors of whom possessed, by chance mutations, the characteristics that allowed them to survive.

 An interesting footnote to this event is the idea that drastic reductions in the amount 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 are responsible for annihilating species of reptiles and amphibians.

 Whatever the mechanics, the Cretaceous-Paleogene extinction event is the most widely known of its kind, but it is decidedly not akin to something an infectious disease pathogen could do. I mention this event only to draw a distinction between an actual mass extinction event and what a severe human pandemic is capable of doing.

For many species – unequipped by evolution for changes in habitat, predator-prey relationship variations, and myriad other factors – micro-extinction events occur continuously.

Amongst these micro-extinction events, there has been only one semi well-established infectious disease extinction event—that of the Christmas Island rat by Trypanosoma lewisii, a mosquito-borne protozoan (related to the causes of the human infectious diseases African Sleeping Sickness and Chagas Disease). In this instance, the poor rodent, stuck on an island and unequipped to leave it, had nowhere to run. Incidentally, there is an effort to de-extinct this rat using modern technology.

However, between a fleeting infectious disease outbreak and an extinction level event there is a lot of room for disaster. I agree with most experts who do not think an extinction event is possible. However, there is a concern for what are termed global catastrophic biological events (GCBRs). These events, which are caused by infectious disease outbreaks, have the capacity to lead to dire consequences for modern industrial society as the resources needed to contain them outstrip national governments and the private sector.

The COVID-19 pandemic, with its relatively low mortality ratio of <1%, has proved to be such a case. The early failures to see it as the looming threat it was — and eventually became — reflect either a degree of evasion or a failure to understand the threat matrix of infectious diseases. The events of this pandemic exposed major vulnerabilities in what were deemed the world’s most prepared nations. There have been several times that I have been baffled and frustrated by the response. This was especially true in the early stages where inaction followed by wrong actions could not have been more perfectly calibrated to orchestrate disaster if they were planned. For example, ineffectual travel bans, flawed testing criteria, the lack of testing capacity, the lack of personal protective equipment (PPE), the failure to fortify nursing homes, and the general reactive evasive nature of the response set the stage for the million plus deaths that followed in the U.S.

When it comes to infectious diseases, it is events such as these that induce people to worry about the future of the species, societal collapse, and economic ruin.

The human species, for the vast majority of its existence, has struggled against infectious diseases of one sort or another. And the explosive increase in our average life span, a very recent occurrence, can be directly attributed to the control of infectious diseases through sanitation, vaccination, and antimicrobial therapies. So, for most of mankind’s history, infectious diseases were the existential threat. And time after time, they have proven their success at killing humans and impacting civilizations. The emotion of fear, given this context, is quite understandable. The luxury of death from cancer, heart disease, or stroke in our eighth decade of life has only emerged in the modern era, when industrialized societies learned to mitigate many infectious diseases. Idyllic childhoods – free from watching siblings and friends die from outbreaks of typhoid, scarlet fever, smallpox, or measles – were not the norm for most of our ancestors. Even today, some parts of the world still face such threats.

Extinction Event is the result of my daily engagement in this field which ranges from treating patients, to speaking to the media, to thinking deeply about the role of infectious diseases and human societies. My aim is to provide you, the reader, with an important context by which to gauge any infectious disease outbreak by providing you a grounding in the key factors that govern an infectious disease’s trajectory, grasping the significance of certain facets of historical outbreaks, understanding other variables that set boundaries for infectious disease outbreaks, and recognizing the key tasks of pandemic and emerging infectious disease preparedness.

In what follows, I will alternate between discussing outbreaks, epidemics and pandemics, because much can be gleaned from looking at extreme and varied cases to elucidate, and set limit conditions, of what will be most likely to occur. Also, and crucially, preparations for the mitigation of these events are similar, utilize the same infrastructure, and engender expertise in outbreak response fundamentals. By executing the right actions for the most minute threat such as a limited salmonella outbreak or the occurrence of a single case of a high consequence pathogen, the threat of larger occurrences is lessened.

It is important to emphasize that when it comes to humans and infectious disease outbreaks, we cannot evolve our way out of them. Whether it is influenza, COVID-19, or plague, the key question to ask is how to diminish the societal disruption that will be engendered. This can only be accomplished by knowing the key questions to ask, acquiring knowledge iteratively, and ultimately taking the right actions.

Though I will argue against an infectious disease being able to cause an extinction or even a global catastrophic biological event for humans it should not be construed as minimizing the impact and importance of extreme resiliency against infectious disease threats. What my discussion does provide is a framework to better focus preparedness on the most crucial elements. How can we minimize the chance that infectious disease threats cause disarray? If a low lethality pandemic like COVID-19 can wreak such havoc, what would happen if something far more dangerous took hold.

As part of my argument, I will introduce several themes or principles that will provide a framework that I, personally, rely on as a lens to understand past infectious disease events, gauge the impact of current threats, and try and predict those that lie in the future. Whether or not they are exhaustive, at minimum this framework provides an integrated and principled way of thinking about this field. I consider the below points my primaries, first principles, or starting points:

1.    For an extinction level event to occur, an infectious disease will have to possess certain attributes that allow it to first cause a pandemic. Not every infectious disease has pandemic potential.

2.    By its very nature a pandemic pathogen must be capable of transmitting efficiently between humans, putting bounds on which of the myriad members of the microbial world are capable of this feat.

3.    The human immune system, which evolved in the midst of our microbial planet, is a major constraining factor on the impact of infectious disease threats because of how it operates.

4.     The human mind’s ability to develop new tools to attenuate the impact of infectious disease threats — in increasingly more rapid fashion — has grown increasingly formidable through our species’ existence.

Any human pathogen — whether pandemic, epidemic, or outbreak worthy — will have to overcome these factors.

So, here again is the crucial question I began with, but reformulated: why couldn’t an infectious disease constitute an existential level threat to humans?

Holding Out For a Hero: A Long 6 Years without DA Henderson

It’s been six years since DA Henderson died and I think it is painfully obvious to everyone — not just those in infectious disease and public health — how much he’s needed. As has become my tradition, I am going to list several questions I have for him. Thought it is a pale comparison to the terms when I could just walk through the office and find him at his desk reading and just ask him, I find it useful to refine my own thinking on the issues of the day and wonder how his unrivaled mind might approach the problem. Sometimes, it just makes me appreciate just what it was like to be in the presence of such a person.

Interestingly, just a few days ago I was excited and not surprised to see DA’s name in print in the Washington Post as an anecdote from over 20 years ago in which he warned of the threat of monkeypox was recounted.

So here are my questions for DA.

1. What do you think the trajectory of monkeypox will be? Is this something that will burn itself out as people become immune through vaccination and prior infection while also changing their behavior? Do you think sustained spread is possible in the US outside of men-who-have sex with men? Is this clustering among MSM akin to how meningococcus can do the same thing?

2. What do you think of Jynneos’s effectiveness? I know you always swore by Dryvax and it’s modern equivalent, ACAM2000, because it — with you driving its use — banished smallpox from the planet. Would you favor the use of ACAM2000 in select cases (I know I would). Also, what about Lc16m8, the Japanese 2nd generation vaccination you favored. I remember a story you told me about how after the anthrax attacks the Jynneos (or MVA) was prioritized over the existing Lc16 m8 for reasons you never quite understood (a good story for a journalist to try to uncover)

3. As COVID-19 becomes more manageable with all the medical countermeasures that have been developed how do you help people risk acclimatize to a never-abating threat?

4. What should be done about circulating vaccine derived polio viruses (cVDPVs) ? Following what you taught me I draw a distinction between wild poliovirus and these Sabin-vaccine derived strains. Should we just move to full Salk for the rest of the world to eliminate this problem? Why do people conflate wild polio — which exists in just Afghanistan, Pakistan, and Mozambique -0 with cVDPVs?

5. Do you think that waning immunity against ordinary respiratory viruses due to decreased social interaction because of COVID is responsible for pediatric hepatitis cases and off season RSV? What will happen with flu as some strains have become extinct ?

6. How do you think the CDC should be reformed? What was your final impression of it’s promise after spending so much time there? I think there was a reason you didn’t ever direct the organization that stemmed from who “they” wanted at the helm vs. who is best qualified.

These are just 6 questions I want to know DA’s answer to — there are so many more.

One last point to make. As infectious diseases have, understandably, taken center stage DA’s presence and voice would be unequalled. His would be an intransigent voice that spared no one’s feelings, one that would not be carefully calibrated to curry favor with any political party, leader, or administration, and one that provide a resolute direction for clinicians, the public health workforce, and the whole country and planet. Would that a DA-like figure emerge again — I hope his qualities are not a once in a century appearance.

Hail to the Chief: DA Henderson's Mind was the Ultimate Pandemic Countermeasure

The infectious disease world has been without DA Henderson for exactly 5 years and his presence is something that is needed more than ever. i don’t think there’s every going to be a time when we don’t need his mind, his knowledge, his experience, and his wisdom.

Each year on the anniversary of his death I pose questions to him that I wish I could hear him answer. His booming voice, his certainty, his ability to see things exactly for what they were drawing on decades and decades of battling — and annihilating — humankind’s greatest scourges are a far cry from what we hear and see today. Given the current environment, I just wish he could take over the whole infectious disease apparatus and extinguish this pandemic, recalibrate public health, and silence politicians whose continual incompetence is to blame for over 600,000 lives.

Each day I have questions for DA and these are a selection of my latest ones.

1. How do you counsel the population about a new infectious disease that is going to become endemic? How do you dial down people’s sense of alarm to one in which they learn to risk calculate? You did this, I am sure, with the 1957 and 1968 influenza pandemics, Legionnaire’s Disease, HIV, and countless others.

2. This is a related question. How do you transition people away from an abstinence only message to one of harm reduction? This must have been something you thought about in the early days of the HIV pandemic. Harm reduction works but was jettisoned early on in the pandemic and stunted people’s ability to risk calculate — a skill they need to acquire immediately as COVID-19 is not going away

3. What is the value of chasing mild cases of COVID-19 in vaccinated individuals? How is there an end game if that becomes the goal? During H1N1 in 2009, I remember how quickly things changed when the severity was downgraded. Isn’t that what vaccination is doing to COVID.

4. This is less of a question but more of a request to be regaled with another of your innumberable stories bout how you put a politician, a president, a dignitary in their place when they were pursuing a policy you didn’t think highly of. These are my favorite WWDAD thought experiments. I am smiling thinking of the time the Secretary of HHS was waiting to speak at a conference and wanted to interrupt your talk and someone approached the podium the Secretary was there and you replied deadpan “I know” and continued your talk. We could use a lot more of that now.

5. What is going on with those melioidosis cases in 4 different states in which there is no travel history or linkage? Where do you think they came from? An imported product? A real mystery that is overshadowed by COVID

6. Is polio eradication in the new Afghanistan even possible? You were so skeptical it could be accomplished a decade ago and now the situation is way way worse. Should it be abandoned and just become part of regular disease control?

7. What do you think of the Ebola cases in the Ivory Coast? It’s the Zaire strain again not the Cote d’Ivoire or another strain. How do the different strains circulate ? How does one spillover and another doesn’t

These are just the first 7 out of an endless list of questions I have for DA. Tomorrow there’ll be a slew more new ones that occur to me.

One of the aspects of DA that is impossible for me to fully articulate is the feeling I got being around a mind like his. It was a feeling that allowed me to think that insoluble problems were soluble and that a human mind could tame the most wickedly virulent microorganisms.

If those of us that had the opportunity to work alongside him and be mentored by him could pool just a fraction of what he imparted to us, the world would look a lot different now. Emerging infectious diseases would be running scared with just a hint of our commander-in-chief.

Thoughts About Immunity and Booster COVID-19 Vaccine Doses

The recent announcement by the Biden Administration that fully COVID-19 vaccinated adults would be offered booster vaccine doses 8 months after their 2nd dose prompted a lot of thinking and my doing a lot of explaining about immunity and vaccines. 

I wanted to think a little on paper to try to explain what immunity means, what to expect from a vaccine, and draw some conclusions regarding the impending booster program.

So, what is important about COVID-19 vaccines? Their most important aspect is their ability to prevent severe disease, hospitalization, and death. That is what they were designed to do, and they are doing it brilliantly with a combination of antibodies and T-cells. Indeed, the FDA authorization was based on the ability of the vaccines to stop disease (i.e. symptoms) not clinically silent infections. Hospitalized COVID patients are, for the most part, not vaccinated. There has not been waning of the ability of vaccines to prevent these outcomes (though the White House said it “could”) despite crude Israeli data that cannot be taken as evidence given the statistical paradox present. 

The human system is very complex and hard to simply describe. We have innate (or ready-to-go non-specific immunity) and a more targeted specific type of immunity that takes time to develop called adaptive immunity. Adaptive immunity “adapts” or is directed towards specific pathogens. In broad strokes, there are two aspects to adaptive immunity: humoral (or antibody) mediated immunity and cell-mediated immunity. Both are very critical and work in concert. A major component of cell-mediated immunity are T-cells. There are various types of T-cells including T-cells that can kill infected cells, T-cells that orchestrate the operation of the immune system, and T-cells that dampen inflammation. 

 The most common evidence cited for the need for boosters is waning antibody levels. However, this is not – in and of itself – enough. First, we do not know what level of antibody (and the rarely accounted for T-cell immunity) is needed for immunity. We also do not have clinical evidence of true vaccine failure against important outcomes like hospitalization. There is non-peer reviewed data from Moderna showing higher efficacy with higher antibody titers but importantly, as the paper states, it is limited by the fact that efficacy against severe COVID was not assessed.

 It is well known that antibody levels fall and then spring back up post-exposure (to the virus or the vaccine). That is how the immune system works – it is anamnestic. It “remembers” after the primary response and mounts a heightened response that staves off severe illness using both T-cells and antibodies in the secondary response. We fully expect antibodies to fall as time from exposure to vaccine or infection increases and we fully expect them to rise upon re-exposure. This isn’t vaccine failure; it’s just how the immune system works. That, infections in the vaccinated are generally mild is evidence of this process working.

When the CDC recommended a modification of the primary immunization series for the immunocompromised – which is distinct from a booster – it did so based on clinical evidence that amongst the relatively rare COVID hospitalizations of vaccinated individuals, the immunocompromised were overrepresented (~45% in a non-peer reviewed paper). Additionally, a study in solid organ transplant patientsrevealed not only did they, as expected based on experience with other vaccines, fail to mount a robust (or sometimes any) antibody response but had a 485X increased chance of COVID hospitalization versus someone without a transplant. That type of clinical evidence was then integrated with data on 3rd doses of mRNA vaccines increasing antibody levels in these populations. 

With this booster recommendation to the public, none of that type of clinical data appears to be available for analysis. It is even unclear 

Vaccines are not bug zappers; they are not forcefields. That breakthrough – the term itself falsely connotes vaccine failure – infections are mild is a vaccine success (even as they may increase in frequency). We must remember it is disease not clinically irrelevant infections we are targeting and that is done with 1st and 2nddoses, not 3rd’s. COVID is an endemic respiratory virus, it cannot be eliminated or eradicated. There is marginal utility in the general healthy population getting booster vaccinations at an 8-month interval. It is currently unclear that a 3rd dose will diminish the rare transmission risk posed by the fully vaccinated which prompted CDC guidance on masks to be modified. Granted, there is little harm but is chasing mild infections in the fully vaccinated an important task when a substantial proportion of the eligible population of this country does not even have one dose. Will this change the trajectory of the pandemic in the US or the world? Does putting 3rd doses in the arms of the heavily vaccinated change the situation in Mississippi? 

There may come a time when boosters are needed and it’s important to be proactive and have streamlined approval and distribution pathways, but I don’t think that time is 8 months.