Emerging Pandemic Diseases: How We Got to COVID-19

Introduction

Unimagined just a few short months ago, the ongoing COVID-19 pandemic has upended our entire planet, quickly challenging past assumptions and future certainties. It possesses simultaneously three characteristics that have allowed it to render an historic assault on the human species, triggering a virtual global “lockdown” as the only weapon against uncontrolled spread. It combines the characteristics of being a virus that to our knowledge has never before infected humans in a sustained manner, together with its extraordinary efficiency in transmitting from person to person and its relatively high level of morbidity and mortality, especially among seniors and those with underlying co-morbidities. It indeed is the perfect storm of an emerging infectious disease.

Yet, pandemics such as COVID-19 are not entirely new phenomena. Newly emerging (and re-emerging) infectious diseases have been threatening humans since the neolithic revolution, 12,000 years ago, when human hunter-gatherers settled into villages to domesticate animals and cultivate crops (Dobson and Carper, 1996; Morens et al., 2020b; Morens et al., 2008a). These beginnings of domestication were the earliest steps in man’s systematic, widespread manipulation of nature. Ancient emerging zoonotic diseases (see Box 1 ) with deadly consequences include smallpox, falciparum malaria, measles, and bubonic/pneumonic plague. Some, e.g., the Justinian plague (541 AD) and the Black Death (1348 AD), killed substantial proportions of humans in the “known” world, i.e., the world known to those whose recordings of it survive, predominantly in Asia, the Middle East, and Europe.

Only a century ago, the 1918 influenza pandemic killed 50 million or more people, apparently the deadliest event in recorded human history (Morens and Taubenberger, 2020). The HIV/AIDS pandemic, recognized in 1981, has so far killed at least 37 million. And the past decade has witnessed unprecedented pandemic explosions: H1N1 “swine” influenza (2009), chikungunya (2014), and Zika (2015), as well as pandemic-like emergences of Ebola fever over large parts of Africa (2014 to the present).

Since there are four endemic coronaviruses that circulate globally in humans, coronaviruses must have emerged and spread pandemically in the era prior to the recognition of viruses as human pathogens. The severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) emerged from an animal host, likely a civet cat, in 2002–2003, to cause a near-pandemic before disappearing in response to public health control measures. The related Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) emerged into humans from dromedary camels in 2012, but has since been transmitted inefficiently among humans (Cui et al., 2019). COVID-19, recognized in late 2019, is but the latest example of an unexpected, novel, and devastating pandemic disease. One can conclude from this recent experience that we have entered a pandemic era (Morens et al., 2020a; Morens et al., 2020b). The causes of this new and dangerous situation are multifaceted, complex, and deserving of serious examination.

Infectious Diseases that Have Emerged in the Past

In thinking about these recent infectious disease emergences, it is necessary to first consider currently existing infectious diseases that newly emerged in the past and then over time became endemic (prevalent in humans) or enzootic (prevalent in animals) (Fauci and Morens, 2012; Morens et al., 2020b; Morens and Fauci, 2012; Morens et al., 2004). Such existing diseases may provide important clues about the mechanisms of disease emergence and persistence and why thus far we have been largely unable to prevent and control many of them.

The fact that many past emerging infectious microbes and viruses (hereafter grouped together as “microbes”) have adapted to stable co-existence with humans is evidenced by the presence of endogenous retroviruses in human DNA (Johnson, 2019) and by latently infecting herpesviruses such as herpes simplex (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and varicella-zoster virus (VZV). VZV, for example, is a highly cytolytic, highly contagious, and potentially fatal virus that has adapted to long-term survival in human populations via a complex survival mechanism. Unlike other highly contagious human-adapted respiratory viruses such as measles—whose survival requires very large populations in order to avoid exhausting susceptible persons—VZV establishes latent non-cytolytic infections in human ganglia, periodically reactivating into an infectious/cytolytic form (zoster) that can be transmitted—even in populations without circulating varicella (“chicken pox”)—to new birth cohorts of susceptible persons to be manifested as highly contagious varicella.

Human infectious agents such as retroviruses, herpesviruses, and many others tell us that long-ago emergences of certain diseases can result in long-term microbial survival by co-opting certain of our genetic, cellular, and immune mechanisms to ensure their continuing transmission. In the terminology of British biologist Richard Dawkins, evolution occurs at the level of gene competition and we, phenotypic humans, are merely genetic “survival machines” in the competition between microbes and humans (Dawkins, 1976). It may be a matter of perspective who is in the evolutionary driver’s seat. This perspective has implications for how we think about and react to emerging infectious disease threats.

From the human point of view, the fact that modern endemic diseases emerged and became established, at some unobserved time in the past (Table 1 ) (Morens et al., 2004), and that some of these diseases survived by adopting complicated long-term survival strategies, provides a compelling rationale for dual strategies for immediate and long-term control. First, in the immediate sense, it is important to mitigate spread of infection, illness, and death. Second, it is critical to prevent the persistence of microbes that may lead to additional emergences that are cumulatively as deadly, or more so, than the original emergences (Dobson and Carper, 1996). That viral genetic descendants of the 1918 influenza pandemic virus are still causing seasonal outbreaks throughout the world, and still killing cumulatively millions of people a century later (Morens and Taubenberger, 2020), is a powerful reminder that single disease emergences can have consequences beyond immediate morbidity and mortality. In the ancient ongoing struggle between microbes and man, genetically more adaptable microbes have the upper hand in consistently surprising us and often catching us unprepared.

The latest example of this, the COVID-19 pandemic, which emerged in December 2019, is still exploding globally (Figure 1 ). At time of writing, over 22 million cases have been detected, with over 800,000 deaths recorded (World Health Organization); however, these are undoubtedly significant undercounts, reflecting early and still problematic access to diagnostic testing coupled with incomplete diagnoses of fatal cases. As COVID-19 is caused by a novel virus (SARS-CoV-2) producing a spectrum of disease whose clinical, pathologic, and epidemiologic patterns have never before been observed, we are gaining insights only incrementally. At some time in the future we will be better able to compare and contrast COVID-19 to other important emerging diseases; however, at this time we are still just entering a steep learning curve that will surely keep surprising us as we struggle to control what is already among the deadliest pandemics of the past century.

Definitions of Emerging Infectious Diseases

The once-emerging/now prevalent diseases mentioned above, e.g., many viruses causing upper respiratory, enteric, or dermal/mucosal infections, are not considered to be truly emerging even when they vary seasonally or geographically; however, upon this background of existing diseases, new diseases still continue to emerge.

Emerging diseases have been categorized as newly emerging, re-emerging, or “deliberately emerging,” that is, associated with bioterrorism (Table 2 ; Figure 2 ) (Morens and Fauci, 2012; Morens et al., 2004, 2008a). To these we add “accidentally emerging” human-generated diseases, such as repeated emergences of vaccine-derived polioviruses (VDPVs) resulting from naturally occurring back-mutations of live virus vaccines, as well as a live human-engineered vaccine that escaped to cause a new epizootic disease: naturally transmitted vaccinia (Lum et al., 1967). Although these four categories are distinct, they are also interrelated: newly emerging diseases can persist and then re-emerge and can also become agents of deliberate or accidental release. An example crossing the latter two categories is the 1979 Sverdlovsk (now Yekaterinaberg) anthrax accident, in which an unintentional explosion in a Russian bioweapons factory released anthrax into the air, resulting in at least 100 human deaths (Meselson et al., 1994). Such deliberately emerging and accidentally emerging diseases represent a special case in which emergence/epidemicity is best prevented by global biosafety cooperation.

Among possible ways to achieve such cooperation are by strengthening the United Nations and its agencies, particularly the World Health Organization and the Office International des Épizooties (OIE; World Organisation for Animal Health); by supporting collaborative multinational research in prevention of disease emergence; by studying high-consequence pathogens under appropriate safety and containment conditions; by demanding renewed international intergovernmental efforts at the global level to collaborate on research related to the risks of global pathogen emergence risks and how to prevent them; and by preventing bioweapons development.

A fifth related category, significant because it emphasizes the importance of responding to disease emergence threats with countermeasures, is that of diseases that are “de-emerging,” i.e., those that have been eliminated or even eradicated or that are in the process of elimination and/or eradication (Table 3 ) (Dowdle and Cochi, 2011; Hopkins, 2013; Tomori, 2011). Smallpox and the veterinary disease rinderpest were declared eradicated in 1980 and 2011, respectively. SARS, which emerged in 2002–2003 and spread globally to 29 countries, infecting 8,096 people and killing 813, was controlled and ultimately eliminated from human spread by effective public health efforts (Cui et al., 2019). By some definitions, SARS was thereby eradicated, although it presumably remains in enzootic circulation and could re-emerge from nature, as Ebola viruses have been doing for the past 44 years (Baseler et al., 2017).

Table 3.

Selected Human Infectious Diseases

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Variables that relate to their potential for eradication. (Top) Selected infectious diseases that have either been eradicated, are now being targeted for eradication, or are being significantly controlled by public health and medical or veterinary actions. (Bottom) Human infectious diseases that are currently considered non-eradicable but for which some important disease aspects could potentially be eliminated with existing tools (e.g., eliminating human rabies without or before eradicating rabies in wild animals). The information is based on published data reflecting 2008 determinations (https://www.cartercenter.org), supplemented by additional widely available publications. Columns show disease features that favor eradicability (blue circles), are of uncertain relevance to eradicability (yellow), or are expected to make eradication more difficult or impossible (red). Some of these features (e.g., ease of detecting disease and immunity, seasonality in tropical versus temperate climates) are subjective and situationally variable; see text and references for the individual diseases.

^∗Sterile immunity for life refers to the ability of a natural infection or vaccine to induce a type and degree of immunity that prevents infection/reinfection and eliminates carriage and transmissibility to others and to animal and environmental reservoirs.

Other diseases nearing eradication include dracunculiasis, lymphatic filariasis, measles, polio, and rubella (Table 3). Such successes in eradication/control reflect the availability of improved tools and strategies for prevention and control, as well as international public and private efforts to reduce their substantial mortality and morbidity. Successes in eradication and control of infectious diseases remind us that we are not helpless in the face of emerging diseases. Eradicating/controlling existing diseases and preventing/controlling newly emerging diseases are related efforts demanding the same scientific, public health, and civic/political focus that will be required to successfully address this formidable challenge.

Variables in Disease Emergence: The Agent, Host, and Environment

Microbes that cause human diseases by definition have existed in some other environmental niche before emerging to infect humans and other animals. While some such organisms have long been human pathogens that mutated into new forms—e.g., re-emergences of antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA)—most are, and historically have been, zoonotic (Woolhouse and Gowtage-Sequeria, 2005; Woolhouse et al., 2005). Such zoonotic microbial emergences are often associated with mutational mechanisms allowing host-switching from animals to humans, as discussed below.

The triad of causations of emerging and other diseases, as conceptualized for over a century, represents interactions between infectious agents, their hosts, and the environment (Figure 3 ). This conceptualization acknowledges the reality that, while infectious diseases themselves are necessarily “caused” by microbial agents, emergences that produce epidemics and pandemics are also significantly determined by co-factors related to the host and to host-environmental interactions (Centers for Disease Control and Prevention, 2011).

Emergence of Diseases Leading to Epidemicity and Endemicity

Whatever human behaviors lead to the emergence of infectious diseases, the newly emerged organism cannot survive continually in humans without adapting to one of several direct or indirect mechanisms of person-to-person spread (Table 4 ). Many emerging organisms, such as the hantaviral agents of hantavirus pulmonary syndrome and Korean hemorrhagic fever, or the arenaviruses causing Argentine, Bolivian, and Lassa hemorrhagic fevers, result from dead-end exposures to reservoir rodents and rarely spread from person to person. Preventing and controlling these types of emergences thus focus on the enzootic reservoir.

Person-to-person transmissibility, a necessary step in establishing epidemicity and pandemicity after host-switching, can occur via one or more of four basic mechanisms (Table 4): respiratory;gastrointestinal; environmental spread via an intermediate environmental state such as waterborne, foodborne, and fomite-mediated; and environmental spread via inoculation, including vectorborne. It is noteworthy that these mechanisms reflect not only human societal practices such as sanitary practices, embracing physical closeness, and sexual activities but also ways in which people interact with the environment such as storage and drinking of water from different sources, food procurement, and food preparation practice. Even so, many variables interact to produce different clinical and epidemiologic aspects of disease transmitted from person to person. For example, while both Ebola and SARS-CoV-2 are potentially fatal diseases transmitted person to person, SARS-CoV-2 is, like most respiratory diseases, associated with asymptomatic infection in many and is often transmitted to others by an asymptomatic or pre-symptomatic infected person. Ebola, on the other hand, has a lower frequency of asymptomatic infection and is of low transmissibility right up to the time of illness onset. Moreover, the mechanisms of person-to-person transmission are distinct for these two diseases. SARS-CoV-2 is transmitted via hands and fomites, respiratory droplets and aerosol, including transmission by superspreading events where large numbers of individuals are infected by a single person, almost invariably in closed crowded settings. Ebola, on the other hand, is transmitted via virus-contaminated bodily secretions, and infection is usually acquired by persons touching contaminated fluids or fomites, for example in providing nursing care, burial services, handling towels, bed linens, utensils, etc. (Baseler et al., 2017). Although general principles of infection transmission are understood, specific diseases may vary in clinical and epidemiologic features that bear upon the type and intensity of transmission.

In this context, ongoing research into the origin of SARS-CoV-2 seeks to learn where, how, and why the virus emerged as a human pandemic disease (Boni et al., 2020; Latinne et al., 2020). SARS-CoV-2 clusters phylogenetically within an extensive but still not fully characterized universe of wild bat β-coronaviruses found in many species over much of the globe (Anthony et al., 2017; Cui et al., 2019; Hu et al., 2017; Letko et al., 2020; Lu et al., 2020; Morens et al., 2020a; Zhang and Holmes, 2020; Zhou et al., 2020b). The discovery that its closest identified viral relatives are enzootic in horseshoe (Rhinolophus) bats (Zhou et al., 2020a, 2020b) indicates that SARS-CoV-2 probably emerged from an as-yet-unidentified bat reservoir either directly or after infection of an intermediate host such as a pangolin (Boni et al., 2020; Letko et al., 2020; Li et al., 2020; Zhou et al., 2020a, 2020b). As was true of SARS-CoV 18 years ago, the specific determinants of SARS-CoV-2 emergence remain obscure. Gaining a better understanding of the enormous reservoir of bat coronaviruses has been an urgent priority since the 2002 SARS epidemic, and remains so today. Considerable surveillance and phylogenetic and experimental work remains to be done. In 2020, it is among our most urgent research priorities (Latinne et al., 2020).

One of the most important unanswered questions we face in the ongoing COVID-19 pandemic relates to the evolutionary potential of human-adapted SARS-CoV-2. Will it, similar to human IAVs in recent centuries, evolve to persist as a permanent human pathogen by mutating to escape the population herd immunity it creates? And if it does persist, will it attenuate over time, as the four endemic coronaviruses may have done centuries ago? Or, on the other hand, will it increase in pathogenicity as the pandemic H3N2 IAV has done over the past 52 years? Because SARS-CoV-2 lacks a segmented genome, we are spared at least one genetic trick (gene reassortment) underlying IAV pandemic emergences; however, like human IAVs, SARS-CoV-2 can be expected to evolve by mutation as it spreads through human populations, and it has the additional capacity of evolving by genetic recombination. Enzootic evidence supports a very high degree of recombination of SARS-like CoVs in nature. Will these capacities allow SARS-CoV-2 to escape from population immunity elicited by natural infection or future vaccination? Only additional time, and much important research, will begin to answer these questions.

The Enigma of Host-Switching

Perhaps the single biggest mystery of emerging diseases is how microorganisms, including animal-adapted microorganisms, switch species to infect humans. Host-switching from animal to human has long been conceptualized as the crossing of a fitness valley, in which a virus adapted to transmitting between members of host species A must somehow simultaneously develop the capacity to productively infect cells of new host species B (Figure 5 ) (Dolan et al., 2018; Geoghegan and Holmes, 2018; Kuiken et al., 2006; Parrish et al., 2008). In this paradigm, the depth of the fitness valley reflects host-to-host barrier challenges that have to be overcome. Our understanding of mechanisms of viral evolution and host-switching is nevertheless incomplete, in part because of inability to reconcile experimental within-host viral evolutionary findings and natural-world findings that examine viral evolution during outbreaks, including new disease emergences (Geoghegan and Holmes, 2018). Among many complicating factors, rapid intense person-to-person transmission of new viruses in large human populations often produces complex genetic diversity, confounding attempts to link viral variation to viral phenotypic changes and selection pressures eliciting them.

The situation is particularly complicated for the most important category of newly emerging disease agents: the RNA viruses, which include SARS-CoV, SARS-CoV-2, MERS, Ebola, and influenza, as well as dengue, Zika, and other arboviruses. These viruses evolve as, and are transmitted as, complex quasispecies, or viral swarms, which contain many viral variants of differing degrees of relatedness. It is unclear whether and/or to what extent transmission/host-switching reflects Darwinian evolution of novel virus variants, as opposed to evolution based on whole-quasispecies fitness (Geoghegan and Holmes, 2018). In the latter conceptualization, viral quasispecies evolve together as a diverse array of optimally fit, less optimally fit, and least optimally fit variants, trading off perfect host fitness for adaptational flexibility.

While it has long been assumed that the major determinants of host-switching are the evolutionary closeness of hosts A and B and the diversity of their transmitting quasispecies, recent research suggests that pathogen opportunity may be the major determinant of host-switching (Anishchenko et al., 2006; Araujo et al., 2015). In essence, even a virus poorly fit to a potential host can adapt to infect that host if given enough chances. The implications are profound. If host-switching is opportunity driven, e.g., for SARS- CoV and CoV-2, Nipah, and Hendra, then prevention and control will have to focus not only on the infectious agents themselves but also on human behaviors, such as the animal-human interface, represented by shopping in live animal markets, preparation and consumption of bush meat, intensive farming/animal husbandry, environmental degradation, and other human behaviors (Allen et al., 2017; Carroll et al., 2018).

Looked at another way, infectious diseases may be emerging into humans with greater frequency than appreciated; however, historically they have not usually achieved sustained-enough transmission that would lead to detection of the emergence. For example, before the recognized emergence of Zika, low human seroprevalence rates had been detected in enzootic areas for decades, but without detection of human outbreaks. Before the emergence of SARS-CoV-2, antibodies to it or to closely related sarbecoviruses were detected in humans exposed to bat coronaviruses (Wang et al., 2018). MERS has emerged from dromedary camels to humans on multiple occasions; however, despite limited chains of subsequent human-to-human spread, it has not become an established human disease. H5N1 avian influenza has infected millions of humans; however, only a small percentage manifest a recognized disease (often severe or fatal), and human-to-human transmission has been rarely reported (Morens and Taubenberger, 2015). These and many other examples suggest that disease emergence into humans may be common; however, sustained transmission between humans has been a rare occurrence resulting from incompletely understood factors. But in looking at the recent spate of deadly emergences noted above, we must now ask whether human behaviors that perturb the human-microbial status quo have reached a tipping point that forecasts the inevitability of an acceleration of disease emergences.

Such enigmas need to be better understood if we are to control emergences of infectious diseases (Dobson et al., 2020). Better understanding of the obscure mechanisms of emergences might allow us to anticipate emergence risks by (1) surveilling and characterizing taxonomic groups of potentially pre-emergent viruses, including viruses that may be the nearest to emerging, e.g., coronaviruses, henipaviruses, flaviviruses, arenaviruses, and filoviruses; (2) conducting intensive research on suspected high-risk viral categories to identify, in experimental animals, conserved epitopes for vaccine development and targets for antiviral therapies; (3) characterizing mechanisms of potential human transmission in experimental animal studies; (4) developing control mechanisms in areas such as animal husbandry, wildlife interaction, and rodent, vector, and mosquito/tick control; (5) devising environmental, land management, wildlife conservation/control programs; and (6) utilizing new virologic, informatic, and technological approaches to understand viral evolution and even predict emergence potential (Allen et al., 2017).

There are many examples where disease emergences reflect our increasing inability to live in harmony with nature. Nipah virus emergence followed agricultural burning of forests, which led to displacement of infected bats; bats then went to roost in trees that shaded intensively farmed pigs that were crowded into small areas, which led to infection of pigs via bat droppings, which in turn led to human outbreaks in pig farmers (Morens et al., 2004). Fish meal farming by fishermen in waters around the globe damages ecosystems by over-fishing and deprives local residents of food sources, leading to poverty and human movement, which exacerbate the potential for disease emergence. In Asia, the fish meal is used for breeding and over-feeding of farmed animals, often in intensive farming practices, which increase the likelihood of zoonotic diseases. Yellow fever, dengue, chikungunya, and Zika are all associated with urban crowding, poor sanitation, and water storage. Over many centuries, urbanization and crowding has led to rodent infestation and to rodent-borne diseases such as plague, murine typhus, and rat-bite fever. The ongoing COVID-19 pandemic reminds us that overcrowding in dwellings and places of human congregation (sports venues, bars, restaurants, beaches, airports), as well as human geographic movement, catalyzes disease spread.

Living in greater harmony with nature will require changes in human behavior as well as other radical changes that may take decades to achieve: rebuilding the infrastructures of human existence, from cities to homes to workplaces, to water and sewer systems, to recreational and gatherings venues. In such a transformation we will need to prioritize changes in those human behaviors that constitute risks for the emergence of infectious diseases. Chief among them are reducing crowding at home, work, and in public places as well as minimizing environmental perturbations such as deforestation, intense urbanization, and intensive animal farming. Equally important are ending global poverty, improving sanitation and hygiene, and reducing unsafe exposure to animals, so that humans and potential human pathogens have limited opportunities for contact. It is a useful “thought experiment” to note that until recent decades and centuries, many deadly pandemic diseases either did not exist or were not significant problems. Cholera, for example, was not known in the West until the late 1700s and became pandemic only because of human crowding and international travel, which allowed new access of the bacteria in regional Asian ecosystems to the unsanitary water and sewer systems that characterized cities throughout the Western world. This realization leads us to suspect that some, and probably very many, of the living improvements achieved over recent centuries come at a high cost that we pay in deadly disease emergences. Since we cannot return to ancient times, can we at least use lessons from those times to bend modernity in a safer direction? These are questions to be answered by all societies and their leaders, philosophers, builders, and thinkers and those involved in appreciating and influencing the environmental determinants of human health.

Summary and Conclusions

SARS-CoV-2 is a deadly addition to the long list of microbial threats to the human species. It forces us to adapt, react, and reconsider the nature of our relationship to the natural world. Emerging and re-emerging infectious diseases are epiphenomena of human existence and our interactions with each other, and with nature. As human societies grow in size and complexity, we create an endless variety of opportunities for genetically unstable infectious agents to emerge into the unfilled ecologic niches we continue to create. There is nothing new about this situation, except that we now live in a human-dominated world in which our increasingly extreme alterations of the environment induce increasingly extreme backlashes from nature.

Science will surely bring us many life-saving drugs, vaccines, and diagnostics; however, there is no reason to think that these alone can overcome the threat of ever more frequent and deadly emergences of infectious diseases. Evidence suggests that SARS, MERS, and COVID-19 are only the latest examples of a deadly barrage of coming coronavirus and other emergences. The COVID-19 pandemic is yet another reminder, added to the rapidly growing archive of historical reminders, that in a human-dominated world, in which our human activities represent aggressive, damaging, and unbalanced interactions with nature, we will increasingly provoke new disease emergences. We remain at risk for the foreseeable future. COVID-19 is among the most vivid wake-up calls in over a century. It should force us to begin to think in earnest and collectively about living in more thoughtful and creative harmony with nature, even as we plan for nature’s inevitable, and always unexpected, surprises.