Pandemic origins and a One Health approach to preparedness and prevention: Solutions based on SARS-CoV-2 and other RNA viruses

COVID-19 is the latest human pandemic caused by an RNA virus (5). In the past half century, there have been multiple RNA virus epidemics or pandemics (influenza 1957, 1968, and 2009; HIV; SARS-CoV; Middle East Respiratory Syndrome (MERS)-CoV; Zika; SARS-CoV-2; and others), thousands of recognized outbreaks, and the emergence of previously unknown pathogens (Fig. 1 and SI Appendix, Tables S2 and S3 ) (2, 6). Understanding how these outbreaks originate can guide how to prevent, mitigate, or respond to future EIDs, including non-RNA virus pathogens (7). Analyzing underlying drivers of EIDs indicates where future pathogens are likely to emerge and focuses resource allocation for prevention or control (6). EID hot spots are predominantly in countries with rich biodiversity, dense and growing human populations, rapidly developing economies dependent on transformative land use, and expanding livestock and crop production (8). Climate change already affects disease emergence and is projected to drive increasing future viral spillovers (9). The wildlife trade has grown significantly in complexity and scale, expanding threats to human and animal health (10, 11). Traditional wildlife hunting to provide food for small rural communities, particularly in Southeast Asia and southern China, has been transformed into an industrial-scale process that employed around 14 million people in China alone in 2016 (12). Wildlife trade supply chains now include thousands of wildlife farms with mixed captive-bred and wild-caught animals transporting live animals, carcasses, or products regionally and nationally, while the international trade in live animals and their products has continued to expand (11). Zoonotic spillovers, whether from wildlife, livestock, or domestic animals, are an urgent communicable disease threat, even though many are unable to spread efficiently among people (e.g., MERS-CoV) or lack the human-to-human connectivity essential for community spread (e.g., Ebola virus in isolated rural communities) (SI Appendix, Table S2 ) (1). RNA viruses, constituting up to 44% of all EIDs, are adept at circumventing these barriers due to short generation times, error-prone replication cycles, and faster evolutionary rates that may increase capacity for successful spillover from animals to humans and subsequent spread (6, 13 –16).

In this report, we review past RNA virus outbreaks; examine the origins, evolution, and lessons from COVID-19; and identify approaches to reduce threats and consequences of future outbreaks.

Influenza type A illustrates lessons pertinent for many other emergent RNA viruses (Box 1 and SI Appendix, Tables S2 and S3 ). Influenza A virus infects multiple host species, such as birds, swine, aquatic mammals, bats, and humans. Interspecies transmission, usually associated with reassortment of the segmented influenza genome, leads to periodic pandemics in people or epizootics in animals. For example, the 1997 Hong Kong outbreak of highly pathogenic avian influenza (HPAI) A H5N1 was traced to infected poultry in live markets, triggering a cull of all poultry in Hong Kong markets and farms and control of the outbreak virus. However, active surveillance of imported poultry demonstrated that precursor viruses remained in circulation elsewhere. By 2004, 10 countries in Asia reported outbreaks of HPAI in poultry, with zoonotic spillover in 4 countries. By 2005, the virus reached the Middle East, Africa, and Europe via migratory wild birds and the poultry trade (17). While some countries recognized its introduction and intervened to control spread, it remained enzootic where surveillance was weak, delaying timely interventions. HPAI reassortants (H5N6, H5N8) appeared worldwide, with >500 million birds in more than 80 countries killed by disease or culled for control and over 900 cases of human disease with 490 deaths (18). In contrast, no locally acquired zoonotic avian influenza A virus spillovers occurred in Hong Kong after 1997, attributable to active surveillance and evidence-based interventions implemented in a One Health context (19).

The 2009 influenza A pandemic was due to an H1N1 virus resulting from sequential reassortment of swine, human, and avian influenza A viruses. Its H1 hemagglutinin was derived from the 1918 influenza A virus, which remained the classical swine influenza virus for decades. It took 7 y to identify its immediate ancestor. Emergence was facilitated by the global trade in domestic livestock and the introduction of a precursor virus, Eurasian avian-like swine influenza virus, to North America. As the 2009 human pandemic virus spread globally, it spilled back into swine around the world, genetically reassorting with existing swine influenza A viruses, enhancing the diversity of swine influenza A viruses worldwide, and increasing future influenza A pandemic potential. The time line of emergence and repeat spillovers for influenza A, other RNA viruses, and Monkeypox virus over the past 25 y reveals that both emergence and repeat spillovers are extremely common (Fig. 1).

The emergence of three coronaviruses (CoVs) causing highly consequential human outbreaks in the past two decades points to the importance of this virus family as a future pandemic threat. The history of CoVs is enlightening. First discovered in 1931 during investigation of a fatal respiratory disease of poultry (20), CoVs are a large diverse family circulating in wildlife, with more than 4,800 sequences reported thus far (21). They are divided into four genera: alpha- and beta-CoVs with a broad mammalian host range extending to humans and gamma- and delta-CoVs, predominantly in avian species, a few mammals, and rarely, in humans (SI Appendix, Fig. S1 ). Presently, there are just seven known human CoVs, including four common cold viruses that occasionally cause pneumonia in high-risk hosts and three that cause severe acute respiratory syndromes (SARS, MERS, and COVID-19) (Box 2 and SI Appendix, Table S3 ).

Molecular clock analyses of common cold CoVs indicate that the original zoonotic spillovers occurred at least 100 to 1,000 y ago (Fig. 2). Common cold CoVs have since become endemic in humans, transmitted via respiratory droplets, aerosols, or fomites. The remarkable emergence of three highly consequential new CoVs (SARS-CoV, MERS-CoV, and SARS-CoV-2) in humans in the past two decades likely reflects increased spillover risks via land use change; greater contact between humans, livestock, and wildlife; and expanding wildlife farming, trade, live food markets, and global travel and trade.

The ancestral hosts of the SARS-CoV and SARS-CoV-2 viral lineages are thought to be Rhinolophus (rhinolophid) spp. bats (22) and Pipistrellus and Neoromicia (vespertilionid) bats for MERS-CoV (23) (SI Appendix, Fig. S1 ). Evidence indicates SARS-CoV and MERS-CoV emerged indirectly from bats via an intermediate animal host subsequently transmitting infection to people. For SARS-CoV, it most likely involved infected masked palm civets (Paguma larvata) or possibly common raccoon dogs (Nyctereutes procyonoides) or Chinese ferret badgers (Melogale moschata) in live animal markets (SI Appendix, Table S3 ). There were four individual zoonotic infections in China a few months after the initial SARS-CoV outbreak, but no subsequent zoonotic spillovers were identified (24); however, there is no basis to presume SARS-CoV has become extinct. Closely related CoVs expressing spike (S) proteins binding to angiotensin-converting enzyme (ACE2), the human receptor protein, have been identified in bats, raising the possibility that a virus closely related to SARS-CoV could reemerge (22, 25). MERS-CoV was circulating endemically in dromedary camels (Camelus dromedarius) for decades before human cases appeared. It remains endemic in these animals, resulting in continuing zoonotic spillovers (26).

Animal CoVs are a substantial risk to farmed animals and people because of their ability to mutate, recombine, and become more transmissible and/or virulent and their history of cross-species and zoonotic transmission (27). They provide a One Health perspective in nature to help us better understand CoV evolutionary trajectories and the risk of human spillovers (Box 3).

For example, mutations, deletions, and recombination events have created multiple lineages of porcine CoVs with altered virulence, tissue tropism, and potential for cross-species infections (Box 3, Fig. 2, and SI Appendix, Table S4 ) (11). These include transmissible gastroenteritis virus (TGEV), described in 1946; porcine epidemic diarrhea virus (PEDV), which emerged in Europe in the 1970s, recently reappeared as a highly virulent variant in China and the United States, and now is endemic worldwide; recombinants that include elements of both; and porcine respiratory coronavirus (PRCV), a TGEV deletion variant with respiratory tract tropism that transmits via aerosols (28). Avian-origin porcine delta-CoV has recently been recovered from humans with febrile illnesses (29), raising concerns that it could mirror recombination events for influenza viruses and potentially become a future World Health Organization (WHO) pandemic disease “X” (30). The bat-origin swine acute diarrhea syndrome CoV emerged in pigs in 2016 (31) and also replicates in primary human airway epithelial cells, suggesting it too has future spillover potential to humans (32).

The increasing global population of farmed and domestic animals provides other cross-species transmission opportunities. Canine CCoV, feline coronavirus (FCoV), and TGEV are a single CoV species within a multihost reservoir community in dogs, cats, and pigs (33), with rare spillovers to humans (Hu-CCoV) (SI Appendix, Table S3). Beta-CoVs circulating in cattle and wild cervids occasionally infect birds or humans (34 –36). Recent spillover of SARS-CoV-2 from humans to white-tailed deer may represent another long-term reservoir community with spillback potential to humans (SI Appendix, Table S4 ) (37, 38). Spillover of SARS-CoV-2 from humans to farmed mink and mink-to-human spillback are already well described (39). Evolution of these viruses in susceptible animal hosts represents a plausible threat for future disease outbreaks among animals and humans.

Analyzing the origin, early spread, and pandemic emergence of SARS-CoV-2 is critical to understand how to prevent and control future zoonotic viral emergence. The initial phase of COVID-19, from December 2019 through January 2020 in Wuhan, China, began with the recognition of a cluster of patients with SARS-like illnesses. By early January 2020, a novel Severe Acute Respiratory Syndrome-related coronavirus (SARSr-CoV; subsequently renamed SARS-CoV-2) was identified by next-generation sequencing (NGS) of human respiratory samples. This quickly led to a PCR diagnostic to track virus spread within and outside of China (SI Appendix, Fig. S2 ) and evidence of human-to-human transmission within families. On 30 January 2020, WHO declared the outbreak a Public Health Emergency of International Concern.

The prevaccine phase 2, from February to the end of 2020, was an unnecessary tragedy as national leaders in many countries denied the seriousness of the outbreak, failed to provide reliable information to the public, or failed to promote the use of effective public health measures (40). Early warnings without follow-up actions have limited impact. By the end of 2020, over 100 million cases and 2 million deaths had occurred, and many countries were struggling to sustain patient care and public health capacity. The major triumph was the development and emergency use approval of vaccines. However, production was insufficient for global needs, further compromised when some high-income countries made advance purchase agreements for most of the supply. This practice, characterized as “vaccine nationalism,” precluded equitable vaccine sharing based on a strategic plan to control pandemic spread and impact at the global level. Monoclonal antibodies and antivirals were also approved, but infusion capacity limited utilization of antibodies while therapeutics became available in just a few countries.

The vaccine and emerging variants phase 3 has continued from January 2021 to the present. While several vaccines have been safe and highly effective in reducing severe illness and death, even in high-risk individuals, in some countries many people with access to these vaccines have hesitated or simply refused to be immunized. Continuing transmission of infection increases the likelihood of emerging variants, an expected consequence of mutations accumulating when an RNA virus outbreak is not contained. By the end of 2021, WHO had designated five strains as variants of concern because their attributes suggested potential enhanced transmission, virulence, or immune evasion. Two, Delta and Omicron, surged sequentially in mid- to late 2021, each displacing the prior circulating variant and increasing infections, hospitalizations, and deaths. The future is uncertain as more transmissible Omicron variants emerge and spread globally. By 1 August 2022, WHO reported well over half a billion cases and more than 6.4 million deaths worldwide. The real toll of SARS-CoV-2–related deaths is considerably greater, with at least 14.91 million excess deaths reported by 31 December 2021 or 9.49 million more than previously attributed to SARS-CoV-2 (https://www.who.int/data/stories/global-excess-deaths-associated-with-covid-19-january-2020-december-2021).

A recent analysis of 10 community-based longitudinal studies of patients in the United Kingdom with a diagnosis of COVID-19 in their electronic health care records identified 7.8 to 17% with symptoms persisting beyond 12 wk, termed “long COVID” (long coronavirus disease) (41). This represents an additional long-term health and economic burden of the pandemic. Unfortunately, systematic clinical research of long COVID has just begun, the underlying pathophysiology is not understood, and there are no clearly effective interventions. We may also be at the cusp of another epidemiological phase of COVID-19, with continued community circulation, evolution of the virus, and increasing endemicity in humans and animals (39, 42).

COVID-19 is the latest in a continuing series of RNA virus outbreaks (Fig. 1); however, its health, social, behavioral, economic, and political consequences have been enormous. These impacts are precisely why we must learn from the ongoing pandemic, look forward, and identify things we can change to reduce the risk of future pandemics, prevent them when possible, or rapidly mitigate and control them when necessary.

There are three fundamental approaches: first, “smart” surveillance to coordinate surveillance with risk assessment for animals and people, focusing on the places, communities, and animal–human interfaces where evidence shows that emerging diseases are likely to originate; second, basic and translational research informed by smart surveillance to identify priority pathogens, enhance pandemic preparedness, and design better prototype vaccine and therapeutic platforms; and third, governance structures and policy measures to prevent future EIDs by reducing the influence of factors that drive spillover risks from wildlife or farmed wild animals to people.

Vaccines are central to reducing pandemic consequences, and their development requires long-term research investments, exemplified by the importance of prior platform vaccine research to enable the rapid development of safe and effective SARS-CoV-2 vaccines. Access to research tools also permitted evaluation of therapeutics developed for other pathogens, such as Remdesivir, as therapy for SARS-CoV-2. Some also show efficacy against “prepandemic” bat CoVs, such as WIV-1 and MERS-CoV (SI Appendix, Table S7 ). Smart surveillance can inform preparedness research and development (R&D) by identifying viral targets with high emergence potential for vaccines and therapeutics before an outbreak emerges (64). More platform technologies for additional families of potentially epidemic pathogens would speed product R&D for a newly emerging threat, even if not timely enough to mitigate the first wave. This is why current enthusiasm for platform technologies must not detract from continuing One Health efforts to reduce the risk of emergence itself.

Vaccination of animal reservoirs can reduce threats to people: for example, oral baits have been used to vaccinate wild raccoons against rabies (65). Proposed self-disseminating vaccines for wildlife might reduce the risk of spillover of other zoonotic pathogens (66). Immunization of critical amplifier hosts could potentially limit virus evolution toward enhanced transmission or virulence. Examples include vaccinating poultry or swine for emerging animal influenza A strains or camels for MERS-CoV in endemic countries (67).

Given the rise of vaccine hesitancy and the politicization of COVID-19 responses in the United States, Europe, and many other countries, research into how people access and process scientific research findings, public health advice, misinformation, and disinformation is critical (40, 62, 64).

Wildlife farming, trade networks, live markets, and expanding domestic livestock production are sources and drivers of EIDs (68). Permitting current wildlife farming and trade to continue indefinitely is a high-risk and unsustainable policy that urgently needs rethinking. However, incentives to consume wildlife are often deeply rooted in centuries-old cultural practices, so policies to modify rather than ban this system are more likely to succeed in reducing spillover risk. Interventions informed by smart surveillance at relevant interfaces include behavior change programs, risk education, more effective communication, enforcement of regulations, and incentives for more sustainable food production. Expansion of wildlife farming and trade is often linked to economic growth in developing countries that are also EID hot spots (8), and the disconnect between profits driven by private sector enterprise and deferred health costs primarily borne by the public sector can make prevention policies ineffective (69). Systematic long-term efforts to explain their importance to politicians and the public will be critical.

Global consumption patterns often exploit natural resources in EID hot spots for the benefit of those living far away, linking one country's consumption to another’s disease burden, such as wildlife farming in Asia to produce fur for fashion products largely sold elsewhere. This challenge is reflected by the Chinese Government’s decision to close all wildlife breeding farms for food animals on 24 February 2020 but specifically exclude wild animals farmed for the fur trade, including mink, raccoon dogs, and foxes, all susceptible to SARS-CoV-2 infection. Policy changes based on scientific evidence from smart surveillance, understanding optimal intervention points, and partnerships with economically important industries to reduce spillover potential would likely benefit public health. To be most effective, this ultimately requires broad social transformative changes in behavior and consumption patterns.

Infectious diseases will continue to emerge or reemerge. RNA viruses, especially those with a propensity to mutate and/or recombine among strains affecting multiple host species (influenza A viruses and CoVs), pose a “clear and present danger.” History shows that we have failed to heed the lessons from past EIDs, and science shows that the rate of emergence is accelerating. An integrated One Health strategy going forward offers the potential to mitigate emergence and implement rapid response when necessary to reduce impact.

The following recommendations for translating what we have learned into action reflect an underlying core principle that the capacity for prevention and preparedness is as important as the capacity for response. This can only be achieved through the adoption and application of a One Health approach.