Four years after the last emergent epidemic of zoonotic SARS-coronavirus in 2003, researchers at the University of Hong Kong asked if the world was ready for the re-emergence of SARS (Cheng et al, 2007).
Despite over 4000 publications since 2003, the assessment highlighted the persistent gaps in scientific achievement relating to the perception of zoonotic coronaviruses. Up until 6 months ago, this evaluation in the face of anticipated further epidemics of a coronavirus still held true (Cheng et al, 2007; Mubarak et al, 2019).
This article-the second in a series on the science behind the pandemic-explores the opportunities for learning from previous human epidemics of coronaviruses and highlights the unintended consequences of underestimating the evolutionary aptitude of this family of viruses to ensure species survival into the next generation.
Zoonotic infectious disease
Zoonoses may be bacterial, viral or parasitic and are defined as any disease or infection that is naturally transmissible from a vertebrate species to humans (WHO, 2020). Zoonoses, as with many infections, can be transmitted through direct contact or indirectly via food, water or the environment. It is estimated that <0.1% of animal viruses are zoonotic with some inherent ability to replicate in humans (Warren and Sawyer, 2019).
For the spilling over into a new host species to be successful, zoonosis requires that progenitor viral variants are compatible with a new host environment: the predilection for failure is biased by the multiple host-specific protein interactions that must be successfully navigated for survival at this primary stage of transmission.
El-Aziz and Stockand (2020) described how the Coronaviridae family contains four genera, which include alpha-coronavirus (alphaCoV), beta-coronavirus (betaCoV), delta-coronavirus (deltaCoV) and gamma-coronavirus (gammaCoV). Although zoonotic disease is not a new concept in the field of human infection, if conditions are fit for the mutation and amplification of a virus, the opportunity is likely to produce a new disease that, once introduced, adapts to enable transmission within that animal species (Cheng et al, 2007).
Coronaviruses are an established source of disease in animal species. Natural reservoirs from which zoonotic outbreaks of disease have emerged include bats, rodents and dromedary camels, while the role of intermediary hosts such as civet cats and pangolins enabling species transcendence is not fully understood (El-Aziz and Stockand, 2020; Hamid et al, 2020). High genetic diversity and the ability to infect multiple host species are a result of high-frequency mutations in CoVs, which occur due to the instability of RNA-dependent RNA polymerases along with higher rates of homologous RNA recombination (Dhama et al, 2020).
SARS-CoV-2 is most closely genetically related to group 2 of the Coroniviridae family, showing 90.6% nucleotide identity with BatCoV RaTG13 in one study (Zhang et al, 2020). Although SARS-CoV-2 is believed to be zoonotic, the theories of when the virus successfully interacted with a human host via natural selection may predate the Wuhan reference made in the literature (Anderson et al, 2020).
Structurally, coronaviruses are similar, and the characteristic coronet ‘spike’ proteins on the surface of the virus particle (Figure 1) are a site of investigation for the mechanism of action as to how inter host transmission can occur once zoonosis has occurred.
Figure 1. Structure of SARS-CoV-2
Without prior exposure and, therefore, no inherent immunity, the initial impact on a population of a zoonotic disease can be considerable. Understanding which mutant characteristics of a virus can then facilitate human to human transmission is important to suggest future organism candidates for zoonotic capability and to inform human vaccine and therapeutic sites for intervention. A recent study by Ortega et al (2020) observed mutations in the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein subunit S1. The series of observed amino acid substitutions and deletions in the RBD may explain the significant effect on SARS-CoV-2 spike/ACE2 receptor interaction, which induced a reduction in binding energy, compared with the one of the Bat-CoV to the same ACE2-receptor binding site.
The variance in the host receptor specificity for the viral spike protein may account for the rapid human-to-human spread of SARS-CoV-2 and offer some insight as to the origins of this and future zoonotic coronavirus outbreaks (Ortega et al, 2020; Wong et al, 2020).
Phylogenetically related species of beta-coronavirus have been responsible for significant outbreaks of emergent infectious disease in recent years, including severe acute respiratory syndrome (SARS-CoV) in 2002 and Middle East respiratory syndrome (MERS-CoV) in 2012.
SARS-CoV and MERS-CoV: what can be learnt to combat COVID-19
In November 2002, the first known case of severe acute respiratory syndrome (SARS) occurred in Foshan, Chin; a remarkable effort led to the identification of SARS coronavirus (SARS-CoV) in early April of that year, optimised by effective co-ordination by the WHO (De Wit et al, 2016).
Ten years later, in June 2012, a novel coronavirus (MERS-CoV) was identified from the sputum of a man who died of acute pneumonia and renal failure in Saudi Arabia. A cluster outbreak in Jordan from April that year was retrospectively confirmed as MERS-CoV with sporadic cases continuing to be identified internationally, often associated with nosocomial transmission originating in the Middle East (De Wit et al, 2016).
The outbreaks caused by previous SARS and MERS coronaviruses can be characterised by similar respiratory pathology, progression and epidemiology, yet they differ in scale when compared with SARS-CoV-2.
Although the progenitors of SARS-CoV and MERS-CoV were probably bats, both SARS-CoV and SARS-CoV-2 are believed to have required an incidental intermediary host that may have amplified the genetic supremacy, which resulted in the zoonotic transmission (Du et al, 2009; De Wit et al, 2016; Liu et al, 2020).
The coronaviruses-mammalian and avian-initially target the epithelial cells of the host and produce symptoms consistent with local inflammation. All three of the zoonotic genetic variants can initiate severe respiratory disease in humans as a result of local infiltration of the respiratory epithelial mucosa and aberrant inflammatory responses. High viral load and shed is associated with established infection in acutely unwell patients exhibiting systemic disease. This may account for the phenomenon observed in both MERS-CoV and SARS-CoV-2, of higher-than-population average rates of infection observed in healthcare workers. During the SARS-CoV outbreak, in mainland China by February 2003, more than around one-third of the 300 cases reported were in healthcare workers (De Wit et al, 2016).
The implications of a higher number of infected healthcare workers are multiple. A potentially disproportionate reproduction number (R0) in healthcare facilities through direct contact is likely to increase healthcare-acquired infections and impact on staffing capability. Indirect nosocomial transmission is possible as a result of MERS-, SARS- and influenza-contaminated surfaces and equipment in hospitals and care facilities (Otter et al, 2020).
MERS, SARS and SARS-CoV-2 are each associated with poorer outcomes where co-morbidities pre-exist (Park et al, 2020). Patient risk factors of advanced age and being male are associated with progression to severe disease (Liang, 2020; Lu et al, 2020). In MERS-CoV patients, chronic conditions such as diabetes mellitus, hypertension, cancer, renal lung and co-infections (de Wit et al, 2016) were negatively associated with outcome and, in the recent epidemic of SARS-CoV-2, excess weight (measured as a BMI>25kg/m²), has been identified as an additional major risk factor (Public Health England (PHE), 2020a).
In the UK, during the SARS-CoV-2 pandemic, a disproportionate number of people identifying as black or from an ethnic minority group have a greater risk of acquiring COVID-19, of dying of COVID-19 or both (PHE, 2020b). Although the Chief Medical Officer-commissioned report does not account for the effect of occupation, comorbidities or obesity, it does state that ethnicity and income inequality are independently associated with COVID-19 mortality (PHE, 2020b). Individuals from black and minority ethnic (BAME) groups are more likely to work in occupations with a higher risk of COVID-19 exposure, and the outcomes of BAME healthcare colleagues, therefore, warrant further urgent research.
The SARS and MERS epidemics affected significantly fewer people and spread to a much lower number of countries than is being observed in the COVID-19 pandemic. Through human-to-human transmission, SARS-CoV affected 8096 people, and 774 deaths were reported between November 2002 and July 2003, representing a mortality rate of 10% (De Wit et al, 2016). Originating in China, SARS-CoV was spread by infected international travellers to 30 countries, including Vietnam, Hong Kong and Canada (Guan et al, 2004).
MERS-CoV was associated with cluster outbreaks predominantly in Saudi Arabia, the Middle East and Korea. As of February 2019, 2279 confirmed cases of MERS had been reported, including 806 deaths spanning 27 countries, reflecting a significantly higher crude mortality rate of 35% than that experienced globally during the SARS-CoV outbreak of 2003-4 (Mubarak, 2019).
Park et al (2020) reflected on the positive learnings from the previous epidemics. Earlier and timely communication with the relevant global surveillance agencies within 4 weeks of the first of SARS-CoV-2 in China is a feature of this latest epidemic, in contrast to the SARS outbreak, when the delay was 4 months. Prompt and candid sharing by China on 12 January, of the genetic code for the 2019 novel coronavirus, the given nomenclature at that time, enabled countries such as South Korea to expand testing capacity eight-fold within 8 weeks (WHO, 2020b).
Possibly due to the advances in technology and bioinformatics since the original zoonotic epidemic of SARS, this facilitated the identification of the novel pathogen using whole-genome sequencing and the development of PCR-based diagnostic tests. Subsequent sharing of the bioinformatics expedited the identification of cases in Europe: the UK extended PCR testing capability from one tertiary PHE laboratory to a national programme of rollout delivered by PHE regional laboratories, NHS trusts and universities.
Compiling the data sets of coronavirus variance is a live process. Underwritten by the WHO and provided by scientists and virologists, genetic sequences, clinical and epidemiological data as well as geographical and species-specific data associated with avian and other animal viruses, is contributing vast evolution and transmission information to a central hub (GISAID, 2020). Researchers are using this database to track how viruses evolve and spread during epidemics and the ongoing pandemic.
The experience of SARS and MERS has meant there are defined themes of research, and immunogenics is one of these (London School of Hygiene and Tropical Medicine, 2020). Seeking predictive markers of why some people exposed to SARS-CoV-2 develop COVID-19 and others do not is equally relevant. ‘Cytokine storms' are thought to be major contributors to the severity of many viral lower respiratory tract infections, such as influenza and SARS (Parks et al, 2020). The severity of the diseases that are caused by emerging coronaviruses highlights the need to develop effective therapeutic measures against these viruses (De Wit et al, 2016). Although several treatments for SARS and MERS (based on inhibition of viral replication with drugs or neutralising antibodies or on dampening the host response) have been identified in animal models and in vitro studies, efficacy data from human clinical trials are urgently needed.
Despite monumental efforts by the WHO to coordinate ongoing research to date, no effective prophylaxis or treatment has resulted in any specific treatment or vaccine against MERS-CoV or SARS-CoV; therapies are targeted at symptom control and supporting respiratory, cardiac renal and gastrointestinal system function (Mubarak et al, 2019).
These earlier significant clusters and epidemics of coronavirus in the human population have been described as ‘self-limiting’; infection prevention and public health measures were largely responsible for control and not attributable to any chemotherapeutic interventions to enhance a protective host immune response to infection or inhibit immunopathogenesis (Parks et al, 2020).
Exposure to infection and the human experience of disease caused by SARS-CoV-2 is neither consistent nor equitable. Is it too simplistic to consider that disease spread and the emergence of zoonotics are largely the product of human activity and choice (WHO, 2004)? Diversity in infection control and public health knowledge, access to veterinarians, antimicrobial usage and use of animal husbandry technology in lower- and middle-income countries inevitably means variance in the choices local communities can make. Further, this rather ignores the role of natural selection to ensure species survival, for which significant pathogenesis is a critical technique.
Conclusion
Unlike the previous outbreaks of SARS and MERS, despite rigorous global containment and quarantine efforts, the incidence of COVID-19 continues to rise, with more than 16 million cases and over 646 000 attributed deaths worldwide (WHO, 2020c). It is, without, doubt a pandemic, and the ubiquitous spread of this viral pathogen necessitates a global solution.
The learning here is perhaps that a collaborative scientific investigation is needed, focused on minimising the genomic opportunism exhibited by selected viruses. As these organisms exploit their unique structural characteristics that enable inter-species conduction, the human community must respond with and this demands an equally unified, informed and international approach to infection prevention and control.
KEY POINTS
- The virus responsible for the ongoing 2020 COVID-19 pandemic is a novel one that was transmitted zoonotically to human beings
- However, lessons on infection prevention and control can be learnt from previous outbreaks of similar zoonotic coronaviruses, namely, SARS-CoV and MERS
- Groups of society particularly vulnerable to COVID-19 have been identified (e.g. older adults and men)
- Chemotherapeutic interventions for infection prevention and control are not as effective as public health measures
- Collaborative scientific investigation should focus on minimising the genetic opportunism shown by these viruses
CPD REFLECTIVE QUESTIONS
- What are the potential origins of the SARS-Co-2 pandemic?
- At what point is the initial interaction between the host and virus cells a favoured target for research into therapeutic intervention?
- How might the experience of SARS, MERS and now COVID-19 help us to develop community practice strategies to protect the most vulnerable in society?