The history of Covid-19 within context of coronaviruses

By Dr Lara Marks, Visiting Research Fellow, Department of Medicine, University of Cambridge and Managing editor of WhatisBiotechnology.org

Publication date: 1 May 2020

Covid-19 is a disease caused by a new human virus that was first identified by Chinese scientists on 7 January 2020 after reports began to surface that workers from Huanan Seafood Wholesale Market in Wuhan had developed unusual pneumonia. Worryingly, the respiratory illness resembled that of severe acute respiratory syndrome (SARS). This was a disease that rapidly spread through the world between 2002 and 2003 as a result of the emergence of a novel virus, subsequently called SARS-Cov, in the Guangdong province of southern China. Because of this, the International Committee on Taxonomy of Viruses decided to call the new virus 'severe acute respiratory syndrome coronavirus 2' (SARS-CoV-2). The disease associated with the virus was subsequently called the 'Corona Virus Disease 2019', shortened to Covid-19, by the World Health Organisation. The number '19' denotes the year 2019 when the virus was first seen (Anon; ICTV).

One of the first people to suspect there could be an outbreak of a new SARS-like viral infection was Ali Fen, the director of the emergency department at Wuhan Central hospital in China. According to an interview she gave to the Chinese Magazine, Renwu (China's People), Fen received a screenshot of a WeChat conversation at noon on December 30th 2019 from one of her former medical school classmates at Tongji Hospital in Wuhan. It said: 'You don't want to go to Huanan [Market] just now, there are lots of people with high fever'. Fen replied by sending him a 11-second video of a CT scan she had just performed on a patient with a pulmonary infection who had come from the market that morning into the emergency department. Just four hours later Fen read a diagnostic report shown to her by one of her colleagues. It indicated that the oral cavity and or respiratory tract of another patient, who had also presented with pneumonia, had been colonised by a 'SARS coronavirus'. The report was accompanied by a supplementary note which stated: 'SARS coronavirus is a single-stranded positive-strand RNA virus. The main mode of transmission of the virus is close-range droplet transmission or contact with respiratory secretions of patients, which can cause an unusual pneumonia that is highly contagious and can affect multiple organ systems, also known as atypical pneumonia (Bik;Kuo).

Ai Fen

Photograph of Ai Fen, credit: Renwu, https://archive.vn/y6fTu. Ai Fen played a key role in sounding the alarm about COVID-19. She became head of the emergency department at Wuhan Central Hospital in 2010.

Disturbed by what she read, Fen broke out in a cold sweat. What worried her was that this was not the first time she had seen such a result. She had also read a similar report for another patient she examined on 16 December 2019 and another from someone she had seen on 27 December 2019. The first patient had been a delivery worker from Huanan Seafood Wholesale Market and the second a 40-year-old nephew of an emergency doctor in Fen's department. All the tests had been performed on bronchoalveolar fluid samples taken from the patients using genetic sequencing (Bik;Kuo).

On reading the latest report, Fen immediately phoned the division of public health and infectious disease in the hospital to call attention to the problem. Following this, she showed the report to the director of the respiratory department who happened to be passing by her office. One look from the director confirmed her suspicions that the matter was serious. After circling the word 'SARS' in red, Fen took a photo of the report and sent it to a doctor in another Wuhan hospital, who she had been with at medical school. That evening Fen's hospital's officials told her not to share the information to avoid causing panic among the public. By then, however, it was too late. Fen's photo had already spread to many other doctors in Wuhan. One of these was Li Wenliang, an ophthalmologist at Wuhan Central Hospital, who the same day posted Fen's photo on to a private WeChat group composed of his former medical school classmates. The very next day, December 31st, Fen was summoned by the head of the hospital's disciplinary inspection committee and severely reprimanded (Bik).

Wenliang Li

Photograph of Wenliang Li (1896-2020), credit: Wikipedia. Born in Leizhen, Lianoning, a city in North-East China, Li completed a degree in medicine at Wuhan University School of Medicine in 2011. He took up a position as an ophthalmologist at Wuhan Central Hospital in 2014. On January 3rd 2020, Li was summoned to the Chinese Public Security Bureau for his part in spreading Ai Fen's photo. One of eight people investigated by the Chinese police, for what they alleged 'spreading rumours on the internet', Wenliang was made to sign a letter to apologise for having distrubed the social order. A few days later, on January 10th, Li developed a cough and the next day a fever. He was hospitalised two days later and diagnosed with the coronavirus on January 30th. Wenliang died on 7 February 2020 aged 33 years old. His death sparked widespread outcry on Chinese social media, with people expressing their gratitude for his front-line service and willingness to speak out about the slowness of Wuhan's medical officials to respond to the outbreak. So great was the pressure, that the Chinese authorities were forced to undertake an investigation into what had happened. The report from the investigation exonerated Wenliang (Green).

Over the course of the next few days Fen continued to hear of new cases, with more and more patients coming from a wider radius. Effectively silenced by her superiors, Fen poured her energy into getting staff within her emergency department to wear protective clothing. She also advised them to put masks on themselves and their patients. Meanwhile, the hospital's internal operations committee refused to countenance her staff wearing isolation gowns for fear that it would cause panic. By January 11th had received a report of the first nurse who had become infected within the hospital - Hu Ziwei. Thereafter, other healthcare workers in the hospital were struck down. Those least affected were the ones working in the emergency and respiratory department who early on took measures to wear protective clothing (Bik).

On December 31st 2019 the World Health Organisation was informed of the events happening in Wuhn and the Wuhan Municipal Health Commission issued its first warning to the public not to go to enclosed public places in the city and suggested face masks be worn. The next day the Chinese National Health Commission set up a team of experts to go out and investigate the outbreak and to determine what emergency response should be taken. All travel to and from Wuhan city WAS banned from January 23rd and soon a national emergency response began to be rolled out throughout China. So quick was the spread of infection, that seven days later the World Health Organisation (WHO) declared the outbreak to be a 'public health emergency of international concern'. By now scientists around the world had begun to work on the disease. They were helped by the fact that a group of Chinese scientists, led by Yong-zhen Zhang at Shanghai Public Health Clinical Centre and Public Health, completed the genome sequence of the novel virus on January 5th. The first full sequence was shared with the world on open platforms on January 12th (Cohen).

Covid-19 has been established to be caused by a new coronavirus which measures 80 billionths of a metre in diameter. Such viruses are made up of a single strand of ribonucleic acid (RNA), which is their genetic material. Coronaviruses have the longest single strand RNA genomes. The RNA is wrapped in a fatty outer layer of lipids called an 'envelope'. Like other viruses, coronaviruses cannot reproduce on their own. They replicate by invading the host cell and hijacking its machinery to produce more copies of themselves, which then infect other cells. Coronaviruses are able to enter human cells by hooking themselves on to a specific receptor found on the outer surface of certain cells in the body. Once inside the cell they use an enzyme called RNA-dependent RNA polymerases to replicate. While coronoviruses have a proof reading function, which involves a viral ribonuclease enzyme, this process is highly prone to error. This means that coronaviruses can mutate although their mutation rate is considerably less than other RNA viruses. A mutation can provide the virus with new characteristics, such as the ability to penetrate new cell types or jump from animals to humans (Makin).

Components of SARS-CoV-2

Components of SARS-CoV-2. Credit: Avesta Rastan, https://lnkd.in/eMN6rmV. Scientists have established that the Spike (S) protein found on the surface of the virus has a strong capacity to bind to a receptor called angiotensin-converting enzyme 2 (ACE2) found on the surface of certain cells, particularly in the lungs, arteries, heart, kidney and intestines. The ACE2, a transmembrane protein, serves as the entry point for the virus. Research is now underway to see if the S protein can be prevented from binding to the ACE2 receptor human cells as part of the effort to develop a vaccine and effective treatment (Sheridan).

Coronaviruses are not new. The first coronavirus was found as a result of an outbreak of a new respiratory disease among baby chicks in North Dakota in 1931. Occurring in chicks aged 2 days to 3 weeks, the new disease was characterised by gasping and listlessness. Between 40 and 90 per cent of those infected died. Found to be easily transmissible, the nature of the infectious agent responsible for the new disease was not immediately obvious. Early on it became clear that the new disease, called avian infectious bronchitis, was not caused by a bacteria or a toxin and its cause remained a mystery. In 1937 a virus was identified as the culprit. This was done by Fred Beaudette and Charles Hudson, two American veterinary microbiologists based at the New Jersey Agricultural Experiment Station. They managed to isolate the virus and then cultivate it chick embryos (Beaudette, Hudson; Fabricant).

For many years coronaviruses were assumed to be primarily associated with animal disease. This all changed in the early 1960s after scientists isolated viruses in humans with unusual properties in samples taken from people with the common cold. The first, labelled B814, was detected by a team of British scientists led by David Tyrrell at the Medical Research Council and Ministry of Health Common Cold Research Unit in Salisbury. Found in 1962 the virus was detected in throat swabs and nasal washings taken from boys (aged -12-17) residing at a boarding school in Surrey, all of whom had the common cold. Each of the boys had an acute infection of the upper respiratory tract with nasal blockage and discharge (Kendall, Bynoe, Tyrrell). Initially the researchers struggled to grow B814 in the laboratory in routine cell culture, but they eventually found a way to cultivate it in trachea-derived organ cultures and found that it could transmit the common cold when given to human volunteers.

Soon after managing to grow B814, Tyrrell's team received another virus specimen, called the virus 229E, from Dorothy Hamre, a virologist based at the University of Chicago. She and her colleagues had isolated it from samples taken from the human respiratory tract of six medical students at Chicago School of Medicine suffering from colds in the winter of 1962. Tyrrell's group found that 229E, like B814, could transmit the symptoms of the common cold to volunteers after it was grown in organ cultures. Both viruses were found to be highly susceptible to being broken down by ether, a solvent that could dissolve fat. This suggested that coronaviruses, like myxoviruses (a family of viruses that cause influenza), had an outer lipid membrane. Yet, serological tests, which measure the immune response to a pathogen, indicated the new viruses were unrelated to myxoviruses (Hamre, Pockrow;Bradburne, Bynoe, Tyrrell).

Unable to actually see the viruses, the only way that Tyrrell and his team could confirm they had successfully cultivated them was by inoculating volunteers with them to observe if they developed the symptoms of the common cold. Keen to find a method to detect a virus that did not necessitate the use of volunteers, Tyrrell turned to Tony Waterson, a new professor of virology at St Thomas' Hospital in London. By chance, Waterson had just hired June Almeida, a virologist who was highly skilled in uncovering the structure of viruses using an electron microscope. This was not an easy process. The chief difficulty was being able to distinguish between what was a virus and other cell components like a protein. Some progress had been made in the late 1950s through the introduction of negative staining. Formulated by Sydney Brenner and R W Horne, two scientists based in the Cavendish Laboratory in Cambridge, UK, this method involved mounting air-dried droplets of biological particles on grids and then spraying them with a solution that contained potassium phosphotungstate, a heavy metal, which helped to stain the background, leaving the specimen untouched. This made it possible to detect a virus more clearly (Brenner, Horne).

Despite the breakthrough, electron microscopy was difficult without purified preparations of the virus. This was a major challenge for Tyrrell because the viruses he was studying only infected a small proportion of cells in organ culture. He was therefore only able to get a very small concentration of viral material. Almeida, however, had pioneered a method in 1963 that enhanced the negative staining procedure. Known as immune electron microscopy, Almeida's technique enabled the visualisation of semi-purified preparations under the electron microscope as they occurred within the cell. It involved mixing virus preparations with antibodies raised in goats and rabbits to enable the virus particles to bind to antibodies in clumps. This provided a good concentration of viral particles together, which made it easier to distinguish them from other objects under the microscope. The virus could be picked out because the antibodies were much smaller than them and they also had a different shape (Rowlands; Almeida, Howatson; Almeida, Tyrrell).

June Almeida

Photograph of June Almeida (née Hart) (1930-2007), credit Joyce Almeida, (Boos, August). Almeida grew up in a flat in a tenement building in Glasgow and left school at the age of 16. Originally trained as a laboratory technician in histopathology, Almeida went on to become an internationally renowned virologist as a result of pioneering immune electron microscopy. She first published her technique with colleagues at the University of Toronto, in 1963. It was first tried out on the Verruca Vulgaris Virus and the Polyoma Virus (Almeida, Cinader, Howatson). To read the full story of June Almeida’s life and work click here.

What was attractive about Almeida's method was that it provided a means to directly detect virus particles at high resolution growing in the organ cultures provided by Tyrrell. Accordingly, Tyrrell's group sent a collection of organ tissue samples in bottles by train to London for Almeida to investigate. This included samples the team had infected with well-known viruses such as influenza and herpes as well as B814. On negatively staining the tissue samples and examining them under a microscope Almeida noticed the B814 virus appeared to be very similar, but not the same, in appearance to influenza viral particles. They also resembled viral particles she had previously found when studying mouse hepatitis liver inflammation and infectious bronchitis of chickens. From her observations she was convinced that a new group of unrecognised viral species had been identified. The question was what to call the new viruses. Based on the fact that under the microscope the virus particles appeared to display short spikey projections on their outer surfaces, which made them look like a crown, Almeida, Tyrrell and Waterson decided to call them coronaviruses. The term was derived from the Latin word 'corona', meaning 'crown' or 'halo' (Tyrrell, Fielder).

Despite Almeida's breakthrough, the paper she wrote describing the new virus was initially turned down for publication. This was because its reviewers judged Almeida's images of the B814 virus to be just 'bad pictures of influenza virus particles' (Winter; ECDC 2020). Almeida's findings were eventually published in a paper she jointly authored with Tyrrell in 1967. Their paper highlighted the fact that both B814 and 229E shared the same characteristics of avian infectious bronchitis (IBV) (Almeida, Tyrrell 1967). Soon afterwards Kenneth McIntosh and colleagues, working in the laboratory of Robert Chanock at the National Institutes of Health (NIH), reported that they had successfully cultivated 6 strains of viruses using the same organ culture method devised by Tyrrell. One of the viruses was labelled OC43. The viruses originated from specimens taken from the respiratory tract of NIH employees with acute respiratory illness. Like B814 and 229E, the viruses proved to be ether sensitive and to have the same characteristics as IBV when viewed under the electron microscope (McIntosh et al).

Image of 229E coronavirus

Image of 229E coronavirus, 1975. Credit: Fred Murphy, 1975, CDC.

The task of identifying human coronaviruses in clinical samples, however, remained very difficult in the 1960s and 1970s. In part, this was because tissue culture, the means by which many viruses are grown and maintained, was still very primitive. Most tissue cultures used fragments from living tissues. Tyrrell's method, for example, used tissue fragments prepared from the tracheas of human embryos that were incubated with a medium in petri dishes. Once prepared, Tyrrell dripped into the tissue culture the nasal washings taken from volunteers with the common cold. Following this, the medium had to be removed each day from the tissue culture and mixed with broth to be stored at a very cold temperature for ten days after which it was fixed with a particular solution and stained (Tyrrell, Bynoe). The process of tissue culturing was therefore a laborious and cumbersome process. As McIntosh recalled, it demanded 'intensive attention to the welfare of tissue cultures over the course of 3 or 4 weeks' as well as an ability to spot subtle changes in the cells (McIntosh).

Over the next three decades it became clear that there were a number of human coronavirus strains associated with a variety of respiratory illnesses. In the 1970s these were broadly grouped into two groups. Those in group 1 were strains that were biologically and genetically related to the 229E strain described by Hamre. Such coronaviruses could be grown from clinical specimens in tissue culture, albeit with some difficulty. Group II covered coronaviruses related to the OC43 virus identified in Chanock's Laboratory. These viruses could only be grown in organ cultures of human embryonic trachea. Some were antigenically related to the mouse hepatitis virus and grew in the brains of suckling mice (McIntosh).

While human coronaviruses were considered interesting, for a long time they were not seen as important pathogens for humans. This was because the majority of symptoms they caused were mild. Most infections were also self-limited. Nonetheless, the viruses could on occasion cause pneumonia in infants and young adults. They also sometimes exacerbated asthma in children and caused chronic bronchitis in adults and the elderly (Kahn, McIntosh).

Meanwhile researchers were beginning to uncover new coronaviruses linked to diseases in multiple species of animals. Originally detected in chickens, the viruses were soon found to also be present in other birds, rats, mice, calves, dogs, cats and pigs. In addition to causing respiratory disorders, the coronaviruses were established to be associated with gastroenteritis, hepatitis, encephalitis, pneumonitis, sialodacryoadenitis and infectious peritonitis in animals (Kahn, McIntosh).

For a long time it was assumed that coronaviruses were a relatively minor pathogen for humans. They were primarily seen as responsible for the common cold or mild respiratory infections in people with compromised immune systems. This attitude, however, changed as a result of the outbreak of SARS. Taking the world by complete surprise in November 2002, SARS quickly spread to more than 33 countries. Its primary route of transmission was human to human contact. By the time when SARS was brought under control, in July 2003, 8,098 people had been infected. Approximately one in ten of those who contracted SARS died. Its high fatality rate and rapid spread led David Heyman, the head of the World Health Organisation, to declare, in April 2003, that SARS could pose a more serious global health threat than any other other new disease in the previous twenty years, with the sole exception of AIDS (Ross; Kahn, McIntosh; WHO; ECDC 2020a). In the end, SARS caused 774 deaths. What stopped the disease from claiming more lives was the strong international response based on quarantine measures, contact tracing and strict isolation of potential sources of infection (Salata, Calistri, Parolin, Palu).

Numbers of publications referencing coronavirus

Number of publications with 'coronavirus/es' as text words (blue) or in titles (orange), source PubMed Legacy. Each point represents one year, but the rightmost points cover only the first 12 weeks of 2020. Credit: JK Aronson, Coronaviruses - a general introduction, 25 March 2020.

As the first infectious disease to emerge from a new virus in the twenty-first century, SARS ignited new energy into research to better understand the virology and pathogenesis of coronavirus infections. This is illustrated by the graph above which shows a great leap in the number of publications that began to appear around coronaviruses following the outbreak of SARS. Such work was helped by the emergence of the polymerase chain reaction (PCR) technique in the 1980s. The new technology made it possible to amplify a targeted DNA sequence from just a few samples to billions of copies within just a couple of hours. This made it much easier to detect the coronaviruses in a clinical sample. In addition, the new virus proved remarkably easy to grow in tissue culture (McIntosch).

Early epidemiological studies suggested that SARS was caused by a novel coronavirus that had jumped from animals into humans. Initially, scientists thought the virus had passed into humans from palm civets (Paguma larvata) sold in a live animal market. This was because antibodies against the virus that causes SARS were detected in both civets and their human handlers. Subsequent genomic studies of farmed and wild-caught civets, however, revealed that in fact they were only intermediary hosts and that the new coronavirus virus originated from a related strain that had been prevalent in bats for a very long time (Cui, Fang, Zheng-Li).

Ten years after the onset of the SARS epidemic, another new lethal viral human respiratory disease emerged. Called Middle East respiratory syndrome (MERS), the first case was reported in Saudi Arabia in April 2012. The infection was soon established, in September 2012, to be caused by a new coronavirus (MERS-CoV) that was likely to have spilled over from bats to dromedary camels over three decades before (Cui, Fang, Zheng-Li). Unlike SARS, which was brought under control within a year of it surfacing, MERS has continued to cause human disease to this day. As of January 2020 there had been 2,519 MERS cases detected in 27 countries with 866 deaths. The majority of cases were reported from the Middle-East. MERS has a fatality rate of 34 per cent (Rodgers).

To date Covid-19 has killed more people than SARS and MERS combined. This is despite the fact that it appears to have a relatively lower fatality rate than either SARS or MERS. What is distinctive about the new virus is the fact that it spreads much more easily. In the case of SARS and MERS, the virus that causes the diseases requires much closer human to human contact in order to spread. Much of the transmission of SARS MERS took place either within the healthcare setting between healthcare workers and patients, or family members. It was therefore possible to limit their spread by improving infection control and prevention in hospitals (Wilder-Smith, Chiew; Rodgers).

Scientists still do not totally understand how COVID-19 spreads, but, as in the case of SARS and MERS, its main transmission route is thought to be via respiratory droplets that get expelled when an infected person sneezes, coughs or talks which then get inhaled by a person nearby. The new virus, SARS-CoV-2, can also be picked up by a person touching a contaminated surface or shaking hands and then touching their mouth, nose or eyes, although this transmission route is less common (CDC 2019). What is different about COVID-19 is that most people who get infected often do not exhibit any symptoms in the early days. A number of studies suggest that the infection may have an asymptomatic incubation period of between 2 and 14 days. This means infected people can spread the virus without even knowing they have it, which could account for its fast-spreading nature (Prompetchara, Ketloy, Palaga; Chen; CDC, 2020).

Many questions remain as to how SARS-CoV-2 compares with other coronaviruses and other viral infections like influenza. One of the pressing issues at the moment is understanding how long immunity lasts after a person recovers from COVID-19. Previous studies of the immune response with other coronaviruses do not induce very long immunity. Most people who recovered from the SARS epidemic acquired an immunity that lasted eight to ten years. Yet, those who recovered from MERS only developed immunity that lasted only one or two years (Mandavill). How long immunity lasts after getting infected with SARS-CoV2 remains unknown. It is an issue that scientists are currently racing to find out.

Acknowledgements

I would like to thank Stephen Baker for his insightful comments in the preparation of this article and for the support of Gordon Dougan and his team at the Department of Medicine, Cambridge University. Many thanks also go to Professor David Rowlands and Professor Hugh Pennington for taking the time to talk to me about June Almeida and the history of virology and coronaviruses.

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