On December 31, 2019, the first cases of a novel coronavirus were identified in Wuhan City, Hubei Province, China. Since then, the disease, now officially known as COVID-19, has been declared a pandemic, spread to most countries and claimed the lives of over 1,948,236* people.
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How has the pandemic unfolded?
As of January 12, 2021, cases of the virus had been confirmed in over 200 countries and territories. You can keep up to date with the spread of the virus with this outbreak tracker from researchers at John Hopkins University.
Following a number of discussions, what was initially an outbreak of disease was declared a PHEIC (Public Health Emergency of International Concern) by the WHO on January 30, 2020, signifying the global public health risk of the disease and the need for a coordinated international response. By this time, preventative measures such as travel restrictions had already begun to be put in place. One study has suggested that quarantine on a cruise ship had resulted in more coronavirus patients. However, were infected passengers to have left the ship, new epicenters of disease may well have been established. This reiterates the importance of effective quarantine measures.
Initially, many people were using face masks in a bid to protect themselves; but the effectiveness of this has been called into question. The WHO has since advised governments to encourage the use of non-medical face coverings amongst the general public where physical distancing is not possible. These are not designed to protect the wearers from infection, rather to reduce infected individuals spreading the disease to others when they speak, cough and sneeze.
Research suggests that SARS-CoV-2 is re-emerging in many locations, following the relaxation of lockdown restrictions, a situation that seems likely to continue for some time to come.
What you need to know about coronavirus
What is a coronavirus?
Coronaviruses (CoV) are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV). Other coronaviruses circulate among animals including camels, cats and bats. Occasionally, animal coronaviruses may acquire mutations that enable them to infect people and then spread between people. In 2002-2003, an outbreak of SARS originating in southern China eventually caused 8,098 cases across 37 countries, resulting in 774 deaths. Consequently, in the light of the recent outbreak, there was understandable fear of the potential for an epidemic or pandemic.
Characterizing the SARS-CoV-2 virus
For scientists to develop effective treatments, preventatives and diagnostics, they need good information about the virus’s structure and genetics.
By February 2020, the complete genome had been sequenced, now one of many SARS-CoV-2 genome sequences, and made publicly available for researchers around the world. Genome interrogation enabled scientists to determine firmly that the SARS-CoV-2 virus was not genetically engineered, as had been suggested, but was a product of natural selection. It was revealed that the lineage that gave rise to the virus has been circulating in bats for decades and likely includes other viruses with the ability to infect humans. These findings could have implications for the prevention of future pandemics stemming from this lineage. Pangolins have been proposed as a possible route for the current outbreak from animals into people.
Isolates of SARS-CoV-2 continue to be sequenced around the globe, tracking the virus’s evolution, as the pandemic progresses. During this work, a genetic mutation was identified in a variant circulating in Europe and the US that significantly increased the virus’s ability to infect cells.
Beyond the genome, understanding the structure of SARS-CoV-2 enables researchers to assess more effectively how it infects cells and interacts with our body and immune system. This enables scientists to design therapeutics to block the infection process and choose vaccine candidates that are likely to be immunogenic.
The spike protein is known to be an important structure in coronaviruses for cell entry. Cryogenic electron microscopy (cryo-EM) was used to create the first 3D atomic scale map of the spike protein. Nanobodies, a type of antibody used in research, with high affinity for the spike protein have been used to stabilize the structure, helping to improve the images obtainable with cryo-EM. Cryo-EM in combination with computation has also been used to improve the speed and accuracy of spike protein snapshots in their natural states whilst still attached to the virus. At least ten distinct structural states of the spike protein have been identified associated with different stages of receptor binding and infection, when in contact with the human virus receptor angiotensin converting enzyme 2 (ACE2), through which it makes its entry into cells.
The main protease, that enables the virus to reproduce, has been measured using room-temperature X-ray analysis.
Mass spectrometry has been an invaluable tool in structural investigations as well as for biomarker detection. A coalition of more than 500 scientists from around the world has been created to share data on COVID-19 gleaned from the technique. Neutron crystallography has also been used to create a 3D map, revealing the location of every atom in an enzyme molecule critical to SARS-CoV-2 reproduction.
Primary clinical signs include fever and breathing difficulties, associated with the development of pneumonia, however chills, loss of smell and/or taste, sore throat and headache have also been described by those affected. Seven “forms of disease” have been identified according to the symptom groups experienced. Whilst some individuals may experience only mild clinical signs, infection can be fatal, particularly in the elderly or those with underlying medical conditions. Comprehensive virological examinations have detailed the clinical course of infection, helping to determine when it is safe to discharge COVID-19 patients, and highlighted the variation in clinical presentation between patients. COVID-19’s effects on the brain have also been investigated, although psychiatric symptoms largely seem to be a result of stressful hospital experiences, rather than clinical signs unique to COVID-19.
Person-to-person spread is thought to occur via respiratory droplets and airborne spread, for example when speaking or singing, in a similar way to the spread of influenza. Tears and breast milk have both been shown to be a low risk for infection spread and a recent study has also confirmed that mosquitoes do not transmit the virus. Whilst the potentially important role that children play in the spread of infection is still being debated, they have been shown to carry a much higher viral load than adults who have needed intensive care whilst themselves exhibiting no or only mild clinical signs. Whilst a pet cat in the UK was confirmed to be infected with SARS-CoV-2, pets have not generally been considered a high-risk source of infection. There is, however, some concern that people could spread the infection to wild mammal populations, creating a hazardous reservoir of infection.
Initially the role that airborne spread, distinct from respiratory droplets, plays in potentially transmitting SARS-CoV-2 was not acknowledged by most public health organizations, including WHO. However, following a plea from 239 leading scientists in July 2020 for this to be properly addressed, guidelines for precautions, particularly for indoor environments, were revised to reflect airborne spread as a factor in disease transmission. Many ventilation systems, particularly in communal spaces like offices, have been suggested to increase the risk of COVID-19 spread because of the way many recycle and displace air that may contain virus particles between individuals. A need to give more attention to reducing airborne spread in hospitals and nursing homes has since been highlighted.
The coronavirus has been shown to be stable on surfaces for hours to days depending on the material, with the greatest survival on non-porous surfaces such as plastic and metal. One study reported survival on common surfaces for as long as 28 days. Environmental conditions, such as air humidity and temperature, have also been shown to impact the duration for which viral particles are able to survive in aerosol droplets, human sputum and nasal mucus.
The incubation period for SARS-CoV-2 is estimated to be around 5.1 days with 97.5% of people who develop clinical signs doing so within 11.5 days. Even before clinical signs develop, a person may be infectious. Many infected individuals do not develop obvious signs of infection and this “stealth transmission” lead to rapid spread of disease in many areas. Consequently, quarantining for 14 days is recommended to prevent potential spread. For those who do develop clinical signs, clinical recovery is no guarantee that they are no longer infectious. Therefore, tests for live virus are important to ensure someone is clear of infection.
Studies have examined the ways in which SARS-CoV-2 interacts with the host, indicating that odor-sensing cells in the nose are a key entry point with decreasing infectivity of cells and viral replication moving away from the nasal cavity towards the lungs. SARS-CoV-2 has been found to recognize a protein called neuropilin-1 on the surface of human cells to facilitate viral infection. ACE2 is key in SARS-CoV-2 cell entry, however, it was found to be unable to utilize ACE2 without a carbohydrate called heparan sulfate which acts as a co-receptor for viral entry.
Using bioengineered human alveolar cells combined with precise mass spectrometry, scientists have been able to map the molecular responses of human lung cells to infection by SARS-CoV-2. This has identified host proteins and pathways whose levels change upon infection, providing insights into disease pathology and potential therapeutic targets. SARS-CoV-2 has also been shown to block production of protective cellular proteins, including immune molecules, without hindering its own replication.
Post-mortem examination of patients that died from COVID-19 identified extensive lung damage, including significant thrombus formation and abnormal cells, in most. These observations may in part explain some of the lingering signs seen in “long COVID” sufferers. Artificial lungs are helping scientist to understand more about the triggers for these events.
Whilst primarily a respiratory infection, it appears that, particularly in older patients, SARS-CoV-2 is able to invade and damage heart cells. This has been linked to the ACE2 receptor used by SARS-CoV-2 to enter cells. This is thought to be upregulated by heart cells as we age. The virus has also been shown to cause structural abnormalities in cardiomyocytes, including severely fragmented sarcomeres and missing nuclear DNA.
There has been some evidence of transplacental transmission of SARS-CoV-2 from a mother to her unborn child, however this has been a rare event, likely because placental cells minimally express the receptor ACE2 required by the virus for cell entry.
By understanding the infection process, scientists are able to focus therapeutics on key targets to prevent cell entry in vulnerable tissues, such as creating a decoy version of the ACE2 receptor. Whilst often not expressing ACE2 receptors themselves, endothelial cell function can be dysregulated in COVID-19 patients, leading to reduced lung function. Work suggests this occurs via indirect activation of the endothelium that may result from surrounding tissue damage, providing another potential therapeutic target.
Analyses of blood samples from COVID-19 patients revealed metabolites indicative of multi-organ effects as well as biomarkers that may be predictive of how a specific patient is likely to be affected by the infection, that are useful in guiding treatment plans. Animal models of infection have also played an important part.
How is the infection diagnosed?
Immune susceptibility and disease predictions
Our immune system is an important line of defense in short- and long-term protection from invading pathogens such as SARS-CoV-2. However, the immune system is incredibly complex and there are many factors that impact its ability to fight infection and keep us healthy.
Genetic differences between individuals impact the ability of immune cells to recognize pathogens. Those whose cells are less able to recognize pathogens are more susceptible to infection. As a consequence of our relatedness, populations in certain geographical regions are therefore more susceptible to SARS-CoV-2 infections than others. It is important however to remember that this is only one aspect of a complex system. Differences in the immune systems and blood vessels of children compared to adults have also been postulated to offer them protection from severe COVID-19.
Once a patient has contracted SARS-CoV-2, differences in immune responses can also be used to predict disease progression and severity. These early “immune signatures” during infection can act as a warning sign to indicate those patients who are at an increased risk of developing more severe disease.
Innate and adaptive immune response
The immune system consists of innate immunity and adaptive immunity. Innate immunity is the body’s first line of defense, providing a rapid but relatively indiscriminate response against anything considered non-self. The adaptive immune system on the other hand takes longer but responds specifically to a given threat and ultimately is responsible for developing long-term immune memory. This is achieved through the generation of specific antibodies and memory B and T cells that are able to respond to protect us if we were to encounter the same threat again in the future.
A number of immune cell types, including phagocytic neutrophils, macrophages and dendritic cells, are key to combatting viral infections. A newly discovered type of dendritic cell has been found to be important for respiratory infections and a novel group of macrophages identified in the lungs are also important for the inflammatory process. Cytokines are released that coordinate the body’s response to infection and trigger inflammation, an important part of fighting off invading pathogens. The complement system, one of the most evolutionarily ancient parts of our immune system, consists of a number of interacting plasma proteins that aid pathogen opsonization and the induction of inflammation.
When our cells are infected, they produce a “call to arms” – releasing interferons to attack the viral intruder – and a “call for reinforcements” - releasing chemokines to tell cells of the innate immune system there’s an intruder. However, SARS-CoV-2 has been found to interfere with this process, resulting in a very strong call for reinforcements, but a very weak call to arms, impairing the immune system’s ability to respond effectively.
Whilst our immune system is important in protecting us, it can also do us harm. Data suggests that a potentially lethal overreaction of the immune system is key in COVID-19 progression. This overreaction is known as a “cytokine storm” and results from a buildup of chemokines, proteins used in cellular communication and immune cells. There is also evidence that these cytokine storms may prevent the development of effective long-term immunity. Overactivity in the complement system has also been associated with more severe disease.
Inflammatory proteins produced during infection have been found to cause platelet hyperactivity in some patients that may lead to heart attack, stroke and other complications. High levels of inflammation from a post-COVID syndrome have also been found to damage the heart in some children. Enhanced levels of proinflammatory molecules were also associated with those suffering severe COVID-19.
Tracking the immune composition of patients’ blood could help to predict who is likely to need additional treatment and those likely to experience more or less severe disease. Higher levels of neutrophil extracellular traps (NETs) in blood, released by neutrophils to ensnare invaders, were associated with more severe COVID-19.
The adaptive immune system is key to the development of long-term immunity to infection, be it through natural infection or vaccination. Studies have identified SARS-CoV-2 epitopes that are targeted by naturally occurring antibodies following infection, helpful in vaccine development efforts.
The generation of antibodies alone doesn’t necessarily mean they are protective, and they vary widely in their efficacy. Neutralizing activity – the ability of an antibody to effectively block a virus from entering a cell – is a key indicator of an efficacious adaptive response. Measuring neutralizing activity is useful for vaccine development when it is not feasible or ethical to challenge the individual with live virus. Data suggests that, in the case of SARS-CoV-2, whilst the amount of antibodies generated by recovered patients varies widely, most do generate at least some with neutralizing activity, encouraging for vaccine development. Those who recovered from severe infection were found to have elevated neutralizing antibody levels at least four months post-infection. Whilst in many, antibody levels appear to wane following recovery, a subset of patients recovered faster and sustained anti-virus antibody production several months following infection suggesting they may be mounting a more effective and durable immune response.
Many of us are familiar with the role that antibodies play in long-term immunity, however, memory T cells are also important for this process. Even as antibody levels fall, memory T cells appear to remain high, improving the chances of fighting infection on re-exposure. Robust T-cell responses were still identified even six months after initial infection and much evidence points to a larger role for T cells than antibodies in combatting the illness. Data suggest that individuals who have previously had COVID-19 are highly unlikely to contract the illness again for at least six months following their first infection. T cells are also a mine of information on the way our bodies perceive and respond to pathogens, which can be valuable for guiding the development and refinement of effective therapeutics and preventatives. Whilst T cells are a key part of our antiviral response, moderation is required to prevent an overreaction which can result in the killing of healthy cells and consequently tissue damage. In some cases it appears that the “brake” mechanism preventing an overaction is absent, leading to severe COVID-19 clinical signs.
Data demonstrating a robust antiviral response through multiple mechanisms is good news for vaccine developers amid fears that the virus may elude ongoing efforts.
As well as disease severity indications from innate response analysis, deep immune profiling has identified three distinct immunotypes in the adaptive responses of patients corresponding to differing COVID-19 severity. This demonstrates the power of the immune system analysis as a window into disease.
Data suggests that in some patients, the adaptive response may kick in too soon, interfering with the innate immune response. This offers a possible target for therapeutic intervention.
Whilst the immunosuppressants taken by many transplant patients to avoid organ rejection can leave them open to infection, indications are that these individuals are still able to achieve good immunity to SARS-CoV-2.
Herd immunity has been discussed a lot in the context of COVID-19. It occurs when a sufficient proportion of the population has immunity to a given infection, such that it slows or prevents disease spread, protecting “at-risk” individuals. Immunity can occur through natural infection but means the individual must contract the disease, mount an immune response and develop enduring immune memory. Alternatively, vaccination can be used, which introduces the body to a form of the pathogen that will not cause the disease in the individual but still enables them to generate a protective response in a controlled way.
In the absence of an effective vaccine, natural infection is the only way to potentially achieve herd immunity. However, in the case of COVID-19, there are many unknowns, such as: What proportion of the population would need to be infected to achieve herd immunity? And, how long does immune memory last in recovered individuals? Is herd immunity even possible for this pathogen?
Whilst a herd immunity approach by promoting natural infection has some advocates, many are also skeptical and highlight the dangers of a herd immunity strategy.
Antibody testing has been used widely as a method to identify the proportion of the population that have had SARS-CoV-2. Despite being hard-hit during the height of the pandemic, estimations published in July 2020 indicated that only around 5% of the Spanish population had antibodies to SARS-CoV-2 – not even close to the levels estimated to be required for natural herd immunity.
However, antibody testing may not accurately represent the true proportion that have been infected. Studies suggest that public immunity is probably higher than antibody testing has so far suggested as people who contract SARS-CoV-2 but have mild or no clinical signs still develop so-called T-cell-mediated immunity to the virus, which may protect them but fails to be detected by antibody tests.
Indications thus far suggest that only around 60% of recovered patients develop protective antibodies towards SARS-CoV-2 and that antibody levels towards SARS-CoV-2 decline rapidly in the months following infection. This could have important implications for antibody-based surveillance and vaccine development strategies.
Antibodies as therapies
Antibodies can protect an individual from disease, but they can also be extracted and used to protect others too. Purified anti-SARS-CoV-2 antibodies from recovered patients have potential therapeutic benefits for those in early infection. This avenue of treatment is being explored further.
What treatments are available?
COVID-19 is a viral infection, meaning antibiotics are not a viable treatment option. Most patients will make a full recovery without treatment. Those with severe infections can be given supportive treatment such as oxygen or artificial ventilation to keep them alive until they start to recover themselves.
Developing new drugs and vaccines can take years. Existing drugs may offer a possible "quick response" to the pandemic. Improving understanding of the virus, including it's structure, may also help to expedite the vaccine development process.
An open-access global COVID-19 Clinical Trial Tracker has been launched to help facilitate greater collaboration between critical stakeholders involved in tackling the COVID-19 outbreak.
Soluble ACE2 receptor
Soluble versions of the angiotensin-converting enzyme 2 (ACE2) receptor are being explored for treatment of SARS-CoV-2. A recombinant form of the human angiotensin-converting enzyme 2 known as APN01 is currently in a Phase II human clinical trial.
SARS-CoV-2 surveillance and epidemiology
Whilst testing of individuals plays a vital role in outbreak detection and monitoring, surveying a population on a larger scale can be invaluable for focusing further investigations and providing early warnings of potential problems as they arise. Getting a snapshot of case load in the wider population, including asymptomatic individuals, can also offer valuable time and money savings.
Wastewater monitoring has emerged as one such tool, bringing together the world’s leading experts on wastewater management. SARS-CoV-2 genetic material, shed by infected individuals in their effluent, passes into the sewage system where it can be detected. Analysts can then trace back focal areas of rising case numbers, enabling authorities to act accordingly. Studies from around the globe, including the US, Barcelona, The Netherlands, Germany, China and Australia have shown the potential value in wastewater monitoring using a variety of detection systems including paper-based devices, RT-PCR, electrochemical and optical sensors and even incorporating the Internet of Things (IoT). A recent study evaluated the most effective way to detect SARS-CoV-2 in wastewater. Researchers around the globe have now joined forces to form the COVID-19 WBE Collaborative, an initiative striving to centralize and coordinate COVID-19 wastewater-based epidemiology efforts.
Whilst portable and wearable sensors for detecting viruses and bacteria in the surrounding environment may seem like technology of the future, scientists are investigating how to use materials engineered for this purpose to detect SARS-CoV-2 in the air. This sort of sensor could be incorporated into underground transportation ventilation systems to monitor virus spread in real time or be used to direct people away from a virus-containing environment.
Simulating environmental spread
Simulation scenarios, either using dummy material or purely mathematical computer simulations, can play an important role in helping researchers to understand how infection spreads, make predictions about situations yet to arise and therefore provide advice and guidance accordingly to help to minimize future spread. Examples include the aerodynamics of confined indoor spaces, spread across a hospital ward within a train carriage and across the globe. Mathematical models can also help to predict the effectiveness of different measures designed to limit spread.
Internet of Things
The Internet of Things (IoT) is playing its part in pandemic monitoring, providing data on a host of metrics that can help with ensuring quarantine compliance, dissecting the links in an outbreak and improve management of patient care.
COVID-19 risk factors
Poor air quality, in particular fine particulate pollution, was singled out as a potential risk factor in the development of COVID-19 early on in the pandemic, likely as a consequence of early foci of infection in areas of China and Italy renowned for their terrible air quality. A number of studies have since looked to assess this link and determine whether it is causal or coincidental.
Smoking has been suggested to increase the risk of severe COVID-19 as cigarette smoke appears to stimulate the lungs to express more ACE2,the protein used by SARS-CoV-2 to enter human cells.
Genetic risk factors are another avenue of investigation with a number of studies pointing to an association of blood group and susceptibility, with a particular focus on a gene cluster located on chromosome three. A recent analysis of this cluster suggests it is inherited from Neanderthals.
Interestingly, despite the respiratory link, asthma has been shown not to be a risk for contracting or increased severity of COVID-19.
A modeling study estimated that a combined approach of physical distancing interventions, including quarantine, school closures, and workplace distancing, is most effective at reducing the number of SARS-CoV-2 cases. Emphasis has also been placed on good hand hygiene to reduce spread of the virus as soap is very effective at killing SARS-CoV-2. A recent study showed that even concerted cleaning efforts of frequently touched surfaces often fall short, emphasizing the need for diligence.
For those working in high risk professions, such as healthcare workers, researchers urged caution if laundering potentially contaminated uniforms at home.
Social distancing of two meters, or six feet, was implemented in many areas to reduce person-to-person spread, however, data from a number of studies suggests this rather arbitrary distance may not be far enough.
Whilst it is now compulsory to wear face coverings in many countries where social distancing is not possible, such as on public transport and in shops, data indicates that the face shields and masks with exhalation valves used by some are ineffective at reducing viral spread. Valves allow air to leave the mask without filtering it, which defeats the purpose of the mask.
Air filters are being developed that trap airborne virus particles, an important source of infection especially in public spaces, that pass through and destroy them. A mask has also been developed that contains titanium oxide nanowires, capable of eliminating pathogens such as SARS-CoV-2.
Restaurants and other food retailers are also making changes to minimize the risk of transmission through premises, personnel and products.
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The global scientific machine has jumped into action to combat the coronavirus, but there are still many unanswered questions surrounding the nature of immunity, whether the virus is mutating and how effective a vaccine may be. This video takes a look at the big questions six months on.
Indirect consequences of COVID-19
Missed medical treatments and vaccinations
A major measles outbreak is predicted for 2021 as many children have missed routine vaccinations during the pandemic.
Whilst efforts to fight SARS-CoV-2 have seen huge investment in vaccine research, diagnostics and efforts to understand how the virus spreads, other fields of research have largely ground to a halt.
Throughout 2020 we have seen laboratory and clinical studies conducted at a revolutionary speed, generating data in volumes that are somewhat incomprehensible. There are some concerns that the speed at which research is being conducted could compromise the quality.
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*Data retrieved from the Johns Hopkins University Coronavirus Resource Centre.