On the shoulders of giants: What we know about Covid-19 comes from decades of research

All this information has proved critical for developing vaccines and treatment strategies for the novel coronavirus.

BySwetha Godavarthi
On the shoulders of giants: What we know about Covid-19 comes from decades of research
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As of writing this article, 42,33,504 people are infected with the novel coronavirus (SARS-CoV2) and 2,89,932 people have died worldwide of the resulting coronavirus disease 2019 (COVID-19). The only strategy currently against this virus is preventing its spread by isolating the infected people, the carriers of the virus.

However, once the virus is inside the human body, modern medicine has no way of either boosting our body’s strength to fight the virus (through vaccines) or destroying the virus itself through drugs. As our understanding grows and improves of how the virus spreads among people, infects a person, and the resulting problems it causes, we add more and more types of arsenal to our modus operandi to protect ourselves against these invisible bullets.

This is happening through basic and translational research on SARS-CoV2, which is taking place with urgency and through global collaboration leading to around 155 drugs and 79 vaccines which are currently being tested for their effectiveness against SARS-CoV2/COVID-19.

Speed of research

The closest pandemic for comparing the speed of scientific response is the severe acute respiratory syndrome, or SARS, which started in China in 2002-2004 and spread to 28 other countries infecting about 8,000 people and killing 774.

SARS first appeared in November 2002. It was characterised as a coronavirus in late March 2003, and the details of the study were published in late May 2003. The response time of five months to publish the genetic details of SARS coronavirus was an astonishing scientific speed and considered to be the fastest and most effective response to a public health emergency.

Since then, science has had to get faster. The following Zika epidemic in 2015-2016 and Yellow Fever in 2016 taught researchers to work together and to share their data quicker.

That the open data sharing ethos and scientific innovations helped researchers in the race to understand and prevent COVID-19 is evident when we see that what took months for SARS was done in days for COVID-19. Cases of a mysterious pneumonia were reported between December 12-29, 2019. By January 3, the causative agent was identified to be a coronavirus and the whole genome sequence of this virus, SARS-CoV2, was shared publicly. By February 2, a web-based software was developed, and shared freely, which rapidly identified and classified coronavirus sequences (it can analyse the whole viral genome in one minute).

This allowed scientists all over the world to compare the virus sequences they were isolating from COVID patients in their countries, indicating that it was a global outbreak. This tool also allowed researchers to track new viral mutations as the outbreak expands, information which is absolutely essential for developing diagnostics, drugs and vaccines.

Building on previous knowledge

Coronaviruses make up a large family of viruses (Coronaviridae) infecting humans and other animals. Historically, human coronavirus infections are mild and associated with common cold symptoms. However, veterinarians have for many decades reported the deadliness of these viruses. Coronaviruses were causing fatal diarrhea in pigs, peritonitis in cats, and bronchitis in chickens.

New coronavirus strains emerge when the virus acquires the ability to infect a different cell type/tissue/host (tropism) and or changes how harmful it is to the host (virulence). This can either happen when an existing strain undergoes mutation or when two different strains of the virus combine (recombination).

For coronaviruses, cross-species transmission is not unprecedented. For example, the coronavirus infecting pigs can cross-infect cats and dogs although the extent of severity of disease may vary. That coronaviruses may quietly emerge from other animals and cause potentially fatal diseases in humans, and the need to be prepared for them was brought into stark light by two epidemics.

When SARS started in China in 2002, and Middle East respiratory syndrome (MERS) started in Saudi Arabia in 2012, work began on developing vaccines and drugs for this family of viruses. However with the containment and waning of the epidemic, governments, people and funding organisations soon lost interest, and the work on prevention and treatment was shelved. However, it is this very knowledge gained from research on the earlier coronaviruses that is now enabling scientists to work at an accelerated pace to aid in combating the novel coronavirus and the current pandemic COVID-19.

How the virus spreads

The novel coronavirus is similar to, and yet different, from its other family members. Understanding how the novel coronavirus spreads among people has been an important aspect of developing strategies to contain its spread.

Based on the travel history information and symptom onset dates from patients from Wuhan. which were translated and freely shared by researchers, a group in Netherlands determined by February 6 that the incubation period (the time between when you first contract the virus and when your symptoms start) for SARS-CoV2 was four to six days. Information about the incubation period is critical to screening and contact tracing, estimating the size of the epidemic, estimating transmission potential, and essential in determining the quarantine period.

Nearly all infected people developing symptoms will do so within 12 days of infection (hence a 14-day quarantine period for infected people). Three percent of infected people will develop symptoms within two days of exposure, while most of the infected people (97 percent) will develop symptoms within 11 days of exposure.

These studies identified a most troubling aspect of how SARS-CoV2 spreads. One out of 100 infected cases were found to develop symptoms after 14 days of active monitoring or quarantine. Although initially it was thought that, similar to other coronaviruses, SARS-CoV2 is also transmitted by symptomatic infected people alone, it was later found that even infected people who are not showing symptoms can transmit the virus to others. The long incubation period of the virus in some individuals, coupled with the cryptic transfer of the virus by asymptomatic infected people, is what makes containing the spread of COVID-19 so difficult.

How physical isolation reduces the spread of COVID-19. Owing to transmission by both symptomatic and asymptomatic COVID-19 patients, researchers recommend physical isolation as much as possible, and to engage in activities outside home only when absolutely necessary along with appropriate protective gear.

How physical isolation reduces the spread of COVID-19. Owing to transmission by both symptomatic and asymptomatic COVID-19 patients, researchers recommend physical isolation as much as possible, and to engage in activities outside home only when absolutely necessary along with appropriate protective gear.

Immunity against the virus

As the virus is new and humans have never been infected by it before, our immune system does not have the arsenal to fight the virus. So, when a person gets infected, our immune system launches a severe response to the virus resulting in the symptoms associated with COVID-19.

There are several methods to “train” the immune system, such as exposing it to a weakened form of the virus (live vaccine) or exposing it to only non-infective parts of the virus without making you sick. This can include either the virus proteins (dead vaccine) or DNA/mRNA (gene-based vaccine) or, in other words, active immunisation (as opposed to passive immunisation, which we’ll discuss later).

Each of these is being explored to generate a vaccine against SARS-CoV2. Successful vaccines are frustratingly hard to create and a majority of them fail at early stages or in clinical trials. There are 76 such vaccines under development.

Usually, prior to testing in humans, vaccines are tested in animals to determine their safety and efficacy. Given the urgent need for a vaccine against SARS-CoV2, the animal and human testing is being conducted simultaneously. The only drawback has been that animals like mice, which are typically used for testing, are not susceptible to SARS-CoV2. Pathogen specific rodents were specifically engineered in the wake of the SARS outbreak. To make these rodents susceptible to infection, scientists adorned the mouse cells with a human molecule allowing certain viruses to slip inside.

As the SARS epidemic resolved, the funding for studies dried up and researchers could no longer afford to maintain these animals in their laboratories. These are the mice being tested for SARS-CoV2 infection and immunisation.

The elucidation and publication of the whole genome of SARS-CoV2 allowed the quick identification of target proteins/RNA/DNA sequences from the virus which could be used in vaccines.

For example, by January 13, following the publication of SARS-CoV2 genome, Moderna announced that it was developing an mRNA vaccine (mRNAs, or messenger RNAs, are one form of RNA present in cells directly coding for the sequence of amino acids in a protein). This entails injecting a synthetic mRNA for the surface protein of the virus. The cells in our bodies then produce copies of this viral protein, which raises an immune response by exposure, and may help in combating the actual virus when infected. The first patient was dosed in phase 1 of the trial on March 16 (a phase 1 trial goal is typically assessing the relative safety of a treatment strategy, and not its efficacy) . On May 7, they were cleared to start phase 2 of their clinical trials (this phase tests the efficacy of the treatment strategy).

BioNTech is also developing RNA vaccines which are in phase 1, while Inovio is developing a DNA vaccine. (The DNA sequence will in turn be converted into an mRNA sequence by a process called transcription, which will then go on to form viral proteins.)

Others are entwining a snippet of SARS-CoV2 genetic code with a harmless virus. Healthy volunteers are exposed to this novel infection, spurring antibody production. This method was used for developing the Ebola vaccine, and is in the news nowadays due to the promising phase 1 results from the University of Oxford.

Companies like Sinovac are developing inactivated versions of SARS-CoV2 which are currently in phase 1. Vaccines against hepatitis A, hepatitis B, swine flu, and avian flu have previously been developed on this principle.

Phase 2 of vaccine development can last from several months to two years, which is why the best estimates for the approval of a potential vaccine are thought to be no earlier than the beginning of next year . While I have listed the vaccines which are already in different phases of clinical trials, the remaining 71 vaccines (from the 76) are still in developmental (or preclinical) stages, and will presumably take even longer to come into markets.

It is important to note here that due to shortcomings arising from the accelerated nature of vaccine development, we need to hedge our bets and pursue all possible vaccine strategies.

What happens inside the patient?

Once the whole genome of the virus was sequenced, it allowed scientists to compare it to previously identified viruses. The comparison and classification of the virus was important to understanding how the virus behaved. Once we knew that the virus belonged to the family of coronaviruses we could harness our knowledge about how other coronaviruses acted to rapidly understand how SARS-CoV2 invades a human cell.

SARS-CoV2 was found to share 80 percent of its whole genome with SARS-CoV1- which caused SARS, the first pandemic of the 21st century. The years of work on understanding and developing treatments for other deadly viral diseases like SARS, HIV, Ebola and hepatitis C — along with current studies showing how SARS-CoV2 is similar or dissimilar to other coronaviruses — is helping to chart the drug development strategy for COVID-19.

The life cycle of SARS-CoV. As shown in this figure, SARS-CoV starts its life cycle when it binds to receptor ACE2 on the target cell via its S protein. The virus particle is taken up the cell. Its S protein changes conformation to facilitate release of RNA genome into the target cell. The mRNA of the virus is translated into some proteins which in turn aid in replicating the genomic RNA and other proteins which are important for assembling new viral particles containing the replicated genomic RNA and proteins. These particles are subsequently released out of the target cell.

The life cycle of SARS-CoV. As shown in this figure, SARS-CoV starts its life cycle when it binds to receptor ACE2 on the target cell via its S protein. The virus particle is taken up the cell. Its S protein changes conformation to facilitate release of RNA genome into the target cell. The mRNA of the virus is translated into some proteins which in turn aid in replicating the genomic RNA and other proteins which are important for assembling new viral particles containing the replicated genomic RNA and proteins. These particles are subsequently released out of the target cell.

Credits: http://jtd.amegroups.com/article/view/1209/html

Similar to other members of the coronavirus family of viruses, SARS-CoV2 enters a cell by binding to a protein called the angiotensin converting enzyme 2 (ACE-2). ACE-2 is present on the surface of the cell and when bound by the spike (S) protein of the virus, provides a gateway into the cell. The S protein is slightly different between COVID and the SARS/MERS virus in that it has a very high affinity for ACE-2.

Thus, cells which express low levels of ACE-2 and would not be infected by viruses causing SARS/MERS are easily infected by SARS-CoV2 . This is what confers the virus its high rate of infectivity and high rate of transmission. Other proteins have also been reported to provide an entry point to the virus, such as CD147 located on T lymphocytes.

Drugs are under development to prevent the spike protein from binding to the cell membrane and thus prevent the entry of the virus into the cell. Camostat is one such drug being studied. The results are expected by December 2020. APN01 is another drug which emerged from SARS research and is currently being tested for SARS-CoV2.

Once inside the cell, the membrane surrounding the virus is broken down by the cell, releasing the mRNA of the virus. Blocking the cell proteins which help in breaking down this membrane is another potential target for drug development.

Inside the cell, the viral RNA is translated into proteins. The RNA from SARS-CoV2 encodes for non-structural proteins which play a critical role in viral RNA synthesis, and structural proteins that are important for the assembly of the virus. Drugs are being tested to block the translation of the viral RNA.

Remdesivir is one such drug. It was originally developed for hepatitis C (it proved ineffective) and then tested for Ebola (it proved ineffective). It was again tested as a potential treatment for SARS/MERS epidemic where it was found to reduce viral replication in cell culture and displayed promising results in animal models. Remdesivir is in phase 3 of clinical testing (being tested on thousands of patients) in six different trials. The results from the trials are expected around April 2021.

Favipiravir is another drug which is used for treating influenza in Japan. Four studies are ongoing to test its efficacy for COVID-19. Darunavir, another retroviral used for HIV-treatment, is also being tested for action against COVID-19. The results are expected by December 2020.

The structural proteins help in packaging the virus particles which are then released from the cell. Drugs like Lopinavir + ritonavir (a combination treatment used for HIV treatment), which prevent the release of the assembled viral particles from the cell, are being tested for COVID-19. However, early results are not promising. In one trial, the rate of detectable viral RNA did not differ between patients getting the combination therapy vs standard treatment. There are 11 more ongoing trials and the expected timeline for their results is around July 2020.

Researchers have found that when the immune system encounters the virus, it launches a two-phase response. One arm of the immune system creates an immunological “memory” after its initial response to a specific pathogen (this “acquired” adaptive immunity is the basis for vaccination). For launching a protective immune response in the early stages, the person has to be in good health and appropriate genetic background (genetic differences are known to contribute to individual variations in immune response to pathogens).

During the incubation and non-severe stages of COVID-19, the adaptive immunity is working to eliminate the virus and prevent disease progression in the body, but as it has never encountered the pathogen before, its response to the virus is impaired. Therefore, strategies that boost the immune response such as convalescent sera (which introduces antibodies from patients who have recovered from COVID and therefore have the “memory” of the virus into an infected patient: passive immunisation) are important.

Interferons are chemicals released by the body to modulate the response of the immune system against bacteria, viruses, cancer and other foregin substances that invade the body. They do not fight the virus itself but they boost the body’s own virus defence. Interferon beta 1a, used in treatment for multiple sclerosis, is currently being tested for COVID-19 and results are expected in 2021.

In the absence of appropriate adaptive immune response, the virus will propagate and it will invade tissues with high ACE-2 expression, like the lungs and kidneys, causing damage to these organs . Unfortunately, the story does not end here. Our damaged cells now release chemical factors called cytokines to recruit immune cells to the site of injury. These immune cells constitute the innate immune system.

The ensuing inflammation is to create a physical barrier to prevent further spread of infection, clear the pathogen, and promote healing of the damaged tissue. However, in some patients excessive or uncontrolled levels of cytokines are released which then activate more immune cells, resulting in hyperinflammation.

This overreaction by the immune system, known as cytokine storm, is the main cause of the life threatening acute respiratory distress syndrome (ARDS) seen in some COVID-19 patients. Therefore, once lung damage occurs, efforts have to be made to suppress excessive inflammation. Anti-inflammatory drugs are being tested and developed to treat ARDS. GM-CSF is one such cytokine that has been shown to be a key driver of lung inflammation in COVID-19. Antibodies are being developed to neutralise GM-CSF and thereby block its action.

Immunosuppressants like Tocilizumab and Sarilumab, used to treat rheumatoid arthritis (an autoimmune disease arising from the immune system attacking the body’s own proteins), are also under clinical trials for their use in managing COVID-19.

Although chloroquine and hydroxychloroquine have been touted as potential drugs for COVID-19 by either affecting the replication of virus or affecting the immune system by mediating an anti-inflammatory response, recent trials do not indicate any evidence for its efficacy either as a prophylactic or for treatment. Moreover, the drug can have severe side effects in some patients, worsening their clinical outcome.

The road ahead

Our understanding of COVID-19 is evolving on an almost daily basis. Scientists around the world have trained all their resources to understand what our enemy looks like, how it invades our body, and what we can do to prevent it from invading our bodies. Although the enemy is invisible, the threat to lives is very real.

Back when just a few hundred cases had been reported, scientists already understood how it was transmitted from person to person, and had quantified how contagious the disease actually was and were recommending “best practices” to minimise infections and deaths. Even though those recommendations were not sufficiently heeded, our scientific and medical knowledge has continued to aid us in the fight against this ongoing global pandemic.

The swift response from the scientific and medical community of researchers was aided by technical advancements which enabled the whole genome of the virus to be sequenced in a matter of days and rapid structural details of the virus itself, coupled with powerful bioinformatic tools allowed precise classification of the new pathogen.

It is heartening to see the emergence of open sharing ethos among researchers of the world. Researchers are no longer restricting themselves to share their findings through journal publications. They are sharing their findings through posts, blogs and preprint servers.

However, this rapid experimentation and communication of science comes with its own caveats. Decades of research in the fields of virology, immunology, structural biology, bioinformatics, epidemiology, and many more have allowed researchers to identify the mechanism of how the virus invades a cell and how the body responds to the invasion at breakneck speed. All this information has proven to be critical for developing vaccines and drug and treatment strategies for COVID-19.

Knowledge in science is incremental. To an outsider, research may seem monotonous and esoteric, with research questions often seeming impractical and unlikely to improve the quality of human lives. The COVID-19 pandemic is not the first or the worst one to have such a widespread toll across the world, and will not unfortunately be the last one either.

But through the amazing response of the scientific community to COVID-19, we can see how decades of research in seemingly fundamental, non-disease related areas — coupled with translational research — is helping us make sense of these new diseases and develop strategies for management and treatment, reiterating the need for the public to invest and put faith in scientific research.

The author thanks Ajit Ray for critical reading and inputs.

Swetha Godavarthi is a neuroscientist at University of California San Diego.

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