Potential Drug Treatments and Therapy for SARS CoV-2 infection in COVID-19
ROSANNA VUKSANAJ
Abstract
The now notorious coronavirus, scientifically known as SARS-CoV-2 infection is the cause of the COVID-19 pandemic. This virus is highly pathogenic, particularly for those with weak immune systems. There are three phases of COVID-19, mild infection, pulmonary infection and the inflammatory phase. This research paper will assess the treatments of Remdesivir, dexamethasone, monoclonal antibodies, hydroxychloroquine/chloroquine and lopinavir/ritonavir against SARS-CoV-2 based on their mortality rates and clinical trial results. The most promising of these treatments being Remdesivir, dexamethasone and monoclonal antibodies, the least promising being hydroxychloroquine/chloroquine and lopinavir/ritonavir. Currently, there is a rise in cases again. Much of Europe has entered back into lockdown to try to curb infection rates. Further research involving Remdesiver, dexamethasone and monoclonal antibodies should be focused on finding the best therapeutic doses and the candidates for treatment that would be benefited the most. Research should also focus on finding the best combination of these three most promising treatments, monoclonal antibodies paired with dexamethasone or Remdesiver. Further research on COVID-19 itself is necessary in regard to infection susceptibility after initial illness, and whether symptoms are persistent post-infection.
Introduction
There are many different coronaviruses (CoV’s), seven of which are known to infect humans and others that infect animals. These coronaviruses are all similar to one another in their shape, structure, single stranded RNA and spike proteins (Jahanshahlu & Rezaei, 2020). The human coronaviruses, HCoV’s, before 2003, were typically only mildly infectious, resulting in common colds(Ye et al., 2020). The tendency for recombination and adaptation of viruses to become more efficient against humans lead to the pathogenic development of these coronaviruses. The most dangerous HCoV’s are MERS (Middle Eastern Respiratory Syndrome), SARS-CoV (Severe Acute Respiratory Syndrome), also known as atypical pneumonia, and the now notorious SARSCoV-2, the cause of COVID-19. There are four classifications for coronaviruses, alpha, beta, gamma and delta. Alpha and beta coronaviruses are evolved from bat and rodent genes and gamma and delta from birds (Ye et al., 2020). The alpha-CoV’s are HCoV-229E and HCoV-NL63 which are coronaviruses that cause mild infections, such as the common cold. The first appearance of these alpha-CoV’s was in 1966. HCoV-OC43 and HCoV-HKU1 are beta-CoV’s that also, like the alpha-CoV’s, cause mild symptoms. Typically, they manifest as common colds. SARS-CoV-2, the main target for this review, as well as SARS-CoV and MERS-CoV are also beta-CoV’s. All three of these viruses are severely pathogenic and target the lower-respiratory tract for infection. SARS infection was first discovered in 2003, MERS was discovered in 2013 and COVID-19 in late 2019 (Ye et al., 2020). All were highly infectious, infecting many thousands of people. It is not known for sure, but due to a common trend of bats transmitting viruses to humans (such as rabies and Ebola viruses), through interspecies transmission or direct transmission, it is likely the case that bats transmitted coronaviruses to humans. The reason that viruses can be transmitted from bats to humans, is because there is a common ancestor, allowing for both genomes to be similar to one another (Ye et al., 2020). Due to the ever-evolving nature of viruses to become more effective at infecting it’s hosts and the coronavirus nature in particular to have high RNA replication mutation rates, the first HCoV likely mutated into these more dangerous strains (Ye et al., 2020).
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The symptoms for COVID-19 vary greatly for every individual. Some of the most common symptoms are the following as listed by the Centers for Disease Control (CDC): “fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste and/or smell, sore throat, congestion or runny nose, nausea or vomiting and diarrhea” (“Symptoms” CDC, 2020 ). It is suggested that one seek emergency medical attention if any of the following warning signs for COVID-19 are observed: “trouble breathing, persistent pain or pressure in the chest, new confusion, inability to wake or stay awake, bluish lips or face” (“Symptoms” CDC, 2020 ). It is emphasized that not all of the possible symptoms are listed, but those are considered to be the most common and consistent through observation. It is considered common knowledge at this point that symptoms can appear anywhere from 2-14 days after coronavirus exposure (“Symptoms” CDC, 2020). This is why the suggested quarantine is 14 days after perceived exposure, to allow adequate time for the virus to incubate and symptoms to appear and be expressed. A phenomenon seen with this disease is that it is possible for people to be asymptomatic. This causes high risk of exposure, as said asymptomatic person can be spreading the virus unconsciously, especially if they do not follow protocols laid out by the CDC. The virus is said to be transmitted mainly through droplets or small airborne particles from an infected person, being inhaled by another (“FAQ, Spread” CDC, 2020). There is great room for potential further research in this area of symptoms and their lasting effects that will be discussed in this review.
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There are three distinct phases of COVID-19 which is a result of the agent SARS-CoV-2, mild infection, pulmonary phase and the inflammatory phase. The mild phase, the intial phase, requires only symptomatic treatment. The pulmonary phase usually results in hospitilization and often involves fever, low oxygen blood levels and lungs being filled with liquid instead of air. This phase requires mostly antiviral treatment. Some potential treatments for this phase are remdesivir and chloroquine/hydroxychloroquine. The inflammatory phase is the final phase, in which patients will develop ARDS, Acute Respiratory Syndrome. This final phase is often treated by immunosuppresent drugs, such as dexamethasone, lopinavir/ritonavir and monoclonal antibodies (Magro, 2020).
The COVID-19 pandemic has worldwide impacts. Millions of people have died from this virus. In the US alone, there have been over 9.5 million cases and over 200 thousand deaths. Worldwide, there have been almost 48 million cases and over one million deaths. An effective drug treatment could help decrease morality rates and incidences of infection. This research paper will examine Remdesivir, chloroquine/hydroxychloroquine, lopinavir/ritonavir, monoclonal antibodies and dexamethasone as potential treatments for COVID-19. Each of these treatments will be evaluated based on their methods of action and clinical trials results.
Discussion
SARS-CoV and SARS-CoV-2 Relationship
Research shows that although SARS-CoV and SARS-CoV-2 both bind strongly to the ACE2 receptor in humans which is why they can invade cells so easily, SARS-CoV-2 has slightly stronger binding affinity paralleling its increased infection rate (Nguyen et al., 2020) The relative KD values as done in a study (Nguyen et al., 2020) show SARS-CoV to have 10.2-20.4 times, 4.2 times or 2.5 times greater KD values than SARS-CoV-2, proving that the binding affinity of SARS-CoV-2 is noticeably more effective (see table 1). The higher binding affinity of SARS-CoV-2 is the reason why COVID-19 is much worse than the original SARS-CoV. SARS-CoV-2 binds to the host cells, human cells with greater efficiency than SARS-CoV and because of this, it infects the host more affectively. This greater binding affinity is the cause of this current pandemic. SARSCoV-2 is more infectious, easily transmitted, dangerous and in the end, deadly (see figure 2). This knowledge of the difference between the two SARS, gives a good target for drug development, those areas which make SARS-CoV-2 have a higher binding affinity
Pulmonary Phase Treatment
Remdesivir
Remdesivir is a drug of the class antivirals that was originally created for the treatment of Ebola. This drug shows broad-spectrum antiviral activity, showing that it has potential for other virial disease treatments (Zhai et al., 2020). This is why it was considered as a candidate for SARSCoV-2 infection pulmonary phase treatment. Remdesivir’s mode of action is through attacking the viral RNA chain, embedding itself, and resulting in chain termination (Mehta, Mazer-amirshahi, Alkindi, & Pourmand, 2020).
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This drug seems to be very promising for potential COVID-19 treatment against SARSCoV-2. In vitro, this drug proves to be very successful, inhibiting SARS-CoV-2 and all other human and animal coronaviruses that were tested. It shows affect in animal models and human trials showed at least some affect as well (Wang et al., 2020). In a clinical trial study, (Wang et al., 2020), done in Hubei, China, the benefit of Remdesivir was not statistically significant, but there was a faster clinical time to improvement in the experimental group as compared to the control (placebo) group. An interesting finding of this study was that it was actually terminated before completion because the outbreak of the disease in China was brought under control. Another clinical trial, (Beigel et al., 2020), executed similarly, but in the United States, Denmark, the United Kingdom, Greece, Germany, Korea, Mexico, Spain, Japan and Singapore. This trial was also done comparing Remdesivir treatment to placebo. This trial also proved that Remdesivir was effective in reducing the clinical time to recovery, having a median of 11 days as opposed to the placebo at 15 days (Beigel et al., 2020). There was also a mortality rate difference with Remdesiver being 4.8% less than the control group (Beigel et al., 2020). This drug seems to be very promising, especially if it were researched even further to find the therapeutic dosage and in combination with other treatments to get maximum efficiency. There were some side effects that accompanied the use of this drug, but in the Beigel et al., 2020 trial, the placebo group actually faced more adverse events. Remdesivir treatment was accompanied by, mainly, gastrointestinal adverse events (Mehta et al., 2020). The sample of this study was well rounded including patients from many different sites around the world. Further research should follow and improve upon this structure. This drug was previously only allocated upon request, but manufacturers are working to make it more readily available, particularly because it seems to be one of the most promising options for treatment (Beigel et al., 2020).
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Another pulmonary phase treatment that was tested against COVID-19 is chloroquine, an antimalarial, and one of its analogs, hydroxychloroquine. The development of hydroxychloroquine was inspired by the lack of availability of the original chloroquine (Xu et al., 2020). The mode of action for these drugs is by increasing endosomal pH levels which interrupt virus cell fusion and it interferes with receptors of SARS-CoV (Zhai et al., 2020). This drug was considered to be very promising at the beginning of research investigations but has proved to not be significantly effective. In vitro, chloroquine was able to prevent infection, but not in animal or human trails (Xu et al., 2020). This information lead to the idea for testing it as more of a preventative treatment. Hydroxychloroquine was used post SARS-CoV-2 exposure to see if it could prevent the development of COVID-19 disease. It proved more potent than chloroquine, with a lower EC50 value, and more effective than placebo having more promising results (Xu et al., 2020). There is much controversy surrounding the legitamecies of these trials with hyroxychloroquine. Only 20 out of 26 patients were included in the final results without further explanation (Xu et al., 2020). The sample size is already extremely limitied and unlikely to have clinical significance, especially with the missing data. Another trial using hydroxychloroquine, in a more legitimate study, as a preventative treatment hydroxychloroquine proved to be more effective in a 150 patient study against standard treatment (Tang et al., 2020). Another study with 821 asymptomatic patients had similar resuts (Boulware et al., 2020). In the end, hyrdoxychloroquine and chloroquine both did not prove to be effective enough to be clinically significant, had higher adverse events and the methodology seems impractical for most people with little to no benefit.
Chloroquine and Hydroxychloroquine
Another pulmonary phase treatment that was tested against COVID-19 is chloroquine, an antimalarial, and one of its analogs, hydroxychloroquine. The development of hydroxychloroquine was inspired by the lack of availability of the original chloroquine (Xu et al., 2020). The mode of action for these drugs is by increasing endosomal pH levels which interrupt virus cell fusion and it interferes with receptors of SARS-CoV (Zhai et al., 2020). This drug was considered to be very promising at the beginning of research investigations but has proved to not be significantly effective.
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In vitro, chloroquine was able to prevent infection, but not in animal or human trails (Xu et al., 2020). This information lead to the idea for testing it as more of a preventative treatment. Hydroxychloroquine was used post SARS-CoV-2 exposure to see if it could prevent the development of COVID-19 disease. It proved more potent than chloroquine, with a lower EC50 value, and more effective than placebo having more promising results (Xu et al., 2020). There is much controversy surrounding the legitamecies of these trials with hyroxychloroquine. Only 20 out of 26 patients were included in the final results without further explanation (Xu et al., 2020). The sample size is already extremely limitied and unlikely to have clinical significance, especially with the missing data. Another trial using hydroxychloroquine, in a more legitimate study, as a preventative treatment hydroxychloroquine proved to be more effective in a 150 patient study against standard treatment (Tang et al., 2020). Another study with 821 asymptomatic patients had similar resuts (Boulware et al., 2020). In the end, hyrdoxychloroquine and chloroquine both did not prove to be effective enough to be clinically significant, had higher adverse events and the methodology seems impractical for most people with little to no benefit.
Inflammatory Phase Treatment
Lopinavir and Ritonavir
Lopinavir is a protease inhibitor that was previously used for HIV treatment. This drug in combination with ritonavir, another protease inhibitor, is being considered for potential COVID19 treatment because of its in vitro activity. This combination of drugs was successful against SARS-CoV in 2004. The mode of action of lopinavir is through enzyme inhibition of coronavirus (Zhai et al., 2020).
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In a trial with 41 patients, there was significant decrease in mortality in relation to ARDS. This combination of drugs, ritonavir supporting lopinavir and increasing efficacy, seems useful for treatment of the inflammatory phase of coronavirus, but is a weak antiviral (Xu et al., 2020). In a different trial with 199 patients that were confirmed to be infected with SARS-CoV-2, there was no notable benefit in lopinavir/ritonavir treatment as opposed to standard care with an increase in adverse gastrointestinal events (Cao et al., 2020). This data shows that although this combination of drugs was effective in vitro and against SARS-CoV, that does not mean that it is effective against the new SARS-CoV-2.
Immunotherapy Treatment
Monoclonal Antibodies
One of the most recent treatments against SARS-CoV-2 infection are monoclonal antibodies. Monoclonal antibodies are laboratory made antibodies that act against the antigens of an invading body; cell, virus, etc. (Monoclonal antibody drugs for cancer, 2019). These monoclonal antibodies are also used for cancer treatments, their mode of action, binding to the antigens on cancer cells to “flag” them for the immune system detection (Monoclonal antibody drugs for cancer, 2019). These monoclonal antibodies can be developed for treatment of COVID-10 infections and can be used independently or in combination with other antibodies (Zhai et al., 2020). The mode of action of the monoclonal antibodies against SARS-CoV-2 infection is to flag either the S1 subunit or the S2 subunit depending on the antibody used (Jahanshahlu & Rezaei, 2020). This, if done successfully, can block the binding of SARS-CoV-2 spike protein onto the human ACE2 receptor which causes infection. The way that these monoclonal antibodies would be used methodically in treatment of SARS-CoV-2 is through plasma therapy (Jahanshahlu & Rezaei, 2020).
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What seems to be most effective, according to research (Jahanshahlu & Rezaei, 2020), is combining different antibodies to cover various subunits to increase the chance of neutralization. The most promising of these neutralizing antibodies are B38, H4 and 47D11. B38 and H4 are of human origin and compete with ACE2 for binding to RBD, the receptor binding domain of SARSCoV-2 (Jahanshahlu & Rezaei, 2020). Because these antibodies compete with ACE2 for binding to RBD, that greatly improves the chance of inhibiting infection because SARS-CoV-2 will bind to the antibody instead of the host cell. 47D11 is an antibody that was derived from mice that had SARS-CoV-2, but then developed antibodies and fought it off. The 47D11 antibody shows that it can inhibit the S protein of SARS-CoV-2, but further research is needed (Jahanshahlu & Rezaei, 2020). Treatment using monoclonal antibodies seems very promising and affective, the main issue is availability. Large-scale production is expensive, difficult and not time efficient typically, but there is potential to clone these effective antibodies in systems that could be time efficient and cost affective (Jahanshahlu & Rezaei, 2020).
Dexamethasone
Dexamethasone is a corticosteroid that is used for its anti-inflammatory and immunosuppressant properties and now as a treatment for COVID-19 infection (COVID-19: Dexamethasone, CDC, 2020). Dexamethasone is a derivative of cortisol that is 30 times more active and can have longer lasting effects (Patel, 2020). Dexamethasone has many modes of action. This drug induces the production of different anti-inflammatory cytokines and can inhibit the production of pro-inflammatory cytokines (Patel, 2020). In SARS-CoV-2, there is an autoimmune event involving cytokines, taking place in the lungs, where the host’s immune system will start attacking its own cells. The use of dexamethasone in severe SARS-CoV-2 infection, can lower the damaging effects of this autoimmune event (Patel, 2020). There is controversy surrounding the use of this cortisol derivative due to the potential harmfulness of inhibiting the natural immune system, particularly the inhibition of T cell functions. As a solution to this problem, it was suggested that dexamethasone be used in combination with immunoglobulins (Patel, 2020). There are current trials testing out this suggestion that have yet to be finished.
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Dexamethasone was tested in 2104 patients with confirmed SARS-CoV-2 infection in the RECOVERY clinical trial (Horby P et al., 2020). The results show that those patients treated with dexamethasone had decreased mortality rates, lower risk for ventilation progression and shorter length of stay in comparison to the standard care control group. Those patients who were on oxygen support saw a 12.1% improvement in mortality rates as opposed to the standard care group. Those patients who were not on oxygen support saw a 2.8% improvement in mortality rates as opposed to the standard care group (Horby P et al., 2020). This trial proved that dexamethasone could be effective at decreasing mortality rates, particularly for those with severe cases. This trial lead to the UK government approving dexamethasone treatment for critically ill COVID-19 patients (Patel, 2020).
Treatment Comparisons
Throat-swab nucleic-acid results showed chloroquine treatment was more effective, 5/10, in treating COVID-19 infection than lopinavir/ritonavir, 3.10 (Liu et al., 2020). Remdesivir and dexamethasone both seem to be very promising candidates for SARS-Cov2 infection, particularly in severe cases. Remdesivir treatment had a mortality rate 4.8% better than standard care (Beigel et al., 2020). Dexamethasone had a mortality rate 2.8% better than standard care for patients who were not on oxygen support, but a 12.1% better rate for those who were on oxygen support (Horby P et al., 2020). This shows that dexamethasone is the best treatment available so far for patients on ventilation systems, decreasing the rate of mortality significantly. Remdesivir follows behind, still rather successful, but about 3 times less than dexamethasone for serious cases. Dexamethasone is about 4 times less effective for patients who are not on ventilation than those who are.
Conclusion
The purpose of this research paper is to determine which of the five listed drug therapies for COVID-19 are the most promising based on clinical trial results. The most promising drugs currently being researched are Remdesivir and dexamethasone. These two drug therapies have the greatest potential because they have proven to be the most effective at decreasing mortality rates. Dexamethasone proved to be the most effective at lowering the mortality rate in patients who were on oxygen support. Remdesiver followed second, and dexamethasone, again, in severely ill patients who were not on ventilation. Monoclonal antibodies are also very promising. The flagging of the spike protein of SARS-CoV-2 is an incredible mode of action and hits the drug target perfectly, without having to use a traditional drug. If the cost effective and time efficient suggestion were to be executed, monoclonal antibody therapy alone, or in combination with other drugs like dexamethasone or Remdesivir, can be the solution to the COVID-19 pandemic.
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Chloroquine and hydroxychloroquine as well as lopinavir/ritonavir were once thought to be very promising candidates. The research presented in this paper has proven this to be false. Chloroquine, hydroxychloroquine and lopinavir/ritonavir are not the most effective options for SARS-CoV-2. They show little to no effect, statistically insignificant results and seem to do more harm than good with poor efficacy and prevalent adverse events.
Continuing research studies on Remdesiver, dexamethasone and monoclonal antibody therapies can lead to the finalized treatment for COVID-19 and SARS-CoV-2 infection. There is much room for further research in the nature of COVID-19 itself. Some proposed areas for further research are the following. Is it possible to contract COVID-19 again if an individual already had it once? In response to that, even if you cannot contract infection a second time, can you still carry and spread the virus? These two questions can significantly impact society. If the virus cannot be contracted or spread after initial infection and resolution, life could return to a somewhat normal state. Another question is whether or not symptoms can remain post infection. In particular, one area of concern is with the associated symptom of loss of taste and smell. Another area of concern is with respiratory function for people who have asthma. If an asthmatic person contracts and overcomes SARS-CoV-2, would it worsen their lung function post-infection? The control group could be observing the level of difficulty in patients with SARS-CoV-2 infection who do not also have asthma. Another suggestion for further research is to see if inhibiting the human ACE2 receptor could be effective, especially in combination with a treatment that targets the spike protein of SARS-CoV-2, like monoclonal antibodies. It is of significant importance to see if the systems for potential cloning of the promising monoclonal antibodies, B38, H4 and 47D11, could truly be rapid and cost effective.
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Entering year two of the COVID-19 pandemic, societies should follow the recommended CDC guidelines, have lockdowns when necessary to curb the high infection rates and promote self-care. It is a difficult and uncertain time, but people have been adapting to the new times and will continue to do so. These three treatments, Remdesiver, dexamethasone and monoclonal antibodies are promising candidates for a response to the COVID-19 pandemic and hopefully will give some reassurance. Scientists, doctors and health officials all around the world are working collectively to find the best treatment. There is hope yet.
Acknowledgments
I would like to thank the Biology Department at Manhattanville College for the academic support and resources provided in the development of this paper. I would like to thank Dr. Wendy McFarlane in her guidance and for her time and effort in being my mentor for this project. I would also like to thank my peer review partner Adelle Clark for her feedback, assistance and support throughout this process as well. A final thanks to the reader for taking the time to review my work.
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Rosanna Vuksanaj '21
Rosanna Vuksanaj is a senior at Manhattanville College. She is a Castle Scholar with a major in Biochemistry and minors in Art History and Psychology. This literature review was part of their Research Methods Life Sciences course taken Fall 2020.