COVID-19 - drugs, vaccines and a possible resolution

Current treatment

At the moment, there is no specific antiviral treatment that is available to cure the COVID-19 disease. It can, however, be treated and managed depending on the severity of the symptoms. Self isolation, rest, plenty of fluids and monitoring symptoms are suggested by many governments for mild cases of COVID-19, while more severe cases require hospital treatment. During a hospital visit, doctors will assess the severity of the illness and treat the patient accordingly. Often, oxygen levels in the blood are checked using a clip-on finger monitor and the lungs are examined using a stethoscope, a chest x-ray or a CT scan. Patients could be provided oxygen through a nasal cannula. The patient might also be connected to a ventilator, which mechanically pumps oxygen into the lungs from a tube that passes through the mouth into the windpipe. This treatment is used in cases where the patient experiences severe breathing issues and they cannot breathe properly on their own. Pain relievers such as ibuprofen or paracetamol, and cough syrups or other cough medication may also be administered to provide supportive care and ease the symptoms of the virus.

Drug trials

The names of drugs such as remdesivir, dexamethasone, and hydroxychloroquine have been prominent in recent news. These are existing drugs that have been used in COVID-19 trials, with remdesivir being FDA approved for hospitalised patients with severe COVID-19 symptoms.

Remdesivir is a broad spectrum antiviral drug which works by posing as an RNA building block consisting of an RNA nucleotide sequence. It is generally administered by injection into a vein. The enzyme RNA-dependent RNA polymerase is responsible for copying the genetic material of coronaviruses in order for viral replication to occur once a virus has invaded the cell. Due to the resemblance of remdesivir to the RNA building block, the RNA-dependent RNA polymerase enzyme is tricked into incorporating the active metabolite or remdesivir into the RNA strands of new virus particles. After the incorporation of remdesivir, the enzyme is unable to add any further nucleotides into the RNA sequence, halting the process of genome replication. This means that the virus can no longer invade and infect any further host cells, slowing the growth of the virus in the human body. Scientists believe that the reason remdesivir acts as an inhibitor of RNA-dependent RNA polymerase is the fact that remdesivir takes on a shape that does not fit the active site of the enzyme. However, this is still only a theory, and many more clinical trials must be done in order to come to a conclusion.

Gilead Sciences, the biopharmaceutical company responsible for the development of remdesivir, have been conducting clinical trials to test the safety and efficacy of the drug. The data from three of their randomised controlled clinical trials have shown that remdesivir has improved clinical outcomes in patients with severe COVID-19 patients who also show signs of pneumonia. These results were garnered from both a five day and a ten day course of treatment. They also reported that early intervention in disease prognosis with a five day course treatment can significantly improve clinical outcomes to a greater extent in comparison to intervention at a later stage. This could be due to the fact that the sooner remdesivir is administered to halt the genome replication, the fewer human body cells that the virus can invade, making the recovery process quicker. Currently, remdesivir is approved for commercial use in patients infected with the virus only in Japan. Other countries are still investigating the drug, which is only approved by the FDA for emergency use in patients with severe symptoms. The side effects of the drug are yet to be determined, and the results of the Gilead clinical trials have not been peer reviewed. These are the reasons why the drug has not been approved for commercial use in many countries.

The corticosteroid dexamethasone is also being investigated for efficacy against COVID-19. Corticosteroids are a class of drugs that are prescribed to lower inflammation in the body. Dexamethasone has been used to reduce inflammation in several diseases, including cancer, since the 1960s. The WHO reports that dexamethasone can reduce mortality in patients with severe COVID-19 symptoms based on the RECOVERY trial run by the University of Oxford in the UK. This trial showed that death was reduced by one-third in patients on ventilators, and by one-fifth in patients requiring only oxygen. The mechanism behind the mortality-reducing effect of this drug could be because of its ability to calm inflammation. This ability could be applicable to the lungs of any patient with severe respiratory symptoms. This drug is not only widely available, but it is also affordable, making it a good treatment option for COVID-19. However, it is important to acknowledge that this drug has only been tested on hospitalised patients showing severe symptoms. Corticosteroids also reduce immune system activity, hence it would not be advisable for patients with mild symptoms to take dexamethasone, as this could lead to a reduced immune response and worsening of symptoms as a result. It is also not advisable to take this drug as a preventative measure, as this would increase susceptibility to infection in unaffected individuals due to the reduced immune response. Additionally, steroids are known to cause a range of side-effects, including stomach irritation and ulcers, difficulty sleeping and high blood pressure.

The final drug, hydroxychloroquine, belongs to a class of antimalarial drugs used against the protozoan parasite Plasmodium, which is known to cause malaria, with a mosquito being used as a vector to spread the disease. The drug is used to reduce fever and inflammation, which also happen to be symptoms of COVID-19, hence researchers are interested in investigating whether this drug could be used to treat the disease. While many studies of this drug have been completed, they yielded mixed results. Early studies showed some evidence of hydroxychloroquine being able to shorten the duration of typical COVID-19 symptoms, however, more recent studies showed no beneficial effects at all. Oxford’s RECOVERY trial has also reported that there was no beneficial effect of hydroxychloroquine in patients with severe symptoms. The mortality rate over a 28 day period was 25.7% for patients who were administered the drug, compared to 23.5% in patients receiving standard hospital care. The FDA has also warned healthcare practitioners of the risks associated with hydroxychloroquine, mainly severe heart rhythm problems. Due to all these factors, it has been concluded that hydroxychloroquine is not a treatment for COVID-19, and the drug has been withdrawn from clinical trials.

Convalescent plasma therapy

Another potential treatment option, aside from drugs, is convalescent plasma therapy. Convalescent plasma refers to blood plasma from survivors of a specific illness, in this case, COVID-19. Plasma is the liquid portion of the blood that does not contain blood cells, but carries proteins, hormones, and antibodies. Antibodies are a type of protein produced by the immune system when the body has been infected by a pathogen. Each antibody has a binding site that is specific to the antigens of a certain type of pathogen. An antigen is a molecule on the surface of a cell that distinguishes it from other cells. The immune system will trigger the production of antibodies if it recognizes a foreign antigen, which usually indicates the presence of a foreign cell, such as a pathogen.

The aim of convalescent plasma therapy is to utilise the antibodies specific to SARS-CoV-2 from a patient who has recently recovered, in order to treat patients currently suffering from COVID-19. The plasma from the recovered individual is taken and inserted intravenously into the blood of a patient currently suffering from COVID-19. The goal is for the antibodies in the transplanted blood plasma to be able to destroy the coronavirus particles in the patient’s bloodstream and speed up the recovery process. This treatment is being considered for any patient who is not responding to any other treatment. The risks of this treatment are that it could cause allergic reactions, lung damage or transmission of other infections such as hepatitis B or C.

Vaccine development

While drugs are a necessary part of fighting the coronavirus pandemic, vaccines are extremely vital in preventing the further spread of the virus. Generally, a vaccine drug is first found in the preclinical stage based on the responsiveness of the immune system to the proper antigen. After this, the drug is tested on transgenic organs to determine the reactions and side effects of the drug on the human body. The drug trial will also focus on pharmacodynamics and pharmacokinetics. Pharmacodynamics is the study of the possible biochemical and physiological mechanism of the drug inserted into the organism and pharmacokinetics is the investigation of the means through which the chemical or chemicals will be excreted from the body.

The vaccine must also be tested on humans, which involves trials in four phases. The whole testing process usually takes three to nine years, however, there has been a relatively rapid pace for the development of the COVID-19 vaccine. This is partially due to the already sequenced and shared genomes of SARS and MERS, where 77% and 50% of the genomes are shared respectively. However, in addition to genome sequencing there is also epitope mapping, which is the process of experimentally identifying the binding site, or "epitope", of an antibody on its target antigen. In this case, it is the spike glycoprotein of SARS-CoV-2 to which the paratope (binding site) of an antibody attaches itself to initiate an immune response.

The major target of a vaccine for SARS-CoV-2 is the spike proteins which enable fusion with the cell membrane through binding to the ACE2. By neutralizing these domains the virus will be prevented from fusing and penetrating the cell membrane to facilitate viral replication.

The two potential forms of a COVID-19 vaccine are the live attenuated and inactivated vaccines. The live attenuated vaccines (abbreviated as LAV) are alive and reproducing viral particles which are avirulent to allow for long lasting immunity with a single dose and without physical symptoms as the virus will replicate but at a lower rate so that there is a constant antigen presence. These vaccines are developed by inserting a viral population into a foreign host, where one of the hosts will possess a mutation, allowing for the virus to infect the new host. Selection pressures will allow for mutation of the viral particles to acclimate to the new host, where the final viral particles will not be compatible with the original host. This process is known as passage where the viral particles are not harmful to the vaccinated individual. A possible issue with LAVs is that they can mutate and revert to a pathogenic form which will harm an immunocompromised individual, especially when the pathophysiology of the virus has not been fully explored. The vaccines must be kept cold, as they are unstable, otherwise silent codon mutations could occur, causing a loss of reproductive potential for the avirulent viral particles. This would lead to the immunization of an individual for only a short time period.

On the other hand, inactivated vaccines use viral particles which have been chemically or physically inactivated so they are not able to replicate. While they are safer than LAVs, their inability to replicate allows only for short term immunization, as the creation of memory cells specific to the antigen decreases due to the lack of constant presence of the antigen. Consequently, boosters are needed, especially in aging individuals with an immune system in senescence.

A potential end?

The perturbing question on everyone’s minds right now - ‘when will the pandemic end?’ Countries have begun to ease lockdown restrictions, whether they are virus free or not, in order to restore their economies. It is important to understand that the pandemic will end at different times for different countries due to a variety of factors. Dr. Ali Khan, a previous disease detective for the Centres of Disease Prevention and Control suggests that the best way to move forward and combat COVID-19 is to prevent it, considering that, at the moment, there is no available vaccine for it. The public health strategies are different depending on the nation, meaning that the end of the pandemic will also be different. For example, in China, where the outbreak originated, there have been only three hundred positive cases detected out of nine point nine million people tested over a nineteen day period at the end of May. This is due to their strict and early enforcement of lockdowns in the epicentre, Wuhan, and other affected cities in order to control the spread of the virus. To contrast China, the United States has seen at least twenty thousand cases on the daily, with an average of 200 deaths per day. The country has the highest death toll in the world, and it is continuing to rise. The severity of the outbreak in the USA can be attributed to a severe lack of contact tracing, a lack of adequate testing measures, especially during the start of the outbreak, differing lockdown approaches from state to state, and now the recent relaxation of restrictions despite the extremely high count of active cases and death toll.

From the examples discussed, there is clear support for Dr. Khan’s theory. The stronger the public health strategy, the easier it should be to end the pandemic. Interestingly, Ed Yong, a science writer, was one of hundreds of writers who wrote articles explaining why a global pandemic was inevitable. His article was published two years ago, and now, here we are, amidst a global pandemic, having been completely unprepared despite all the warning signals. Ed Yong has also written articles about how a pandemic will end, stating three potential situations - the unlikely way, the dangerous way and the long way.

The first option - the unlikely way - involves the world’s nations working together to combat the pandemic by enforcing strict lockdown and quarantine measures and implementing mass-testing rollouts. The reason that this is termed ‘unlikely’ is because of the slow and weak responses of some major world powers in enacting testing and nation-wide lockdowns. Due to this, it would be unlikely for the whole world to come together to combat the virus in such a way. Many simulations to predict the progression of COVID-19 have predicted that the USA, being one of the world’s most technologically advanced nations, would be amongst the first countries to develop a vaccine against the virus. However, that is clearly not the case, and instead the country has been unable to reduce the spread of the virus amongst its own population. This further strengthens the argument for why the first option is quite unlikely at this point in time.

The second option - the dangerous way - involves herd immunity. This is where the majority of the world’s population is allowed to become infected by the virus, in this case SARS-CoV-2, so that those who survive will develop the antibodies specific to it and become immune to the disease. Unfortunately, if this approach was taken, the damage and loss of human life would be severe. It is predicted that if this approach was applied to COVID-19, a million people would die in the US alone, with ten to twenty million deaths worldwide. Another factor to consider is that the immunity developed for the virus could be short-lived, making an attempt at herd immunity futile.

The final option - the long way - is the most plausible one at the moment. Social distancing and quarantine measures will have to be maintained, until a vaccine is developed, with an increased focus in areas with severe outbreaks. It is estimated that an effective vaccine could take anywhere between 12-18 months to be available, maybe even more.

With regards to when the pandemic will actually end, scientists need to look into two factors - the virus’ seasonality and its duration of immunity. Unfortunately, for now, we can only maintain social distancing and follow preventive measures, such as wearing masks in public places and maintaining optimal hygiene, until researchers and scientists have managed to develop an effective vaccine and make it commercially available.

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