Where Does Science Stand in the Face of Coronavirus
Can an old drug save us from this pandemic?
(Article written by Lic. Julian F. Fernández, Lic. Ezequiel Fernández Navone and Juan Ignacio Badariotti. Edited by Candela Capra Coarasa)
What do we know about coronavirus? Why has no country come up with a cure yet? Why is it taking so long to find it? Is it true that there are some promising drugs? How long will it take for them to come out to the market? These are some of the questions that we hear in everyday conversations or in the media.
Worldwide, we can see how more and more countries (quite late in some cases) are entering lockdown. In times where tough political decisions have to be made and where the media's appetite for the latest news is voracious, it is understandable that broadcasters feel a huge temptation to be the first ones to announce a possible cure for this disease.
We decided to write this article so that, after reading it, you will not only be informed about the latest advances in the development of a treatment against the disease, but you will also be able to understand where these developments come from and how they evolve; and, thus, you will be able to draw your own conclusions without getting carried away by false expectations or fake news.
An Invisible Enemy
Considering the amount of information that is constantly overflowing us, it is important to clarify what is the world’s trending topic all about. Generally speaking, a virus is a microscopic infectious agent that needs a host (a cell) to replicate. Daily, we cohabit with many of the millions of viruses estimated to exist in nature, however, only a few of them are capable of causing diseases in humans, while almost none of them are capable of causing a pandemic (except influenza viruses, where luckily we have seasonal developments of new vaccines and antiviral treatment). Therefore, an obvious question arises: what makes Sars-coV-2 so special?
Before going any further with our analysis, it is important to distinguish between the terms SARS-coV-2 and COVID-19. The scientific name of the virus that caused the pandemic that threatens the world with its explosive contagious capacity is SARS-coV-2, while the disease that it causes was baptized as COVID-19 [1].
So, let’s come back to the question: why is this virus so special? Unfortunately, it must be included in the answer that, in addition to the high growth rate of infected people, it is our lack of knowledge what makes it highly dangerous. But, what do we know about it?
To begin with, we know that this virus falls into the positive-sense single-stranded RNA virus classification, which means that it belongs to the same virus group as other famous ones that are responsible for yellow fever, the flu and polio, among other diseases. Quite an unpleasant family, isn't it?
One characteristic of this type of virus is that its mutation rate is really high, but fortunately, this does not necessarily imply that it is impossible to control! While it is true that it probably complicates things, we were able to beat the rest of the family after all.
We also discovered (perhaps too late) that it is transmitted between humans very quickly, and that it causes severe respiratory disorders, especially in people over 65 years of age (8.8% of the global population, over 670 million people).
We are facing an enemy that we cannot see, that we can pass on to each other and of which we know little about.
What tools does science have to fight it? Why is it taking so long to find them?
Drug discovery, which stages are illustrated in the chart below, is a long, difficult, expensive and risky process that only a few companies and countries can face. It generally takes about 12 years from the discovery of a drug in a laboratory until it is used in patients, and costs approximately several billion dollars. At the end of the day, the company that comes up with a solution will earn more than the investment just by patenting the treatment.
No drug candidate can be commercialized on a large scale until the last clinical trial is completed, but in the fight against COVID-19 we do not have that much time.
The world can have the money, but it cannot buy time with it.
Fortunately, an immense number of scientists from all over the world are working on finding a new drug that will cure the disease, while others are untiringly searching for an effective treatment. But what are they doing? Below, we will explain their strategies and the latest advances reported.
Where are we in this process? What are the latest developments?
It can be easily observed how countries around the world are rapidly competing in order to develop an effective treatment, but it is important to understand that any new development must go through every stage of the trial pathway mentioned above. Skipping any of the steps would represent an inconceivable risk.
To be clearer about where the advancements are, it is convenient to divide our analysis into two main groups: vaccines and traditional drugs.
Vaccines
A vaccine is a preparation destined to generate acquired immunity against a disease by stimulating the production of antibodies. Its methodology, broadly speaking, consists of supplying the microorganism that causes the disease to patients in a safe manner (generally the microbe is either dead or weakened). This stimulates the patient’s immune system, which responds by generating antibodies to attack the present disease, while, at the same time, rendering the individual immune to the virus. The latter is the most important characteristic of this type of medicine: they prevent diseases.
For a more in depth explanation about the process, this video gives an outstanding description of how vaccines work:
https://www.youtube.com/watch?v=rb7TVW77ZCs.
Let's see then where we stand regarding vaccines. Last week a large amount of news circulated around the world about this matter, most of which claimed that there was already a finished drug. Far from that, trials on humans of possible vaccines are just starting. In our opinion, this shows a secondary global crisis: that of disinformation. We should be able to recognize fake news.
The development of a vaccine could take years.
The competition between different countries and companies to announce the creation of a vaccine is also visible. Currently, at least 9 vaccines are known to be in development by laboratories from 5 different countries.
Firstly we can group all mRNA vaccines, that are being developed by three companies: Moderna Therapeutics (in the United States, the only one in clinical phase), BionTech and Curevac (both based in Germany and in preclinical phase) [2], [3]. These vaccines are different from the traditional ones because that they supply messenger RNA to the patient, which acts like a barcode that can be read by the cells so that they produce antibodies to attack the pathogen following the instructions from the information that they have obtained. Unfortunately, to date, no vaccine of this type has reached the market [4].
We can identify, in a second group, companies developing vaccines that contain engineered viruses. But, what is an engineered virus? Basically, it is genetic material from the coronavirus, but modified somehow so it is harmless to the patient. This is the case of Cansino Biologics, a Chinese company that already obtained approval for stage 1 of clinical testing. Among this group, it is important to mention companies like Johnson & Johnson (United States) and Sanofi (France) that also reported ongoing developments, both in preclinical stages.
Finally, three other companies have stated that they are in preclinical stages of vaccine development: Arcturus Therapeutics (United States), Inovio (United States and China) and GSK/Clover (in the United Kingdom and China).
Drugs
Another approach in the strategy to face diseases is the search for a treatment that involves the use of drugs or small molecules. Regular medicines are generally made of an active ingredient (the drug) and other components that improve the action of said active ingredient, which is what really acts on the disease.
How do they do that? In most cases, it consists of these small molecules interacting with specific areas of larger molecules (proteins) and in a way that they interrupt some biologically relevant process in any of the virus replication stages.
We can describe this type of research with the following analogy: finding a small active molecule against a protein, is like finding a key to a lock among a bunch of million keys. Only one of them can interact with the protein correctly and, eventually, be turned into a medicine.
When the key that we find is new, it may happen that it can open other locks in our bodies, which may cause side effects. In many cases, those are only discovered after reaching phase 1 and 2 of the clinical trials, when the testing is carried out on humans, since they don't appear in previous experiments in test tubes or animals. This is one of many reasons why it is very important to respect and follow every stage previously mentioned in the drug discovery process.
With this in mind, we can have a better understanding of the strategies that are being used to obtain treatment. Let’s think: what does a scientist need to be able to investigate in this area? Mainly three things: a database (different sets of keys), virus proteins (locks) and, once the key has been selected, it needs to be able to be produced on a large scale.
The key to understanding where scientific research is headed in this area is in the virus databases and proteins. As we observed in the second chart, to be approved, a drug must go through many stages and that could take an average of 12 years. Now, what if we use a database of drugs that we already know are safe and have already been tested in humans? Perhaps one has a relatively good probability of success and we can test it directly on patients.
On the other hand, the more locks we know, the more times we can try the different sets of keys that we have available. And this is why the scientific community is making a tremendous effort in the search for the structures of such proteins, from which 29 have been reported so far [6].
By using already known drugs we can speed up the process.
With these in mind is easy to spot where to find the most recent advances, and now we can understand why some drugs are already being tested in humans. We will focus our analysis in four cases that the World Health Organization considers to be the most promising ones and for which has announced a massive multi-country mega trial called “Solidarity”[7].
The drug that seems to be the most promising one is the antiviral Remdesivir, previously developed by the pharmaceutical company Gilead (United States) to treat ebola, and it is the only one that is already in phase 3. This drug is designed to be transformed into its active ingredient once inside the body, and then stop virus replication by inhibiting the protein RNA polymerase, vital for this process[8].
Human tests of this antiviral have so far worked quite well, with at least two patients recovering successfully [9]. The expectation is so high with this drug that the laboratory that produces it had to suspend its distribution in emergency cases because it was overdemanded [10].
The second group of drugs is chloroquine and hydroxychloroquine, mainly used for the treatment of malaria and some other autoimmune diseases, such as rheumatoid arthritis and lupus. Its effectiveness against coronavirus remains unknown, with various studies showing evidence in its favor and others radically against it.
Both drugs have long been considered broad-spectrum antiviral agents. However, evidence suggests that they act upon a mechanism by which most viruses typically access the cells, but SARS-coV-2's entryway is a different one [11]. That is why there is skepticism regarding the effectiveness of these drugs.
Another drawback they have that is worth mentioning, is that these drugs were never approved for their use as antiviral agents, probably because the dose necessary to be effective in humans is very high.
Last but not least, new studies in patients of these drugs in combination with Azithromycin (an antibacterial), have shown that they seem to be effective in reducing viremia (the number of viruses in the bloodstream) [12]. However, the authors suggest that these outcomes need to be reconfirmed and broaden in further clinical trials.
All in all, it is important to be cautious so as to prevent that what happened in the United States is not to be repeated: Donald Trump praised chloroquine and hydroxychloroquine, which led to several deaths from poisoning since some people decided to consume these substances [13].
The other two groups of drugs included in WHO's mega trial involve drugs specifically used in combination in HIV treatment: Lopinavir and Ritonavir.
How do they work? Lopinavir inhibits a key protein in the replication of the HIV virus, which is similarly present in different types of coronaviruses. As this molecule is usually quickly deactivated by the body, its action is necessary in conjunction with Ritonavir, which makes the deactivation process much slower.
So far, the only human trial of this drug combination hasn’t shown promising results, but such an experiment was done in very sick patients, and the drug may have arrived too late for them [11].
The fourth option proposed in the study involves the last two drugs that were mentioned, but in this case together with interferon-beta. This one, unlike the others, is an entire protein and not a small molecule. It is used as anti-inflammatory medication and its effective action has already been demonstrated when successfully tested in monkeys infected with other types of coronaviruses, responsible for Middle East Respiratory Syndrome, which is why it is now being tested in human patients [11].
The ones listed above constitute the four most promising groups of drugs for WHO. For the study to have significant results, it needs to be conducted on thousands of patients around the world, and to show a consistent outcome between them. Argentina, Canada, France, Iran, South Africa, Spain, Switzerland and Thailand are among the countries that agreed to participate in the trail, and more than $43 million have already been raised.
The essay will seek to answer questions such as:
- Are any of these treatments effective?
- If so, are they effective in all all stages of the disease or only when the viral load is very low?
- Can we eliminate the virus from the body?
- Are there any side effects?
What options prevail if all fails? To tell the truth, many other antivirals are being tested to see their effectiveness against COVID-19. Although WHO decided to carry out trials only with the drugs that we analyzed, they clarified that they do not rule out the possibility of adding new ones.
Conclusions
The world of science is moving at a speed never seen before to deal with a single subject. The number of scientists trying to collaborate, in their own capacity so that this pandemic ends, is innumerable.
Some are devoted to researching the nature of the virus, others to developing new tests, and others to discovering a treatment. Many even volunteered to perform diagnostic tests on patients. The entire scientific community is working so that the enemy is less and less invisible, less and less unknown.
However, despite all these efforts, we still don't know how long will the wait for the mass production of a drug be, and we are faced with the possibility that a vaccine might take even longer to be created and approved. As it could be observed, the best strategy lies in the search for medicines that have already been approved for some other use, or that have at least passed the first safety tests on humans. Contrary to what several politicians have hastily announced, we are still far from finding a cure, but we can say that we have reasons to have hope.
As of today, the only effective strategy against COVID-19 is suppression (explained here), and especially social distancing and self-isolation. It is the only tool we have at the moment to fight this war. While science progresses, let's take care of each other.
Meanwhile, it’s your time to fight against coronavirus. Stay at home.
Spanish translation available here.
We deeply appreciate the time spent reading and reviewing the article by Drs. Jorge Palermo and Martin Lavecchia and Lic. Ivan Priet from CONICET and also to Dr. Jan Jiricek from Novartis.
We also thank for the support of all our family and friends who have collaborated so that this article can come to light.
We couldn’t have finished without your help, thank you very much!
