The COVID-19 pandemic, which has emerged in Wuhan, China, and has been spreading worldwide since November 17, 2019, currently (on this day, April 12th 2020) counts 1.7 millions infected individuals, more than 100’000 victims as well as billions of people isolated in quarantine. In order to fight the new coronavirus, responsible for the pandemic, effectively treat sick people, and prevent a new epidemic from the beginning of fall 2020, a large number of scientific laboratories have focused on different therapeutic solutions. Several types of vaccines are being developed, both in academic institutions and in the industrial and pharmaceutical sectors. Unfortunately, the development of a vaccine, the validation of its effectiveness as well as its safety, including preclinical, and especially clinical trials, can take an average of 18-24 months if not much more in normal conditions. There is therefore an urgent need to find an alternative solution to curb the pandemic and avoid a second one during the winter of 2020-2021.
What is SARS-CoV-2 virus?
The coronavirus SARS-CoV-2 (at the origin of the COVID-19 pandemic – Coronavirus Disease 2019) is the 7th coronavirus attacking humans. It belongs to the family of Coronaviridae, viruses with positive single stranded RNA and which have the appearance of a crown. Finding source generally in animals but also infecting humans, these viruses are at the origin of diseases ranging from simple colds or gastrointestinal disorders to very severe respiratory diseases (for a review, please refer to Vincent and colleagues, 1). Among these, three coronaviruses, SARS (”Severe Acute Respiratory Syndrome coronavirus”) – CoV (at the origin of the first SARS epidemic in Asia in 2003), MERS (Middle-East Respiratory Syndrome) – CoV (at the origin of the epidemic in Saudi Arabia in 2012) and SARS-CoV-2 are the most dangerous and their infection can be fatal to humans. Still, it seems that SARS-CoV-2 is the most contagious, and also the one that causes the highest mortality. It should be noted that SARS-CoV-2 is genetically more similar to SARS-CoV than to MERS-CoV.
Virus structure and life cycle: key elements
The knowledge of the molecular structure of the SARS-Cov-2 virus is based on the publication of its genome (resulting from a collaboration between Chinese scientific teams and the Pasteur Institute at the beginning of this year, then other international teams)2 , as well as on the knowledge acquired from the structures of SARS-CoV and MERS-CoV, viruses isolated and analyzed before. SARS-CoV-2 is composed of an envelope containing its genetic material. This envelope is coated with Spike or S glycoproteins, giving it the appearance of a crown; it also has membrane proteins M, nucleocapsides N, and proteins of the envelope E.
Binding to the receptor ACE2
To infect the human cell, using the sequence called Receptor Binding Domain (domain of attachment to the receptor) located within the protein S, the virus binds with a very high affinity (even more solidly than SARS-CoV) to its target receptor, called ACE2 (for angiotensin-converting enzyme 2) receptor. ACE2 is involved in the maturation of angiotensin, whose physiological role is to participate in the control of vasoconstriction and blood pressure and is located in the lungs, heart, kidneys and intestines. By binding to the receptor, the virus then fuses with the cell membrane to enter it. To develop the infection, the virus uses the machinery of the host cell, and translates its own genetic material (in particular using RNA polymerase) in order to be able to produce and assemble (in particular with the help of a protease) other virions which will then be released by the cell to continue propagation.
Recycling drugs for the fight against COVID-19: pros and cons
The treatments that will be developed with the aim of eradicating/preventing the virus infection will target the proteins and pathways that the virus uses to infect the cells. These drugs will mostly play a role in blocking viral entry in the cell, inhibiting a virally encoded protein or blocking virus particle assembly. Here is an overview of the treatments that are tested and considered.
SOLIDARITY: An international WHO trial
In March 2020, the World Health Organization (WHO) announced the launching of the international SOLIDARITY trial, which will compare therapeutic strategies to fight the COVID-19 pandemic, and find ways to reduce mortality. In order to target and block key functions of the SARS-CoV-2 virus, described earlier in this article, the primary objective of the study is to test molecules that have been already used to combat viruses known to induce other diseases, such as Malaria, Ebola or HIV (for a further description, please see references 3 and 4).
Chloroquine and Hydroxychloroquine
Widely seen in the media, and approved by the American Food and Drug Administration (FDA), chloroquine and its derivative hydroxychloroquine have been tested in several preclinical and clinical studies. Used in patients affected by malaria, lupus and rheumatoid arthritis, these drugs are able to reduce the acidity of the compartments called endosomes that viruses use as a mode of transport to enter the cell and cause infection. Despite its promising potential in vitro, studies show that this treatment is not as effective in the human organism, where the SARS-CoV-2 virus instead acts by using its protein S to bind to its preferred receptor expressed on the surface of human cells. It also appears that hydroxychloroquine combined with an antibiotic, azithromycin, increases the beneficial effect in patients with COVID-19, a very cited clinical trial led by a French team reported5. However, the doses used can cause significant toxicity in the patient, as well as heart problems, an effect that needs to be tested in more details.
The second drug, remdesivir, developed by Gilead Sciences, has been used as a treatment for the Ebola virus, but has failed to efficiently treat the disease. Its mechanism of action is based on the inhibition of RNA polymerase, essential for virus replication. Today, the drug is redirected to the fight against SARS-CoV-2, as it has been shown to effectively kill the virus in a petri dish mode. Approved by the FDA to be administrated only to severely affected COVID-19 patients, in clinical trials, it has been used for the treatment of hundreds of individuals in the United States, and it may have the best potential for infections in the few days following the first symptoms of the disease.
Lopinavir and Ritonavir
Similarly, a combination of the drugs lopinavir and ritonavir, developed by Abbott Laboratories, used to inhibit the HIV virus protease, an enzyme that helps building new viruses, is also on the list on the SOLIDARITY study. Already administered to patients infected with SARS-CoV and MERS-CoV, the combination appears to be promising in these cases, but has not yet shown significant effects in individuals with COVID-19. This is why, to this treatment will be added interferon-beta, a molecule regulating inflammation. Provided that this triple therapy is administered in the early stages of the disease, it could generate promising results.
Additional potential drugs tested
Other approved therapies include favipiravir, a medication developed by Fujifilm Toyama Chemical and used to combat influenza, as it blocks virus replicationIt is mainly applied to patients with moderate symptoms.
In addition, camostat mesylate, a drug principally used to reduce inflammation during pancreatitis, is also able to block the cellular entry of SARS-CoV-2It gave promising results when used in mice as it reduced mortality following SARS-CoV infection in doses similar to the ones used in a clinical setting.
Finally, a study published by the end of March 2020 described the potential of the antiviral molecule EIDD-28016, already used against influenza, Ebola, coronaviruses or Venezuelan equine encephalitis virusWorking in a preclinical setting, the authors show that given to mice, the molecule introduces genetic mutations into the virus’ RNA, so that the virus is not able to infect the cells anymore, and is eradicated.
Taking benefits from the serum from convalescent patients as a promising treatment
In early days of March 2020, experts in the field of immunotherapy7 described the use of serum/plasma from patients who had been infected with the SARS-CoV-2 coronavirus, and who had recovered from the disease, as an effective and rapid treatment option. In fact, convalescent individuals developed immunity against the coronavirus in the form of neutralizing antibodies which could benefit those infected during the course of the illness or individuals who have not contracted the disease but are susceptible to develop it. This is the basis of passive antibody therapy.
Passive antibody therapy: a definition
Developed already since the end of the 19th century, passive antibody therapy consists of delivering antibodies against an infectious agent to an individual at risk and aims to prevent and treat a disease initiated by this agent. Unlike active vaccination, which may take time to develop an immune response in the body, passive antibody therapy can initiate an immediate response in people susceptible to develop the disease. Importantly, previous epidemics initiated by the SARS-CoV and MERS-CoV coronaviruses show that the sera of convalescent patients contain antibodies neutralizing these viruses and could already be used as a treatment against these agents.
Authors in favor of passive antibody therapy describe that the process would be first based on the production of high concentrations of antibodies, then on their introduction, prophylactically (that is to say in prevention), to fragile or at risk individuals (with chronic diseases), to healthcare professionals who face COVID-19 every day, and to people living in the immediate vicinity of the infected individual. A key element in this process is that passive antibody therapy is generally most effective when administered for prevention as well as in the first few days after symptoms of the disease develop. This is explained by the fact that antibodies modify the inflammatory response more easily during the initial phases of the immune response. The efficiency of this process is immediate and therefore dependent on the amount of antibodies administered, and protection can last for months.
Although very few, experts in the field include several risks in the use of passive antibody therapy. On one hand, those can be associated with blood transfer, such as infections. Another theoretical risk could be the phenomenon of facilitation of antibody infection, already observed in infections with the HIV or Dengue fever viruses and which induce an increase in viral infection by blocking certain parts of the immune response. On the other hand, the immune response can also be attenuated by the administration of antibodies to those exposed to the coronavirus, thus inducing re-infection.
Serological tests applied to convalescents’ patients: preliminary results
Despite the promise of this method, several days ago, a preliminary study in Shanghai8 involving 175 patients shows that the levels of neutralizing antibodies in 30% of COVID-19 convalescent patients are, surprisingly, very low. If this proves to be a constant, and if these results are confirmed in other studies countries, two observations can be made. Provided that the method used to demonstrate the level of neutralizing antibody is completely valid and approved, these results may suggest that the coronavirus does not induce a significant immune response, at least in certain individuals, adding yet another enigma to the infection process and the immune system recognition system that it induces in our body. If this is the case, and if the levels of neutralizing antibodies in at least 30% of convalescent individuals’ serum are low, then a combination of sera from several individuals would be necessary to treat only one patient.
Conclusions: the fight against COVID-19 will be complex
If the new virus responsible for the global biological drama COVID-19 is similar to the previous coronaviruses that caused the SARS and MERS epidemics, and which we can learn a lot from, there is no doubt that the SARS-CoV-2 has undergone genetic mutations and thus developed a more efficient mechanism to infiltrate cells and create better transmission between individuals, whose immune system is not yet adapted. The proof is that the virus already counts a little less than two millions of infected people in less than five months, while its brother, SARS-CoV and its cousin, MERS-CoV, have infected a total of 8000 and just under 2,500 people respectively to date. To eliminate the new coronavirus, or in any case to curb the pandemic, several solutions which are discussed here are taken into account, but each of them has advantages but also real disadvantages. The fight against this virus is therefore still far from being won.
Unless we decide to test everyone for immunity against the virus in order to redefine a therapeutic and preventive strategy… It is precisely at the time of this writing that the world is preparing for an international diagnosis, based on serological tests, the purpose of which will be to scan immunity by the presence of antibodies against SARS- CoV-2 within the community. It will be a question of evaluating the percentage of individuals having already been immunized against the virus, in order to be able to make a decision in relation to a relaxation of the confinement rules as well as of the behavior to have in the following months. In order for the epidemic to be eradicated, 70% -80% of the population must be immunized. A crazy bet for humanity.
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