A week after China notified the WHO of the first cases of severe pneumonia of unknown origin, on December 31, 2019, the agent was identified: a new coronavirus, since named SARS-CoV-2. A few days later, his genome was already available. In just under three months, more than 970 scientific articles appeared on the PubMed database.
VSKnowing the biology of the virus facilitates the construction of therapeutic (antiviral) and preventive (vaccines) strategies. We know that its genome has 79% similarity to the SARS-CoV-1 virus (responsible for SARS – severe acute respiratory syndrome), that the key to entry of the virus into our cells is protein S, and that its fixation passes through the ACE2 receiver.
Protein S of SARS-CoV-2 has 76% similarity to that of SARS-CoV-1, and its affinity for the ACE2 receptor is higher. This may explain why the new coronavirus is more contagious and more transmissible than SARS-CoV-1. The entry of the virus is also facilitated by a protease located in the cell itself, called TMPRSS211.
Once the SARS-CoV-2 virus is inside the cell, it turns on several of its genes. Among the most important are those that produce RNA polymerase (RdRp), an enzyme that replicates the genome of the virus, as well as the proteases C3CLpro and PLpro, which are involved in the processing of viral proteins. These genes are similar to those of SARS-Cov-1 at 95, 95 and 83% respectively.
In just three months, several therapeutic and vaccine proposals have emerged to combat this new coronavirus. Science has never advanced so much in such a short time to fight an epidemic. Many of these proposals come from research groups that have worked for years against other viruses, including those of SARS and MERS (Middle East Respiratory Syndrom – Middle East respiratory syndrome). All this accumulated knowledge made it possible to advance at an unprecedented speed.
Antiviral therapies to cure
Knowing in detail the genome of the virus and how it multiplies in cells allows us to offer antivirals that block it and inhibit its multiplication.
Inhibit entry of virus
Chloroquine has been used for years against malaria. We know that this drug (widely used and inexpensive) is also a powerful antiviral that blocks the virus’s access to cells. For this reason, several research groups are interested in its effectiveness in reducing the viral load in patients with SARS-Cov-2.
Some of the viruses that are surrounded by an envelope, such as SARS-CoV-2, enter the cell by endocytosis, forming a small vesicle. Once inside, a drop in pH promotes the fusion of the envelope of the virus with the vesicular membrane that contains it, so that it is released in the cytoplasm.
In the case of SARS-CoV-2, chloroquine would prevent this drop in pH, which would inhibit membrane fusion in order to prevent the entry of the virus into the cell cytoplasm. For now, we have seen that hydroxychloroquine, a less toxic derivative, inhibits the response of SARS-Cov-2 in vitro in cell cultures.
It is not the only proposal currently under consideration to prevent the coronavirus from entering cells. Baricitinib, an anti-inflammatory drug approved to treat rheumatoid arthritis, may inhibit the endocytosis of the virus. Camostat mesylate, a drug approved in Japan for inflammation of the pancreas, inhibits the cellular protease TMPRSS2 needed for entry of the virus. This compound has been shown to block the entry of the virus into lung cells.
Inhibit viral RNA polymerase
One of the most promising antivirals against SARS-Cov-2 is remdesivir, a nucleotide analogue that inhibits viral RNA polymerase, which stops the virus from multiplying inside the cell.
Remdesivir has already been used against SARS-Cov-1 and MERS-CoV, and has been successfully tested during the last Ebola epidemics as well as other RNA viruses. It is therefore a broad spectrum antiviral. At least twelve phase II clinical trials are already underway in China and the United States, and another phase III trial has started with 1,000 patients in Asia.
Favipiravir is another broad-spectrum viral RNA polymerase inhibitor for which clinical trials have started: initial results from 340 Chinese patients have been satisfactory. This drug has been approved as an influenza virus inhibitor and has been tested against other RNA viruses.
It has been suggested that the combination of ritonavir and lopinavir may inhibit the proteases of SARS-CoV-2. These compounds are already used to treat HIV infection.
Lopinavir is a protease inhibitor of the virus, which degrades easily in the patient’s blood. Ritonavir acts as a protector and prevents the breakdown of lopinavir, which is why they are given together.
Unfortunately, an article which has just been published shows after tests on 199 patients that this combination ritonavir-lopinavir is ineffective against the coronavirus.
Good news, however, that at least 27 clinical trials are underway on different combinations of antiviral treatments, such as interferon alpha-2b, ribavirin, methylprednisolone and azvudine.
These treatments remain experimental, but it is hoped that some will be useful for the most serious cases.
Vaccines for the future
The other strategy for controlling the virus is through vaccines. Remember that they are preventive: they can protect us from the next wave of the virus, if it returns. WHO already has a list of at least 41 candidates.
One of the most advanced is perhaps that proposed by a Chinese team, a recombinant vaccine based on an adenoviral vector containing the S gene of SARS-CoV-2. It has already been tested on monkeys, and is known to produce immunity. A phase I clinical trial testing three different doses should start with 108 healthy volunteers, aged 18 to 60 years. The aim is to ensure the safety of the vaccine (assess possible side effects) and to determine which dose induces the strongest response in terms of antibody production.
Other proposals come from CEPI, an international association in which public, private, civil and philanthropic organizations collaborate, with the aim of developing vaccines against future epidemics. CEPI is currently funding eight SARS-CoV-2 vaccine projects, which include recombinant vaccines, protein vaccines and nucleic acid vaccines.
Here they are :
Recombinant vaccine using measles virus as a vector (Institut Pasteur, Themis Bioscience and University of Pittsburgh)
It is a vaccine based on an attenuated measles virus. This is used as a vehicle inside which is a gene encoding a protein from the SARS-CoV-2 virus. The vector virus delivers the SARS-CoV-2 antigen to the immune system to induce a protective response.
This consortium has already demonstrated its experience in the development of such vaccines, directed against MERS, HIV, yellow fever, West Nile virus, dengue fever and other emerging diseases. Their vaccine is in the preclinical phase.
Influenza virus-based recombinant vaccine (University of Hong Kong)
It is also a live vaccine that uses an attenuated influenza virus as a vector, which has removed the virulence gene NS1 to make it non-virulent and added a gene for the SARS-Cov-2 virus.
This approach has some advantages: it could be combined with any strain of seasonal flu, and thus serve as a flu shot at the same time. This could be made quickly in the same production lines as flu vaccines, and could be administered as an intranasal spray vaccine. This vaccine is currently in the preclinical phase.
Recombinant vaccine using the vector of the Oxford chimpanzee adenovirus, ChAdOx1 (Jenner Institute, University of Oxford)
This attenuated vector is also capable of transporting a gene coding for a coronavirus antigen. In this case, the recombinant adenovirus contains the SARS-CoV-2 glycoprotein S gene. It has been tested on volunteers with models for MERS, influenza, chikungunya and other pathogens such as malaria and tuberculosis.
This vaccine can be produced on a large scale in cell lines of poultry embryos. He is in the preclinical phase.
Vaccine based on recombinant proteins obtained by nanotechnology (Novavax)
The company already has phase III clinical trial vaccines against other respiratory infections such as adult flu (Nano-Flu) and respiratory syncytial virus (RSV-F). It has also produced vaccines against SARS-CoV and MERS-CoV.
Its technology is based on the production of recombinant proteins which are assembled into nanoparticles and are administered with a patented adjuvant, Matrix-M. This compound (a mixture of plant saponins, cholesterol and phospholipids) is a well-tolerated immunogen capable of stimulating a strong and lasting nonspecific immune response.
Recombinant protein vaccine (University of Queensland)
This approach consists of creating chimeric molecules capable of maintaining the original three-dimensional structure of the viral antigen. They use a technique called “molecular clamp” (molecular clamp), which makes it possible to produce vaccines using the genome of the virus in record time. He is in the preclinical phase.
MRNA-1273 vaccine (Moderna)
It is a vaccine made up of a small fragment of messenger RNA containing the instructions necessary to synthesize part of the protein S of SARS-Cov-2. The idea is that once introduced into our cells, they make the viral protein, which would act as an antigen and stimulate the body’s production of antibodies. It is in clinical phase and trials have started on healthy volunteers.
Messenger RNA vaccine (CureVac)
It is a proposal similar to the previous one, based on the use of recombinant messenger RNA molecules which are easily recognized by cellular machinery and produce large quantities of antigens. They are packaged in lipid nanoparticles or other vectors. In the preclinical phase.
DNA INO-4800 vaccine (Inovio Pharmaceuticals)
This platform manufactures synthetic vaccines based on DNA from the coronavirus surface protein S gene. This company had already developed a prototype directed against MERS-CoV (vaccine INO-4700), currently in phase II clinical trial.
Recently, Inovio Pharmaceuticals published the results of the phase I vaccine INO-4700: these prove that it is well tolerated and leads to a good immune response (which results in high levels of antibodies and good response of the cells T, which lasts for at least 60 weeks after vaccination). In the preclinical phase.
Many other tracks
The Spanish proposal has just received express funding from the government. This vaccine proposed by the group of Luis Enjuanes and Isabel Sola consists of a live attenuated vaccine which could be easier to manufacture than others and much more immunogenic, that is to say endowed with a better capacity boost the immune system.
The idea is to take RNA from the coronavirus and reverse transcribe it into DNA, and then use this molecule to produce non-virulent mutants. In other words, it’s about making a modified copy of the virus, incapable of producing the disease, but which would still be able to activate our immune defenses.
No SARS-Cov-2 antiviral or vaccine has been approved today. All of these proposals are in the experimental phase. Some will not work, but the chances of success are high, however.
In addition, a review of the entire therapeutic arsenal and research and development vaccines against other human coronaviruses, such as SARS-CoV and MERS-CoV, has just been published.
To date, there are over 2,000 patents relating to these two coronaviruses. 80% of them relate to therapeutic agents, 35% to vaccines and 28% to diagnostic techniques (a patent can cover several aspects, it is normal for the total to exceed 100%). The list includes several hundred patents on antibodies, cytokines, RNA interference therapy and other interferons to fight SARS-CoV-1 and MERS-CoV. These tracks are currently in the research and development stage, and some could work well against the new SARS-CoV-2.
There are also dozens of patents on potential SARS and MERS vaccines that we can take advantage of to fight SARS-CoV-2. These are vaccines of all kinds: inactivated vaccines, live attenuated vaccines, DNA, RNA vaccines, VLP vaccines (Like Particle Virus)… The immense amount of scientific knowledge already existing will speed up clinical and experimental trials intended to combat this new coronavirus.
Science and solidarity
WHO has announced a large international clinical trial called Solidarity, which aims to find an effective treatment with COVID-19. To date, Argentina, Bahrain, Canada, Spain, France, Iran, Norway, Switzerland, South Africa and Thailand are participating in this large-scale global clinical trial project. scale, and more and more nations should join it.
Without a doubt, this is the time for science and solidarity.
This article was translated from Spanish by Nolwenn Jaumouillé.
Ignacio López-Goñi, Catedrático de Microbiología, Universidad de Navarra
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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