Rodolfo Matías Ortiz Flores1* and Corina Verónica Sasso2
Received: November 15, 2023; Published: January 10, 2024
*Corresponding author: Rodolfo Matías Ortiz Flores, Department. Human Physiology, School of Medicine, Campus Teatinos C/Boulevar Luis Pasteur, University of Malaga 29010, Malaga, España, Spain
DOI: 10.26717/BJSTR.2024.54.008559
Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by a virus called SARS-CoV-2. It first emerged in December 2019 in Wuhan, China, and has since spread to every country in the world. As of October 4, 2023, the World Health Organization (WHO) has reported over 628 million confirmed cases of COVID-19 and over 6.5 million deaths. SARS-CoV-2 is a respiratory virus that can spread through respiratory droplets produced when an infected person coughs, sneezes, or talks. It can also spread through contact with contaminated surfaces or objects. The most common symptoms of COVID-19 are fever, cough, fatigue, shortness of breath, and muscle aches. In some cases, COVID-19 can lead to more serious complications, such as pneumonia, acute respiratory distress syndrome (ARDS), and death. There is no specific cure for COVID-19, but there are treatments that can help relieve symptoms and prevent complications. The most effective way to prevent COVID-19 is to get vaccinated. COVID-19 vaccines have been shown to be highly effective in preventing infection, hospitalization, and death. Other ways to help prevent the spread of COVID-19 include wearing a mask, social distancing, washing your hands frequently, and practicing respiratory etiquette. The COVID-19 pandemic has had a devastating impact on the world. It has caused millions of deaths, disrupted economies, and changed the way we live our lives. The pandemic is not over, and it is important to continue to take steps to protect yourself and others from COVID-19. In this review we will address the molecular characteristics of the virus, the pathogenesis, and we will discuss the types of diagnosis and treatment according to the scientific reports available to date.
Keywords: COVID-19; SARS-CoV-2; Protein S; ACE-2; RT-PCR
Abbreviations: SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2; MERS-CoV: Middle East Respiratory Syndrome Coronavirus; ACE-2: Angiotensin-Converting Enzyme Type 2; AT2: Alveolar Type II; ER: Endoplasmic Reticulum; PCR: Polymerase Chain Reaction; ELISA: Enzyme-Linked Immunosorbent Assay; ARDS: Acute Respiratory Distress Syndrome; WHO: World Health Organization
The pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has represented a great threat to global health, being more severe than that caused by other coronaviruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). During the epidemic in 2002, SARS- CoV infected more than 8000 people worldwide, causing 800 deaths, representing a mortality rate of 10%. While MERS- CoV in 2012 infected 857 people and caused 334 deaths, causing a mortality rate of 35% [1]. As of October 4, 2023, the COVID-19 pandemic has continued to spread around the world, with the World Health Organization (WHO) reporting over 628 million confirmed cases and over 6.5 million deaths. In Argentina, the number of confirmed cases has reached 4,296,000, with 102,000 deaths. In Mendoza, the number of confirmed cases has reached 12,000, with 300 deaths. In Spain, the number of confirmed cases has reached 16,200,000, with 108,000 deaths. In Málaga, the number of confirmed cases has reached 220,000, with 4,000 deaths. The pandemic has had a devastating impact on the world, causing millions of deaths, disrupting economies, and changing the way we live our lives. The pandemic is not over, and it is important to continue to take steps to protect yourself and others from COVID-19:
• The number of cases and deaths continues to increase. As of October 4, 2023, the WHO has reported over 628 million confirmed cases and over 6.5 million deaths. This represents an increase of over 200 million cases and 2 million deaths since July 21, 2020.
• Vaccination rates continue to increase. As of October 4, 2023, over 70% of the world's population has received at least one dose of a COVID-19 vaccine. This represents an increase of over 50% since July 21, 2020.
• New variants continue to emerge. The Omicron variant, which was first identified in November 2022, is now the dominant variant in most countries. Omicron is more transmissible than previous variants, but it is generally less severe.
SARS-CoV-2 was first isolated and identified in December 2019, in patients who had been exposed at a seafood market in Wuhan City, Hubei Province, China [2]. The COVID-19 epidemic was declared by the World Health Organization (WHO) as a public health emergency of international concern on January 30, 2020. SARS-CoV-2 quickly began to spread globally, and the On March 11, 2020, the WHO officially declared the disease a pandemic.In this review we will address the molecular characteristics of the virus, pathogenesis, diagnosis and treatment according to the scientific reports available to date.
Molecular Characteristics of SARS-COV-2
SARS-CoV-2 belongs to the group of coronaviruses, which are a highly diverse group of enveloped single-stranded RNA viruses [3]. These viruses belong to the Coronaviridae family, the virions are pleomorphic and have a size of 118-136 nm, which is why they are considered “large and heavy” viruses. The structure of the viral particle consists of a nucleocapsid formed by the viral genome to which multiple copies of the N protein or nucleocapsid protein are attached. The nucleocapsid adopts a helical structure and is shaped like a ball. As can be seen in Figure 1, surrounding this structure is the envelope composed of a lipid bilayer in which the viral proteins are inserted: S (spike), E (envelope) and M (membrane), which makes it treat of an enveloped virus. The virus has a single-stranded RNA genome of positive polarity, 26-32 kb in length. From this molecule, the total number of proteins necessary to complete the complete replication cycle are synthesized. The viral genome encodes at least 27 proteins, including 16 non-structural proteins and 4 structural proteins: S, E, M and N (nucleoprotein) [4]. These viruses cause various diseases that affect the respiratory, digestive and neurological systems, with varying severity in humans and animals. Coronavirus infections have traditionally caused a low percentage of annual respiratory infections. In the last two decades, two novel coronaviruses have emerged that have caused severe disease in humans: severe acute respiratory syndrome coronavirus (SARS- CoV) and Middle East respiratory syndrome coronavirus (MERS- CoV) [5,6].
The genetic sequence of SARS-CoV-2 shows 80% similarity with SARS- CoV and 50% with MERS- CoV [7,8], the origin of the latter two viruses being in bats [9]. Therefore, it is likely that SARS-CoV-2 originated in bats, although the intermediate host animal that caused infection in humans is still unknown. Therefore, evidence from phylogenetic analysis indicates that SARS-CoV-2 belongs to the betacoronavirus genus, which includes SARS- CoV, and that it can infect humans, bats, and wild animals [2]. Spike envelope protein (S) is a glycoprotein present in the virus membrane, and is responsible for entry into cells. The binding of this protein to a receptor present on host cells is the first step for a viral infection, followed by fusion with the cell membrane. Protein S projects in the form of spicules and is responsible for the crown-shaped appearance. In the case of SARS CoV-2 it is longer, since it is between 16 to 21 nm. It has been described that in the case of SARS- CoV, MERS- CoV and SARS-CoV-2 the protein has between 1104 to 1273 amino acids and comprises an (N)-terminal subunit called S1 and a C-terminal subunit called S2. The S1 domain is responsible for receptor binding; and the S2 domain, causes fusion with the cell membrane [10]. It has been reported that transmission of SARS-CoV-2 in humans occurs through the union between the S protein and the receptor called angiotensin-converting enzyme type 2 (ACE-2). This enzyme is an aminopeptidase that can be bound to the cell membrane or in soluble form that represents ACE-2 circulating in the blood and has a vital role in the cardiovascular and immune systems [11].
ACE-2 is particularly involved in cardiac function and the development of hypertension and diabetes mellitus. This receptor is highly expressed in the respiratory tract, especially in Alveolar Type II (AT2) cells of the lung, esophageal cells and stratified epithelial cells, in addition to other cells, such as enterocytes, myocardial cells, proximal tubule cells of kidney and bladder urothelial cells [12]. Therefore, patients infected with this virus not only experience respiratory tract problems, but also present disorders in the heart, kidneys, and digestive tract.
As shown in Figure 2, once fusion with the cell membrane occurs, activation of the S protein and consequent conformational changes occur, allowing the virus to enter the cells. The genetic material released by this virus is messenger RNA (mRNA), which is ready to be translated into a variety of proteins, both structural and non-structural, that play an important role in its survival, as well as in its virulence power [13]. Finally, the proteins are assembled together with the replicated genome in the endoplasmic reticulum (ER) and in the Golgi complex, forming small vesicles that will be exported out of the cell by exocytosis. Structural and biophysical analyzes have shown that SARS-CoV-2 binds to ACE-2 with approximately 10 to 20 times greater affinity than the S protein of SARS- CoV . The high affinity of the S protein to the human ACE-2 receptor could facilitate the spread of the virus in the human population [14]. Understanding the genetic and phenotypic structure of COVID-19 in pathogenesis is important for the production of drugs and vaccines.
And many studies focus on those structural proteins that interact (as already mentioned) with the cell that SARS-CoV-2 infects. Even so, little information is found on those proteins that also favor the infectivity and pathogenesis of the virus but that are classified as non-structural proteins of the virus. Angeletti et al. (2020) propose a segment within non-structural regions of the SARS-CoV-2 genome, which has no homology with other coronaviruses and suggest that this mutation could explain the contagiousness of SARS-CoV-2 [15,16].
Pathogeny
The incubation period (initial infection until symptoms appear) of COVID-19 can be between 0 and 24 days, with an average of 5-7 days [17,18]. 95% of patients experience symptoms within 12.5 days of contact. This information suggests 14 days of medical observation or quarantine for those who have been exposed to the virus or who have had close contact with a positive patient. The main symptoms include fever, dry cough and fatigue. Other uncommon symptoms may include loss of taste and smell, sputum production, headache, diarrhea, dyspnea, and lymphopenia [14]. There are also some reports of patients presenting with gastrointestinal symptoms, including abdominal pain and diarrhea [19]. People of all ages are susceptible to the disease, including newborns and pregnant women. Most patients have mild to moderate symptoms. However, there is growing evidence that many people develop the disease asymptomatically. These patients present positive detection of the virus by qPCR, but do not present clinical signs or symptoms [20]. This represents a high risk, as they can still transmit the virus to other people and can contribute to the rapid spread of COVID-19. Therefore, it is a great challenge to prevent and control these types of patients globally. Approximately 20% of COVID-19 patients develop severe respiratory disease. Patients with severe disease typically present with fever, dry cough, dyspnea, and bilateral pulmonary infiltrate on chest images.
Complications include respiratory failure, liver injury, acute myocardial injury, acute kidney injury, septic shock, and even multiple organ failure. Risk factors for disease progression are older patient age, male sex, and those with underlying comorbidities.
Diagnosis
During an infection, the virus actively multiplies. When it begins, the virus can be detected in biological samples (throat or nasopharyngeal swab, tracheal aspirate, or bronchoalveolar lavage). In a latency period, it is not possible to detect the immune system response, but after a few days, antibody production begins. Antibodies of the IgM type are first produced until reaching a maximum after 7-10 days and later almost disappear [21]. This primary response is indicative of an acute infection. Subsequently, the secondary immune response will occur, which is faster, more intense and prolonged. IgG type antibodies will be produced and will last longer in the blood. Latest studies show that these antibodies decrease in quantity after 90 days [22]. Furthermore, at the level of mucosal secretions, such as respiratory secretions, IgA plays a predominant role [23]. To detect the presence of the virus (direct detection), two types of tests are used: the Polymerase Chain Reaction (PCR) that detects the genome of the virus or immunological tests that detect the proteins (antigens) of the virus. The third type of test is the one that detects the antibodies that you produce in response to the infection; they are serological tests for indirect detection of the virus. The general process of each test is explained here (Figure 3).
Retro-Transcription-PCR (RT-PCR): Single-stranded RNA molecule of about 30 kb. Once the sample is taken using a nucleic acid extraction kit, viral RNA is obtained. Next, retro-transcription is carried out from the RNA to DNA, using a kit that uses an enzyme called reverse transcriptase or Retro Transcriptase (hence the “RT”, from the name RT-PCR). The virus genome in the form of DNA is then amplified by PCR. This amplification consists of making millions of copies of a DNA fragment, so that we can “visualize” it or detect it using a specific system. The real-time PCR system even allows us to quantify the sample, that is, to know how many copies of the virus we have by quantity. If the reaction is positive, it shows that there was RNA from the virus, meaning that the person was infected. Since the first thing we obtained about the virus was its genome, these types of tests are the first to be developed. In fact, since January 13, the WHO has already published the first protocol [24]. Normally, two tests are carried out: one for screening and a second confirmatory. You can even do an additional third-party confirmation. These three RT-PCR assays are designed to detect three different genes of the virus. These PCR tests are very specific and sensitive. They usually take a few hours to complete. They require specialized equipment and technical personnel. They can test positive in people before they show symptoms, but who already have the virus. Throughout the illness they can allow us to monitor how the infection is going, because when the person has already been cured and does not have the active virus, in principle they should test negative. It is important to highlight that it cannot be ruled out that convalescent patients “without symptoms” may test positive in the RT-PCR and continue to be carriers of the virus.
Antigenic Test: Another way to confirm the presence of the virus is to detect its proteins or antigens. The most common technique here is called enzyme-linked immunosorbent assay (ELISA) based on the nucleocapsid protein (N) and spike protein (S) of SARS-CoV-2. Specific antibodies are fixed on a support that will react against some protein of the virus [25]. If there are viral particles in the sample (the same as for RT-PCR), they will be fixed to the antibody. It is as if the virus has been captured by the antibody [26]. Next, a second antibody against the virus is added so that a sandwich or “sandwich” is formed: antibody- virus-antibody. This second antibody will be labeled or labeled in some way to reveal the reaction. If the reaction is positive, it shows that there were virus proteins, meaning that the person was infected. This type of test based on the detection of molecules is very common in clinical diagnosis. Its basis is the same as traditional drug testing or pregnancy tests. The advantage is that they are much faster, they do not require specific equipment or highly qualified technical personnel. The disadvantage is that they are less specific and less sensitive than RT-PCR, so a specific ELISA method for COVID-19 can be used as a complementary method for RT-PCR to detect SARS-CoV-2 [27]. An additional comment is that although the reaction is positive, it does not imply that the virus is active and infectious. That is, we can detect its genome or its proteins but the virus is not complete, that is, we may be detecting “remnants” of the virus.
Serological Tests: The third approach consists of detecting the immune response to the virus, the antibodies. It is an indirect detection, that is, the virus is not detected, but rather we reveal the immune response to it [28]. In this case, the sample we are going to use is a drop of blood, because we are going to detect the antibodies that you have generated against the virus. In this case, virus proteins are fixed to the support, normally the proteins most exposed to the outside, such as the envelope protein S. If there are antibodies against the virus in the sample, they will stick and become fixed to the proteins of the virus. Next, a second antibody against the human antibody is added. This second antibody will be labeled or labeled in some way to reveal the reaction. If the reaction is positive, it shows that there were antibodies against the virus, that is, that the person has at some point been in contact with the virus and their immune system has reacted by producing antibodies. This does not necessarily mean that you are infected, perhaps you have been cured, or you have simply been in contact with the virus and have not had symptoms [29,30]. The advantage is that they are much faster than PCR, and depending on the type of support, they can be performed in less than a few minutes, and do not require specific equipment or highly qualified technical personnel. The disadvantage is that they are much less specific than RT-PCR, and this type of test requires our body to produce antibodies in detectable quantities. That is, a person can be infected, but during the first days do not test positive in this type of test. Some antibody tests can distinguish the type of immunoglobulin: whether it is IgM, indicative of a recent infection, or IgG, indicative of a secondary response, and therefore more prolonged. However, recent studies have shown that after 90 days, the antibodies generated against SARS-CoV-2 decrease in quantity, returning to the initial levels of the infection [22].
In Argentina: In Argentina, two relevant tests have been produced to help diagnose COVID-19, detecting either parts of SARS-CoV-2 or its genome. The “COVIDAR IgG” test detects anti-SARS-CoV-2 antibodies in blood and serum using the ELISA technique, the same one used, for example, for the detection of HIV and hepatitis B infection. The “NEOKIT- COVID-19” allows testing RNA samples and obtaining results in less than two hours (with similar sensitivity as current RT-PCR techniques) and does not require complete equipment (real-time thermocyclers). Qualitatively determines a positive or negative test for SARS-CoV-2. Its variant is the ELA-CHEMSTRIP which accompanies the kit, a device for incubating at 60°.
In Spain: Two main types of diagnostic tests are available for COVID-19 in Spain: molecular tests and serological tests. Molecular tests detect the genetic material of SARS-CoV-2, the virus that causes COVID-19. The most common molecular test is RT-PCR. RT-PCR tests are highly sensitive but can be time-consuming and require specialized equipment. Serological tests detect antibodies against SARS-CoV-2. Antibodies are proteins produced by the immune system in response to infection. Serological tests can be used to identify individuals who have been infected with SARS-CoV-2 in the past, even if they are no longer contagious. Antigen tests are also available for COVID-19 diagnosis. Antigen tests detect the presence of SARS-CoV-2 proteins in respiratory samples. Antigen tests are less sensitive than molecular tests, but they are faster and easier to perform.
Treatment
There are no specific treatments for COVID-19 at this time. However, therapies being investigated include drugs that have been used to treat malaria and autoimmune diseases; antiviral medications that were developed for other viruses and antibodies from people who have recovered from COVID-19.
Convalescent Plasma: When people recover from COVID-19, their blood contains antibodies that their bodies produced to fight the coronavirus and help them recover. Antibodies are found in plasma, which is the acellular fraction of blood. Convalescent plasma, literally plasma from recovered patients, has been used for more than 100 years to treat a variety of diseases, from bacterial diseases, cancer, and measles to polio, chickenpox, and SARS [31,32]. In the current situation, plasma containing antibodies from a recovered patient is administered by transfusion to a patient suffering from COVID-19. The donor's antibodies would appear to help the patient fight the disease, possibly shortening the duration or reducing the severity of the disease, as well as providing other blood components that the patient himself cannot produce in his convalescent state. Although convalescent plasma has been used for many years, and with varying success, not much is known about how effective it is in treating COVID- 19, since, for example, experts also do not know the best time during the course of the disease. disease to administer plasma, or if hyper immunity does not affect other processes in the body [33].
Immunomodulators: According to data collected by hospitals, around 20% of their coronavirus patients develop this cytokine storm (immunomodulators), especially Interleukin-1 (IL-1) and IL-6, among others, which consists of an excessive and uncontrolled response of the immune system with hyperinflammation, confined, in the case of COVID-19, especially in the lung. This causes severe pneumonia that can cause acute respiratory failure, described as the main cause of mortality from this disease [34,35]. Anakinra is an antagonist of the recombinant human IL-1 receptor, that is, it competes with greater affinity on the specific IL-1 receptors of cells that will participate in said inflammation. Anakinra is approved to treat rheumatoid arthritis and cryopyrin- associated periodic syndromes, specifically neonatal-onset multisystem inflammatory disease [36], however there are very few clinical trial data on the use of IL-1 inhibitors in patients with COVID-19. On the other hand, the selective blockade of IL-6 has been explored with antibodies directed at the IL-6 receptor, such as T ocilizumab and Sarilumab, or directed towards IL-6 itself, such as Siltuximab, and thus achieve inhibit the inflammatory signaling cascade triggered by this interleukin [37]. Again, there is very little clinical trial data on the use of IL-6 inhibitors in patients with COVID-19. Finally, there are insufficient data to recommend for or against the use of interleukin inhibitors [38].
Antiretroviral Drugs: Antiretroviral drugs are specific antiviral medications for the treatment of retrovirus infections. There is currently no specific antiretroviral treatment for COVID-19. However, medications previously developed to treat other viral infections are in the testing phase and could be effective against SARS-CoV-2. Remdesivir It is a prodrug that belongs to the group of nucleotide analogues, specifically adenosine. It has demonstrated in vitro activity against SARS-CoV-2 [39], and in vitro and in vivo activity (based on animal studies) against SARS and MERS [40-42]. Remdesivir binds to viral RNA-dependent RNA polymerase, inhibiting viral replication through premature termination of RNA transcription. An interesting study that emerged specifically for SARS-CoV-2 was that, in a rhesus macaque model infected with SARS-CoV-2, treatment with Remdesivir It started shortly after virus inoculation. Animals treated with Remdesivir had lower levels of lung virus and less lung damage than control animals [43]. Remdesivir _ It is one of the few antiretroviral drugs I recommend for the treatment of COVID-19 in hospitalized patients who require supplemental oxygen, that is, of a serious nature, but there is insufficient data on the optimal duration of therapy, nor that I recommend for or against of Remdesivir for the treatment of patients with mild or moderate COVID-19 [44]. Chloroquine /Hydroxychloroquine has been one of the most studied medications against SARS, but it has been concluded not to be recommended for treatment against SARS-CoV-2 [45,46].
Even the combination of hydroxychloroquine plus azithromycin is not recommended due to the potential for toxicity [47]. Thus, the molecular action of both chloroquine and hydroxychloroquine has been demonstrated in several trials, demonstrating that both compounds increase the endosomal pH , inhibiting the fusion of SARS-CoV-2 and the host cell membranes [48]; that chloroquine inhibits the glycosylation of the cellular receptor of angiotensin-converting enzyme 2, which may interfere with the binding of SARS-CoV-2 to the cellular receptor [49]; and finally, that in vitro , both chloroquine and hydroxychloroquine can block the transport of SARS-CoV-2 from early endosomes to endolysosomes , which may be necessary for the release of the viral genome [50]. However, the available clinical data on the use of chloroquine and hydroxychloroquine to treat COVID-19 come primarily from patients with mild disease. Clinical data on the use of these medications in patients with severe and critical COVID-19 are very limited and the doses used appear to be toxic.Replication of SARS-CoV-2 depends on the cleavage of polyproteins in an RNA-dependent RNA polymerase and a helicase.1 The enzymes responsible for this cleavage are two proteases, 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) Antiviral medications such as Lopinavir / Ritonavir They are inhibitors of 3CLpro of coronaviruses, in vitro, and this protease seems highly conserved in SARS-CoV-2 [51,52]. Even so, Lopinavir / Ritonavir has in vitro activity against coronaviruses, and is believed to have a poor selectivity index, indicating that higher than tolerable levels of the drug may be required to achieve significant inhibition [53].
Apparently, Lopinavir / Ritonavir or other HIV protease inhibitors have not proven to be favorable, due to their unfavorable pharmacodynamics. Lopinavir is excreted in the gastrointestinal tract and therefore coronavirus-infected enterocytes may be exposed to higher concentrations of the drug [54]. These antiviral medications have simply not demonstrated clinical benefit in COVID-19 patients.
Interferons: Interferons, a family of cytokines with antiviral properties, have been suggested as a potential treatment for COVID-19 due to their antiviral properties in vitro and in vivo. However, studies so far have shown that there was no benefit when interferons were used in patients with other coronavirus infections, and the significant toxicities of interferons outweigh the possibility of benefit. Additionally, clinical trial results for COVID-19 patients are lacking. Interferon beta used alone and in combination with ribavirin in patients with SARS and MERS has failed to show a significant positive effect on clinical outcomes [55-57]. During SARS-CoV-2 infection, patients with severe clinical presentation have greatly decreased type I and III IFN activity [58]. On the other hand, the administration of IFN-λ (type III) to infected monkeys confers partial protection against SARS-CoV-1 [59]. But a latest study on ACE2, which is the receptor that SARS-CoV-2 uses as a route of entry into the cell, has shown that the ACE2 gene is modulated by IFN, that is, the levels of ACE2 receptors that “ "open the doors to the virus" could increase in the presence of interferons, and that would facilitate its entry [60].
In Argentina: The Ministry of Health of the Nation clarifies, in its latest modification, that there is not sufficient clinical data to recommend for or against the use of immunomodulatory therapies, chloroquine or hydroxychloroquine, Remdesivir , Lopinavir / Ritonavir , nor immunomodulators or interferon for the treatment of COVID-19, and these recommendations are under permanent review and are subject to updating according to the evolution of the pandemic at a local and international level and the available scientific evidence [61].
In Spain: The Spanish Ministry of Health does not recommend the use of immunomodulatory therapies, chloroquine or hydroxychloroquine, Remdesivir, Lopinavir/Ritonavir, or immunomodulators or interferon for the treatment of COVID-19. The available evidence does not support the effectiveness of these treatments, and some of them can have serious side effects. The Ministry of Health emphasizes the importance of continuing research into potential treatments for COVID-19.
Final Considerations
There are several clinical trials underway worldwide (some of them with active participation of hospitals in our country), but at the moment the results are not conclusive, and the success stories refer to small-scale trials, without statistical validity. More than one hundred vaccines are also in process, in different phases of development and clinical stages. We must be optimistic, but patient. In these circumstances, research is carried out under great pressure and based almost exclusively on the concept of trial and error that has sometimes been used previously against other viruses. This pandemic must help us to definitively make world governments realize the urgent need to invest in the generation of knowledge, and that investment in Science, Education and Health must be the basis on which a fair, egalitarian and society is built. prosperous We cannot forget that, according to a study by researchers at the Boston School of Public Health recently published in the journal Science, even in the case of the apparent elimination of the pandemic in the coming months, estimates for the post-pandemic periods foresee occasional resurgences until 2024 and we have no choice but to be prepared.