COVID-19 InfeCtIOn: DIsease meChanIsm, VasCular DysfunCtIOn, Immune respOnses, markers, multIOrgan faIlure, treatments, anD VaCCInatIOn

The new SarS-CoV-2 virus is a great danger for the worldwide population since there is no known pre-immunity, no specific treatment, and no vaccine. Still, the testing and tracing are the best tools to isolate the infected and prevent the spread of COVID-19. The major goals are to save lives, reduce the mortality rate, increase the survival rate of those are in severe or critical conditions, reduce the hospital stay and accelerate the recovery. This review summarizes the findings on the novel coronavirus that causes COVID-19 and outlines information about symptoms, testing, disease mechanism, vascular dysfunction, immune responses, treatments, and vaccination. At this time no vaccine is available to prevent COVID-19. A literature review reveals that more research is necessary to investigate the interactions between respiratory viruses, human coronaviruses, and the new SarS-CoV-2 virus in the infected population to guide the design of COVID-19 specific therapeutics and vaccines. Almost every government on earth has realized that daily life cannot return to normal until citizens have built up antibodies to safeguard them from the virus. Scientists and manufacturers worldwide are accelerating COVID-19 vaccine research, and pharmaceutical companies are already investing in the large-scale production of vaccines. a synopsis of the most recent sources presented in this review was the starting point for several COVID-19 research projects in the regional Cooperation for Health, Science and Technology (RECOOP HST) Association managed by Cedars-Sinai Medical Center to gain a better understanding of the COVID-19 disease.


mixed messages
On a daily basis the scientific journals bombard physicians and scientists with important, or sometimes "voodoo" information (to heal or do magic), treatment options for SARS-CoV-2 infections. The public and medical communities, confused by the mixed messages they are constantly getting from the vastly undereducated politicians can make inconsistent statements or controversial decisions. Unfortunately, these politicians are the opposite of the voodoo people, since their spirit cannot speak for the infected people who passed away due to their negligence, but they are and will continue creating disastrous consequences for our lives.

facts about the COVID-19 infection
The latest data show that 80 percent of the people who become infected with the COVID-19 novel coronavirus will experience a mild or moderate form of disease. Roughly 15 percent will develop a severe form of the disease requiring hospitalization, and some 5 percent will become critically ill. The industrialized countries have sophisticated health care systems and may be able to cure some critically ill patients, but the danger is that even the most advanced systems may be overwhelmed by the large numbers of people who will need to be hospitalized. The less developed countries are struggling with increasing numbers of patients, lack of trained health care workers, insufficient intensive care unit capacity and shortage of medications all of which together put patient care and the entire population at risk.

spectrum of symptoms
The coronavirus infection actually has a spectrum of symptoms (Table 1) [1].
Asymptomatic people are the super infectors and comprise up to 40% of infected individuals.
The majority of the infections are mild or mode rate, and they are 30% of the COVID-19 population. These individuals have flu-like symptoms, are not hospitalized, and recover at home.
Mild symptoms include a runny nose, sore throat, congestion, and dry cough. In this stage, activation of Natural Killer (NK) cells are pivotal effectors of the innate immunity, and protect individuals from the viral infection. NK cells are the first line of defense against invading viruses, given their substantial ability to directly target infected cells without the need for specific antigen presentation. NK cells can also amplify and modulate antiviral adaptive immune responses. By establishing cellular networks with a variety of cell types, such as dendritic cells that capture antigens with their threadlike tentacles and present the antigens to T lymphocytes (T cells), an immune response is stimulated.
Moderate symptoms include high fever, tiredness and fatigue, and chest pain. In this stage, macrophages produce high amounts of TNF, IL-1, IL-6, IL-8, and IL-12 that spread throughout the patient's body.
Patients with severe symptoms represent 15% of the infected patient population. In this stage, the T a b l e 1  intense production of cytokines causes Respiratory Distress Syndrome. The patient has shortness of breath, increased blood pressure, and decreased oxygen saturation. Also in this stage, endothelial cells increase production of cytokines that could trigger thrombosis. Patients in the Critical Stage constitute about 5% of the infected population. They develop Severe Acute Respiratory Syndrome (SARS) caused by the Cytokine Storm, and experience high fever, chest pain and breathlessness [2].
The median time from onset to clinical recovery for mild cases is approximately 2 weeks and for severe or critical disease is 3-6 weeks [3].

high risk population
People of all ages can be infected by the COVID -19 novel coronavirus. The high-risk population comprises individuals who are older than 60 years and/or have pre-existing medical conditions such as diabetes, heart disease, respiratory disease and hypertension. These individuals are more vulnerable to becoming severely ill with the virus [4,5].

Sex difference
The literature tells us that sex is an important driver of the morbidity and mortality risk in the COVID-19 pandemic. There is evidence that sex hormones can modulate the expression of angiotensin-converting enzyme 2 (ACE2), and this information may help us understand the COVID-19 epidemiological results that demonstrate a sex difference. An enzymatic system involved in this different predisposition between sexes could be represented by ACE2 that is activated and down-regulated by the spike protein of the virus and allows the penetration of SARS-CoV-2 into epithelial cells. Recently published data show that the SARS-CoV-2 virus present in myocardium displays a sex difference [6].
Most importantly we have learned that as the COVID-19 pandemic has worsened, the subdivided sex data can help guide patient care and therapeutic management. These data also address the question of whether or not older men with co-morbidities require additional prevention, surveillance or earlier intensive intervention than women [7].

Social effects -stress
The worldwide spread of the SARS-CoV-2 viral infection has challenged societies and individuals. The isolation and [anti-] social distancing create psy-chosomatic stress on individuals, on families, and on relationships. In health care facilities, the overload of patients and the constant danger of SARS-CoV-2 viral infections are creating endless stressors and chronic stress [8].

testing for COVID-19
Viral tests check samples from the respiratory system, such as a swab from the inside of the nose, to see if the individual is currently infected with SARS-CoV-2, the virus that causes COVID-19.
There are three types of tests available that can detect whether a person currently has COVID-19 or has had it in the past ( Table 2). Polymerase chain reaction (PCR) tests for active infection. The antigen test for active infection uses antibodies that are produced in animals to hunt for proteins embedded on the coronavirus' surface. Serology testing, which tests looks for antibodies against SARS-CoV-2 from a past infection [9,10].

Measures of efficacy [10]
Sensitivity: Sensitivity is sometimes called the "true positive rate." It measures how frequently the test is positive when the person being tested actually has the disease.
Specificity: Specificity is sometimes called the "true negative rate." It measures how frequently the test is negative when the person being tested does not have the disease.
Positive Predictive Value: Positive predictive value is a measure of how likely it is that a positive test is a true positive rather than a false positive. This is dependent on how many people in the population being tested have had the disease. Similar tests are done routinely in clinics for influenza all the time. SARS-CoV-2 antigen test uses antibodies that are produced in animals to catch the proteins embedded on the coronavirus surface. If the antibodies detect viral proteins in a sample, the person most likely has the coronavirus.

the mechanism(s) underlying the infection
Serology test looks for antibodies against SARS-CoV-2 in the blood to determine if there has been an infection in the past. IgM is the first antibody that is formed against a germ, so it appears on tests first, usually within 1-2 weeks. The body then forms IgG, which appears on tests about 2 weeks after the illness starts. IgM usually disappears from the blood within a few months, but IgG can last for years. Some antibody tests detect IgM and IgG, and other tests detect only IgG. In most cases, a nose or throat swab is taken by a health care professional, and that swab is sent to the lab for testing.
An antigen test for SARS-CoV-2 starts with a health care professional collecting a sample of mucus from the back of a person's throat or nose using a swab.
Health care professionals collect a blood sample for the test.
A positive PCR test means that the person being tested has an active COVID-19 infection.
The swab is dipped into a liquid to dissolve the mucus and release the virus. The virus-containing liquid is applied to the surface of a test slide that is coated with antibodies. A second mixture of antibodies is applied to the slide. These antibodies have been chemically modified with a dye that makes them visible to the naked eye or detectable by fluorescent light. If there is no detectable dye, it means the person does not have SARS-CoV-2 or the sample did not have enough viral proteins.
A positive antibody test means that the person being tested was infected with SARS-CoV-2 in the past and their immune system developed antibodies to fight the COVID-19 infection. PCR can be used to determine who has an active infection.
Tony Waterson , named it coronavirus because of the crown or halo surrounding it on the viral image [11][12][13].

sars-CoV-2 virus
The molecular biology of SARS-CoV-2 is revealed through the use of direct RNA sequence data, enabling a detailed view of the viral subgenomelength mRNA architecture. Only α and β coronavi-ruses have the ability to infect humans. The main cause of animal to human transmission of the virus is consumption of an infected animal. The infected person further transmits the virus to healthy persons by droplet, vapor, handshake, hug, or kiss [14,15]. SARS-CoV-2 has a major structural protein spike (S) and attracted great attention because the virus recognizes the angiotensin-converting enzyme 2 (ACE2) receptor. The SARS-CoV-2 virus binds to PCR can help identify people who are contagious to others. PCR can help identify people who are contagious to others.
Antigen tests are far faster and easier to perform than PCR tests. The most time-consuming part of the antigen test process is waiting for the antibody mixtures and the sample to mix completely. A COVID-19 antigen test might take only 15-30 minutes to complete and requires very little expertise.
The test identifies people who had an infection in the past, even if they had no symptoms of the illness. It can help public health authorities and researchers know what percentage of the population has already had COVID-19. It helps to determine who has some level of immunity to COVID-19. It helps to determine who qualifies as a donor of convalescent plasma (blood product that contains antibodies against SARS-CoV-2 and can be used as a COVID-19 treatment). Helps to make decisions about who could safely work in certain jobs. Helps to determine the time of the COVID-19 infection, since we know that IgM is formed before IgG and after two weeks IgM disappears and IgG persists. PCR: • Only helps determine whether a person has an active infection at the time of testing. • Does not help determine who had an infection in the past. • Does not help determine which people who have been exposed to SARS-CoV-2 will develop active infection during the 2 weeks after exposure. In some people, the virus can only be found by PCR for a few days at the beginning of the infection, so the test might not find the virus if the swab is taken more than a few days after the illness starts. In some people, the virus can be found by PCR in the nose and throat for several weeks, even longer than the time that they are actually contagious to other people. This test requires certain kinds of swabs that may be in short supply.
It may be negative if it is used too close to the beginning of an infection, which is why it should not be used to detect active COVID-19 infection. Some antibody tests have low sensitivity and specificity and so may not produce reliable results. Some antibody tests may crossreact with other coronaviruses that are not SARS-CoV-2, the virus that causes COVID-19, leading to false test results.

T a b l e 2. Сontinuation
the receptor-binding motif (RBM) in the receptorbinding domain (RBD). ACE2 is distributed in many organs and cells, such as epithelial and endothelial cells [16,17]. entry point is the lung SARS-CoV-2 binding to the ACE2 receptor requires the surface unit of the viral spike protein. In the lung, ACE2 expression occurs in type 2 pneumocytes and macrophages.
SARS-CoV-2 virus enters the respiratory system and the first point of entry is the ACE2 receptor. Block the ACE 2 receptor, and the epithelial cells become a "Trojan Horse". The virus replicates in the endoplasmic reticulum and surfacing to the blood stream in Golgi. The virus factory starts to work, and it initiates the innate natural immune reaction with lymphocytes: NK cells and cytotoxic T cells [18,19]. The inflamed lung tissue thickens and a barrier against oxygen penetration into blood vessels increases. In COVID-19 immunopathology, as the inflammation increases additional tissue damage is caused in the lung and also in the vascular system.

Dissemination in the body via the cardiovascular system
The vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis. Endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischemia, inflammation with associated tissue edema, and a pro-coagulant state [20,21]. Recruitment of immune cells by SARS-CoV-2 infection and entry of the virus into endothelial cells can result in widespread endothelial dysfunction associated with apoptosis. The SARS-CoV-2 infection facilitates the induction of inflammation and immune response within the endothelium in blood vessels in several organs. Inductions of apoptosis and pyroptosis have a role in endothelial cell injury in patients with COVID-19, could explain the systemically impaired microcirculatory function in different organs [22].

Change in blood coagulation during COVID-19
Cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking stimulate the production of reactive oxygen species in the vascular wall. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases represent major sources of reactive oxygen species upregulated and activated in obesity, hypertension and diabetes [23]. Cardiovascular complications are rapidly emerging as a key threat in COVID-19 in addition to respiratory disease. The mechanisms underlying the disproportionate effect of SARS-CoV-2 infection in patients with cardiovascular comorbidities [24].
We have several unanswered questions about the nature of the coagulopathy associated with COVID-19. The level of D-dimer (a fibrin degradation product indicating thrombosis) in COVID-19 patients is significantly increased to levels above those in patients who have Deep Vein Thrombosis or Pulmonary Embolus and suggests hypercoagulability. Platelet adhesion or activation, and fibrin deposition as the result of coagulation constitute the fundamental processes of thrombus formation. The published literature on septic coagulopathy, monitoring prothrombin time (PT), D-dimer, platelet count, and fibrinogen can be helpful in determining the thrombotic factors [25,26]. D-dimer is a reliable and sensitive index of fibrin deposition and stabilization. Its presence in plasma should be indicative of thrombus formation. D-dimer can be used as a fibrin-related degradation marker for the diagnosis and management of patients with Disseminated Intravascular Coagulation (DIC). D-dimer is one of the most valuable markers of thrombosis-related clinical conditions in COVID-19 [27,28].

Obesity is the most common risk factor in COVID-19
Obesity is associated with an increased risk of diabetes mellitus, cardiovascular disease and kidney disease, and these comorbidities are considered to result in increased vulnerability to COVID-19 pneumonia and associated organ failures. Obesity is shifting the severe form of COVID-19 disease to younger ages [29][30][31][32][33].
Since the discovery of leptin in 1994, it was revealed that many physiological functions such as modulation of vascular function, reproduction, bone metabolism, inflammation, infection, and immune responses, are influenced by central regulation of food intake, energy expenditure and hormone regulation via activation of the leptin receptor (LEPR). Leptin, the forerunner of the adipokine family, is a key sensor of energy metabolism and a cornerstone in the regulation of metabolism-immune system interplay. Leptin regulates both innate and adaptive responses through modulation of immune cell survival and proliferation as well as their activity. In innate immunity, leptin increases the cytotoxicity of NK cells and promotes the activation of granulocytes, macrophages and dendritic cells. Leptin activates B cells to secrete cytokines and modulates B cell development [34].

neurological or psychiatric disease in COVID-19
The COVID-19 infection and consequent inflammation, endothelial dysfunction, and increased production of cytokines by endothelial cells could cause complications in the Central Nervous System (CNS) and Peripheral Nervous System (PNS) that result in neurological and psychiatric diseases. The majority of cerebrovascular disorders such as ischemic stroke, intracerebral hemorrhage, vasculitis, altered mental status with encephalopathy as well as, neuropsychiatric diagnoses including psychosis and neurocognitive (dementia-like) syndrome are consequences of endothelial or vascular dysfunction [35][36][37]. A recently published paper suggests that vagal dysfunction might contribute to thromboembolic incidents. This is an "egg or chicken -which came first" issue. The author proposes the opposite, that vagal dysfunction is the consequence of the endothelial dysfunction, and increased production of cytokines by endothelial cells [38].

search for markers to indicate multiorgan failure
In the severe and critical stages of COVID-19, SARS, endothelial dysfunction, neuropathy and myopathy as well as kidney and other organ failure can occur [39,40].
SARS-CoV-2 infects the host via the ACE2 receptor in the epithelial alveolar lining thereby causing lung injury. The ACE2 receptor is also widely expressed on endothelial cells, which traverse multiple organs. High risk patients with obesity often have respiratory dysfunction, which is characterized by alterations in respiratory mechanisms, increased airway resistance, impaired gas exchange and low lung volume and muscle strength. These individuals are predisposed to hypoventilation-associated pneumonia, pulmonary hypertension and cardiac stress [29]. Monitoring prothrombin time (PT), D-dimer, platelet count, and fibrinogen or other markers (Table 3) could be helpful in determining prognosis in COVID-19 patients with severe or critical symptoms. If these parameters worsen, more aggressive intensive care support is necessary and consideration should be given for more targeted therapies and blood product support as appropriate. If these markers are stable or improving, it gives added confidence for less aggressive treatment as long as the clinical condition is corroborative [25]. In

available treatments and new developments
Presently there are no antiviral drugs approved by the FDA to treat COVID-19. There is an urgent need for better therapies. Currently available treatments and new developments are shown in Table 4. The major goals are to save lives, reduce the mortality rate, increase the survival rate of those are in severe or critical conditions, reduce the hospital stay and accelerate the recovery. Patients admitted with COVID-19 at selected hospitals in the USA may now volunteer to enroll in a clinical trial to test the safety and efficacy of a potential new treat-

Sex difference angiotensin-converting enzyme
Could demonstrate the gender difference stress saliva cortisol level High level of cortisol is related to sustained stress Immunization Immunoglobulins m and g The antigens of SARS-CoV-2 could be detected in saliva and serum by ELISA Inflammation protein C level

Indicates inflammation at a very sensitive level Cytokines IL-1, IL-6, IL-18 and IFNγ
Well-established markers of acute and chronic inflammation leptin Proinflammatory cytokine produced mainly by adipocytes pulmonary capillary barrier dysfunction arginase Mediator of pulmonary capillary barrier dysfunction (hypoxia) endothelial dysfunction thrombomodulin Concentration correlates with endothelial dysfunction and oxidative stress endothelin-1

Reduced oxygen saturation in the blood increases endothelin production soluble e-selectin
Elevation of E-selectin concentration correlates with endothelial dysfunction peroxynitrite level Indicates the formation of hydroxyl radicals and nitrogen dioxide, resulting in vascular disorders Oxidative stress glutathione Very reliable and stable indicator of oxidative stress thrombosis D-dimer Reflects degradation of covalently cross-linked (stabilized) fibrin and indicates formation of intravascular thrombus and its fibrinolysis fibrinogen level Shows increased level in procoagulant potential of blood coagulation system. Fibrinogen is also a protein of acute phase of inflammation partial-products of prothrombin activation (prethrombin, fragment 1-2)

Being products of prothrombin autolysis by thrombin, indicate generation of active thrombin in blood protein C level
Main protein of anticoagulant system that also possess anti-inflammatory action

Soluble fibrin
Soluble complexes of fibrin desA and fibrin(ogen) fragments that appear during the initial action of pathologically generated thrombin on fibrinogen in blood platelet aggregation Could be studied ex tempore by aggregometry method using ADP or collagen as the most common inducers. Most sensitive for showing the cellular response to coagulation disorders

T a b l e 4. Available treatments and new developments pharmacologic Interventions remdesivir
Antiviral agent that is being explored as a treatment for COVID-19 hIV protease Inhibitors lopinavir/ ritonavir Combination therapy with lopinavir/ritonavir plus interferon beta-1b plus ribavirin for the treatment of COVID-19

Corticosteroids
Immunosuppression is reducing treatment time and aiding recovery from Severe Acute Respiratory Syndrome azithromycin Treats certain bacterial infections, such as bronchitis, pneumonia Chloroquine Belongs to a class of drugs known as antimalarials. The Food and Drug Administration (FDA) does not support the use of chloroquine for the treatment or prevention of COVID-19. If the drug is used it has to be in a hospital setting hydroxychloroquine Immunosuppressive and anti-parasite drug. It can treat and prevent malaria. It can also treat lupus and arthritis. The FDA cautions against its use for COVID-19 treatment

Immune-Based therapy Interleukin-1 Inhibitors
Approved by the FDA to treat rheumatoid arthritis, multisystem inflammatory disease, T cell (CAR T-cell)-mediated cytokine release syndrome (CRS) and macrophage activation syndrome (MAS)

indicated by elevated blood levels of IL-6, C-reactive protein (CRP), D-dimer, and ferritin kinase Inhibitors
Have broad immunosuppressive effects. Ongoing clinical trials should help clarify their role in the treatment of COVID-19 adjunctive therapy Vitamin C, Vitamin D, and Zinc, Coenzyme Q10, Magnesium, Vitamin e Omega 3, Vitamin B3 or niacin Promoted for the treatment and prevention of respiratory viral infections; however, their roles in treating COVID-19 are yet unproven. Supplementary therapy helps at the mitochondrial level in the respiratory, cardiovascular, musculoskeletal and neurological systems, supports the energy production of cells and the regulation through the adenosine-5'-triphosphate (ATP) chemical energy system Blood-Derived products Convalescent plasma Convalescent plasma that contains antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mesenchymal stem cells

Under evaluation for the treatment of COVID-19
monoclonal antibodies Previously used to create a cocktail of antibodies that had some efficacy against the Ebola virus, could work against the novel coronavirus that causes COVID-19 early-stage sars-CoV-2 coronavirus therapies: experimental Igg1 monoclonal antibody Neutralizing IgG1 monoclonal antibody directed against the spike protein of SARS-CoV-2 antibody cocktail Cocktail approach to developing REGN-EB3, a novel triple antibody treatment for Ebola that is now under regulatory review by the FDA antiviral drug Favipiravir (Avigan; generic avifavir) antiviral was approved in 2014. Faster viral clearance in the overall population, under regulatory review by the FDA for treating COVID-19 ment for the disease. Studying the impact of earlystage SARS-CoV-2 coronavirus therapies is critical for determining whether well-established FDA approved drugs for other human diseases would work for COVID-19 patients or new experimental drugs can help COVID -19 patients with a wide spectrum of symptoms at different levels of disease severity [41,42].

Vaccine development and categories
At this time no vaccine is available to prevent COVID-19. However, scientists and manufacturers worldwide are accelerating COVID vaccine research activities, and pharmaceutical companies are already investing in the large-scale production of vaccines (Tables 5 and 6) [43 -45].
COVID-19 was first reported in Wuhan, China, on December 31, 2019. This infection caused by the novel coronavirus is a great danger for the population worldwide since there is no known pre-immunity, no vaccine, and no specific treatment. COV-ID-19 is contagious, and everyone is supposed to be vulnerable. A global race has begun to develop and mass-produce an effective vaccine, with accelerated clinical trials already underway [46].

Immune responses: t-cell memory from exposure to "common cold" coronaviruses (CCCs)
Measuring immunity to SARS-CoV-2 is key for understanding COVID-19 and will guide vaccine development [47].
The normal immune response can be broken down into four main components: (i) pathogen recognition by cells of the innate immune system with (ii) cytokine release, (iii) complement activation and (iv) phagocytosis of antigens.
The immune system includes three lines of defense (Table 7) against infections by parasites, bacteria, and viruses: physical and chemical barriers, nonspecific resistance, and specific resistance [48].
The "common cold" coronaviruses (CCCs), such as HCoV-OC43, HCoV-HKU1, HCoV-NL63 and HCoV-229E, widely circulate in the human population, are responsible for mild respiratory symptoms, and can induce immunity [49]. Potential preexisting cross-reactive T-cell immunity to SARS-CoV-2 could explain the COVID-19 differences in immunity that influence herd immunity, and affect the effectiveness of COVID-19 candidate vaccines [50]. The interactions between human coronaviruses, other respiratory viruses and the SARS-CoV-2 virus should be more extensively investigated in the infected population to guide the design of COVID-19 specific therapeutics and vaccines [51]. The scientific community continuously debates the long-term protection provided by T cells, and therefore, the potential for reinfection by SARS-CoV-2 [52].
COVID-19 patients with severe disease compared to mild disease have increased proportions of cytotoxic follicular helper (TFH) cells and cytotoxic T helper cells (CD4-CTLs) that responded to SARS-CoV-2, as well as a reduced ratio of reactive regulatory T cells. Therefore, large-scale single-cell transcriptomic analysis of viral antigen-reactive CD4+ T cells is required to assess the effectiveness of the vaccines [53,54].

Immune-informatics
Immune-informatics is integrating bioinformatics, structural biology, molecular biology and Molecular Dynamics (MD) simulations to verify candidate antibodies that can inhibit the coronavirus [55]. Several classes of pattern-recognition receptors (PRRs), including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells [56].
An important part of immunological memory is T-cell memory. T cells that are trained to recognize specific antigens (e.g., coronaviruses) will trigger a faster and stronger immune response after encountering the same antigen. The T-cell receptor, a major histocompatibility complex (MHC) molecule, and a bound antigenic peptide, play major roles in the process of antigen-specific T-cell activation [57,58]. The immune-informatic approach helps to identify significant cytotoxic T lymphocyte and B cell epitopes in the 2019-novel coronavirus (2019-nCoV) surface glycoproteins. T cells and B lymphocytes play an important role in amplification of cell-mediated immune responses [59]. Advanced epitope maps (Tcell and B-cell) are required to recognize epitopes to trigger a positive resistant reaction against SARS-CoV-2 [60]. The virus-specific immunological memory in T cells would trigger the B cells. B cells are at the center of the adaptive humoral immune system and are responsible for mediating the production of antigen-specific immunoglobulin (Ig). Antibodies may uncover the antigenic viral peptide epitopes that are coded in IgG glycosylation to recognize the virus glycoproteins [61].

Vaccine categories Description live attenuated Virus
Live but weakened ("attenuated") virus that can still reproduce (make copies of itself) and activate a strong immune response but should not make people sick.

Inactivated Virus
Inactivated virus vaccines do not provide as strong an immune response as live attenuated virus vaccines, so additional doses of the vaccine may be needed to get a sufficient immune response.

subunit Vaccines
To treat COVID-19, potential cell-based therapies act, in general, by helping the patient's immune system work better (and not overreact) through releasing signals to other cells in the body to coordinate a proper reaction to the infection and promote healing.

Protein Subunit
Protein subunit vaccines are similar to inactivated virus vaccines in that they do not contain live viruses, but instead contain protein fragments of a killed virus to trigger an immune response that will recognize the protein fragments and therefore recognize the virus.

Virus-Like Particles
Uses only parts of the virus that lack the viral genetic material required to replicate, but resemble the virus closely enough. They mimic the outer shell of the virus to trigger an immune response without causing disease.

nucleic-acid Vaccines
This new approach uses genetic engineering to deliver nucleic acids (DNA or RNA) that carry the instructions for making viral protein(s) (rather than delivering the proteins themselves) into the vaccinated person's cells. Once inside, those cells build the viral proteins that will trigger the immune response.

DNa-Based
DNA-based vaccines work by inserting a genetically engineered blueprint of viral gene(s) into small DNA molecules (called plasmids) for injection into vaccinated people. Cells take in the DNA plasmids and follow their instructions to build viral proteins, which the immune system recognizes as foreign, triggering the immune response that protects against the disease.

rNa-Based
RNA-based vaccines work similarly to DNA-based vaccines, but instead of using DNA, they use a related nucleic acid called RNA, and instead of using plasmids to get into cells, they use lipid nanoparticles as delivery vehicles. Once RNA vaccines are injected into vaccinated people, cells take in the RNAs and build viral proteins to trigger an immune response.

Viral Vector Vaccines
Similar to nucleic-acid vaccines but instead of using plasmids or lipids to get them into the cells of a vaccinated person, these vaccines use weakened viruses (called vectors) other than the virus you are vaccinating against to transport the blueprint of viral genes. replicating Viral Vector Uses a live but weakened viral vector to carry the SARS-CoV-2 viral genetic material into cells, and then the viral vector can replicate within the vaccinated person's cells. The production of viral proteins will be robust, producing a stronger immune response. Non-replicating Viral Vector Non-replicating viral vector vaccines use a killed viral vector to deliver the viral genetic blueprint into cells. Since the vector cannot replicate, in general this type of vaccine does not provide as long-lasting immunity as replicating viral vector vaccines.

pre-Clinical
Initial tests of a potential treatment or vaccine include various tests done in the laboratory called in vitro tests and in vivo studies conducted in animals to evaluate drugs or vaccines that have potential to treat the disease. 139

Clinical
Vaccines and treatments advance to clinical phases when it is publicly reported that the product has been dosed in a trial. Potential treatments and vaccines must be tested in people to find out if they are safe and if they work to treat or prevent the disease. Phase I Clinical trials look at the safety of a potential treatment or vaccine in a small group (usually less than 100) of healthy volunteers. 18 Phase II Clinical trials test a potential treatment or vaccine on a large (often up to several hundred) group of people who will use the drug (patients) or get vaccinated (healthy volunteers), evaluating whether the treatment or vaccine is safe and whether it works effectively.

6
Phase III Clinical trials continue to test the safety and effectiveness of a treatment or vaccine but on a much larger scale, involving up to several thousand people.

T a b l e 6. Research activities to develop vaccines T a b l e 7. The immune system's lines of defense
Immune system defense responses The first line Involves physical barriers such as skin and mucous membranes Skin Acidity inhibits bacterial growth. Unsaturated fatty acids (known as sebum) provide a protective film on the skin and inhibit growth Hyaluronic acid A naturally-occurring polysaccharide located in the skin, joints and eyes that binds and retains water molecules, and is therefore essential for keeping the skin hydrated An enzyme produced in tears, sweat, and saliva Lysozyme, an enzyme that breaks down cell walls and acts as an antibiotic by killing bacteria Gastric secretion Acids in the stomach destroy bacteria and toxins the second line The innate immune system consists of various cell types like neutrophils, macrophages, and monocytes, as well as soluble factors including cytokines and complement Fever Mediated by the release of pyrogenic cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and interferons Inflammation Inflammation occurs when white blood cells flood an area invaded by germs. The response includes swelling, redness, heat, and pain Phagocytes Ingest and destroy microbes that pass into body tissues the third line Lymphocytes The immune system encounters antigens and develops memories of them. Specific immunity adapts to specific antigens because it learns, adapts, and T cells remember these antigens. When B cells encounter the antibodies are produced

Conclusion and recommendations
Almost every government on earth has warned that daily life cannot return to normal until their populations have built up antibodies to safeguard citizens from the virus. Therefore, the most effective ways to protect yourself and others are still: • Wearing a mask.
• Maintaining a distance of at least 6 feet from others.
• Cleaning your hands frequently and thoroughly .
• Avoiding touching your eyes, mouth, and nose.
• Covering your cough with the bend of the elbow or tissue.