key: cord-0889638-qfna5h6j
authors: Singh, Desh Deepak; Han, Ihn; Choi, Eun-Ha; Yadav, Dharmendra Kumar
title: Immunopathology, host-virus genome interactions, and effective vaccine development in SARS-CoV-2
date: 2020-11-20
journal: Comput Struct Biotechnol J
DOI: 10.1016/j.csbj.2020.11.011
sha: 73445a9b2b160e491ad190bb03cf0486227adb31
doc_id: 889638
cord_uid: qfna5h6j

Coronaviruses are a group of enveloped RNA viruses that are diversely found in humans and now declared a global pandemic by the World Health Organization in March 2020. The population's susceptibility to these highly pathogenic coronaviruses has contributed to large outbreaks, evolved into public health events, and rapidly transmitted globally. Thus, there is an urgent need to develop effective therapies and vaccines against this disease. In the primary stage of severe acute respiratory syndrome coronavirus (SARS-COV-2) infection, the signs and symptoms are nonspecific, and many more cases have been observed than initially expected. Genome sequencing is performed regularly to identify genetic changes to SARS-COV-2, and vaccine development is focused on manufacture, production, and based on specific problems, and very few are available on recent developments in the prevention of outbreaks. The aim of this review article to explore recent updates on SARS-COV-2 in the context of pathogenesis during disease progression, and innate acquired mechanisms of defense, This includes advances in diagnostics, susceptibility, and severity of host-virus genome interactions, modes of transmission, active compounds being used in pre-clinical and clinical trials for the treatment of patients, vaccine developments, and the effectiveness of SARS-COV-2 prevention and control measures. We have summarized the importance of pathophysiology immune response, Diagnostics, vaccine development currently approaches explored for SARS-COV-2.

The highly contagious and pathogenic novel SARS-CoV-2, causative agent ongoing COVID-19 pandemic, has spread rapidly and posed a health threat of unprecedented magnitude on the global population. This group includes more than 100 viruses commonly found in various animal species, including bats, pangolins, horses, cats, cattle, camels, goats, and humans [1] [2] [3] . Coronaviruses are classified in order Nidovirales, family Coronaviridae, and positive-sense, single-stranded RNA (ssRNA) viruses with a large genome size of approximately 30 kb. There are seven types of coronavirus found in humans, belonging to "alpha and beta" groups, which frequently mutate and show cross-species transmission. Like the other two highly pathogenic coronaviruses SARS-CoV and MERS-CoV, SARS-CoV-2 also caused severe respiratory illness and even death. The first human coronavirus (alpha-HCoV-229E) was identified in the 1960s and caused an upper respiratory tract infection, like the common cold [4, 5] . Most people are infected with one or more types of viruses. Rarely, coronaviruses infect animals and become new zoonoses, which can infect people and spread in the human population [5] . A new alpha human coronavirus was discovered in 2003, which was associated with pneumonia, rhinorrhea, and laryngotracheobronchitis in children, particularly and its mode of transmission was bat to civet and then, via civet, to humans [2] [3] [4] [5] . A second highly transmissible virus from lineage B was discovered in December 2019 in Wuhan, China, and now known as SARS-CoV-2. Another coronavirus of interest belongs to lineage C and caused an outbreak of Middle East Respiratory Syndrome (MERS) in 2012, from camels to humans [6] .

In 2019 in Wuhan, China there were several unusual cases of pneumonia, presenting with a dry cough, dyspnea, fever, and lung tissue damage [3] . The source of many of these cases was recorded as being the Wuhan wild animal and seafood market [7] . On 12 th January 2020, China shared the genetic sequence of the infectious agent. China reported virus originated from wild bats and was similar to SARS, hence the infectious agent became known as SARS-CoV-2 at the end of January [8] and declared an emergency a pandemic (global outbreak) of disease [1, 9] . SARS-CoV-2 is highly transmissible and 15,296,926 cases and 628,903 deaths from SARS-CoV-2 were recorded in over 200 counties on 24 th July 2020. We compared these figures with other coronavirus outbreaks, such as SARS in 2003, where the number of infected persons was approximately 8,000, with a 9.5 % case fatality rate. MERS in 2012 had approximately 2,500 cases, with a mortality rate of approximately 35 % [10, 11] .

The virus targets the respiratory system and its transmission is by contact, droplets, and fomites from another infected person who may be symptomatic or asymptomatic [12] . The incubation period is around 2 to 14 days [9] . The main symptoms are dry cough, fever, sore throat, and shortness of breath, leading to pneumonia and acute respiratory distress (ARDS), which may require intensive care as shown in figure 1 [13] . Overall, the mortality rate is approximately 3%, and increases with age, over 60. The mortality rate is also higher in people with diabetes, heart disease, and kidney disease [14] . In COVID-19 patients, a characteristic feature is a lymphocytopenia and CT chest scans show ground glass-like features, indicative of viral pneumonia [15, 16] . Diagnosis of SARS-CoV-2 is made with real-time PCR, by identifying the RNA load via nasal swab (NS) and throat swab (TS), and/or by X-ray and CT scans [15] .

The main treatments are supportive, such as antivirals, antimalarials, steroids, and antibiotics [17] . At present, no approved treatments or vaccines are available against SARS-CoV-2 as shown in figure 1. However, randomized multicentric clinical trials are under way to look for treatment and vaccine options.

MERS and SARS share the same mechanism as SARS-CoV-2. Spike protein (S2) binds to the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) receptor protein, which is expressed in epithelial cells [18] . The virus enters the host cells via receptor-mediated endocytosis and is uncoated, releasing RNA genome into the cytoplasm see human SARS-COV-2 life cycle as shown in figure 2 [15] . Spike protein also has another function;

binds to ACE2, causing down-regulation, which leads, eventually, to lung injury [19] . The liver produces an inactive form of angiotensin, which circulates in the blood in response to the enzyme renin released by the kidney, and which converts angiotensin to angiotensin-I [13, 14] .

This circulates in blood in an inactive form and converted to angiotensin-II by an angiotensinconverting enzyme (ACE or ACE1) [20] . This enzyme maintains blood pressure and mediates tissue injury via a series of non-hemodynamic effects [21] . ACE2 would normally cleave angiotensin-II, as part of a negative feedback loop therefore, if ACE2 is downregulated, this would increase blood pressure in SARS-COV-2 patients. Furthermore, angiotensin-II can bind to receptors in the lungs, called type 1a angiotensin-II receptors (AGTR1A), which increases the permeability of the lungs. Here, a problem arises when the downregulation of ACE2 simultaneously upregulates ACE1, due to negative feedback [22] [23] [24] , and this leads to excessive angiotensin-II. This binds to the AGTR1A receptors, which then causes excessive vascular pulmonary activity, the pathology observed in lung tissue associated with pulmonary destruction [22] [23] [24] . 

The entry of immune cells into the lungs to fight SARS-CoV-2 leads to ARDS [25, 26] and it's associated with the upregulation of pro-inflammatory cytokines and chemokines shown in figure 3 [27] . In SARS-CoV-2 infected patients, IL-1β, IL-16, CXC chemokines, and ligand 2 (CCL2) [28] levels are high. Individuals reCoVered from SARS-CoV-2 have shown an early expression of interferons IFN-α, IFN-γ, CXCL-10, and CCL2 [29] . IFN-α is an antiviral protein released by infected cells and serves as a signal to produce other anti-viral proteins, so that nearby host cells are more protected. It activates other immune cells, such as macrophages [29] .

IFN-γ is a part of the immune system that destroys particular cells that are infected with SARS-CoV-2) [30] . Chemo attractants such as CXCL-10 and CCL2 are released to guide other cells to destroy infected cells [31, 32] . The adaptive immune response is known to be vital to survival, severe SARS-CoV-2 infection is related to a failure to switch from an innate immune response to an adaptive immune response. Infected people lose their memory cells, effector cells, or enough antibodies to reduce the viral load, unbalancing the host-pathogen interaction [33] . NF-kB an important pro-inflammatory cytokine that regulates some genes encoding other cytokines and chemokines as shown in figure 3 [34] that are released by cells and which trigger an immune response against the infection. Nucleocapsid proteins (N-proteins) of SARS-CoV-2 bind to viral RNA, as part of the assembly process, and this may be prevented by host proteins such as MDAS and RIG-1 [35] . These proteins detect viral RNA and trigger cell destruction [36] The EB protein of SARS-CoV-2 inhibited by MAD-5 and RIG-1. If MAD-5 and RIG-1 proteins can function, they activate the mitochondrial surface protein MAVS, and this protein activates E3 ubiquitin ligases, leading to the production of NF-kB, which enters the nucleus and activates pro-inflammatory cytokines [37] . The E3 ubiquitin ligases also activate IRF-3 and IRF-7 transcription factors, which enter the nucleus and upregulate interferon α, γ, and activate immune cells (figure 3) [3, 38] . However, the M-protein of SARS-CoV-2 inhibits the phosphorylation of IRF-3 and IRF-7 [36] . Therefore, these transcription factors cannot go to the nucleus and cannot up-regulate the interferon at transcription level [3] . The PLPro protein of SARS-CoV-2 is capable of inhibiting the activation of NF-kB, therefore no response in the nucleus and upregulation of pro-inflammatory proteins. In some cases, the production of sufficient cytokines decreases the number of interferons [35, [39] [40] [41] ].

The gold standard for diagnosis is RT-PCR, and the Centre for Disease Control and Prevention (CDC) has developed an RT-PCR kit based on a specific target sequence shown in figure 1 [42, 43] . Various countries have developed their RT-PCR kits, such as Germany (targeting RdRP, E, and N genes), China (targeting ORF1ab and N), Hong Kong (targeting nsp14 and N genes), Japan (targeting multiple proteins), and Thailand (targeting the N gene).

Various diagnostic assays are being developed to detect the virus. Some kits are only able to detect one strain of SARS-CoV-2, and some are sensitive to any SARS agent. The specificity of RT-PCR depends on the expertise of individuals, and samples must be taken from the lower or upper respiratory tract. Moreover, single negative samples do not rule out MERS-CoV infection [15, 17] .

RT-PCR can often miss the identification together and has only a 70% sensitivity for acute infection. [42] . Tested sample, approximately 3% of those who have negative PCR results have SARS-CoV-2. There could be reasons, for this, perhaps early at the pandemic not enough virus samples for detection and the diagnostic kits were not used correctly [44] . The RT-PCR test may improve over time and suggested, meanwhile, that chest CT is used to identify patients for further testing, which will help to inform isolation and treatment as shown in figure 1 [45, 46] . CT scan is also good technology to screening for testing but due to poor access to laboratory testing, or in a situation where centralized public health workers are overstretched [47] . In patients with SARS-CoV-2 symptoms, such as fever, cough, and shortness of breath, clinicians often carry out chest X-rays, which are relatively cheap and easy. The most common abnormal finding that of ground-glass opacities, portions of the lungs show up on X-ray images as a hazy shade of gray, like frosted glass, instead of being black [48, 49] .

It is important to know that chest X-rays are not very sensitive to SARS-CoV-2. Patients who are highly suspected of having SARS-COV-2 viral pneumonia should probably receive chest CT, even if their chest X-ray is negative [27, 50] . Chest CT provides a more detailed view, with the most common finding, again, being ground-glass opacities scattered throughout the lungs [51, 52] . These represent tiny air sacs or alveoli that are filled with fluid and that turn a shade of grey on the CT scan. In severe and advanced infections, more fluid accumulates in the lobes of the lungs, and the appearance progresses to a solid, white consolidation and finally a crazy-paving pattern, with swelling of the interstitial space along the walls of the lung lobules [53, 54] . A chest X-ray is informative but not very sensitive or specific to SARS-CoV-2;

therefore, individuals should undergo RT-PCR [54, 55] . Many countries have been isolating patients with classic CT findings until laboratory tests help to identify the cause of disease. It is also important to evaluate each patient, based on the severity of the disease [55] . Individuals can be asymptomatic or have a very mild form of the disease; the sensitivity of a chest CT falls to about 50% in the first 48 hours of symptoms or with individuals with the mild disease [51] .

ELISA was used to detect antibodies to MERS-CoV for earlier detection, which is based on the N and S proteins of MERS-Co-V. Micro-neutralization is used to detect specific antibodies in the serum sample, this test is considered more sensitive and specific for the analysis of neutralizing antibodies. The presence of antibodies indicates that the immune response has developed in the infected person, but serology tests are recommended for observation purposes only, not for a diagnosis.

The new CDC list of possible SARS-CoV-2 symptoms includes fever, cough, difficulty in breathing, repeated shaking with chills, muscle pain, headache, sore throat, and loss of taste and smell as shown in figure 1 . In a few cases, patients experience extreme fatigue, diarrhea, and fever 37.8°C or above [3, 9-11, 13, 56] . Symptoms usually occur 2-14 days after exposure to the virus, but may also be observed for up to 28 days. Not all individuals with SARS-CoV-2 show all symptoms and these range from mild to severe [56] . The test result

showed viral nucleic acid declared as a positive SARS-CoV-2 test [14] [15] [16] . Suspected cases are those with symptoms who have been exposed to infected cases [13] . Clinically diagnosed cases are those having symptoms, prior exposure, and the presence of a lung imaging feature consisting of coronavirus pneumonia [34, 46] . Asymptomatic cases are free from symptoms but test positive for viral nucleic acid. SARS-CoV-2 infection is classified into three categories mild, severe, and critical. Mild cases have either no sign of pneumonia or mild pneumonia [27] . Severe cases show problems of oxygenation, breathing, and characteristic radiological findings on a CT-Scan [57, 58] . In severe cases, breathing problems are classified as dyspnea, and patients have a respiratory frequency (RF) > 30/Min [12, 14, 55, 58] .

Severity also classified as an oxygen saturation < 93 % and PF ratio < 300 [55] . The illness is considered to be severe if lung infiltration or pneumonia occupying more than 50% of their lung field and is seen on a chest radiograph or CT-scan [55, 59] . In critical cases, acute respiratory distress syndrome (ARDS) is a major clinical complication of SARS-CoV-2

infection [60] . This syndrome is characterized by hypoxic respiratory failure and bilateral infiltration due to diffuse alveolar damage [61] . This damage can cause respiratory failure, which is associated with VQ mismatch and pulmonary shunting [62] [63] . Large immunemediated cytokine cascades cause lung alveolar damage, patients are unable to successfully ventilate, and develop respiratory failure [64] . Septic shock causes vasodilation and leads to multiple organ dysfunction, especially in the kidney. Some SARS-CoV-2 patients develop renal failure, in addition to respiratory failure, and may require life support [65] . Patients who develop these complications with SARS-COV-2 have much higher mortality rates [66] . The overall case fatality rate in the SARS-CoV-2 pandemic near about 3.5%, but in elderly patients, this rises to 14%. Fatality is higher for patients with cardiovascular disease (10.5%), diabetes (7.3%), chronic respiratory disease (6.3%), and cancer (5.6%) [67, 68] . Some clinicians have reported the presence of blood clots in young adults (aged < 50 years), which causes serious problems such as heart attack and stroke [69] . from Hangzhou were isolated and analyzed by deep sequencing [70] [71] [72] . Researchers said that the virus has acquired mutations that are capable of substantially changing its pathogenicity.

Some of the most pathogenic strains of the virus are more pathogenic than normal strains [73, 74] . One mutated strain of SARS-CoV-2 has been more lethal across Europe and New

York than in other parts of the United States and other countries [75] . The diversity of viral strains under investigation leads to a consideration of the impact of these mutations on the development of vaccines and drugs. Mutations in the virus genome might cause the disease to be more virulent, more severe, or more transmissible [18, 76] . Microbiologists from the Peking School of Life Sciences in Beijing, and the Institute Pasteur of Shanghai, have studied the genome of 103 samples of SARC-CoV-2 [18] . They analyzed the evolutionary relationship between the virus strains and their sequenced genomes. They identified two lineages the milder or less infectious S type and the highly infectious, more virulent, and more severe L type [77] . The genetic difference between S and L lineages is in the receptor-binding domain. The L type is more prevalent (70 %) in current cases [78, 79] . The L type was prevalent in the early stages of the outbreak in Wuhan. Later on, the S type became prevalent in China because of lockdown control [80] . The Chinese lockdown successfully closed down the spread by isolating people, and this approach seemed to reduce the number of cases of L type SARS-CoV-2 in Wuhan after January 2020 [79, 80] .

If the Chinese lockdown halted the L type, the subsequent pandemic may be of the S type, which is believed to be less virulent [79] [80] [81] . There are also the possibility of infection with both viral types in an individual with SARS-CoV-2. One patient in the US has tested positive for both the S and L types, so it appears that both lineages are persisting in the pandemic [81, 82] .

There is no specific treatment currently available drugs for SARS-CoV-2 [70, 71, 77] .

Some drugs are under investigation and being tested as a potential treatment of SARS-COV-2, as shown in tables 1 and 2. The antiviral agent famvir has shown efficacy against SARS-CoV-2, and clinical trials have been conducted in 70 patients in Shenzhen, Guangdong province [72, [83] [84] [85] [86] [87] . Another drug option is remdesevir, an adenosine analog, which is incorporated into the nascent viral RNA chain and results in premature termination. However, the drug is still in a clinical trial [88] , a randomized control trial involving 1063 patients, funded by the US, improved recovery from advanced SARS-CoV-2. Preliminary results indicate that patients treated with remdesevir showed a 31% improvement in recovery time over placebo [88] .

Chloroquine widely used as an anti-malarial and as a treatment for autoimmune disease, and also reported as having anti-viral activity, blocking virus infection by increasing the endosomal pH required for virus-cell fusion as well as interference with glycosylation of the cellular receptor of SARS-CoV-2 [89] . In addition to its anti-viral activity, chloroquine has immunemodulating activity, which may synergistically enhance anti-viral effects in vivo. Meanwhile, a clinician from South Korea has reported the use of an anti-HIV drug combination, lopinavir, and ritonavir, to successfully treat SARS-CoV-2 shown in figure 1 [90, 91] . Researchers in China have reported full recovery from SARS-CoV-2 their blood plasma for possible use as a new treatment of the virus [87, 92] , an approach is known as hyperimmune globin therapy.

Corticosteroids should be avoided because of their potential in prolonging viral replication, as previously observed in MERS-CoV patients. These are the treatment options currently available, but all are under trial, as part of an effort to test more than 60 types of potential therapeutic drugs, as shown in Table 2 . [96] . Potential vaccines needed to be work for all strains and any mutated variants, and likely to be very challenging to find a single vaccine that works for all [88] . The aim of vaccine development to expose the body to the antigen, without causing the disease. However, antigens will still cause an immune response that can block or kill the virus, if persons become infected later. Under progress [111] One challenge that the antibody response against S and L is slightly different [112] , and L type vaccine induces slightly different antibodies, it is unclear if this will confer cross-immunity to S type and vice versa [83] . In the context of the current waves of infection, unclear whether becoming co-infected with both L and S types at the same time leads to more serious illness [113] . SARS-CoV-2 are RNA-based viruses with a 3.4 kbp genome and a couple of changes in the genome of this virus [96, 113] . Mutations have been observed in S2 receptors, which are proteins responsible for the infection of host cells. Unfortunately, these viruses are more transmissible and provided challenges to vaccine development, and also need more study in this field [10] . [163] There are several types of SARS-CoV-2 vaccine currently under trial as shown in table 3 

Neutralizing antibodies (Nabs) of coronaviruses tend to target the turmeric spike (S) protein (S1 and S2) and mediate the entry into a host cell. Which is actively involved in the attachment of cell and fusion of the cell membrane via the formation of a six-helix bundle (6-HB) fusion core [164] . The S protein has AA (Amino Acid) that are 77.5 % identical and bind to ACE2 on human cells through the S1B domain. S1-RBD and S2 are identified as potential targets for Nabs. To identify antibodies that could potentially neutralize SARS-CoV2. SARS-CoV-2 patents generate immunoglobulin F (IgG) types of antibodies, which is binding to SARS-CoV-2 elements after the onset of disease and blocking SARS-CoV-2 entry of host cells, called neutralizing antibody (NAbs) [164, 165] . Possible targets of nAbs on the S protein of SARS-CoV-2as shown in figure 4 . Monoclonal antibody (mAb), antigen-binding fragment (Fab), single-chain variable region fragment (scFv), or single-domain antibody binds to the RBD, S1

subunit (non-RBD, including NTD), or S2 of the viral S protein, blocking binding between the RBD and the respective receptor (for RBD-targeting nAbs), interfering with the conformational change of S (for S1-targeting nAbs), or hindering S2-mediated membrane fusion (for S2targeting nAbs), leading to the inhibition of infection with SARS-CoV-2 in the host cells.

Several human monoclonal antibodies (mAbs) have been developed from memory B cells [166, 167] . A researcher from the field developed 51 cell lines from the humanized mice and evaluate the efficacy and 47D 11 were found active and targeted against the S1B receptor binding domain of SARS-CoV-2. Pseudo typed lentiviral-based neutralization assay was performed to identify the efficacy of Nabs. The potential of pseudo-virus-neutralizing efficacy suggested that the neutralizing capacity of SARS-CoV-2-specific depends on the magnitude and binding affinity of antibodies [165] . Representative SARS-CoV RBD and MERS-CoV RBD-Targeting nAbs are mentioned in table 4. [180] Generatio n Sequencin g

According to the WHO and CDC, hand washing is the most effective procedure to prevent infection. Asymptomatic spreaders may be present in the community, feeling quite well but still able to pass on the virus [45, 72] . It is critical to understand that the asymptomatic spreading of the virus has been shown and that it can be transmitted before symptoms or detection [27] . There are three important concepts: identity, isolation, and information. Once a patient identified, they need to take actions regarding personal hygiene and prevention, such as limiting contact with others as much as possible, staying at home, using available PPE (N-Mask or FFP2-standard masks set by the European Union, gloves, and goggles), and avoid touching the eyes, nose, mouth, and wash hands. Used PPE should be discarded properly to prevent SARS-CoV-2 infection [62] . Hand hygiene should be maintained, such as washing hands for 30 seconds with an effective soap or hand sanitizer with at least 70% alcohol [181] .

High-touch surfaces that may be contaminated with SARS-CoV-2 can also be cleaned, using EPA-approved disinfectants. There is no any disinfectant currently approved by the EPA specifically for SARS-CoV-2, but several disinfectants are available [182] . conditions should be aware of worsening caused by the pandemic. Stress can be reduced by taking care of close friends and family, and by helping others to cope, making the community stronger. It will be better to avoid stressful activities that cause anxiety, to keep updated with accurate information, to meditate regularly, try to eat healthy, balanced meals, exercise regularly, sleep more often, and develop an understanding of the actual risk.

SARS-CoV-2 continues to increase its death toll as more people become infected. More than 215 countries are reporting new cases, and many struggle to limit their spread. SARS- 

The author(s) confirm that this article content has no conflicts of interest.

WHO Declares COVID-19 a Pandemic

SARS-CoV-2: an Emerging Coronavirus that Causes a Global Threat

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Coronavirus envelope protein: current knowledge

Emergence of a novel human coronavirus threatening human health

Middle East respiratory syndrome coronavirus (MERS-CoV): animal to human interaction

An emerging coronavirus causing pneumonia outbreak in Wuhan, China: calling for developing therapeutic and prophylactic strategies

COVID-19: a novel zoonotic disease caused by a coronavirus from China: what we know and what we don't

Clinical characteristics of 140 patients infected with SARS-CoV-2 in

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore

The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses

A novel coronavirus capable of lethal human infections: an emerging picture

Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR

Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review

Treatment options for COVID-19: The reality and challenges

Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor

High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa

Vasopressin and its analogues in shock states: a review

Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations

A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease

Outcomes in Patients with COVID-19 Infection Taking ACEI/ARB

Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence

COVID-19 pathophysiology: A review

CT imaging and clinical course of asymptomatic cases with COVID-19 pneumonia at admission in Wuhan

Managing Cutaneous Immune-Mediated Diseases During the COVID-19 Pandemic

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

Impact of immune enhancement on Covid-19 polyclonal hyperimmune globulin therapy and vaccine development

The protective and pathogenic roles of CXCL17 in human health and disease: Potential in respiratory medicine

SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes

COVID-19: consider cytokine storm syndromes and immunosuppression

COVID-19 in the heart and the lungs: could we "Notch" the inflammatory storm?

Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

Translating IL-6 biology into effective treatments

Immune-epidemiological parameters of the novel coronavirus -a perspective

COVID-19: Immunology and treatment options

Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia

Combination of Biodata Mining and Computational Modelling in Identification and Characterization of ORF1ab Polyprotein of SARS-CoV-2 Isolated from Oronasopharynx of an Iranian Patient

Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan

Evaluating the Safety, Tolerability and Immunogenicity of bacTRL-Spike Vaccine for Prevention of COVID-19

Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland

Coronavirus Infections in Children Including COVID-19

Early CT features and temporal lung changes in COVID-19 pneumonia in

Implications for forensic death investigations from first Swiss post-mortem CT in a case of non-hospital treatment with COVID-19

Deep learning system to screen coronavirus disease 2019 pneumonia

Clinical Time Features and Chest Imaging of 85 Patients With COVID-19 in

A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19

Progress and prospect on imaging diagnosis of COVID-19

Remdesivir for the Treatment of Covid-19 -Preliminary Report

COVIDiagnosis-Net: Deep Bayes-SqueezeNet based diagnosis of the coronavirus disease 2019 (COVID-19) from X-ray images

COVID-19) CT Findings: A Systematic Review and Meta-analysis

Incidence of Ventilator-Associated Pneumonia in Critically Ill Children Undergoing Mechanical Ventilation in Pediatric Intensive Care Unit

Prevention, Coronavirus (COVID-19)

Utility of feline coronavirus antibody tests

Chest Imaging in Patients Hospitalized With COVID-19 Infection -A Case Series

Ventilator-Associated Pneumonia in Critically Ill Patients with Intensive Antibiotic Usage

Point-of-Care Multi-Organ Ultrasound Improves Diagnostic Accuracy in Adults Presenting to the Emergency Department with Acute Dyspnea

Elevated Troponin in Patients With Coronavirus Disease

Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths

Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study

From SARS to COVID-19: A previously unknown SARSrelated coronavirus (SARS-CoV-2) of pandemic potential infecting humans -Call for a One Health approach

COVID-19 pneumonia manifestations at the admission on chest ultrasound, radiographs, and CT: single-center study and comprehensive radiologic literature review

First known person-to-person transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the USA

Epidemiology, genome, and clinical features of the pandemic SARS-CoV-2: a recent view

Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

Recent Advances in Pathophysiology, Drug Development and Future Perspectives of SARS-CoV-2. Front

Repurposing Antiviral Protease Inhibitors Using Extracellular Vesicles for Potential Therapy of COVID-19

Are children less susceptible to COVID-19?

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial

Novel Coronavirus (COVID-19) Pandemic: Built Environment Considerations To Reduce Transmission, mSystems

Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant

Ongoing Clinical Trials for the Management of the COVID-19 Pandemic

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak -an update on the status

Epidemiological and Clinical Aspects of COVID-19; a Narrative Review

COVID-19 pneumonia: different respiratory treatments for different phenotypes?

Genotype and phenotype of COVID-19: Their roles in pathogenesis

Clinical phenotypes of SARS-CoV-2: implications for clinicians and researchers

The Rationale for Potential Pharmacotherapy of COVID-19

Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 -United States

Therapeutic management of patients with COVID-19: a systematic review

High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses

Perspectives on therapeutic neutralizing antibodies against the Novel Coronavirus SARS-CoV-2

Can an effective SARS-CoV-2 vaccine be developed for the older population?

Health, NIH clinical trial shows Remdesivir accelerates recovery from advanced COVID-19

Effective treatment of severe COVID-19 patients with tocilizumab

New Insights of Emerging SARS-CoV-2: Epidemiology, Etiology, Clinical Features, Clinical Treatment, and Prevention

Clinical trials on drug repositioning for COVID-19 treatment

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Favipiravir Combined With Tocilizumab in the Treatment of Corona Virus Disease

Recommendations for Investigational COVID-19 Convalescent Plasma, fda.gov

Machine learning versus traditional risk stratification methods in acute coronary syndrome: a pooled randomized clinical trial analysis

Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution

A Conformation-Dependent Neutralizing Monoclonal Antibody Specifically Targeting Receptor-Binding Domain in Middle East Respiratory Syndrome Coronavirus Spike Protein

Activity of and Effect of Subcutaneous Treatment with the Broad-Spectrum Antiviral Lectin Griffithsin in Two Laboratory Rodent Models

Broad-Spectrum In Vitro Activity and In Vivo Efficacy of the Antiviral Protein Griffithsin against Emerging Viruses of the Family Coronaviridae

Recent developments in anti-severe acute respiratory syndrome coronavirus chemotherapy

Structure and Inhibition of the SARS Coronavirus Envelope Protein Ion Channel

Development of interfering RNA agents to inhibit SARS-associated coronavirus infection and replication

Sun, mRNA Display Design of Fibronectin-based Intrabodies That Detect and Inhibit Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Protein

The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds

Ribavirin suppresses bacterial virulence by targeting LysR-type transcriptional regulators

BCX4430 -A broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease

Nucleoside analogues for the treatment of coronavirus infections

Severe Acute Respiratory Syndrome Coronavirus Replication Inhibitor That Interferes with the Nucleic Acid Unwinding of the Viral Helicase

Evaluation of SSYA10-001 as a Replication Inhibitor of Severe Acute Respiratory Syndrome, Mouse Hepatitis, and Middle East Respiratory Syndrome Coronaviruses

First-line drugs inhibiting the renin angiotensin system versus other first-line antihypertensive drug classes for hypertension

COVID-19 vaccine design: the Janus face of immune enhancement

High throughput and comprehensive approach to develop multiepitope vaccine against minacious COVID-19

Compassionate Use Open-Label Anti-CD14 Treatment in Patients With SARS-CoV-2 (COVID-19)

NCT04336410, Safety, Tolerability and Immunogenicity of INO-4800 for COVID-19 in Healthy Volunteers

Study to Describe the Safety, Tolerability, Immunogenicity, and Potential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults

NCT04299724, Safety and Immunity of Covid-19 aAPC Vaccine

Immunity and Safety of Covid-19 Synthetic Minigene Vaccin

A Phase II Clinical Trial to Evaluate the Recombinant Novel Coronavirus Vaccine (Adenovirus Vector)

University of Oxford Commences Clinical Trial for Vaccine Candidate (ChAdOx1 nCoV-19) Targeting COVID-19, CLINICAL TRIALS, CORONAVIRUS, COVID-19

Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis SARS CoV-2 Infection

double-blinded, placebo-controlled phase II clinical trial for Recombinant Novel Coronavirus (2019-nCOV) Vaccine (Adenovirus Vector

Innovation, Laboratory of Vaccine Materials, nibiohn.go

Vaxart Announces Additional Positive Pre-Clinical Data for its Oral COVID-19

UM alumnus on front lines of COVID-19 research in China

Binex to develop COVID-19 vaccine

Immunogenicity of a DNA vaccine candidate for COVID-19

Covid-19: China to launch clinical trials for coronavirus vaccine

Zydus Cadila launches a fast tracked programme to develop vaccine for the novel coronavirus, 2019-nCoV (COVID-19)

Oxford University's COVID-19 vaccine moves to next stage of human trial

Delivery of mRNA to platelets using lipid nanoparticles

Covid-19: Entos and Takis to work on separate vaccines, pharmaceuticaltechnology

COVID-19 Vaccine Candidates

Serum Institute of India brings Covid-19 vaccine into animal testing

Safety of an Inactivated Enterovirus Type 71 Vaccine in Healthy Adults

BioNTech and Pfizer announce regulatory approval from German authority Paul-Ehrlich-Institut to commence first clinical trial of COVID-19 vaccine candidates

CureVac´s Optimized mRNA Platform Provides Positive Pre-Clinical Results at Low Dose for Coronavirus Vaccine Candidate

Virus-Like particles

pharma-industry-review, ARTES joins fight against COVID-19 with VLP vaccine platforms

Indian Immunologicals and Australia's Griffith University tie-up for COVID-19 vaccine research

Valneva and Dynavax Announce Collaboration to Advance Vaccine Development for COVID-19

Vaxart Demonstrates Efficacy of Oral Avian Flu Vaccine in Preclinical Studies

Dynavax and Clover Biopharmaceuticals Announce Research Collaboration to Evaluate Coronavirus (COVID-19) Vaccine Candidate with CpG 1018 Adjuvant

Test Vaccine Elicits Strong Ab Response to SARS-CoV-2 in Mice

OMV-based vaccine

Sanofi and GSK to join forces in unprecedented vaccine collaboration to fight COVID-19

Heat Biologics' COVID-19 Vaccine Program

Design of a peptide-based subunit vaccine against novel coronavirus SARS-CoV-2

GSK partners with Innovax Biotech on Covid-19 vaccine

OMV-based vaccine

Iavi and merck collaborate to develop vaccine against sars cov-2

Generex Signs Contract with EpiVax to Develop Ii Key Peptide Vaccines to Address the Coronavirus Pandemic

COVID-19 Vaccines Under Pre-Clinical Development

Adenoviral vectors are the new COVID-19 vaccine front-runners. Can they overcome their checkered past?

University of Alberta researchers in race against time to create COVID-19 vaccine

The DZIF focuses on SARS-CoV-2 research, dzif.de

Candidats a vaccí contra la Covid-19, segons l'Organització Mundial de la Salut

Moderna, and INOVIO Lead COVID-19 Vaccine Race; 42 Other Candidates in Pre-Clinical Stage

CoV-2: DZIF scientists and the development of vaccines

Development of an inactivated vaccine candidate for SARS-CoV-2

Humanized single domain antibodies neutralize SARS-CoV-2 by targeting the spike receptor binding domain

Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients' B Cells

Potent neutralization of SARS-CoV-2 in vitro and in an animal model by a human monoclonal antibody

A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2

Human neutralizing antibodies elicited by SARS-CoV-2 infection

Isolation of a human monoclonal antibody specific for the receptor binding domain of SARS-CoV-2 using a competitive phage biopanning strategy

Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model

Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability

Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor

Identification of SARS-CoV RBD-targeting monoclonal antibodies with cross-reactive or neutralizing activity against SARS-CoV-2

Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike

Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study

Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies

Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

Potently neutralizing and protective human antibodies against SARS-CoV-2

Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail

COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics

Strengths, Weaknesses, Opportunities and Threats (SWOT) Analysis of China's Prevention and Control Strategy for the COVID-19 Epidemic

Application of refined management in prevention and control of the coronavirus disease 2019 epidemic in non-isolated areas of a general hospital