Lessons from SARS‑CoV‑2 and its variants (Review)

Qin,Ziwen; Sun,Yan; Zhang,Jian; Zhou,Ling; Chen,Yujuan; Huang,Chuanjun

doi:10.3892/mmr.2022.12779

Lessons from SARS‑CoV‑2 and its variants (Review)

Authors:
- Ziwen Qin
- Yan Sun
- Jian Zhang
- Ling Zhou
- Yujuan Chen
- Chuanjun Huang
View Affiliations

Affiliations: The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250013, P.R. China, Department of Respiratory Diseases, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China, Department of Respiratory Diseases, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250013, P.R. China
Published online on: June 22, 2022 https://doi.org/10.3892/mmr.2022.12779
Article Number: 263
Copyright: © Qin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

COVID‑19 has swept through mainland China by human‑to‑human transmission. The rapid spread of SARS‑CoV‑2 and its variants, including the currently prevalent Omicron strain, pose a serious threat worldwide. The present review summarizes epidemiological investigation and etiological analysis of genomic, epidemiological, and pathological characteristics of the original strain and its variants, as well as progress in diagnosis and treatment. Prevention and control measures used during the current Omicron pandemic are discussed to provide further knowledge of SARS‑CoV‑2.

Introduction

COVID-19, caused by novel coronavirus SARS-CoV-2, has posed a serious threat to human health and public safety globally with rapid transmission and serious pathogenicity (1). Novel variants of the original virus are emerging on a frequent basis. Omicron strain has rapid speed of transmission and has replaced Delta strain as the most prevalent currently, causing large scale global infection, it was first discovered in Johannesburg, South Africa, then identified in Belgium, Israel, Hong Kong and European countries (2). The Omicron cases in South Africa peaked at 40,000 per day (Dec 2021), while UK had >100,000 cases per day (Dec 2021), with Omicron accounting for 90% of all patients with COVID-19 in London (3,4). Omicron has been identified in >100 countries and has caused >1 million daily cases up to 3rd June, 2022 (2).

SARS-CoV-2, a single-stranded RNA β-coronavirus genus, is enveloped by membrane with polymorphic shape, commonly round or oval (5). Glycoproteins on the membrane surface include spike (S) protein, which serves as a receptor-binding and antigenic sites that trigger cytolysis by inducing antigenic response (6); small envelope (E) glycoprotein, which mediates binding to the envelope; membrane (M) glycoprotein, which is responsible for nutrient transmembrane transport, budding release of virus and formation of virus envelope and nucleocapsid (N) protein, which can be used as a diagnostic antigen and encapsulates the viral genome (7). As heavily glycosylated S trimers, S proteins bind to the human angiotensin converting enzyme 2 receptor (ACE2) and mediate viral entry into target human cells, making S protein the most important in the pathogenesis of infection (8). SARS-CoV-2 infects humans by binding to ACE2, which is the same host receptor for SARS-CoV. SARS-CoV-2 binds ACE2 of respiratory epithelial cells before multiplying, passing through the airways and finally entering alveolar epithelial cells (9). Massive viral duplication in the lung triggers the immune response, which causes aggregation and accumulation of inflammatory cells, resulting in typical symptoms of viral pneumonia (10). Acute pulmonary infection can cause complications, the most severe of which are acute respiratory distress syndrome (ARDS) and respiratory failure, which have become the leading cause of death during the epidemic (11,12). A cohort study of 459 intensive care units from 50 countries and 5 continents found that the mortality rate is 26.0-61.5% for patients with ARDS who received critical care and 65.7-94.0% for patients who received mechanical ventilation (12).

Similar to other viruses, the novel coronavirus genome exhibits variations that may alter its biological features. Changes in the affinity of S protein and ACE-2 may affect viral invasion of cells, replication and transmission, production of antibodies during recovery or following vaccination, the neutralization activity of antibody may be impaired (13). Delta variant (B.1.617.2) exhibits 23 mutations compared with the original strain, 12 of which are in the novel S protein (14). The increased number of mutated S proteins make immune recognition and antibodies attachment more difficult, leading to a higher infection rate in human cells (15). The newly reported Omicron strain exhibits a considerable number of mutations in S protein as well. Among 50 mutations, 23 of them are in the S protein, preventing antibodies from attaching to S protein, resulting in increased transmissibility and infectivity (16).

Epidemiological features

SARS-CoV-2 appears to be particularly infectious in crowded places with poor ventilation and the chance of infection following exposure to SARS-CoV-2 is similar between different age groups (17), while people appear to develop a degree of immunity following vaccination or infection.

Compared with the original strain, variants exhibit similar epidemiological features. Although there is no conclusive evidence that Delta variant causes distinct symptoms from Alpha, patients infected by Delta variant exhibit more rapid onset and higher viral expression in the respiratory tract (18). It is hypothesized that the infectiousness of Delta variant is double that of the original strain, indicating a higher potential infection and death rate (19). Omicron variant is notably more contagious compared with Delta as a result of its mutations on the S protein receptor-binding domain (RBD) (20). Patients infected with Omicron variant often present with mild symptoms and severe symptoms are rare (21). In terms of age, it has a greater impact on young and middle-aged people than previous variants (22). Omicron also exhibits greater ability to escape from antibodies, which can lead to more cases of reinfection and infection following vaccination (20).

During outbreaks, however, clinical features differ between age groups. According to a study (23), the incidence of pre-existing comorbidities such as hypertension, diabetes and cardiovascular disorder is higher among the elderly (age, >60 years), who may have more underlying disease and be in poorer physical condition compared with young and middle-aged groups. Regarding pulmonary infection and comorbidities, elderly patients have a higher risk of severe respiratory disease requiring intensive care (24), while younger patients may only exhibit moderate pneumonia, asymptomatic infection or be less likely to develop COVID-19 (23). Additionally, studies have indicated that immunocompromised hosts, such as patients with HIV or active cancer or receiving high-dose steroid therapy, may be more likely to develop complications following infection with SARS-CoV-2 (25,26).

Infected people are the primary source of infection, as well as asymptomatic patients and patients in latent period (27). It is hypothesized that transmission via aerosols is the primary route from infected patients to non-infected people (28). Patients in latent period without symptoms also discharge virus particles into the environment at similar levels to symptomatic patients, which poses a threat to public safety (29).

Droplets are the primary infective agents of SARS-CoV-2. When a patient breathes, coughs or sneezes, respiratory droplets with high viral load are expelled from the mouth and nose (30). Infected people produce an aerosol form of SARS-CoV-2 as particles (diameter, <5 µm) suspended in gas (31). However, the likelihood of infection depends on the distance between the source and the susceptible person (32). Short-distance airborne transmission, including via droplet and aerosol, which is also known as ‘direct contact’, may serve as the principal pathway of virus dissemination (33). On the other hand, ‘indirect contact’ occurs when pathogens exhaled by carriers of SARS-CoV-2 contaminate objects and infect susceptible individuals exposed to them (34).

Epidemiological analysis and pathogenesis indicate the respiratory tract is the primary route of infection (35). ACE2+ cells in the respiratory tract are viral receptors and may be responsible to human-to-human transmission (36). Droplets and aerosol carrying the virus enter the respiratory track of susceptible person, typically in the form of saliva, sputum and nasal secretion, and begin to multiply by binding ACE2 (Fig. 1) (37). Other routes of transmission such as fecal-oral, mother-to-child and body fluid transmission are controversial and lack direct, real-word evidence. Nosocomial infection is a key route of virus transmission. Samples of item surfaces and air from confirmed patient wards were tested positive, implying that SARS-CoV-2 can spread in examination rooms and wards (38), which indicates the necessity of guarding against infection during clinical activity requiring open mouth and contact with body fluids, such as endoscopy, dental treatment and pulmonary function test (39).

Figure 1.

SARS-CoV-2 structure, pathogenesis of SARS-CoV-2 infection, and molecular target of different therapies against COVID-19. SARS-CoV-2 uses its S proteins to bind to ACE2 receptors to enter human cells. Following endocytosis and membrane fusion, uncoated RNA is translated to polypeptide, then non-structural proteins such as RdRp. The viral RNA is synthesized and structural proteins are translated; these and assemble into new viruses before released into human cells. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; S, spike; ACE2, angiotensin-converting enzyme 2; RdRp, RNA-dependent RNA polymerase; TMPRSS2, transmembrane protease, serine 2; 3CL protein, 3-chymotrypsin-like protease.

Clinical and pathological manifestation

Based on an epidemiological survey, the incubation period for COVID-19 is 1–14 days, with the majority of cases lasting 3–7 days (40). Fever, dry cough and exhaustion are reported as the three most prevalent symptoms, while certain patients exhibit expectoration, nasal obstruction, runny nose, sore throat, emaciation, hemoptysis, headache, chest pain, chills, myalgia, gastrointestinal responses and olfactory and taste disorder (41,42). Vaccinated people or those infected with Omicron generally present with asymptomatic infection or mild symptoms, while symptomatic patients primarily manifest with upper respiratory infection (43). Dyspnea and hypoxemia are the main manifestations of severely ill patients and typically develop within one week of symptomatic presentation (30). Severely ill patients rapidly develop ARDS, septic shock, coagulopathy, refractory metabolic acidosis and multiple organ failure. Certain patients develop central nervous symptom disorder and acral ischemic necrosis of the extremities (1). Severely or critically ill patients may present with moderate to low fever, while mild patients present with slight weariness, odor and taste disturbance, as well as low fever, but no visible signs or symptoms of pneumonia (44). According to a study in China, mild cases form the majority of total cases, while severe cases requiring intensive care and critical cases with life-threatening emergency complications represented <20% of the study population (45). As aforementioned, the risk level of COVID-19 varies by age. In addition, age and male are risk factors for cardiovascular disease, therefore, elderly men infected by SARS-CoV-2 may have a higher risk of developing severe cases with respiratory and circulatory failure, while the young and middle-aged people may be able to recover in two weeks (44).

In the early phase of COVID-19, peripheral blood displays lymphopenia and decreased or normal leukocyte count, while certain patients present with high levels of aspartate aminotransferase, lactate dehydrogenase, myoglobin, creatine kinase, troponin and ferritin. In terms of inflammatory indicators, C-reactive protein and erythrocyte sedimentation are increased in the majority of patients (9). Increased expression of D-dimer and decreased peripheral lymphocyte levels may present in severe cases (46). Hypercytokinemia, characterized by high expression of cytokines in plasma, is common in severely and critically ill patients, potentially resulting in death within 16 days of disease onset (47).

Computerized tomography (CT) scanning of the patient chest commonly reveals bilateral patchy shadow or ground-glass opacity with subpleural, centrilobular and diffused distribution (48). The tiny shadows rapidly expand into a scattered distribution as the disease progresses. Organizing pneumonia and fibrosis are primarily observed in the later stages of COVID-19 without pleural effusion (49).

Histological examination shows bilateral diffuse alveolar injury with mucinous exudation of cellular fibers, desquamation of pneumocytes and fibrin deposits and hyaline membrane formation, which indicate the occurrence of ARDS (50). In the course of COVID-19, inflammatory infiltration of mononuclear cells, primarily lymphocytes, occurs in alveoli, which indicates that directional aggregation of lymphocytes may lead to peripheral lymphopenia. Alveolar cells exhibit large nuclei, double cytoplasmic granules and obvious nucleoli, indicating cytotoxic alteration, which is also observed in other organs, such as spleen, hilar lymph node, bone marrow, heart and blood vessels, liver, gallbladder, kidney, adrenal gland, alimentary epithelial cells, brain and testicles (51).

Nucleic acid detection is primarily used for etiological examination. By serological examination, specific IgM induced by SARS-CoV-2 infection can be detected; positive results of IgG antibody may be seen within the first week of onset (52).

A cohort study of patients recovering from COVID-19 reported symptoms including weariness, muscle discomfort, sleeping difficulty and psychological problems such as anxiety or depression 6 months after the onset of COVID-19. Severely ill patients exhibited more obvious symptoms following recovery; in addition to impaired pulmonary diffusion function and damaged (as revealed by chest imaging), cardiovascular, nervous, digestive, urinary and immune symptoms were observed (53,54). Therefore, recovery following COVID-19 still requires long-term epidemiological investigation.

Diagnosis

During the Omicron epidemic, RT-qPCR nucleic acid detection was used as the gold standard for diagnosis of COVID-19 (55). For unvaccinated patients, detection of specific antibodies such as IgM and IgG are used as a diagnostic reference. However, for those who have been vaccinated or have a history of previous infection, these antibodies may not have diagnostic value (56).

Omicron appears to cause more asymptomatic cases and patients with mild symptoms or in the incubation period can lead to wide and undetected viral spread (57). Therefore, early identification and close monitoring of suspected cases are key for public protection against Omicron. Based on current studies (55,57), symptoms caused by SARS-CoV-2 variants vary between infected individuals, which yields limitations in common detection methods. Therefore, absence of respiratory symptoms and pulmonary inflammation or negative PCR test do not mean the patient is non-infectious, indicating that early recognition is critical during clinical tests (58). Diagnostic techniques must be updated to be more sensitive and adaptable to emergence of novel variants.

RT-qPCR is used for rapid detection of SARS-CoV-2. Compared with next-generation gene sequencing (NGS), it is faster and cheaper, provides clear results and has a larger sample capacity (59). Lower respiratory tract samples exhibit higher viral load compared with samples from other sources, with oral and nasopharyngeal swabs being most convenient and commonly used (60). Negative RT-qPCR results from respiratory samples have been obtained while positive results were obtained from intestinal canal and peripheral blood (61), indicating that isolation of live viruses is key to assess virus reproduction (62). The outcome of RT-qPCR nucleic acid detection tends to be inadequate due to complicating factors (57). False negative results can be due to virus mutations that make primers and probes difficult to recognize, low viral load in samples caused by viral mutations or non-standard sampling, different detection reagents and poor quality control (63,64). Therefore, screening hospital patients via RT-qPCR may be insufficient and multiple approaches are needed for confirmation of the novel coronavirus. Specific primers targeting key mutations in S protein rapidly recognize variants of concern that may differ from previous Omicron mutations (65). Metagenomic NGS should also be used to analyze nucleic acid, especially for patients who may be infected with a SARS-CoV-19 variant (66). Loop-mediated isothermal amplification, which is highly specific for mutations, detection with 6–8 specific primer sequences, may be substitute for a RT-qPCR diagnosis (67). Contact tracing is required to avoid the omission of potential transmitters and help to cut off the transmission route.

Serology can be used for diagnosis along with RT-qPCR. Antibody-based techniques are not recommended for early detection owing to the long period for inducing antibody responses, while antigen-based immunoassays such as ELISA assess immune response and disease progression by detecting N or S protein on antibodies (68). However, serology cannot exclude the effects of cross-reactivity caused by factors such as muramidase, rheumatoid factors and heterophile antibodies (69). The intensity and duration of immune responses may differ between individuals and disease stage and serological tests exhibit varying sensitivity and specificity, creating obstacles to their application, while biosensor technologies may improve the specificity and sensitivity of diagnosis (70).

Chest X-ray or CT imaging are also used as diagnostic techniques for the novel coronavirus (71). Bilateral ground-glass opacity is indicative of SARS-CoV-2. The sensitivity of chest CT has been proven as it accurately diagnoses infection in the presence of negative RT-qPCR results (72). Therefore, chest CT combined with repeated RT-qPCR may be a reliable technique for suspected cases with negative initial RT-qPCR detection (73). However, improper technique and atypical manifestation can result in false negatives (71).

Recently, artificial intelligence (AI) as an emerging technology for interpreting chest imaging and quick diagnosis of COVID-19 has been widely discussed (74–76). AI applications are used in imaging platforms, region segmentation for lung infection, clinical assessment and auxiliary diagnosis based on meta-analysis (74). Based on its operational principles of interpreting chest imaging and quick diagnosis (77), it may also contribute to clinical and basic research associated with SARS-CoV-2, in addition to assisting diagnosis in clinical practice. Accurately distinguishing COVID-19 from other respiratory disease improves the efficiency of diagnoses and simplifies workflow, which primarily depends on manual work of radiologists, providing more accurate results and maintaining safety of medical staff during examination (75). At this stage, AI diagnosis still needs to improve image acquisition and expand sample capacity, which is the foundation of segmentation and diagnosis (76). For physicians, AI results of chest imaging must be considered in light of clinical manifestation and laboratory examination (78).

Treatment

Currently, numerous specific targeted medicines have passed phase III clinical trials and proven to have therapeutic efficacy against COVID-19, despite preliminary or controversial results of clinical trials. Existing antiviral drugs and their combination are recommended, while extensive tests are needed to demonstrate the effectiveness and pharmacokinetic and safety profiles of specific targeted drugs before widespread use as a therapy for COVID-19 (Table I) (79).

Table I.

Antiviral and antibody-based therapy for COVID-19.

Table I.

Antiviral and antibody-based therapy for COVID-19.

A, Antiviral therapy

Name	Company	Indication	Mechanism of action	Effectiveness	(Refs.)
Interferon-α, Interferon-β	Multiple	Viral infection and certain types of malignant tumor	Protects lower airway	No obvious therapeutic effect on hospitalized patients with COVID-19	(191)
Interferon-γ	Eiger Biopharma-ceuticals	Early phase of mild COVID-19	Protects upper and lower airway continuously, inhibits cytokine storm	Risk reduction of hospitalizations or ER visits, 50% (trial no. NCT04967430)^a
Lopinavir	Multiple	HIV-1 infection	Inhibits HIV-1 3CLpro	Lopinavir + ritonavir has no obvious therapeutic effect on hospitalized patients with COVID-19 (trial no.ChiCTR2000029308)^a	(89)
Ritonavir	Multiple	HIV-1 and HIV-2 infection	Inhibits CYP3A4 activity, decreases metabolism of antiviral agents
GC-376	N/A	Feline infectious peritonitis	Inhibits SARS-CoV-2 3CLpro	Potential	(192)
PF-07304814, PF-07321332	Pfizer	COVID-19	Inhibits SARA-COV-2 3CLpro	Potential	(193)
Paxlovid (nirmaterevir + ritonavir)	Pfizer	Patients with mild-to-moderate COVID-19 (adults and children aged >12 years) with high risk of transforming into severe cases	Nirmatrevir inhibits SARS-COV-2 3CLpro, ritonavir serves as an adjuvant	Risk reduction of hospitalization or ER visit, 89% (trial no. NCT04960202)^a	(194)
Umifenovir (Arbidol)	BHBT	Influenza	Targets interaction between influenza virus S protein and ACE2 of host cells, induces interferon	Potential (trial no. IRCT20180725040596N2)^a	(195)
GeLactoferrin	N/A		Targets HSPGs, prevents virus attaching to cells.	Potential	(196)
Camostat mesylate	N/A	Acute symptoms of chronic pancreatitis	Inhibits TMPRSS2 and protease, trypsin and matriptase activity	Potential	(197)
Remdesivir (GS-5734)	Gilead Sciences, Inc.	Ebola and Marburg virus, patients with mild-to-moderate COVID-19 (adults and young children aged >28 days and weighing ≥3 kg)	Inhibits expression of viral RNA polymerase	Requires verification. (trial no. NCT04257656.)^a	(198)
Favilavir/Favipiravir (T-705)	FUJIFILM Wako Pure Chemical Corporation	Influenza, RNA virus infection	Inhibits expression of viral RNA polymerase	Requires verification	(199)
Molnupiravir (MK-4482/EIDD-2801)	MSD, Ridgeback Biotherapeutics LP	Patients with mild-to-moderate COVID-19 (adults)	Inhibits expression of viral RNA polymerase	Risk reduction of hospitalization or death, 50%, (trial no. NCT04575597)^a	(108)
Bemnifosbuvir (AT-527)	Roche, Atea Pharmaceuticals	Patients with mild-to-moderate COVID-19 not requiring hospitalization	Inhibits expression of viral RNA polymerase	Requires verification. Did not meet primary clinical endpoint (trial no. NCT04709835)	(109)
Merimepodib (VX-497)	N/A	RNA virus infection	Inhibits IMPDH, suppresses replication of RNA virus	Potential	(200)
Plitidepsin	PharmaMar	Multiple myeloma	Inhibits eEF1A	Potential	(110)
Fluvoxamine	Multiple	Depression, mild COVID-19	Inhibits selective serotonin reuptake	Requires verification (trial no. NCT04342663)^a	(114)
Chloroquine, hydroxychloioquine	N/A	Malaria and rheumatoid arthritis	Inhibit TLRs	Potential but with obvious side effects	(96)

B, Antibody-based therapy

Name	Company	Indication	Mechanism of action	Effectiveness	(Refs.)

Convalescent plasma	N/A	Patients with COVID-19 with high risk factors, rapid progression or severe or critical COVID-19	Purified neutralizing antibody agains t SARS-COV-2 obtained from recovered COVID-19 patients	Potential but controversial	(201)
Polyclonal antibody	N/A	Transplantation reaction, autoimmune disease	Immunizing animals with antigen containing multiple epitopes stimulates multiple B cell clones to produce antibodies against multiple epitopes	Potential	(202)
Miniprotein	N/A		Artificially designed, high affinity binding to RBD of SARS-CoV-2 S protein	Potential	(203)
Nanobody	N/A		Alpaca-derived antibodies, bind to RBD of SARS-CoV-2 S protein, prevent ACE2 binding	Potential	(204)
Tocilizumab (Actemra)	Roche	Rheumatoid arthritis, severe or critically ill patients with COVID-19	Monoclonal antibody, binds to non-signaling site of IL-6 (CD126)	Effective but controversial (trial no. NCT04356937)^a	(205)
Sarilumab (Kevazra)	Sanofi S.A., Regeneron Pharmaceuticals, Inc.	Rheumatoid arthritis, severe or critically ill patients with COVID-19	Monoclonal antibody, targets α subunit of IL-6 receptor complex	Effective but controversial	(132)
Sotrovimab (VIR-7831)	GlaxoSmithKline, Vir Biotechnology, Inc.	Patients with mild-to-moderate COVID-19 (age, >12 years)	Monoclonal antibody, binds to highly conserved epitope of SARS-CoV-2 S protein	Potential but controversial (trial no. NCT04545060)^a	(206)
Bevacizumab (Avastin)	Roche	Metastatic cancer, severe or critically ill patients with COVID-19	Monoclonal antibody, inhibits VEGF to suppress growth of new blood vessels	Potential	(133)
Bamlanivimab (LY-CoV555) + Etesevimab (LY-CoV016/JS016)	Eli Lilly and Company, Top Alliance Biosciences	Patients with mild-to-moderate COVID-19 (age, >12 years) with high risk of severe illness or hospitalization	Monoclonal antibody, binds to RBD of SARS-CoV-2 S protein	Risk reduction of hospitalization or death, 70% (trial no. NCT04427501)^a	(207)
Regdanvimab (CT-P59)	Celltrion	Patients with mild-to-moderate COVID-19	Monoclonal antibody, binds to RBD of SARS-CoV-2 S protein	Potential (trial no. NCT04525079, NCT04593641)^a	(208)
AZD7442	AstraZeneca plc	Patients with mild-to-moderate COVID-19	AZD1061 + AZD8895 monoclonal antibodies, binds two sites of SARS-CoV-2 S protein	Risk reduction of symptomatic COVID-19, 77% (trial no. NCT04625725)^a; risk reduction of hospitalization or death, 50%, (trial no. NCT04501978)^a	(165,209)
BRII-196/BRII-198	02137.HK	Patients with mild-to-moderate COVID-19	Monoclonal antibodies, binds two sites of SARS-CoV-2 S protein	Requires verification (trial no. NCT04501978)^a	(210)
DXP-593/DXP-604	688235.SH	Patients with mild-to-moderate COVID-19	Monoclonal antibodies, binds two sites of SARS-CoV-2 S protein	Potential	(136)
REGEN-COV (Ronapreve)	Regeneron Pharmaceuticals, Inc., Roche	Patients with mild-to-moderate COVID-19	Casirivima B + Imdevimab monoclonal antibodies, binds two sites of SARS-CoV-2 S protein	Risk reduction of symptomatic and asymptomatic COVID-19, 66.4% (NCT04452318)^a; risk reduction of hospitalization or death, 70–71% (trial no. NCT04425629)^a	(130,211)

a Primary endpoint of phase III study. N/A, not applicable; 3CL pro, 3-chymotrypsin-like protease; CYP3A4, recombinant cytochrome P450 3A4; S, spike; ACE2, angiotensin-converting enzyme 2; HSPGs, heparan sulfate proteoglycans; TMPRSS2, transmembrane protease, serine 2; IMPDH, inosine monophosphate dehydrogenase; eEF1A, eukaryotic translation elongation factor 1; TLR, toll-like receptor; B cell, bone-marrow cell; RBD, receptor binding domain; VEGF, vascular endothelial growth factor.

Antiviral medicines for SARS-CoV-2 can be divided into two groups based on the molecular mechanism: Drugs targeting viral protein or RNA and drugs targeting host protein or biological processes that allow viral entry into cells (80). Antiviral therapies should be used in the early stage of disease, especially for patients with higher risk of developing severe illness, as early intervention is more effective compared with treatment in severe cases (81).

Interferon, which confers congenital immunity to viruses, induce the expression of antiviral proteins (AVPs) such as 2′-5′A synthase and protein kinase to impede viral replication (82). Interferon-α has been demonstrated by studies to be effective against SARS-CoV and may be more sensitive against SARS-CoV-2 (83). COVID-19 guidelines in China recommend interferon-α as an antiviral drug (84). Interferon-β has proven useful in certain trials (85,86) but further studies are needed to evaluate its effectiveness in high-risk cases.

Protease inhibitors lopinavir and ritonavir were the first drugs used in clinical trials to target Mpro/3CLpro (87), the primary protease of SARS-CoV-2 that inhibits activation of IFN-α pathway and facilitates natural immune escape and massive viral replication (88). Although lopinavir/ritonavir had no significant therapeutic effectiveness for patients with COVID-19, they are more effective when combined with other drugs such as ribavirin and interferon (89). Drugs to inhibit Mpro, such as GC-376, PF-07304814 and PF-07321332, are in different stages of clinical trials to confirm their effectiveness and practicability for application worldwide (90,91). Paxlovid, an oral drug combined with PF-07321332 and nirmatrelvir, was released by Pfizer, US in 2021; it has a significant effect against COVID-19 and is used to treat adults and children aged >12 years with mild/moderate disease, as well as those at high risk of transforming to severe cases (92). Chloroquine and hydroxychloroquine, antimalarial drugs, are potential but controversial drugs in COVID-19 treatment. Biological studies have proven the effect of hydroxychloroquine on controlling viral load but clinical trials have reported side effects and no significant therapeutic benefit (93,94). High-dose chloroquine for COVID-19 treatment is not recommended due to its toxic side effects, including increased levels of liver enzymes, corrected QT level prolongation and increased death rate (95,96).

Umifenovir (Arbidol) is a broad-spectrum antiviral drug for treatment of influenza that targets the interaction between S protein and ACE2; it has been shown to inhibit membrane fusion, thereby inhibiting virus diffusion into host cells (97,98). Clinical data show that it is more effective compared with lopinavir/ritonavir (89,99), although certain clinical trials have shown contrary results on patients with mild/moderate COVID-19 (100). GeLactoferrin targets heparan sulfate proteoglycans to prevent viral attachment to cells (101). Studies showed that lactoferrin combined with remdesivir has effects against COVID-19 (102,103), providing a basis further investigation in the treatment of clinical cases. Camostat mesylate, developed for treatment of pancreatitis, has been revealed to block virus entry into lung cells (104).

Inhibitors of viral RNA include remdesivir (GS-5734), favilavir (T-705), molnupiravir (MK-4482/EIDD-2801), AT-527, merimepodib and PTC299; their effectiveness for COVID-19 treatment requires investigation (105). Remdesivir, a broad-spectrum antiviral medicine developed for Ebola virus infection, is the first drug to be accepted for clinical trials of COVID-19 treatment (106). The effect of remdesivir is unknown and the high price and intravenous (IV) route of administration prevent its widespread use (107). Molnupiravir is the first orally available drug for COVID-19 that has broad-spectrum anti-RNA virus activity. Early use of molnupiravir for COVID-19 outpatients decreases risk of hospitalization or death (108). AT-527 is also an orally available drug which need further investigation for COVID-19 treatment (109).

By inhibiting host proteins that support viral RNA, drugs such as plitidepsin, fluvoxamine and ivermectin, may be potential treatments for COVID-19 (100). Based on biological studies and mouse experiments (110,111), plitidepsin may exert greater antiviral effects than remdesivir and its safety has been proven in a number of cancer clinical trials (112,113). Fluvoxamine, an antidepressant, was previously suggested to be associated with decreased plasma levels of certain inflammatory mediators and to prevent viral infection of epithelial cells (114). Whether ivermectin decreases risk of SARS-CoV-2 infection is still uncertain and needs further investigation (115).

Convalescent plasma (CP), a blood-derived product obtained from patients who have recovered from COVID-19, has been shown to limit viral expression and modify the inflammatory response (116). It has proven to be an effective COVID-19 treatment by randomized controlled trials and retrospective studies and high-titer CP may have a more significant effect compared with low-titer CP (117,118). It is more effective in severely or critically ill patients with rapid progression of illness (119). The rate of adverse events is low, but there is still the possibility of enhanced infection mediated by antibodies and acute lung damage or allergic reactions associated with transfusion (120).

High-dose intravenous immunoglobulin (IVIg) is a blood-derived product from patients who have recovered from COVID-19 and is used as a treatment for severely and critically ill patients (121). Patients with ARDS or those on mechanical ventilation support may benefit from IVIg137 treatment. This therapy is usually not used alone but combined with other therapies, such as CP and antiviral drugs, to obtain greater clinical effect (122).

Monoclonal antibodies (mAbs) have been shown to neutralize COVID-19 infection both in vitro and in vivo (123,124). Despite the problems of bioavailability, high cost and limited supply using current technology, they may have wider clinical applications due to their ability of self-replicate, which CP does not possess (125). Severely ill patients commonly present with overexpression of IL-6 and cytokine storms in their serology profile; therefore, the inflammatory response may be alleviated by decreasing expression of IL-6 (126). Tocilizumab and sarilumab, high affinity antibodies for IL-6 receptor that are commonly used to treat arthritis and cytokine release syndrome, decrease the inflammatory response in COVID-19 (127). Tocilizumab was found to have no notable benefit for moderately ill patients in terms of decreased risk of transition to severe illness or death, while a multi-center study of critically ill patients revealed that early use of Tocilzumab may contribute to extended survival period (128). REGEN-COV, a mAb cocktails of neutralizing antibodies casirivimab and imdevimab, has an effect on preventing the aggravation of COVID-19 and decreases risk of hospitalization and death for patients with COVID-19 in high-risk groups (129). In addition, subcutaneous injection of REGEN-COV is effective for post-exposure prophylaxis (130). Clinical trials have shown that REGEN-COV may have an antagonistic or synergistic action in combination with anti-inflammatory medications with diverse mechanisms of action; this requires further investigation (129). CT-P59, a fully human anti-SARS-CoV-2 mAb, has high binding affinity for RBD in S protein and prevents interaction with ACE2, which is key to prevent the virus from entering human cells (131). Experiments into the effect of sarilumab and bevacizumab on COVID-19 are ongoing (132,133). DXP-593 (based on SARS-CoV neutralizing mAb) had not meet the endpoint of validity on phase II trials and its action mechanism remains unknown (134,135).

Bamlanivimab (LY-CoV555/LY-CoV016, recombinant, fully human neutralizing IgG1 mAb), sotrovimab (VIR-7831, fully human anti-SARS-CoV-2 mAb), REGN-10933, REGN-109876 and AZD1061 are effective against Omicron (136). In cell culture experiments, Omicron induces weaker neutralization by individual mAbs, thus contributing to immune escape (137–139). A trial investigating the effect of a panel of widely used mAbs against SARS-CoV-2 variants showed that combination of mAbs in low prophylactic doses is effective in preventing infection in mice (136), and high-dose REGEN-COV exhibits a notable therapeutic effect against Omicron infection (140). Although the mechanism SARS-CoV-2 variant immune escape remain uncertain, studies of mAbs indicate that identification of mAbs targeting highly conserved residues in viral S protein is key to avoid drug resistance and maintain effectiveness in treatment of COVID-19 variants (137,139).

Nanobodies (alpaca-derived antibodies), miniproteins (artificially designed proteins), human soluble ACE2 and ACE2 receptor traps can inhibit S protein and have shown potential therapeutic effects; owing to their diverse biological mechanisms, their effectiveness in treatment needs to be confirmed by clinical trials (81).

Corticosteroids relieve the inflammatory response caused by infection via anti-inflammatory and immunoregulatory effects (141). However, studies have shown conflicting results regarding its clinical effects (142–144). For dexamethasone, certain studies have shown decreased death rate and notable benefits especially in severely or critically ill patients receiving invasive mechanical ventilation (145,146), while other studies showed higher death rate and multiple organ dysfunction (147,148). In consideration of rebound phenomena, withdrawal reaction and side effects of corticosteroid therapy, short-term use (3–7 days) is recommended to begin within ten days for patients exhibiting rapid disease progression (144). Attention should also be paid to the dose of corticosteroids; excessive dose may lengthen the time of viral elimination owing to its immunosuppressive effect and induce adverse effects (144).

Active measures, such as prevention and treatment for complications, treatment for primary illness, prevention of secondary infection and timely application of organ function support, which are therapeutic principles for severe and critical cases, are also required (81).

Severely ill patients with arterial O2 partial pressure/fractional inspired O2 levels <300 mmHg should be provided with oxygen therapy immediately and close observation is required following oxygen inhalation by nasal catheter or mask (149). If respiratory distress and/or hypoxemia do not improve within 1–2 h, high-flow nasal cannula oxygen therapy or non-invasive ventilation should be adopted. Invasive mechanical ventilation should be considered if hypoxemia does not improve within 1–2 h or occurs with excessive breathing and tidal volume (150).

Airway management is required to improve humidification of the airway and use of active heating humidifier and close sputum aspiration are recommended. To promote sputum drainage and lung rehabilitation, airway clearance treatment should be performed as early as possible while maintaining stable oxygenation and hemodynamics (151). Extracorporeal membrane oxygenation should be applied as soon as possible when meeting the indications and with no contraindication (152).

Critically ill patients can develop shock as a complication. Vasoactive medication should be used in addition to adequate fluid resuscitation. Changes in blood pressure, heart rate and urine volume, as well as lactic and alkaline residue, must be closely monitored, and hemodynamic monitoring should be performed to guide infusion and use of vasoactive drugs to promote tissue perfusion (149).

Severely and critical patients may be associated with a prothrombotic state, which increases risk of life-threatening venous thromboembolism (153). Therefore, prophylactic use of anticoagulant therapy is recommended for patients with significantly increased levels of D-dimer with no contraindications.

Critically ill patients who present with acute kidney damage may need continuous renal replacement therapy. The balance of water-electrolyte and acid-base must be closely monitored for adverse events such as hypoperfusion and medication (154).

Adsorption, perfusion, plasmapheresis, blood/plasma filtration and other blood purification systems remove inflammatory components and minimize the cytokine storm; these serve as an early or middle-stage therapy for cytokine storm in severe or critical cases (155).

For COVID-19 child patients with multisystem inflammatory syndrome, multidisciplinary cooperation of management is required; treatment for early inflammation, shock, coagulation dysfunction, organ failure and infection should be administered as necessary. Patients with COVID-19 with typical or atypical Kawasaki disease phenotypes are treated similarly to the classic treatment regimen for Kawasaki disease, with IVIgG, glucocorticoids and oral aspirin being the most common treatment (156). Intestinal microecological regulators maintain intestinal microecological balance and prevent secondary bacterial infection (157).

Traditional Chinese medicine (TCM) is used to treat and prevent infectious disease, including COVID-19. TCM therapies have shown therapeutic effects at every stage of the disease with wide application and no reported cases of exacerbation, even in the epidemic caused by Omicron (158). In China, TCM therapies such as decoction, patent medicine and acupuncture are used by >90% of the population (159). In TCM, SARS-COV-2 is classified as ‘epidemic disease’ based on its transmission and clinical features. TCM divides the disease into medical observation and clinical treatment periods that are classified as four stages (mild, general, severe, critical) depending on the severity of disease. Numerous TCM principles and therapies are recommended in China and are usually combined with western therapies in clinical treatment to maximize therapeutic effect (160,161).

Measures to protect vulnerable groups: Vaccination

Vaccination may be the most effective method of overall long-term control of the novel coronavirus. Currently, development of effective vaccines is urgently required to decrease viral infection and provide protection for public health (162). A total of >100 vaccines have been developed based on a range of molecular platforms, such as DNA, mRNA in lipid nanoparticles, inactivated and live attenuated virus, protein subunits and recombinant vectors (163). A number of vaccines have exhibited good immunogenic effects in both clinical trials and real-world data (164,165). To March 2022, ten vaccines have been added to the World Health Organization Emergency Use Listing (EUL), while 20 new vaccines are undergoing EUL evaluation and prequalification (166).

mRNA-based vaccines include mRNA-1273 (Moderna) and BNT162b2 (BioNTech SE/Pfizer). The number of binding sites on SARS-CoV-2 S protein is associated with neutralizing antibody production; protein vaccines exhibit a similar association with neutralizing antibody response (167). mRNA-1273, a lipid nanoparticle-formulated mRNA vaccine that targets S protein of the novel coronavirus, induces a strong neutralizing antibody response (126). CVnCoV (CureVac) is a candidate mRNA vaccine that decreases strong T-cell responses and prevents viral replication in lung of hamsters exposed to wild-type SARS-CoV-2 (168). However, a phase IIb/III trial reported an overall efficacy of 48.2% in all stages of disease and all age groups, which was lower than expected (169). ARCT-154 (Arcturus Therapeutics), the first self-amplifying RNA vaccine, is the third mRNA the third most effective vaccine after Pfizer/BioNTech SE and Moderna. It uses viral self-replicating behavior to continuously express viral protein in large quantities. Compared with conventional mRNA vaccines, ARCT-154 express higher levels of S protein and induces increased production of neutralizing antibodies, stronger T cell response and T helper cell 1 and 2 immune responses (170). However, this self-replication is difficult to control and RNA interference may be required to inhibit overexpression of viral protein (162). A clinical trial in Vietnam showed that ARCT-154 met its immunogenicity primary endpoint and remains effective against Delta and Omicron with a protection rate of 95.3% in severe cases (170).

Inactivated virus vaccines, such as BIBP-CorV (Sinopharm) and CoronaVac (Sinovac Biotech), target the whole virus, while other types of vaccines use S protein as a target antigen. A clinical trial in China has shown high neutralizing antibody production with a low rate of adverse effects induced by inactivated vaccines WIBP and BIBP and protective efficiency >72% in a successful phase III trial (171). Recently, a cohort study in Singapore involving 52,709,899 people double-vaccinated with mRNA1273 (23% of participants), BNT162b2 (74%), CoronaVac (2%) or BIBP-CorV (1%) showed that the effectiveness of mRNA vaccines (mRNA1273 and BNT162b2; 96 and 90% efficiency, respectively) was higher than that of inactivated virus vaccines (BIBP-CorV and CoronaVac; 84 and 54% efficiency, respectively) (172).

Against the prevailing variant strains, all vaccines exhibit notable efficacy against infection with good tolerability (163). People vaccinated with BNT162b2 or mRNA-1273 may exhibit the highest efficacy following full-course inoculation (173,174). A meta-analysis of real-world data (175) showed that the observed effectiveness of Pfizer/BioNTech was 91.2%, Moderna was 98.1% and CoronaVac vaccine was 65.7%. CoronaVac. AZD1222 mRNA vaccine also decreases the rate of severe infection caused by SARS-CoV variants.

Live-attenuated vaccines merit further investigation due to their low cost, strong immunogenicity and long-lasting immune effect. ∆3678 SARS-CoV-2, as a potential candidate for COVID-19 vaccine, has showed validity to a certain extent in mouse models (176). The Bacillus Calmette-Guérin vaccine has showed indirect protection against COVID-19 and live attenuated Varicella Zoster vaccine has proven to decrease risk of infection using multivariate logistic regression analysis (177). DNA vaccines include AZD1222/ChAdOx1 (Oxford/AstraZeneca), JNJ-78436735/AD26.COV2.S (Janssen/Johnson & Johnson), Ad5-nCoV (CanSino Biologics) and ChAdOx1nCoV19 (Covishield) (166). Protein subunit vaccines have also been investigated; S-Trimer (SCB-2019) may be a candidate as it induces neutralizing antibody responses and has an acceptable safety assessment result (178). ZF2001, a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine, is well-tolerated and induced a good immune effect in phase I and II trials and may be a candidate protein subunit vaccine (179,180).

Adverse effects of vaccines can be considered to indicate antigenicity and immunogenicity, implying effective induction of immune responses, and severe adverse events caused by vaccination are rare (181). Aside from normal short-term effects such as fever, rash, weakness, nausea, vomiting, drowsiness, insomnia, pain and induration at injection site and lymphadenectasis similar to ordinary vaccines (182,183), the long-term side effects are unknown due to the short period of monitoring. People with strong immune responses may be susceptible to higher risk of autoimmune disease following vaccination, which is similar to other vaccines (184).

Adherence to hygiene guidelines is still required following vaccination because there is a delay between vaccination and optimal level of immunity; this differs between vaccines (185). Increased asymptomatic cases and emergence of variants increase risk of infection during development of vaccine-induced immunity, indicating the necessity of following hygiene guidelines (20).

Breakthrough infection of fully vaccinated people occurs in rapid spread of Omicron with high infectivity (186). Studies show that serum polyclonal antibody responses induced by vaccination or natural infection may be less effective against Omicron, which may account for immune failure and high levels of breakthrough infection with Omicron (187,188). Moreover, vaccine-induced protection decreases and while patients with breakthrough infections are more likely to have mild symptoms that do not require hospitalization compared with unvaccinated patients (189). Therefore, additional vaccine doses, changes in vaccine formulation or intervention should be adopted to when breakthrough infection cases increase, as well as further studying SARS-CoV-2 variants.

COVID-19 vaccines face challenges. Vaccines limit viremia and infection-associated syndromes via IgG response but do not involve IgA response in local mucosa, which is associated with virus transmission (163). Therefore, the possibility of transmission via droplets expelled from asymptomatic vaccinated patients cannot be ruled out and reinfection following vaccination is also a challenge (20,33). Global strategies are required for affordable global vaccination. Vaccine uptake presents a challenge owing to the poor public understanding and trust of vaccines and regional policies. Ethical and logistical considerations, such as clinical trials, distribution, prioritization, cultural, religious and political factors and regulation, are also challenges to achieving herd immunity (190).

Conclusion

To date, SARS-CoV-2 has been widespread in all regions with highly infectious Omicron variant posing a novel threat to global public health. Real-time guidance and epidemiological analysis should be shared to strengthen global cooperation against the epidemic. At present, the specific pathogenicity and response strategies of COVID-19 are uncertain, requiring further research.

Acknowledgements

Not applicable.

Funding

The present study was supported by The Traditional Chinese Medicine Science and Technology Development Plan Project of Shandong Province, China (grant no. 2019-0231).

Availability of data and materials

Not applicable.

Authors' contributions

ZQ, CH and YC conceived and designed the review, ZQ, CH, JZ and YS wrote the manuscript. YS and JZ prepared the figures. LZ and YC performed the literature search. LZ and CH revised it critically for important intellectual content. All authors have read and approved the final manuscript. All authors are responsible for all aspects of the work and approve the submission in its current form. Data authentication is not applicable

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1	Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 395:497–506. 2020. View Article : Google Scholar : PubMed/NCBI
2	Scott L, Hsiao NY, Moyo S, Singh L, Tegally H, Dor G, Maes P, Pybus OG, Kraemer MUG, Semenova E, et al: Track omicron's spread with molecular data. Science. 374:1454–1455. 2021. View Article : Google Scholar : PubMed/NCBI
3	Dyer O: Covid-19: South Africa's surge in cases deepens alarm over omicron variant. BMJ. 375:n30132021. View Article : Google Scholar : PubMed/NCBI
4	Callaway E and Ledford H: How bad is Omicron? What scientists know so far. Nature. 600:197–199. 2021. View Article : Google Scholar : PubMed/NCBI
5	Giovanetti M, Benedetti F, Campisi G, Ciccozzi A, Fabris S, Ceccarelli G, Tambone V, Caruso A, Angeletti S, Zella D and Ciccozzi M: Evolution patterns of SARS-CoV-2: Snapshot on its genome variants. Biochem Biophys Res Commun. 538:88–91. 2021. View Article : Google Scholar : PubMed/NCBI
6	Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, Zhang Q, Shi X, Wang Q, Zhang L and Wang X: Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 581:215–220. 2020. View Article : Google Scholar : PubMed/NCBI
7	Chen Y, Liu Q and Guo D: Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 92:418–423. 2020. View Article : Google Scholar : PubMed/NCBI
8	Ke Z, Oton J, Qu K, Cortese M, Zila V, McKeane L, Nakane T, Zivanov J, Neufeldt CJ, Cerikan B and Lu JM: Structures and distributions of SARS-CoV-2 spike proteins on intact virions. Nature. 588:498–502. 2020. View Article : Google Scholar : PubMed/NCBI
9	Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS and Manson JJ; HLH Across Speciality Collaboration UK, : COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet. 395:1033–1034. 2020. View Article : Google Scholar : PubMed/NCBI
10	Thacker VV, Sharma K, Dhar N, Mancini GF, Sordet-Dessimoz J and McKinney JD: Rapid endotheliitis and vascular damage characterize SARS-CoV-2 infection in a human lung-on-chip model. EMBO Rep. 22:e527442021. View Article : Google Scholar : PubMed/NCBI
11	Batah SS and Fabro AT: Pulmonary pathology of ARDS in COVID-19: A pathological review for clinicians. Respir Med. 176:1062392021. View Article : Google Scholar : PubMed/NCBI
12	Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, et al: Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 315:788–800. 2016. View Article : Google Scholar : PubMed/NCBI
13	Harvey WT, Carabelli AM, Jackson B, Gupta RK, Thomson EC, Harrison EM, Ludden C, Reeve R, Rambaut A; COVID-19 Genomics UK (COG-UK) Consortium, ; et al: SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol. 19:409–424. 2021. View Article : Google Scholar : PubMed/NCBI
14	Bian L, Gao Q, Gao F, Wang Q, He Q, Wu X, Mao Q, Xu M and Liang Z: Impact of the delta variant on vaccine efficacy and response strategies. Expert Rev Vaccines. 20:1201–1209. 2021. View Article : Google Scholar : PubMed/NCBI
15	Sternberg A and Naujokat C: Structural features of coronavirus SARS-CoV-2 spike protein: Targets for vaccination. Life Sci. 257:1180562020. View Article : Google Scholar : PubMed/NCBI
16	Hoffmann M, Krüger N, Schulz S, Cossmann A, Rocha C, Kempf A, Nehlmeier I, Graichen L, Moldenhauer AS, Winkler MS, et al: The omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic. Cell. 185:447–456.e11. 2022. View Article : Google Scholar : PubMed/NCBI
17	Ahn DG, Shin HJ, Kim MH, Lee S, Kim HS, Myoung J, Kim BT and Kim SJ: Current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (COVID-19). J Microbiol Biotechnol. 30:313–324. 2020. View Article : Google Scholar : PubMed/NCBI
18	Shiehzadegan S, Alaghemand N, Fox M and Venketaraman V: Analysis of the delta variant B.1.617.2 COVID-19. Clin Pract. 11:778–784. 2021. View Article : Google Scholar : PubMed/NCBI
19	Kannan SR, Spratt AN, Cohen AR, Naqvi SH, Chand HS, Quinn TP, Lorson CL, Byrareddy SN and Singh K: Evolutionary analysis of the delta and delta plus variants of the SARS-CoV-2 viruses. J Autoimmun. 124:1027152021. View Article : Google Scholar : PubMed/NCBI
20	Chen J, Wang R, Gilby NB and Wei GW: Omicron variant (B.1.1.529): Infectivity, vaccine breakthrough, and antibody resistance. J Chem Inf Model. 62:412–422. 2022. View Article : Google Scholar : PubMed/NCBI
21	Wang J, Yin XG, Wen Y, Lu J, Zhang RY, Zhou SH, Liao CM, Wei HW and Guo J: MPLA-adjuvanted liposomes encapsulating S-trimer or RBD or S1, but not S-ECD, elicit robust neutralization against SARS-CoV-2 and variants of concern. J Med Chem. 65:3563–3574. 2022. View Article : Google Scholar : PubMed/NCBI
22	Meo SA, Meo AS, Al-Jassir FF and Klonoff DC: Omicron SARS-CoV-2 new variant: Global prevalence and biological and clinical characteristics. Eur Rev Med Pharmacol Sci. 25:8012–8018. 2021.PubMed/NCBI
23	Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, et al: Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet. 395:507–513. 2020. View Article : Google Scholar : PubMed/NCBI
24	Al-Shamsi HO, Alhazzani W, Alhuraiji A, Coomes EA, Chemaly RF, Almuhanna M, Wolff RA, Ibrahim NK, Chua MLK, Hotte SJ, et al: A practical approach to the management of cancer patients during the novel coronavirus disease 2019 (COVID-19) pandemic: An international collaborative group. Oncologist. 25:e936–e945. 2020. View Article : Google Scholar : PubMed/NCBI
25	Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, Cereda D, Coluccello A, Foti G, Fumagalli R, et al: Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the lombardy region, Italy. JAMA. 323:1574–1581. 2020. View Article : Google Scholar : PubMed/NCBI
26	Halpin DMG, Faner R, Sibila O, Badia JR and Agusti A: Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection? Lancet Respir Med. 8:436–438. 2020. View Article : Google Scholar : PubMed/NCBI
27	Luo C, Yao L, Zhang L, Yao M, Chen X, Wang Q and Shen H: Possible transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a public bath center in Huai'an, Jiangsu Province, China. JAMA Netw Open. 3:e2045832020. View Article : Google Scholar : PubMed/NCBI
28	Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, Xing F, Liu J, Yip CC, Poon RW, et al: A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet. 395:514–523. 2020. View Article : Google Scholar : PubMed/NCBI
29	Kampf G, Todt D, Pfaender S and Steinmann E: Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. J Hosp Infect. 104:246–251. 2020. View Article : Google Scholar : PubMed/NCBI
30	Atzrodt CL, Maknojia I, McCarthy RDP, Oldfield TM, Po J, Ta KTL, Stepp HE and Clements TP: A guide to COVID-19: A global pandemic caused by the novel coronavirus SARS-CoV-2. FEBS J. 287:3633–3650. 2020. View Article : Google Scholar : PubMed/NCBI
31	Jayaweera M, Perera H, Gunawardana B and Manatunge J: Transmission of COVID-19 virus by droplets and aerosols: A critical review on the unresolved dichotomy. Environ Res. 188:1098192020. View Article : Google Scholar : PubMed/NCBI
32	Morawska L and Cao J: Airborne transmission of SARS-CoV-2: The world should face the reality. Environ Int. 139:1057302020. View Article : Google Scholar : PubMed/NCBI
33	Gao Z, Xu Y, Sun C, Wang X, Guo Y, Qiu S and Ma K: A systematic review of asymptomatic infections with COVID-19. J Microbiol Immunol Infect. 54:12–16. 2021. View Article : Google Scholar : PubMed/NCBI
34	Pereira LJ, Pereira CV, Murata RM, Pardi V and Pereira-Dourado SM: Biological and social aspects of coronavirus disease 2019 (COVID-19) related to oral health. Braz Oral Res. 34:e0412020. View Article : Google Scholar : PubMed/NCBI
35	Jackson CB, Farzan M, Chen B and Choe H: Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol. 23:3–20. 2022. View Article : Google Scholar : PubMed/NCBI
36	Meyerowitz EA, Richterman A, Gandhi RT and Sax PE: Transmission of SARS-CoV-2: A review of viral, host, and environmental factors. Ann Intern Med. 174:69–79. 2021. View Article : Google Scholar : PubMed/NCBI
37	Wild PS, Dimmeler S and Eschenhagen T: An epidemiological study exploring a possible impact of treatment with ACE inhibitors or angiotensin receptor blockers on ACE2 plasma concentrations. J Mol Cell Cardiol. 141:108–109. 2020. View Article : Google Scholar : PubMed/NCBI
38	Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L and Wang M: Presumed asymptomatic carrier transmission of COVID-19. JAMA. 323:1406–1407. 2020. View Article : Google Scholar : PubMed/NCBI
39	Soetikno R, Teoh AYB, Kaltenbach T, Lau JYW, Asokkumar R, Cabral-Prodigalidad P and Shergill A: Considerations in performing endoscopy during the COVID-19 pandemic. Gastrointest Endosc. 92:176–183. 2020. View Article : Google Scholar : PubMed/NCBI
40	Ludwig S and Zarbock A: Coronaviruses and SARS-CoV-2: A brief overview. Anesth Analg. 131:93–96. 2020. View Article : Google Scholar : PubMed/NCBI
41	Zhang J, Yang S, Xu Y, Qin X, Liu J, Guo J, Tian S, Wang S, Liao K, Zhang Y, et al: Epidemiological and clinical characteristics of imported cases of COVID-19: A multicenter study. BMC Infect Dis. 21:4062021. View Article : Google Scholar : PubMed/NCBI
42	Giacomelli A, Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L, Rusconi S, Gervasoni C, Ridolfo AL, Rizzardini G, et al: Self-reported olfactory and taste disorders in patients with severe acute respiratory coronavirus 2 infection: A cross-sectional study. Clin Infect Dis. 71:889–890. 2020. View Article : Google Scholar : PubMed/NCBI
43	Cele S, Jackson L, Khoury DS, Khan K, Moyo-Gwete T, Tegally H, San JE, Cromer D, Scheepers C, Amoako DG, et al: Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization. Nature. 602:654–656. 2022. View Article : Google Scholar : PubMed/NCBI
44	Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, et al: Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 323:1061–1069. 2020. View Article : Google Scholar : PubMed/NCBI
45	Wong RSY: The SARS-CoV-2 outbreak: An epidemiological and clinical perspective. SN Compr Clin Med. 2:1983–1991. 2020. View Article : Google Scholar : PubMed/NCBI
46	Mohamadian M, Chiti H, Shoghli A, Biglari S, Parsamanesh N and Esmaeilzadeh A: COVID-19: Virology, biology and novel laboratory diagnosis. J Gene Med. 23:e33032021. View Article : Google Scholar : PubMed/NCBI
47	Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, Ma K, Xu D, Yu H, Wang H, et al: Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study. BMJ. 368:m10912020. View Article : Google Scholar : PubMed/NCBI
48	Fang X, Zhao M, Li S, Yang L and Wu B: Changes of CT findings in a 2019 novel coronavirus (2019-nCoV) pneumonia patient. QJM. 113:271–272. 2020. View Article : Google Scholar : PubMed/NCBI
49	George PM, Wells AU and Jenkins RG: Pulmonary fibrosis and COVID-19: The potential role for antifibrotic therapy. Lancet Respir Med. 8:807–815. 2020. View Article : Google Scholar : PubMed/NCBI
50	Ma X, Liang M, Ding M, Liu W, Ma H, Zhou X and Ren H: Extracorporeal membrane oxygenation (ECMO) in critically Ill patients with coronavirus disease 2019 (COVID-19) pneumonia and acute respiratory distress syndrome (ARDS). Med Sci Monit. 26:e9253642020. View Article : Google Scholar : PubMed/NCBI
51	Baruah V and Bose S: Immunoinformatics-aided identification of T cell and B cell epitopes in the surface glycoprotein of 2019-nCoV. J Med Virol. 92:495–500. 2020. View Article : Google Scholar : PubMed/NCBI
52	Sieker JT, Horowitz C, Hu CK, Lacombe-Daphnis M, Chirokas B, Pina C, Heger NE, Rabson AR, Zhou M, Bogen SA and Horowitz GL: Analytic sensitivity of 3 nucleic acid detection assays in diagnosis of SARS-CoV-2 infection. J Appl Lab Med. 6:421–428. 2021. View Article : Google Scholar : PubMed/NCBI
53	Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, Kang L, Guo L, Liu M, Zhou X, et al: 6-month consequences of COVID-19 in patients discharged from hospital: A cohort study. Lancet. 397:220–232. 2021. View Article : Google Scholar : PubMed/NCBI
54	Chams N, Chams S, Badran R, Shams A, Araji A, Raad M, Mukhopadhyay S, Stroberg E, Duval EJ, Barton LM and Hajj Hussein I: COVID-19: A multidisciplinary review. Front Public Health. 8:3832020. View Article : Google Scholar : PubMed/NCBI
55	Stang A, Robers J, Schonert B, Jöckel KH, Spelsberg A, Keil U and Cullen P: The performance of the SARS-CoV-2 RT-PCR test as a tool for detecting SARS-CoV-2 infection in the population. J Infect. 83:237–279. 2021. View Article : Google Scholar : PubMed/NCBI
56	Islam KU and Iqbal J: An update on molecular diagnostics for COVID-19. Front Cell Infect Microbiol. 10:5606162020. View Article : Google Scholar : PubMed/NCBI
57	Kucirka LM, Lauer SA, Laeyendecker O, Boon D and Lessler J: Variation in false-negative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann Intern Med. 173:262–267. 2020. View Article : Google Scholar : PubMed/NCBI
58	Harper H, Burridge A, Winfield M, Finn A, Davidson A, Matthews D, Hutchings S, Vipond B, Jain N; COVID-19 Genomics UK (COG-UK) Consortium, ; et al: Detecting SARS-CoV-2 variants with SNP genotyping. PLoS One. 16:e02431852021. View Article : Google Scholar : PubMed/NCBI
59	Stelzer-Braid S, Walker GJ, Aggarwal A, Isaacs SR, Yeang M, Naing Z, Ospina Stella A, Turville SG and Rawlinson WD: Virus isolation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for diagnostic and research purposes. Pathology. 52:760–763. 2020. View Article : Google Scholar : PubMed/NCBI
60	Kleiboeker S, Cowden S, Grantham J, Nutt J, Tyler A, Berg A and Altrich M: SARS-CoV-2 viral load assessment in respiratory samples. J Clin Virol. 129:1044392020. View Article : Google Scholar : PubMed/NCBI
61	Zhang W, Du RH, Li B, Zheng XS, Yang XL, Hu B, Wang YY, Xiao GF, Yan B, Shi ZL and Zhou P: Molecular and serological investigation of 2019-nCoV infected patients: Implication of multiple shedding routes. Emerg Microbes Infect. 9:386–389. 2020. View Article : Google Scholar : PubMed/NCBI
62	Shen M, Zhou Y, Ye J, Abdullah Al-Maskri AA, Kang Y, Zeng S and Cai S: Recent advances and perspectives of nucleic acid detection for coronavirus. J Pharm Anal. 10:97–101. 2020. View Article : Google Scholar : PubMed/NCBI
63	Bustin SA and Mueller R: Real-time reverse transcription PCR (qRT-PCR) and its potential use in clinical diagnosis. Clin Sci (Lond). 109:365–379. 2005. View Article : Google Scholar : PubMed/NCBI
64	To KK, Tsang OT, Leung WS, Tam AR, Wu TC, Lung DC, Yip CC, Cai JP, Chan JM, Chik TS, et al: Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: An observational cohort study. Lancet Infect Dis. 20:565–574. 2020. View Article : Google Scholar : PubMed/NCBI
65	Thomas E, Delabat S, Carattini YL and Andrews DM: SARS-CoV-2 and variant diagnostic testing approaches in the United States. Viruses. 13:24922021. View Article : Google Scholar : PubMed/NCBI
66	Safiabadi Tali SH, LeBlanc JJ, Sadiq Z, Oyewunmi OD, Camargo C, Nikpour B, Armanfard N, Sagan SM and Jahanshahi-Anbuhi S: Tools and techniques for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 detection. Clin Microbiol Rev. 34:e00228–20. 2021. View Article : Google Scholar : PubMed/NCBI
67	Augustine R, Hasan A, Das S, Ahmed R, Mori Y, Notomi T, Kevadiya BD and Thakor AS: Loop-mediated isothermal amplification (LAMP): A rapid, sensitive, specific, and cost-effective point-of-care test for coronaviruses in the context of COVID-19 pandemic. Biology (Basel). 9:1822020.PubMed/NCBI
68	Chau CH, Strope JD and Figg WD: COVID-19 clinical diagnostics and testing technology. Pharmacotherapy. 40:857–868. 2020. View Article : Google Scholar : PubMed/NCBI
69	Alcoba-Florez J, Gil-Campesino H, Artola DG, González-Montelongo R, Valenzuela-Fernández A, Ciuffreda L and Flores C: Sensitivity of different RT-qPCR solutions for SARS-CoV-2 detection. Int J Infect Dis. 99:190–192. 2020. View Article : Google Scholar : PubMed/NCBI
70	Giuliani C: The flavonoid quercetin induces AP-1 activation in FRTL-5 thyroid cells. Antioxidants (Basel). 8:1122019. View Article : Google Scholar : PubMed/NCBI
71	Ye Z, Zhang Y, Wang Y, Huang Z and Song B: Chest CT manifestations of new coronavirus disease 2019 (COVID-19): A pictorial review. Eur Radiol. 30:4381–4389. 2020. View Article : Google Scholar : PubMed/NCBI
72	Kanne JP: Chest CT findings in 2019 novel coronavirus (2019-nCoV) infections from Wuhan, China: Key points for the radiologist. Radiology. 295:16–17. 2020. View Article : Google Scholar : PubMed/NCBI
73	Nivet H, Crombé A, Schuster P, Ayoub T, Pourriol L, Favard N, Chazot A, Alonzo-Lacroix F, Youssof E, Ben Cheikh A, et al: The accuracy of teleradiologists in diagnosing COVID-19 based on a French multicentric emergency cohort. Eur Radiol. 31:2833–2844. 2021. View Article : Google Scholar : PubMed/NCBI
74	Ghose A, Roy S, Vasdev N, Olsburgh J and Dasgupta P: The emerging role of artificial intelligence in the fight against COVID-19. Eur Urol. 78:775–776. 2020. View Article : Google Scholar : PubMed/NCBI
75	Ozsahin I, Sekeroglu B, Musa MS, Mustapha MT and Uzun Ozsahin D: Review on diagnosis of COVID-19 from chest CT images using artificial intelligence. Comput Math Methods Med. 2020:97565182020. View Article : Google Scholar : PubMed/NCBI
76	Shi F, Wang J, Shi J, Wu Z, Wang Q, Tang Z, He K, Shi Y and Shen D: Review of artificial intelligence techniques in imaging data acquisition, segmentation, and diagnosis for COVID-19. IEEE Rev Biomed Eng. 14:4–15. 2021. View Article : Google Scholar : PubMed/NCBI
77	Bouchareb Y, Moradi Khaniabadi P, Al Kindi F, Al Dhuhli H, Shiri I, Zaidi H and Rahmim A: Artificial intelligence-driven assessment of radiological images for COVID-19. Comput Biol Med. 136:1046652021. View Article : Google Scholar : PubMed/NCBI
78	Vaishya R, Javaid M, Khan IH and Haleem A: Artificial intelligence (AI) applications for COVID-19 pandemic. Diabetes Metab Syndr. 14:337–339. 2020. View Article : Google Scholar : PubMed/NCBI
79	Dror AA, Eisenbach N, Taiber S, Morozov NG, Mizrachi M, Zigron A, Srouji S and Sela E: Vaccine hesitancy: The next challenge in the fight against COVID-19. Eur J Epidemiol. 35:775–779. 2020. View Article : Google Scholar : PubMed/NCBI
80	Mouffak S, Shubbar Q, Saleh E and El-Awady R: Recent advances in management of COVID-19: A review. Biomed Pharmacother. 143:1121072021. View Article : Google Scholar : PubMed/NCBI
81	Gavriatopoulou M, Ntanasis-Stathopoulos I, Korompoki E, Fotiou D, Migkou M, Tzanninis IG, Psaltopoulou T, Kastritis E, Terpos E and Dimopoulos MA: Emerging treatment strategies for COVID-19 infection. Clin Exp Med. 21:167–179. 2021. View Article : Google Scholar : PubMed/NCBI
82	Richtsmeier WJ: Interferon-present and future prospects. Crit Rev Clin Lab Sci. 20:57–93. 1984. View Article : Google Scholar : PubMed/NCBI
83	Lee JS and Shin EC: The type I interferon response in COVID-19: Implications for treatment. Nat Rev Immunol. 20:585–586. 2020. View Article : Google Scholar : PubMed/NCBI
84	Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, Péré H, Charbit B, Bondet V, Chenevier-Gobeaux C, et al: Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 369:718–724. 2020. View Article : Google Scholar : PubMed/NCBI
85	Monk PD, Marsden RJ, Tear VJ, Brookes J, Batten TN, Mankowski M, Gabbay FJ, Davies DE, Holgate ST, Ho LP, et al: Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. 9:196–206. 2021. View Article : Google Scholar : PubMed/NCBI
86	Rahmani H, Davoudi-Monfared E, Nourian A, Khalili H, Hajizadeh N, Jalalabadi NZ, Fazeli MR, Ghazaeian M and Yekaninejad MS: Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial. Int Immunopharmacol. 88:1069032020. View Article : Google Scholar : PubMed/NCBI
87	Joseph BA, Dibas M, Evanson KW, Paranjape G, Vegivinti CTR, Selvan PT, Saravu K, Gupta N, Pulakurthi YS, Keesari PR, et al: Efficacy and safety of lopinavir/ritonavir in the treatment of COVID-19: A systematic review. Expert Rev Anti Infect Ther. 19:679–687. 2021. View Article : Google Scholar : PubMed/NCBI
88	Wu Y, Ma L, Zhuang Z, Cai S, Zhao Z, Zhou L, Zhang J, Wang PH, Zhao J and Cui J: Main protease of SARS-CoV-2 serves as a bifunctional molecule in restricting type I interferon antiviral signaling. Signal Transduct Target Ther. 5:2212020. View Article : Google Scholar : PubMed/NCBI
89	Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, et al: A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 382:1787–1799. 2020. View Article : Google Scholar : PubMed/NCBI
90	Hu Y, Ma C, Szeto T, Hurst B, Tarbet B and Wang J: Boceprevir, calpain inhibitors II and XII, and GC-376 have broad-spectrum antiviral activity against coronaviruses. ACS Infect Dis. 7:586–597. 2021. View Article : Google Scholar : PubMed/NCBI
91	Boras B, Jones RM, Anson BJ, Arenson D, Aschenbrenner L, Bakowski MA, Beutler N, Binder J, Chen E, Eng H, et al: Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19. Nat Commun. 12:60552021. View Article : Google Scholar : PubMed/NCBI
92	Wen W, Chen C, Tang J, Wang C, Zhou M, Cheng Y, Zhou X, Wu Q, Zhang X, Feng Z, et al: Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: A meta-analysis. Ann Med. 54:516–523. 2022. View Article : Google Scholar : PubMed/NCBI
93	Colson P, Rolain JM and Raoult D: Chloroquine for the 2019 novel coronavirus SARS-CoV-2. Int J Antimicrob Agents. 55:1059232020. View Article : Google Scholar : PubMed/NCBI
94	Cuadrado-Lavín A, Olmos JM, Cifrian JM, Gimenez T, Gandarillas MA, García-Saiz M, Rebollo MH, Martínez-Taboada V, López-Hoyos M, Fariñas MC and Crespo J: Controlled, double-blind, randomized trial to assess the efficacy and safety of hydroxychloroquine chemoprophylaxis in SARS CoV2 infection in healthcare personnel in the hospital setting: A structured summary of a study protocol for a randomised controlled trial. Trials. 21:4722020. View Article : Google Scholar : PubMed/NCBI
95	RECOVERY Collaborative Group, . Horby P, Mafham M, Linsell L, Bell JL, Staplin N, Emberson JR, Wiselka M, Ustianowski A, Elmahi E, et al: Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 383:2030–2040. 2020. View Article : Google Scholar : PubMed/NCBI
96	Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, et al: Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 56:1059492020. View Article : Google Scholar : PubMed/NCBI
97	Wang X, Cao R, Zhang H, Liu J, Xu M, Hu H, Li Y, Zhao L, Li W, Sun X, et al: The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discov. 6:282020. View Article : Google Scholar : PubMed/NCBI
98	Li H, Liu R, Zhang R, Zhang S, Wei Y, Zhang L, Zhou H and Yang C: Protective effect of arbidol against pulmonary fibrosis and sepsis in mice. Front Pharmacol. 11:6070752020. View Article : Google Scholar : PubMed/NCBI
99	Zhu Z, Lu Z, Xu T, Chen C, Yang G, Zha T, Lu J and Xue Y: Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. J Infect. 81:e21–e23. 2020. View Article : Google Scholar : PubMed/NCBI
100	Song Y, Zhang M, Yin L, Wang K, Zhou Y, Zhou M and Lu Y: COVID-19 treatment: close to a cure? A rapid review of pharmacotherapies for the novel coronavirus (SARS-CoV-2). Int J Antimicrob Agents. 56:1060802020. View Article : Google Scholar : PubMed/NCBI
101	Wang B, Timilsena YP, Blanch E and Adhikari B: Lactoferrin: Structure, function, denaturation and digestion. Crit Rev Food Sci Nutr. 59:580–596. 2019. View Article : Google Scholar : PubMed/NCBI
102	Hu Y, Meng X, Zhang F, Xiang Y and Wang J: The in vitro antiviral activity of lactoferrin against common human coronaviruses and SARS-CoV-2 is mediated by targeting the heparan sulfate co-receptor. Emerg Microbes Infect. 10:317–330. 2021. View Article : Google Scholar : PubMed/NCBI
103	Salaris C, Scarpa M, Elli M, Bertolini A, Guglielmetti S, Pregliasco F, Blandizzi C, Brun P and Castagliuolo I: Protective effects of lactoferrin against SARS-CoV-2 infection in vitro. Nutrients. 13:3282021. View Article : Google Scholar : PubMed/NCBI
104	Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al: SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 181:271–280.e8. 2020. View Article : Google Scholar : PubMed/NCBI
105	Tian L, Qiang T, Liang C, Ren X, Jia M, Zhang J, Li J, Wan M, YuWen X, Li H, et al: RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic. Eur J Med Chem. 213:1132012021. View Article : Google Scholar : PubMed/NCBI
106	Cao YC, Deng QX and Dai SX: Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence. Travel Med Infect Dis. 35:1016472020. View Article : Google Scholar : PubMed/NCBI
107	McDonald S, Turner S, Page MJ and Turner T: Most published systematic reviews of remdesivir for COVID-19 were redundant and lacked currency. J Clin Epidemiol. 146:22–31. 2022. View Article : Google Scholar : PubMed/NCBI
108	Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, Martín-Quirós A, Caraco Y, Williams-Diaz A, Brown ML, et al: Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 386:509–520. 2022. View Article : Google Scholar : PubMed/NCBI
109	Good SS, Westover J, Jung KH, Zhou XJ, Moussa A, La Colla P, Collu G, Canard B and Sommadossi JP: AT-527, a double prodrug of a guanosine nucleotide analog, is a potent inhibitor of SARS-CoV-2 in vitro and a promising oral antiviral for treatment of COVID-19. Antimicrob Agents Chemother. 65:e02479–20. 2021. View Article : Google Scholar : PubMed/NCBI
110	Martinez MA: Plitidepsin: A repurposed drug for the treatment of COVID-19. Antimicrob Agents Chemother. 65:e00200–21. 2021. View Article : Google Scholar : PubMed/NCBI
111	White KM, Rosales R, Yildiz S, Kehrer T, Miorin L, Moreno E, Jangra S, Uccellini MB, Rathnasinghe R, Coughlan L, et al: Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science. 371:926–931. 2021. View Article : Google Scholar : PubMed/NCBI
112	Rodon J, Muñoz-Basagoiti J, Perez-Zsolt D, Noguera-Julian M, Paredes R, Mateu L, Quiñones C, Perez C, Erkizia I, Blanco I, et al: Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen. Front Pharmacol. 12:6466762021. View Article : Google Scholar : PubMed/NCBI
113	Soto-Matos A, Szyldergemajn S, Extremera S, Miguel-Lillo B, Alfaro V, Coronado C, Lardelli P, Roy E, Corrado CS and Kahatt C: Plitidepsin has a safe cardiac profile: A comprehensive analysis. Mar Drugs. 9:1007–1023. 2011. View Article : Google Scholar : PubMed/NCBI
114	Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, Miller JP, Yang L, Yingling M, Avidan MS and Reiersen AM: Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: A randomized clinical trial. JAMA. 324:2292–2300. 2020. View Article : Google Scholar : PubMed/NCBI
115	Bartoszko JJ, Siemieniuk RAC, Kum E, Qasim A, Zeraatkar D, Ge L, Han MA, Sadeghirad B, Agarwal A, Agoritsas T, et al: Prophylaxis against covid-19: Living systematic review and network meta-analysis. BMJ. 373:n9492021. View Article : Google Scholar : PubMed/NCBI
116	Wang X, Guo X, Xin Q, Pan Y, Hu Y, Li J, Chu Y, Feng Y and Wang Q: Neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in coronavirus disease 2019 inpatients and convalescent patients. Clin Infect Dis. 71:2688–2694. 2020. View Article : Google Scholar : PubMed/NCBI
117	Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, Esteban I, Caballero MT, Wood C, Berrueta M, et al: Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. 384:610–618. 2021. View Article : Google Scholar : PubMed/NCBI
118	Abolghasemi H, Eshghi P, Cheraghali AM, Imani Fooladi AA, Bolouki Moghaddam F, Imanizadeh S, Moeini Maleki M, Ranjkesh M, Rezapour M, Bahramifar A, et al: Clinical efficacy of convalescent plasma for treatment of COVID-19 infections: Results of a multicenter clinical study. Transfus Apher Sci. 59:1028752020. View Article : Google Scholar : PubMed/NCBI
119	Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, et al: Treatment of 5 critically Ill patients with COVID-19 with convalescent plasma. JAMA. 323:1582–1589. 2020. View Article : Google Scholar : PubMed/NCBI
120	Joyner MJ, Bruno KA, Klassen SA, Kunze KL, Johnson PW, Lesser ER, Wiggins CC, Senefeld JW, Klompas AM, Hodge DO, et al: Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin Proc. 95:1888–1897. 2020. View Article : Google Scholar : PubMed/NCBI
121	Cao W, Liu X, Bai T, Fan H, Hong K, Song H, Han Y, Lin L, Ruan L and Li T: High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019. Open Forum Infect Dis. 7:ofaa1022020. View Article : Google Scholar : PubMed/NCBI
122	Cao W, Liu X, Hong K, Ma Z, Zhang Y, Lin L, Han Y, Xiong Y, Liu Z, Ruan L and Li T: High-dose intravenous immunoglobulin in severe coronavirus disease 2019: A multicenter retrospective study in China. Front Immunol. 12:6278442021. View Article : Google Scholar : PubMed/NCBI
123	Scialo F, Daniele A, Amato F, Pastore L, Matera MG, Cazzola M, Castaldo G and Bianco A: ACE2: The major cell entry receptor for SARS-CoV-2. Lung. 198:867–877. 2020. View Article : Google Scholar : PubMed/NCBI
124	Shi R, Shan C, Duan X, Chen Z, Liu P, Song J, Song T, Bi X, Han C, Wu L, et al: A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature. 584:120–124. 2020. View Article : Google Scholar : PubMed/NCBI
125	Shepard HM, Phillips GL, D Thanos C and Feldmann M: Developments in therapy with monoclonal antibodies and related proteins. Clin Med (Lond). 17:220–232. 2017. View Article : Google Scholar : PubMed/NCBI
126	Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, McCullough MP, Chappell JD, Denison MR, Stevens LJ, et al: An mRNA vaccine against SARS-CoV-2-preliminary report. N Engl J Med. 383:1920–1931. 2020. View Article : Google Scholar : PubMed/NCBI
127	Khan FA, Stewart I, Fabbri L, Moss S, Robinson K, Smyth AR and Jenkins G: Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19. Thorax. 76:907–919. 2021. View Article : Google Scholar : PubMed/NCBI
128	Gupta S, Wang W, Hayek SS, Chan L, Mathews KS, Melamed ML, Brenner SK, Leonberg-Yoo A, Schenck EJ, Radbel J, et al: Association between early treatment with tocilizumab and mortality among critically Ill patients with COVID-19. JAMA Intern Med. 181:41–51. 2021. View Article : Google Scholar : PubMed/NCBI
129	Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Xiao J, Hooper AT, Hamilton JD, Musser BJ, et al: REGEN-COV antibody combination and outcomes in outpatients with Covid-19. N Engl J Med. 385:e812021. View Article : Google Scholar : PubMed/NCBI
130	O'Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan KC, Sarkar N, Bar KJ, Barnabas RV, Barouch DH, Cohen MS, et al: Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N Engl J Med. 385:1184–1195. 2021. View Article : Google Scholar : PubMed/NCBI
131	Ryu DK, Kang B, Noh H, Woo SJ, Lee MH, Nuijten PM, Kim JI, Seo JM, Kim C, Kim M, et al: The in vitro and in vivo efficacy of CT-P59 against gamma, delta and its associated variants of SARS-CoV-2. Biochem Biophys Res Commun. 578:91–96. 2021. View Article : Google Scholar : PubMed/NCBI
132	Lescure FX, Honda H, Fowler RA, Lazar JS, Shi G, Wung P, Patel N and Hagino O; Sarilumab COVID-19 Global Study Group, : Sarilumab in patients admitted to hospital with severe or critical COVID-19: A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 9:522–532. 2021. View Article : Google Scholar : PubMed/NCBI
133	Pang J, Xu F, Aondio G, Li Y, Fumagalli A, Lu M, Valmadre G, Wei J, Bian Y, Canesi M, et al: Efficacy and tolerability of bevacizumab in patients with severe Covid-19. Nat Commun. 12:8142021. View Article : Google Scholar : PubMed/NCBI
134	Tuccori M, Ferraro S, Convertino I, Cappello E, Valdiserra G, Blandizzi C, Maggi F and Focosi D: Anti-SARS-CoV-2 neutralizing monoclonal antibodies: Clinical pipeline. MAbs. 12:18541492020. View Article : Google Scholar : PubMed/NCBI
135	Dejnirattisai W, Huo J, Zhou D, Zahradník J, Supasa P, Liu C, Duyvesteyn HME, Ginn HM, Mentzer AJ, Tuekprakhon A, et al: SARS-CoV-2 omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses. Cell. 185:467–484.e15. 2022. View Article : Google Scholar : PubMed/NCBI
136	Cao Y, Wang J, Jian F, Xiao T, Song W, Yisimayi A, Huang W, Li Q, Wang P, An R, et al: Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies. Nature. 602:657–663. 2022. View Article : Google Scholar : PubMed/NCBI
137	Mannar D, Saville JW, Zhu X, Srivastava SS, Berezuk AM, Tuttle KS, Marquez AC, Sekirov I and Subramaniam S: SARS-CoV-2 omicron variant: Antibody evasion and cryo-EM structure of spike protein-ACE2 complex. Science. 375:760–764. 2022. View Article : Google Scholar : PubMed/NCBI
138	Miller NL, Clark T, Raman R and Sasisekharan R: Insights on the mutational landscape of the SARS-CoV-2 omicron variant. bioRxiv. doi: 10.1101/2021.12.06.471499 (Preprint).
139	Shah M and Woo HG: Omicron: A heavily mutated SARS-CoV-2 variant exhibits stronger binding to ACE2 and potently escapes approved COVID-19 therapeutic antibodies. Front Immunol. 12:8305272021. View Article : Google Scholar : PubMed/NCBI
140	Chen RE, Winkler ES, Case JB, Aziati ID, Bricker TL, Joshi A, Darling TL, Ying B, Errico JM, Shrihari S, et al: In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains. Nature. 596:103–108. 2021. View Article : Google Scholar : PubMed/NCBI
141	Kakoulidis I, Ilias I and Koukkou E: SARS-CoV-2 infection and glucose homeostasis in pregnancy. What about antenatal corticosteroids? Diabetes Metab Syndr. 14:519–520. 2020. View Article : Google Scholar : PubMed/NCBI
142	Bartoletti M, Marconi L, Scudeller L, Pancaldi L, Tedeschi S, Giannella M, Rinaldi M, Bussini L, Valentini I, Ferravante AF, et al: Efficacy of corticosteroid treatment for hospitalized patients with severe COVID-19: A multicentre study. Clin Microbiol Infect. 27:105–111. 2021. View Article : Google Scholar : PubMed/NCBI
143	Tang X, Feng YM, Ni JX, Zhang JY, Liu LM, Hu K, Wu XZ, Zhang JX, Chen JW, Zhang JC, et al: Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-intensive care unit patients with COVID-19 pneumonia: A multicenter, single-blind, randomized control trial. Respiration. 100:116–126. 2021. View Article : Google Scholar : PubMed/NCBI
144	van Paassen J, Vos JS, Hoekstra EM, Neumann KMI, Boot PC and Arbous SM: Corticosteroid use in COVID-19 patients: A systematic review and meta-analysis on clinical outcomes. Crit Care. 24:6962020. View Article : Google Scholar : PubMed/NCBI
145	So C, Ro S, Murakami M, Imai R and Jinta T: High-dose, short-term corticosteroids for ARDS caused by COVID-19: A case series. Respirol Case Rep. 8:e005962020. View Article : Google Scholar : PubMed/NCBI
146	Kolilekas L, Loverdos K, Giannakaki S, Vlassi L, Levounets A, Zervas E and Gaga M: Can steroids reverse the severe COVID-19 induced ‘cytokine storm’? J Med Virol. 92:2866–2869. 2020. View Article : Google Scholar : PubMed/NCBI
147	Yuan M, Xu X, Xia D, Tao Z, Yin W, Tan W, Hu Y and Song C: Effects of corticosteroid treatment for non-severe COVID-19 pneumonia: A propensity score-based analysis. Shock. 54:638–643. 2020. View Article : Google Scholar : PubMed/NCBI
148	Lu X, Chen T, Wang Y, Wang J and Yan F: Adjuvant corticosteroid therapy for critically ill patients with COVID-19. Crit Care. 24:2412020. View Article : Google Scholar : PubMed/NCBI
149	Rello J, Belliato M, Dimopoulos MA, Giamarellos-Bourboulis EJ, Jaksic V, Martin-Loeches I, Mporas I, Pelosi P, Poulakou G, Pournaras S, et al: Update in COVID-19 in the intensive care unit from the 2020 HELLENIC Athens International symposium. Anaesth Crit Care Pain Med. 39:723–730. 2020. View Article : Google Scholar : PubMed/NCBI
150	Lentz S, Roginski MA, Montrief T, Ramzy M, Gottlieb M and Long B: Initial emergency department mechanical ventilation strategies for COVID-19 hypoxemic respiratory failure and ARDS. Am J Emerg Med. 38:2194–2202. 2020. View Article : Google Scholar : PubMed/NCBI
151	Wong DJN, El-Boghdadly K, Owen R, Johnstone C, Neuman MD, Andruszkiewicz P, Baker PA, Biccard BM, Bryson GL, Chan MTV, et al: Emergency airway management in patients with COVID-19: A prospective international multicenter cohort study. Anesthesiology. 135:292–303. 2021. View Article : Google Scholar : PubMed/NCBI
152	Cook TM, El-Boghdadly K, McGuire B, McNarry AF, Patel A and Higgs A: Consensus guidelines for managing the airway in patients with COVID-19: Guidelines from the difficult airway society, the association of anaesthetists the intensive care society, the faculty of intensive care medicine and the royal college of anaesthetists. Anaesthesia. 75:785–799. 2020. View Article : Google Scholar : PubMed/NCBI
153	Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, Auvray M and Merouani K: High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 18:1743–1746. 2020. View Article : Google Scholar : PubMed/NCBI
154	Ronco C, Reis T and Husain-Syed F: Management of acute kidney injury in patients with COVID-19. Lancet Respir Med. 8:738–742. 2020. View Article : Google Scholar : PubMed/NCBI
155	Ronco C, Bagshaw SM, Bellomo R, Clark WR, Husain-Syed F, Kellum JA, Ricci Z, Rimmelé T, Reis T and Ostermann M: Extracorporeal blood purification and organ support in the critically Ill patient during COVID-19 Pandemic: expert review and recommendation. Blood Purif. 50:17–27. 2021. View Article : Google Scholar : PubMed/NCBI
156	Kabeerdoss J, Pilania RK, Karkhele R, Kumar TS, Danda D and Singh S: Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: Immunological mechanisms, clinical manifestations and management. Rheumatol Int. 41:19–32. 2021. View Article : Google Scholar : PubMed/NCBI
157	Megyeri K, Dernovics Á, Al-Luhaibi ZII and Rosztóczy A: COVID-19-associated diarrhea. World J Gastroenterol. 27:3208–3222. 2021. View Article : Google Scholar : PubMed/NCBI
158	Lu ZH, Yang CL, Yang GG, Pan WX, Tian LG, Zheng JX, Lv S, Zhang SY, Zheng PY and Zhang SX: Efficacy of the combination of modern medicine and traditional Chinese medicine in pulmonary fibrosis arising as a sequelae in convalescent COVID-19 patients: A randomized multicenter trial. Infect Dis Poverty. 10:312021. View Article : Google Scholar : PubMed/NCBI
159	Zhao Z, Li Y, Zhou L, Zhou X, Xie B, Zhang W and Sun J: Prevention and treatment of COVID-19 using traditional Chinese medicine: A review. Phytomedicine. 85:1533082021. View Article : Google Scholar : PubMed/NCBI
160	Ren JL, Zhang AH and Wang XJ: Traditional Chinese medicine for COVID-19 treatment. Pharmacol Res. 155:1047432020. View Article : Google Scholar : PubMed/NCBI
161	Ni L, Chen L, Huang X, Han C, Xu J, Zhang H, Luan X, Zhao Y, Xu J, Yuan W and Chen H: Combating COVID-19 with integrated traditional Chinese and western medicine in China. Acta Pharm Sin B. 10:1149–1162. 2020. View Article : Google Scholar : PubMed/NCBI
162	Anand U, Jakhmola S, Indari O, Jha HC, Chen ZS, Tripathi V and Pérez de la Lastra JM: Potential therapeutic targets and vaccine development for SARS-CoV-2/COVID-19 pandemic management: A review on the recent update. Front Immunol. 12:6585192021. View Article : Google Scholar : PubMed/NCBI
163	Tregoning JS, Flight KE, Higham SL, Wang Z and Pierce BF: Progress of the COVID-19 vaccine effort: Viruses, vaccines and variants versus efficacy, effectiveness and escape. Nat Rev Immunol. 21:626–636. 2021. View Article : Google Scholar : PubMed/NCBI
164	Hou Z, Tong Y, Du F, Lu L, Zhao S, Yu K, Piatek SJ, Larson HJ and Lin L: Assessing COVID-19 vaccine hesitancy, confidence, and public engagement: A global social listening study. J Med Internet Res. 23:e276322021. View Article : Google Scholar : PubMed/NCBI
165	Sharif N, Alzahrani KJ, Ahmed SN and Dey SK: Efficacy, immunogenicity and safety of COVID-19 vaccines: A systematic review and meta-analysis. Front Immunol. 12:7141702021. View Article : Google Scholar : PubMed/NCBI
166	Francis AI, Ghany S, Gilkes T and Umakanthan S: Review of COVID-19 vaccine subtypes, efficacy and geographical distributions. Postgrad Med J. 98:389–394. 2022. View Article : Google Scholar : PubMed/NCBI
167	Canedo-Marroquín G, Saavedra F, Andrade CA, Berrios RV, Rodríguez-Guilarte L, Opazo MC, Riedel CA and Kalergis AM: SARS-CoV-2: Immune response elicited by infection and development of vaccines and treatments. Front Immunol. 11:5697602020. View Article : Google Scholar : PubMed/NCBI
168	Rauch S, Roth N, Schwendt K, Fotin-Mleczek M, Mueller SO and Petsch B: mRNA-based SARS-CoV-2 vaccine candidate CVnCoV induces high levels of virus-neutralising antibodies and mediates protection in rodents. NPJ Vaccines. 6:572021. View Article : Google Scholar : PubMed/NCBI
169	Kremsner PG, Ahuad Guerrero RA, Arana-Arri E, Aroca Martinez GJ, Bonten M, Chandler R, Corral G, De Block EJL, Ecker L, Gabor JJ, et al: Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): A randomised, observer-blinded, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 22:329–340. 2022. View Article : Google Scholar : PubMed/NCBI
170	Pollock KM, Cheeseman HM, Szubert AJ, Libri V, Boffito M, Owen D, Bern H, O'Hara J, McFarlane LR, Lemm NM, et al: Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial. EClinical Medicine. 44:1012622022. View Article : Google Scholar : PubMed/NCBI
171	Al Kaabi N, Zhang Y, Xia S, Yang Y, Al Qahtani MM, Abdulrazzaq N, Al Nusair M, Hassany M, Jawad JS, Abdalla J, et al: Effect of 2 inactivated SARS-CoV-2 vaccines on symptomatic COVID-19 infection in adults: A randomized clinical trial. JAMA. 326:35–45. 2021. View Article : Google Scholar : PubMed/NCBI
172	Premikha M, Chiew CJ, Wei WE, Leo YS, Ong B, Lye DC, Lee VJ and Tan KB: Comparative effectiveness of mRNA and inactivated whole virus vaccines against COVID-19 infection and severe disease in Singapore. Clin Infect Dis. Apr 12–2022.(Epub ahead of print). PubMed/NCBI
173	Zhang Z, Mateus J, Coelho CH, Dan JM, Moderbacher CR, Gálvez RI, Cortes FH, Grifoni A, Tarke A, Chang J, et al: Humoral and cellular immune memory to four COVID-19 vaccines. bioRxiv. doi: 10.1101/2022.03.18.484953 (Preprint).
174	Islam N, Sheils NE, Jarvis MS and Cohen K: Comparative effectiveness over time of the mRNA-1273 (Moderna) vaccine and the BNT162b2 (Pfizer-BioNTech) vaccine. Nat Commun. 13:23772022. View Article : Google Scholar : PubMed/NCBI
175	Mohamed K, Rzymski P, Islam MS, Makuku R, Mushtaq A, Khan A, Ivanovska M, Makka SA, Hashem F, Marquez L, et al: COVID-19 vaccinations: The unknowns, challenges, and hopes. J Med Virol. 94:1336–1349. 2022. View Article : Google Scholar : PubMed/NCBI
176	Liu Y, Zhang X, Liu J, Xia H, Zou J, Muruato AE, Periasamy S, Plante JA, Bopp NE, Kurhade C, et al: A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions. bioRxiv. 2022.02.14.480460. 2022.
177	Merzon E, Green I, Somekh E, Vinker S, Golan-Cohen A, Israel A, Gorohovski A, Frenkel-Morgenstern M and Stein M: The association of previous vaccination with live-attenuated varicella zoster vaccine and COVID-19 positivity: An Israeli population-based study. Vaccines (Basel). 10:742022. View Article : Google Scholar : PubMed/NCBI
178	Richmond P, Hatchuel L, Dong M, Ma B, Hu B, Smolenov I, Li P, Liang P, Han HH, Liang J and Clemens R: Safety and immunogenicity of S-Trimer (SCB-2019), a protein subunit vaccine candidate for COVID-19 in healthy adults: A phase 1, randomised, double-blind, placebo-controlled trial. Lancet. 397:682–694. 2021. View Article : Google Scholar : PubMed/NCBI
179	Yang S, Li Y, Dai L, Wang J, He P, Li C, Fang X, Wang C, Zhao X, Huang E, et al: Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: Two randomised, double-blind, placebo-controlled, phase 1 and 2 trials. Lancet Infect Dis. 21:1107–1119. 2021. View Article : Google Scholar : PubMed/NCBI
180	Jin P, Guo X, Chen W, Ma S, Pan H, Dai L, Du P, Wang L, Jin L, Chen Y, et al: Safety and immunogenicity of heterologous boost immunization with an adenovirus type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001): A randomized, observer-blinded, placebo-controlled trial. PLoS Med. 19:e10039532022. View Article : Google Scholar : PubMed/NCBI
181	Kuhn M, Campillos M, Letunic I, Jensen LJ and Bork P: A side effect resource to capture phenotypic effects of drugs. Mol Syst Biol. 6:3432010. View Article : Google Scholar : PubMed/NCBI
182	Menni C, Klaser K, May A, Polidori L, Capdevila J, Louca P, Sudre CH, Nguyen LH, Drew DA, Merino J, et al: Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID symptom study app in the UK: A prospective observational study. Lancet Infect Dis. 21:939–949. 2021. View Article : Google Scholar : PubMed/NCBI
183	Vetter V, Denizer G, Friedland LR, Krishnan J and Shapiro M: Understanding modern-day vaccines: What you need to know. Ann Med. 50:110–120. 2018. View Article : Google Scholar : PubMed/NCBI
184	Akinosoglou K, Tzivaki I and Marangos M: Covid-19 vaccine and autoimmunity: Awakening the sleeping dragon. Clin Immunol. 226:1087212021. View Article : Google Scholar : PubMed/NCBI
185	Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, et al: Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 384:403–416. 2021. View Article : Google Scholar : PubMed/NCBI
186	Lipsitch M, Krammer F, Regev-Yochay G, Lustig Y and Balicer RD: SARS-CoV-2 breakthrough infections in vaccinated individuals: Measurement, causes and impact. Nat Rev Immunol. 22:57–65. 2022. View Article : Google Scholar : PubMed/NCBI
187	Dejnirattisai W, Shaw RH, Supasa P, Liu C, Stuart AS, Pollard AJ, Liu X, Lambe T, Crook D, Stuart DI, et al: Reduced neutralisation of SARS-CoV-2 omicron B.1.1.529 variant by post-immunisation serum. Lancet. 399:234–236. 2022. View Article : Google Scholar : PubMed/NCBI
188	Brown CM, Vostok J, Johnson H, Burns M, Gharpure R, Sami S, Sabo RT, Hall N, Foreman A, Schubert PL, et al: Outbreak of SARS-CoV-2 infections, including COVID-19 vaccine breakthrough infections, associated with large public gatherings-barnstable county, massachusetts, July 2021. MMWR Morb Mortal Wkly Rep. 70:1059–1062. 2021. View Article : Google Scholar : PubMed/NCBI
189	Tay MZ, Wiehe K and Pollara J: Antibody-dependent cellular phagocytosis in antiviral immune responses. Front Immunol. 10:3322019. View Article : Google Scholar : PubMed/NCBI
190	Forni G and Mantovani A; COVID-19 Commission of Accademia Nazionale dei Lincei Rome, : COVID-19 vaccines: Where we stand and challenges ahead. Cell Death Differ. 28:626–639. 2021. View Article : Google Scholar : PubMed/NCBI
191	Bagheri A, Moezzi SMI, Mosaddeghi P, Nadimi Parashkouhi S, Fazel Hoseini SM, Badakhshan F and Negahdaripour M: Interferon-inducer antivirals: Potential candidates to combat COVID-19. Int Immunopharmacol. 91:1072452021. View Article : Google Scholar : PubMed/NCBI
192	Cáceres CJ, Cardenas-Garcia S, Carnaccini S, Seibert B, Rajao DS, Wang J and Perez DR: Efficacy of GC-376 against SARS-CoV-2 virus infection in the K18 hACE2 transgenic mouse model. Sci Rep. 11:96092021. View Article : Google Scholar : PubMed/NCBI
193	Heilmann E, Costacurta F, Geley S, Mogadashi SA, Volland A, Rupp B, Harris RS and von Laer D: A VSV-based assay quantifies coronavirus Mpro/3CLpro/Nsp5 main protease activity and chemical inhibition. Commun Biol. 5:3912022. View Article : Google Scholar : PubMed/NCBI
194	Mahase E: Covid-19: Covid-19: Pfizer's paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ. 375:n27132021. View Article : Google Scholar : PubMed/NCBI
195	Nojomi M, Yassin Z, Keyvani H, Makiani MJ, Roham M, Laali A, Dehghan N, Navaei M and Ranjbar M: Effect of arbidol (Umifenovir) on COVID-19: A randomized controlled trial. BMC Infect Dis. 20:9542020. View Article : Google Scholar : PubMed/NCBI
196	Chang R, Ng TB and Sun WZ: Lactoferrin as potential preventative and adjunct treatment for COVID-19. Int J Antimicrob Agents. 56:1061182020. View Article : Google Scholar : PubMed/NCBI
197	Hoffmann M, Hofmann-Winkler H, Smith JC, Krüger N, Arora P, Sørensen LK, Søgaard OS, Hasselstrøm JB, Winkler M, Hempel T, et al: Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine. 65:1032552021. View Article : Google Scholar : PubMed/NCBI
198	Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, et al: Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 395:1569–1578. 2020. View Article : Google Scholar : PubMed/NCBI
199	Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A, Kadam J, Wu W, Caracta CF and Tandon M: Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int J Infect Diss. 103:62–71. 2021. View Article : Google Scholar : PubMed/NCBI
200	Şimşek-Yavuz S and Komsuoğlu Çelikyurt FI: An update of anti-viral treatment of COVID-19. Turk J Med Sci. 51:3372–3390. 2021. View Article : Google Scholar : PubMed/NCBI
201	Wood EM, Estcourt LJ and McQuilten ZK: How should we use convalescent plasma therapies for the management of COVID-19? Blood. 137:1573–1581. 2021. View Article : Google Scholar : PubMed/NCBI
202	Schmidt F, Weisblum Y, Rutkowska M, Poston D, DaSilva J, Zhang F, Bednarski E, Cho A, Schaefer-Babajew DJ, Gaebler C, et al: High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape. Nature. 600:512–516. 2021. View Article : Google Scholar : PubMed/NCBI
203	Case JB, Chen RE, Cao L, Ying B, Winkler ES, Johnson M, Goreshnik I, Pham MN, Shrihari S, Kafai NM, et al: Ultrapotent miniproteins targeting the SARS-CoV-2 receptor-binding domain protect against infection and disease. Cell Host Microbe. 29:1151–1161.e5. 2021. View Article : Google Scholar : PubMed/NCBI
204	Guo K, Wustoni S, Koklu A, Díaz-Galicia E, Moser M, Hama A, Alqahtani AA, Ahmad AN, Alhamlan FS, Shuaib M, et al: Rapid single-molecule detection of COVID-19 and MERS antigens via nanobody-functionalized organic electrochemical transistors. Nat Biomed Eng. 5:666–677. 2021. View Article : Google Scholar : PubMed/NCBI
205	Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, et al: Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med. 383:2333–2344. 2020. View Article : Google Scholar : PubMed/NCBI
206	Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, Sarkis E, Solis J, Zheng H, Scott N, et al: Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab. N Engl J Med. 385:1941–1950. 2021. View Article : Google Scholar : PubMed/NCBI
207	Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, Huhn G, Cardona J, Mocherla B, Stosor V, et al: SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med. 384:229–237. 2021. View Article : Google Scholar : PubMed/NCBI
208	Kim JY, Jang YR, Hong JH, Jung JG, Park JH, Streinu-Cercel A, Streinu-Cercel A, Săndulescu O, Lee SJ, Kim SH, et al: Safety, virologic efficacy, and pharmacokinetics of CT-P59, a neutralizing monoclonal antibody against SARS-CoV-2 spike receptor-binding protein: Two randomized, placebo-controlled, phase I studies in healthy individuals and patients with mild SARS-CoV-2 infection. Clin Ther. 43:1706–1727. 2021. View Article : Google Scholar : PubMed/NCBI
209	Levin MJ, Ustianowski A, De Wit S, Launay O, Avila M, Templeton A, Yuan Y, Seegobin S, Ellery A, Levinson DJ, et al: Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for prevention of Covid-19. N Engl J Med. 386:2188–2200. 2022. View Article : Google Scholar : PubMed/NCBI
210	ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group, : Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): A randomised controlled trial. Lancet Infect Dis. 22:622–635. 2022. View Article : Google Scholar : PubMed/NCBI
211	Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Musser BJ, Soo Y, Rofail D, Im J, et al: REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med. 384:238–251. 2021. View Article : Google Scholar : PubMed/NCBI