key: cord-0717719-7kkr719z
authors: Murugan, Chandran; Ramamoorthy, Sharmiladevi; Guruprasad, Kuppuswamy; Murugan, Rajesh Kumar; Sivalingam, Yuvaraj; Sundaramurthy, Anandhakumar
title: COVID-19: A review of newly formed viral clades, pathophysiology, therapeutic strategies and current vaccination tasks
date: 2021-10-25
journal: Int J Biol Macromol
DOI: 10.1016/j.ijbiomac.2021.10.144
sha: 69dc5f58d840a0ce40f4d9cc00bbb8770f60bc3f
doc_id: 717719
cord_uid: 7kkr719z

Today, the world population is facing an existential threat by an invisible enemy known as severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) or COVID-19. It is highly contagious and has infected a larger fraction of human population across the globe on various routes of transmission. The detailed knowledge of the SARS-CoV-2 structure and clinical aspects offers an important insight into the evolution of infection, disease progression and helps in executing the different therapies effectively. Herein, we have discussed in detail about the genome structure of SARS-CoV-2 and its role in the proteomic rational spread of different muted species and pathogenesis in infecting the host cells. The mechanisms behind the viral outbreak and its immune response, the availability of existing diagnostics techniques, the treatment efficacy of repurposed drugs and the emerging vaccine trials for the SARS-CoV-2 outbreak also have been highlighted. Furthermore, the possible antiviral effects of various herbal products and their extracted molecules in inhibiting SARS-CoV-2 replication and cellular entry are also reported. Finally, we conclude our opinion on current challenges involved in the drug development, bulk production of drug/vaccines and their storage requirements, logistical procedures and limitations related to dosage trials for larger population.

Coronavirus (CoV) is a major pathogen predominantly affecting the human respiratory system [1] . The Latin etymology of the term corona hails from its crown form Hence, the current state of affairs may be different, and have shown modified methodologies to deal with these kind of viruses. By using various molecular medicine based tools and techniques, the research communities from various countries have developed host-based and virus-based targets/vaccines to fight SARS-CoV-2 infections.

In this review, we have comprehensively summarized the physiochemical features, J o u r n a l P r e -p r o o f [42] [43] [44] [45] Envelope (E) protein ORF-6 Virion entry, viral mutation and viral production [46] Membrane (M) glycoprotein ORF-7 Leaving a short NH 2 and a long COOH terminus on outside and indoor of virus (cytoplasmic domain), attach with other structural proteins and determine the shape of viral envelope. [47, 48] Nucleocapsid (N) protein ORF-8a Viral assembly, viral replication cycle and viral-host cellular infection [49, 50] pp1a ORF-1a Express the virus exploit a slippery sequence as 5′-UUUAAAC-3′, contain the nsps 1-11 [51] pp1ab ORF-1b Express the virus exploit a slippery sequence as 5′-UUUAAAC-3′, contain the nsps 1-16 [51] 7a ORF-7a Increases the expression of JNK, NF-κβ, and p38 MAP kinase. It involves in cell cycle arrest, inhibits host translation and stimulate apoptosis. [52] 3a ORF-3a Increases the expression of JNK, IL-8, NF-κβ, and RANTES. It involves in cell cycle arrest, ion-channel activity and stimulate apoptosis. [52] 13 3b ORF-3b Stimulate type-I IFN production, and prevents cell signaling, cell cycle arrest and induces apoptosis. [52] Region of nsp1coding nsp1 Antiviral host response and trigger mRNA degradation [50, 51] Unknown nsp2 Unknown function and often bind to prohibiting proteins [51] Papain-like protease nsp3

Involves in viral polyprotein cleavage. It Interacts with N protein and can block the host immune response. [52] Transmembrane domain nsp4 DMV formation and combines with nsp3 and nsp6. It also involves in proliferation of cellular membrane and more important for DMVs structure. [52, 53] 3CLpro nsp5

Involves in viral polyprotein cleavage. [53] Transmembrane domain nsp6 DMV formation and complex with nsp3 and nsp4. [54] Unknown nsp7 Primase, hexadecameric complex with nsp8 [52, 55] Primase nsp8 Primase activity, hexadecameric complex with nsp7 [55, 56] Unknown nsp9 Activity of RNA/DNA binding [57] Unknown nsp10 complex with nsp14, proliferation of cellular membrane and maintaining the activity of 2′-O-MTase activity [52, 58] Unknown nsp11 short peptide at ORF-1a end [54] 14 RNA dependent RNA polymerase nsp12 Viral replication [54, 59] Superfamily 1-helicase nsp13

Helicase, viral replication, virulence and tropism affection [50, 60] 3′-5′-Exonuclease nsp14 Exonuclease 3′-5′ activity and viral replication [50, 60] N7-methyltransferase Nidoviral endonbonuclease specific for U nsp15 Viral replication and poly(U)-specific endoribonuclease [61] S-adenosylmethinonine dependent nbose 2′ -Omethyltransferase nsp16 Viral replication, 2'-O-ribose methyltransferase inhibition and IFN antagonism [60, 61] The most bountiful structural constituent of the viral envelope is the M glycoprotein produced by the M gene, which contains 222 aa (23 kDa). It extends the membrane bilayer three times, flees a concise NH 2 -terminal domain on the lateral side of the virus, and a long COOH terminus (cytoplasmic domain) on indoors of the virion [71] . It delineates the shape of the viral envelope by forming the homotypic interaction between them. It often interacts with the envelope E protein present in the host cell membrane budding compartment, produces the viral envelope and accountable for constructing virus-like particles (VLPs) [72, 73] . During the assembly and budding process, M protein is performing a dominant aspect in retaining the S protein by its interaction. It interacts with N protein, assists in RNA packaging and functions in viral immunoevasion [74, 75] . The envelope (E) protein is a smallest single-pass type ΙΙΙ transmembrane protein (8 kDa), consists of approximately 76-109 aa that are prevailing in tiny amounts on the viral envelope [76] , as shown in Figure 5 . The E protein is an exceedingly perpetuate protein across β-CoV as only 3 variants have been raised until now. Its homopentamer facet supports virus assembly, budding, envelope formation and pathogenesis [77] [78] [79] . It also serves as viroporins that self-assemble into the host membrane, emerging pentameric protein-lipid pores participate in ion transport and the apoptosis induction by persuading the pore formation of the host cell membrane [80] .

While an extensive amount of E protein is let out during the viral replication process, only a minimal amount is unified into the viral envelope. However, much of the protein is found at the site of intercellular trafficking [81] .

J o u r n a l P r e -p r o o f Figure 5 . The structure of E protein pentameric ion channel predicted by nuclear magnetic resonance (NMR) spectroscopy (Adapted and reprinted with permission from ref. [82] , copyrights © 2018 Elsevier).

The N protein (50) (51) (52) (53) (54) (55) (56) (57) (58) (59) (60) are phosphoproteins that interact with viral genetic material in a beads-on-a-string pattern, producing the helically symmetric nucleocapsid [83] . During the replication and transcription process, the N-terminal domain (NTD) of N protein interacts with nsp3 of replicase-transcriptase complex (RTC) to tether with genomic RNA, regulating the viral RNA synthesis and altering the metabolism in infected host [84, 85] . After translation, a helical ribonucleocapsid (RNP) plays a prominent role in virion assembly [86] . permission from ref. [87] , copyrights © 2020 Elsevier).

In addition to these four proteins, SARS-CoV-2 encodes at least six or more accessory proteins (3a, 6, 7a, 7b, 8b, and 9b) that are produced by ORF-3a, ORF-6, spreading and infection [89] . Using a yeast two-hybrid system, ORF-6 associates with nsp8 and promoting RNA polymerase activity [90, 91] . Besides, ORF-7a, a type I transmembrane protein situated within the endoplasmic reticulum (ER) and Golgi network, is linked to the trafficking of the protein. Both ORF-6 and ORF-7 show protruding performance in SARS-CoV-2 pathogenesis [92] . While SARS-CoV has two ORF-8 proteins (ORF-8a and ORF-8b), SARS-CoV-2 has only a single ORF-8 protein with 366 nucleotides that encodes a protein with 121 aa [93] . A recent report has shown that ORF-8 interacts with ORF-6 and N protein, whereby it serves as a possible type I IFN signalling pathway inhibitors. IFN is the chief component of the host innate immune system protecting the host from the viral infection [94] . ORF-10 is the tiny accessory protein that consists of a 38-residue peptide with the highest number of immunogenic epitopes that could alter SARS-CoV-2 pathogenicity [95] .

Insights into the entire genome sequence of reference (Wuhan genome) and mutated SARS-CoV-2 species will succor in prospective vaccine and drug development.

In general, RNA viruses, except for Nidoviruses, are susceptible to random mutations due to the scarcity of exonuclease proofreading activity of the virus-encoded RNA polymerases [96] . The first complete SARS-CoV-2 genome sequence was available on January 5, 2020, in the National Center for Biotechnology Information (NCBI) Genbank, and thousands of genomes have been sequenced till date [97] . 

A clade is a name for a group of a virus with genetic variations. It is also named as subtypes, genotypes or groups that all arise from a common ancestor [107] . SARS-CoV-2 is itself a clade inside the family Coronaviridae and the genus betacoronavirus.

SARS-CoV-2 genome has changed by numerous mutations in the past few months, as they moved across the globe. A recent report displayed 11 major mutation occurrences, which are defined in five major clades according to its respective amino acid mutations:

D392 (ORF1ab, G392D), S 84 

The clade G 614 has been widespread globally with the non-coding variant 241

C>T along with 3037 C>T and ORF1ab P 4715 L [108] . The most prevalent mutation of transversion altered 23,403 rd nucleotide adenosine into guanosine (A 23403 G) in the spike protein of SARS-CoV-2 genome G-clade, which is widespread in Europe, Oceania, South America and Africa. The clade G and its two derivative GH and GR having four mutations, namely C 3037 T, C 241 T, A 2340 3G and C 14408 T. The ORF3a further characterizes first SARS-CoV-2 type (reference genome NC_045512.2) to appear in Wuhan in 2019

December. It mutated into clade S in the following month, and it gave rise to clade V around mid-January 2020. The clade G also appeared around the same period. By the end of February 2020, clade G gave rise to GR and GH clades and started to spread across the globe. Notably, L and V clades have gradually disappeared over the same time. Similarly, the clade S is also declining but still could be seen in US and Spain [104] . Apart from these clades, few infrequent mutations are also seen, and grouped These deletions may also be accompanying with diverse mutations in the CoV S protein binding region, including those stated in farmed mink infections and mutations that have been exposed to play a crucial role in the virus's ability to evade human immune systems. A truncated ORF8 gene is also present in B.1.1.7 and the deletions in this region is associated with a decreased severity of the disease as per previous observations [118] . As a result, it is most prominant to determine the functional effects of these mutations and deletions, especially the combination that is present in B. change was also detected in South Africa [116] . Though it has a separate lineage from the UK variant, it also showed higher transmissibility for the virus.

The N501Y change was also detected simultaneously in Australia and US (June-July 2019) and Brazil (April 2019). Hence, there was no clarity whether it was imported from UK. As 501 position is in RBD, this mutation significantly reduces the neutralising ability of antibodies and leads to high transmissibility [121] . Various studies on different monoclonal antibodies showed that one antibody (LYCoV016) exhibited decreased efficacy against SARS-CoV-2 variants having mutation at 501 position. Presently, there are no neutralization data for N501Y mutation obtained from polyclonal sera of natural infections. Recently, Dr Shibo Jiang, Fudan University, Shanghai, reported the SARS-CoV-2 with 501Y mutation linked with high infectivity and virulence in mouse models. It displayed that N501Y mutation triggers to increase the SARS-CoV-2 binding affinity with the mouse ACE2 receptor and also increase virulence [122] .

It is also known as 501Y.V2 in the GH clade, emerged in late 2020 in Eastern Cape, South Africa, and found to be high transmissibility [123] . B.1.351 contains 9 spike mutations (in addition to D614G) in various domains such as NTD (e.g. a cluster of mutations at 242-244del and R246I), RBD (three mutations at K417N, E484K and N501Y) and one mutation (A701V) near the furin cleavage site [124] . The E484K mutation plays a crucial role in the loss of neutralizing activity of some monoclonal antibodies as well as most convalescent and vaccine sera against variant B.1.351.

There is a growing concern that these new variants could impair the efficacy of current mAb therapies and vaccines as these mutations reside either in the antigenic supersite J o u r n a l P r e -p r o o f of NTD or in the ACE2-binding site (also known as the receptor-binding motif (RBM), which is a major target of potent virus-neutralizing antibodies) [123, 125] . The receptorbinding domain mutations largely driven by E484K, provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization. Further, K417N and N501Y mutations act together against some important antibody classes [125] . J o u r n a l P r e -p r o o f [140], copyrights © 2020 Cell press). 

As mentioned earlier, SARS-CoV-2 easily enters the host body through droplet infection and makes its way into the respiratory tract. Homotrimers transmembrane S glycoprotein made by 1273 amino acids protruding the exterior of SARS-CoV-2 facilitates viral entry into host epithelial cells [141, 142] . SARS-CoV-2 S glycoprotein is a type I viral fusion protein that require protease cleavage for its activation and subsequent fusion. Subsequently, two subunits (S1 and S2) are participating in viral fusion with the host cell membrane [143] , as shown in Figure 8 . While the S1 receptor subunit consists of three domains, namely a single peptide, an extracellular N-terminal domain (14-305 aa) and RBD (319-541 aa), only the single peptide is used for tethering SARS-CoV-2 to host cells. The S2 subunit consists of a well-maintained fusion peptide (788-806 aa) and double heptad repeats (HR1 (912-984 aa) and HR2 (1163-1213 aa)) followed by a transmembrane region (1214-1237 aa) and a cytoplasm domain (1238-1273 aa) [144] . The S2 subunits interact with ACE2 receptor of host cells and initiate the viral-host cell membrane fusion process. Both S protein domains (S1 and S2) are separated from each other through a flexible loop comprising a cleavage spot accessible to host cell proteases [145] . Two-step proteolytic cleavages are occurring for the activation of S protein: 1) the cleavage at the site between S1 and S2 and 2) the activation cleavage at the site of S2 [146] . The S protein of SARS virus is activated by endosomal host proteases, namely transmembrane protease and serine 2 (TMPRSS2) [147] . While the S2 cleavage position in both viruses is identical, the cleavage site in S1/S2 differs. The S1/S2 cleavage site of SARS-CoV-2 is Arginine (Arg) 815, whereas it is Arg 797 for SARS-CoV [148, 149] . The different host proteases such as trypsin, cathepsin L, furin, TMPRSS-4, TMPRSS-2 and human airway trypsin-like protease (HAT) are required depending upon the cell types for the cleavage of S protein [150, 151] . ACE2 is an integral membrane glycoprotein known to have the highest expression in organs such as kidneys, lungs and heart [152] . The ACE2 is strongly expressed in The C-terminal domain consists of a ferredoxin-like fold "Neck" domain engaged with small extracellular domain, the single transmembrane hydrophobic helix and an intracellular segment [156] . The S1 domain of SARS-CoV-2 is attached to a helix 1 (Lys31 and Tyr 41) and b5 region (Lys353) of the PD domain of ACE2. Subsequently, the cleavage occurs at C-terminal (aa 697 to 716) by the activity of TMPRSS2 that enhances the S-protein-driven viral entry, as shown in Figure 8 . The ACE2 binding affinity with SARS-CoV-2 S protein is higher (~15-40nM) than SARS-CoV S protein [157, 158] . Also, the expression of ACE2 protein at the lung alveolar epithelial cell exterior permits the respiratory tract infection by SARS-CoV-2. Recent reports displayed that men have overexpression of ACE2 in lung alveolar cells than females, and ACE2 expression was higher in Asian people than Caucasian and African American people [159, 160] . The renin-angiotensin system (RAS) has a major role in regulating blood pressure, electrolytes and fluid balance in the human body. ACE2 form angiotensin (1-7) by interacting and cleaving angiotensin II, and the resulting complex of ACE2/angiotensin-(1-7)/MAX axis counteracts the negative impact of RAS. This complex causes inflammation, hypercoagulation, major adverse cardiovascular event, insulin resistance, endothelial dysfunction and respiratory problems [161] [162] [163] . SARS-CoV-2 is entering into the cells of central nervous system, gastrointestinal tract and respiratory tract including the pancreas via the ACE2 receptor, and thus, causing adverse tissue damages [164] . Recent reports displayed that the SARS-CoV-2 causes acute pancreatitis, which induces the self-digestion of pancreas, secretion deficiency and formation of large endocytic vacuoles in acinar cells [165, 166] . After the viral attachment, SARS-CoV-2 enters into host cells through endocytosis, thereafter enters into endosomes, and finally, the membrane fusion occurs between viral and lysosomal membranes [167] . 

The viral genome is discharged into the host cell cytosol, wherein its replicase gene (ORF1a and ORF1ab) is translated to formulate replicase pp1a and pp1ab. The translated polyprotein cleaves and gets transformed to 16 nsps by PL-pro and 3CLpro [168] [169] [170] . PL-pro cleaves nsp1, nsp2 and nsp3 from the polyprotein N terminal, whereas 3-CL pro cleaves the remaining nsps from the C terminal. These non-structural proteins then carry the viral replication and transcription processes. The viral proteins such as nsp3, nsp4 and nsp6 subunits, are altered in the endoplasmic reticulum (ER) to direct the formation of viral replication organelles (ROs) [171, 172] . The viral genome replication takes place in the DMV of these viral ROs. This helps in immune evasion as they protect the viral RNA from innate immune responses [173] . The RNA-dependent subsequent extension by the nsp12. The helicase enzyme (nsp13) unwinds the doublestrand RNA for nsp12 polymerase [55] . The RTC complex plays a major role in replication process as it generates negative sense genomic RNAs, which would act as a template for positive-sense genomic RNA (gRNA) and subgenomic RNA (sgRNA) (by discontinuous replication) [175] . The nascent RNA strands synthesized are then proofread for misincorporated nucleotides by nsp14 exonuclease enzymes. The genomic and sgRNAs are then polyadenylated at their 3' end and capped at their 5' end as it protects them from the host antiviral response and degradation by cellular exonucleases [176] . Then, the capping process is performed by a GTPase, nsp13, progeny is released from host cells via exocytosis [178] [179] [180] , as shown in Figure 9 .

The international spread of SARS-CoV-2 is correlated with the host immunological naivety, accessibility of social dynamics, global communication and subdued innate immune responses [181] . The innate immunity is the preliminary virus removal system in the human body that induces adaptive immunity through the secretion of chemokines and cytokines [182] . The first line of innate immunity is activated by the binding of viral S protein with alveolar lung cells, which causes the activation of Pattern Recognition Receptors (PRRS), a local immune response that induces co-stimulatory signals for T lymphocytes (adaptive immune cells) [183] . [187] , as shown in Figure 10 .

Notably, severely affected patients with SARS-CoV-2 validate remarkably impaired IFN-I cytokine production than mild or moderately infected patients [188] . The increased production of cytokines in severely infected SARS-CoV-2 patients such as IL-2, TNFα, IL-6, IL-10, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP1α), interferon-γ-inducible protein 10 (IP-10) and granulocyte colony-stimulating factor (G-CSF), leads to severe lung and even systemic pathology [ Table 3 ]. The high-level of cytokine production causes increased vascular permeability, plasma leakage and accumulation into the alveolar cavity. These kinds of events cause pneumonia, tissue damage in vital organs, respiratory failure and even multiple organ failure [189, 190] . The pro-inflammatory phase is followed by the immune suppression stage, which is characterized by a reduction in peripheral lymphocyte count.

Lymphopenia is commonly seen in severe cases as they have reduced lymphocytes counts such as CD8 + T cells, B cells, CD4+ T cells and natural killer (NK) cells [191] .

Thus, the adaptive immune response cannot be effectively initiated due to the reduction and dysfunction of these lymphocytes. Hence, the degree of lymphopenia could be used to predict the prognosis even at an early stage. The uncontrolled viral infection, inefficient viral clearance and weak antibody production stimulate the activation of more macrophages and resulting in severe cytokine storms that lead to death [192] . The patients with underlying medical conditions like chronic kidney disease, asthma, serious heart conditions, diabetes, severe obesity and immunocompromised (due to cancer treatment, smoking, bone marrow or organ transplant and prolonged use of J o u r n a l P r e -p r o o f Journal Pre-proof corticosteroids) are severely affected by SARS-CoV-2 infection and worst treatment outcomes [193] . 

The brain glial cells and neurons express ACE2 receptors on their cell surface, which are a potential target for cellular infection by SARS-CoV-2. The SARS-CoV-2 can pass from the general circulation into the cerebral circulation by rupturing the endothelial lining and infect the neurons. It also leads to bleeding within the cerebral tissue [194] . About 88% of severe SARS-CoV-2 patients had impaired consciousness with hyposmia and acute cerebrovascular diseases at the early stages [195] .

Acute cardiac injury is a major complication in SARS-CoV-2 infection caused by various mechanisms such as direct viral infection, cytokine storm, respiratory dysfunction and hypoxemia [196] , as shown Figure 11 . The elevated myocardial injury biomarkers (e.g., higher cardiac troponin and creatine kinase) were often seen in patients treated in intensive care units (ICU), showing its severity [197] . The elevated J o u r n a l P r e -p r o o f levels of troponin T, C-reactive protein and N-terminal pro-brain natriuretic peptide are linking myocardial injury to the severity of inflammation and ventricular dysfunction induced mortality [198] . The meta-analysis, a quantitative, formal and epidemiological study, revealed that the mortality rate of patients without myocardial injury (11.2%) was lower than patients with myocardial injury (67.1%) [199] . The cytokine storm and increased D-dimer level directly activates coagulopathy in severe cases (20-30%) of SARS-CoV-2 infection [200, 201] . The coagulation pathway is activated by multiple mechanisms. For instance, the SARS-CoV-2 binding with alveolar ACE2 receptors induces inflammation and reduces the pulmonary vasoconstriction, which causes the depletion of blood oxygen (O 2 ) level. The reduced O 2 level is described as a hypoxia condition. The vascular response to hypoxia is controlled by hypoxia-inducible transcription factors (HIF), facilitated by thrombus formation, leading to blood clots [202] . In other words, antiphospholipid antibodies (produced from immune cells) cause severe tissue damage due to coagulation [203] . Besides, the destruction of alveolar and capillary endothelial cells causes more inflammation and blood clots. Further, the increased rate of inflammatory cytokines, including TNF-α, IL-6 and IL-8, can cause venous thromboembolism (VTE) by activating the blood coagulation. The abnormal blot coagulation is associated with poor treatment outcomes and reduced survival rate in SARS-CoV-2 infected patients [204] .

Recent reports have found that the lymphocyte infiltration and severe acute aggregates [206] . In a recent report, a clinical investigation on kidney injury of SARS-CoV-2 patients showed high serum creatinine, new-onset proteinuria, the infiltration of lymphocytes like CD68+ macrophage into tubulointerstitium and the enhanced deposition of complement, C5b-9 on the tubules [207] . Further, it showed the direct viral infection on kidney organoids for shed viral progeny, which further confirms its ability to cause acute renal failure in humans [208] .

The patients with SARS-CoV-2 were reported to have developed rhabdomyolysis with symptoms of muscle pain and weakness. It could have resulted from the direct viral infection as severe immune response to the viral infection causes cytokine storm and muscle tissue damage. Further, the circulating viral toxins could directly destroy muscle cell membranes [209] . The elevated level of SAA was identified in 80% SARS-CoV-2 patients and utilized as an auxiliary index for diagnosis [213] 4

Platelet count High platelet-to-lymphocyte and thrombocytopenia (TC) ratio was correlated with poor outcome and increased TC was associated with the incidence of myocardial injury in SARS-CoV-2

Expressed as a biomarker at early stage of disease progression, CRP level was positively linked with disease severity, lung lesions and risk of acute myocardial injury. [ [221] [222] [223] 8

The occurrence of IL-18 was to be main in antibodies producing B cell that is most important in the recovery.

[224]

9

Lymphocyte count Lymphocyte count is correlated with disease severity.

[225]

10 IL-4 Some reports displayed IL-4 was found to have potential mediator effect or correlated with impaired lung lesions. [226] J o u r n a l P r e -p r o o f

Neurological manifestations of SARS-CoV-2 are neurological and other extra respiratory symptoms that occur in patients as a direct result of the virus's neuroinvasive features or as an indirect outcome of downstream multi-organ dysfunction and abnormal biochemistry.

The virus causes neuropsychiatric problems in some patients, including altered consciousness and encephalopathy. More serious neurological consequences such as cerebrovascular accidents and seizures, were uncommon, however occurring in only 3

and 0.5% of cases, respectively. Neurological problems were shown to be more common in those who had "severe" SARS-CoV-2 infections [227, 228] . A recent report discovered that the majority of neurological manifestations occurred early in the disease, which could be a strong indicator of future clinical worsening. Severe neurological diseases such as bleeding of cerebral vein thrombosis, ischemic stroke etc. were more important and potentially enduring neurological sequelae by SARS-CoV-2 in patients that lead to a significant proportion death [229, 230] .

The percentage of thromboembolic complications in patients with SARS-CoV-2 revealed the incidence of ischemic stroke to be 1.6% and 2.5%, respectively. Beyond regular cardiovascular and metabolic comorbidities and those associated to a prolonged stay in intensive care amenities, there are obviously added risk factors that predispose individuals with SARS-CoV-2 to develop thromboembolic stroke [231, 232] . The SARS-COV-2 patients with thrombo-inflammatory conditions showed increase in concentration levels of platelet (62%), interleukin-6 (IL-6) (100%), D-dimer (100%) and fibrinogen factors, and (ii) the damage to the capillary endothelium that leads to a dysregulation of its antithrombotic capabilities. Thus, both of these factors lead to the formation of microvascular thrombosis, which has the ability to embolize the entire body [233] .

GBS is a significant neurological complication associated with SARS- CoV 

In recent years, the investigation of waterborne infections is considered as an important tool to know more about the localised infections and disease origins [236] . It helps us in controlling viral infections and devising a better preventive strategy. Similar investigations show the evidence of presence of SARSCoV-2 in surface/ground water, sewage stream lines and contaminated drinking water [237] [238] [239] . SARS-CoV-2 has been proposed as a waterborne virus that enters and contaminates water sources via infected faeces [240] . Although the fecal-oral transmission of SARS-CoV-2 has not

been confirmed yet, a detailed investigation is necessary to determine the impact of fomite-based vertical and faeco-oral transmission can indeed be ruled out given the growing body of evidence [242] . However, SARS-CoV-2 needs to be explored for its ability to sustain in water, transmissibility through water and potential to infect humans.

When compared to non-enveloped viruses, the enveloped viruses such as coronaviruses (CoVs) have various structural and survival features to stay alive for longer time in water [243, 244] . Hence, wastewater management is seen to be a viable method for tracking the spread of CoVs in a particular locality, i.e. viral clusters. The monitoring of critical reservoir on a regular basis will aid in detecting increasing viral concentrations or indicators, which might be used as early warning signs of an epidemic [245, 246] . Such reports can reveal the actual virus burden in communities, thus allowing proper control measures to be implemented to prevent further spread of SARS-CoV-2. Furthermore, when handling the stools of SARS-CoV-2 positive individuals, stringent personal hygiene (hand hygiene) and preventive measures must be followed.

The appropriate disinfection strategies have to be followed for waste and sewage water 

The high specificity and accurate clinical diagnostic methods for SARS-CoV-2 infection are desirable for dealing with the earlier diagnosis and appropriate treatment ( Figure 12 and Table 4 ). The symptoms observed from SARS-CoV-2 affected patients are non-specific and could associate with various other respiratory infections [247] . As per the initial report by Guan et al., the patients' data collected from china showed that the most common symptom was fever in 43.8% of patients and 88.7% patients had developed fever after hospitalization. The other symptoms, cough and diarrhea, were observed in 67.8 and 3.8% patients, respectively [248] . In advanced molecular J o u r n a l P r e -p r o o f Journal Pre-proof biotechnology, the nucleic acid detection method based on Polymerase Chain Reaction (PCR) has been referred as the gold standard for detecting the virus [249] . Conversely, computed tomography (CT) scan could also be used to examine any abnormalities present in the lungs, and hence, the diagnosis of the virus at earlier stage is possible [250] [251] [252] . Besides, molecular tests employing non-PCR based methods and novel emerging diagnostic methods (e.g., isothermal amplification, protein testing, Point of Care (POC) detection and SHERLOCK) are also under development. Following this, we have briefly reviewed and discussed various diagnostic methods used for the detection of SARS-CoV-2.

PCR is an enzymatic method separating two DNA strands to produce multiple gene copies, and primer marks the location of the gene segment present in DNA strands.

Further, DNA polymerase starts formulating a new DNA strand by adding nucleotides, forming two identical DNA copy from a short RNA segment [219] . This method is mainly used to obtain more DNA copies from minimal quantity of biological samples to make it adequate for laboratory study. In general, the viral genomic RNA is transferred into cDNA using reverse transcription [263, 264] . Then, PCR is carried out and the virus is detected using specialized methods. Among them, the sequencing and gel visualization techniques are conventional for the detection of CoVs. The designing of kits generally involves two main steps [255] . [256] .

The assay has been made as a dual-target system with 2 sets of primers, wherein one set detects various coronaviruses and another set of primers specifically detects SARS-CoV-2 [255] . After designing suitable probes and primers, the assay conditions (e.g., J o u r n a l P r e -p r o o f incubation times, temperature and reagent conditions) were optimized prior to PCR testing. Though RT-PCR can be executed through one step or two-step assays, combining the reverse transcription and PCR amplification in a single step provides rapid and reproducible results. Despite such advantages, the difficulties in optimizing the reverse transcription process and PCR amplification (mostly due to simultaneous occurrence) result in lower amplification than the desired target. Since the reaction is performed sequentially in two distinct tubes, two-step assay is highly sensitive than onestep assay. However, it is time consuming and slow that results in low number of test per unit time.

RT-PCR is analytically specific but not reliable due to its high false-negative rate [257] . Unfortunately, the positivity rate with RT-PCR is only 30-50% for laboratory confirmed SARS-CoV-2 patients, particularly in the early stage of the infection and if the samples were collected from upper respiratory tract [258] . It was shown in another report that 3% people confirmed for infection in chest computed tomography (CT) were given false-negative report after RT-PCR testing [259] . 

CT of the chest uses X-ray equipment to examine the abnormalities and helps in diagnosing the cause of unknown cough, fever, shortness of breath and other respiratory symptoms [251, 252] . The high-resolution CT test could be utilized for earlier show bilateral occurrence of uneven ground-glass opacities, which can coalesce into the spherical shaped randomly distributed deep-clustered lesions along the periphery of the lung [260] . In addition to this, an irregular paving pattern (Irregular shaped paved stone pattern) was also observed along with an increase in consolidation in the lungs [261] . It is worth noting that the ground-glass opacities are prominent in the initial period of 0 to 4 days after symptom onset. However, the drawback of CT scan is its specificity J o u r n a l P r e -p r o o f Journal Pre-proof for SARS-CoV-2 infection (~ 25%) as its inability to distinguish SARS-CoV-2 infection from normal pneumonia virus affects its specificity [262] .

Various diagnostic methods for SARS-CoV-2 identification in the given biological samples.

The isothermal amplification technique includes recombinase loop-mediated isothermal amplification (LAMP), polymerase amplification and helicase-dependent amplification [263] . LAMP retains some fundamental advantages such as exclusion of a handling of a large number of samples is possible without any difficulty [269] . The reaction time is less than one hour and the detection limit is nearly 75 copies/μL.

Overall, this procedure is simple to follow, easy for visualizing the detection, has less background noise and doesn't need a thermocycler. Optimizing the primers and reaction conditions are the challenges in the LAMP technique.

The microarray detection method is a rapid and high throughput technique in which coronavirus RNA produces labeled cDNA with probes through reverse [275] . Though there was no cross-binding with S1 subunit of SARS-CoV S antigen, some cross-reactivity was noted with SARS-CoV N antigens when it was added with the serum sample of SARS-CoV-2 patients.

Recently developed CRISPR has taken molecular diagnosis to the next level due to its benefits such as speed, precision, specificity, strength, efficiency, versatility, portable and inexpensive [276] . The CRISPR system enables researcher to alter gene function by making changes in genomic sequence. It closely resembles the pair of molecular scissors that can precisely cut the DNA strands. This system is a family of DNA sequences found in archae and bacteria, and is composed of two major parts: (i)

Cas endonuclease and (ii) guide RNA. The former is responsible to break the target genomic site, whereas the latter is used to identify and lead the Cas endonuclease to the target [277] [278] [279] 

SHERLOCK is a nucleic acid detection approach, wherein the viral RNA sensing is carried out by Cas13a ribonuclease enzyme [287] . In this technique, the viral RNA is converted to cDNA by reverse transcription, followed by isothermal amplification of cDNA using Reverse Polymerase Amplification (RPA) [288] . The Cas13a forms a complex with RNA guide sequence and gets attached with the amplified RNA. When it binds with the target, Cas13a gets activated and produces a fluorescent signal by breaking and releasing the surrounding fluorophore quencher probes. It is highly sensitive and specific as it can detect a single molecule in 1 µL sample volume of DNA and RNA targets [287] . It is also reported that the scaling up of preamplification content can detect even a single-molecule in large sample volumes [289] . In terms of specificity, two similar viruses can easily be distinguished from one another (e.g., dengue and zika virus) [290] . The reason is that Cas13 doesn't get activated when there are more than one mismatches in crRNA target duplex. In the detection of cancer-associated mutations, human genotyping and single base distinction, the specificity can also be increased by introducing mismatchs into the crRNA. Another promising feature of SHERLOCK is rapid detection. However, the SHERLOCK technique is limited due to multi-step nucleic acid amplification that affects the target quantification [287] .

Pont of care diagnostics is the method of detection in which the sensing is carried out without any need for laboratory or centralized facilities. Among these techniques, the lateral flow assays are made of paper-based membrane strip with two lines marked on it [291] . J o u r n a l P r e -p r o o f

The unfortunate pandemic of SARS-CoV-2 in early 2020 has caused a challenge to all researchers to find the potential therapeutic agents for the treatment. However, there was no reliable vaccines or drugs available for either treating or controlling SARS-COV-2 virus. Hence, the scientific communities were actively involved in the examination of approved/existing drugs for other diseases for drug repurposing efforts for the treatment of SARS-COV-2. In the initial period of pandemic, the drugs utilized in clinical trials were based on empiric data, which were actually developed for other viruses or parasites [304] . The antiviral therapies were developed to induce direct effect on SARS-CoV-2 either by blocking the viral entry to host cells or controlling the viral enzymes having significant contribution for genome replication [305] . Alternatively, other therapeutic agents were also developed with the aim of boosting the innate immunity towards viruses or hindering the inflammatory response that cause lung injury [306] . analogs as an antiviral agent that could prominantly inhibit FPV [324] [325] [326] . The EC 50 value was noted to be 61.88 µM/L for FPV towards Vero E6 cells infected with SARS-CoV-2. The FPV bioavailability is very high at about 98% in human. Its metabolites are mostly renally cleared, and its half-life is calculated to be 2 to 5.5 h [327] . The clinical trials were executed for FPV towards SARS-CoV-2 in China and Italy in Mid-2020 as both the countries were severely affected in that time period. The FPV doses were started with 1600 mg/day (twice) for a few days, followed by 600 mg twice a day for the next 9 days. It acts as a mutagen and has shown 3-fold increase in total mutation than control [328, 329] . Recently, the repeat dose toxicity studies in rats, monkeys and dogs showed the notable adverse effects of oral favipravir on hematopoietic system such as the reduction of red blood cell (RBC) production and increase of the liver function parameters (e.g., alanine aminotransferase, total bilirubin, aspartate aminotransferase, alkaline phosphatase and increased vacuolization in hepatocytes). Besides, Testis toxicity was also noted. Hence, the administration of favipiravir should not be recommended for women suspected or confirmed for pregnancy [330].

Sofosbuvir (SFV) is a pyrimidine nucleoside analog with a hydrophobic masked phosphate group used for SARS-CoV-2 treatment due to its potential advantages such as low toxicity and high stability of the active molecule [331] . The hydrophobic masked phosphate group of SFV enables it to uptake into the infected cells, and then, it gets changed into its active triphosphate form by cellular enzymes [332] . The activated drug 

The viral replication depends on the proteolytic cleavage of either one or several viral polyproteins encoded by the virus genetic information. These proteolytic processes are essential for the functions of polyproteins and cleavage of the host protein, facilitating infection, and for the cellular entry and viral replication of SARS-CoV-2.

Therefore, viral proteases are a major target in the development of SARS-CoV-2 drug.

The diverse range of repurposed drugs and their targets are mentioned in Figure 14 .

Ivermectin (IVM) is a familiar anti-helmintic agent used as an antiviral agent against flaviviruses such as Japanese encephalitis, dengue fever, chikungunya and tickborne encephalitis [335, 336] . It is worth noting that there are no approved indications by FDA for the above-mentioned applications. However, its anti-inflammatory properties make it ideal for veterinary use for diseases caused by parasitic worms such as onchocerciasis and intestinal strongyloidiasis [337, 338] . In SARS-CoV-2 infection, J o u r n a l P r e -p r o o f the nuclear transport of viral protein is essential for viral replication. IVM targets importin α/β1 heterodimer mediated transport of viral proteins by dissociating IMPa/b1

heterodimer. It also prevents the transport of viral protein into the nucleus [339] . Hence, IVM causes hyperpolarization by triggering gamma amino butyric acid (GABA)-gated-Cl − channels and paralyses the infesting organism [340] . Besides, IVM affects the host response immunomodulation by increasing IL-6 and C-reactive protein levels and activating the neutrophils [341] . It has been reported that 5 μM of IVM could curtail SARS-CoV-2 RNA up to 5,000-fold at 48 h without any toxicity. The IC 50 value of IVM was calculated to be ~2 μM towards SARS-CoV-2 [342] . Notably, the over dosage (higher than recommended dose) with orally administered formulation found to be lethal in mice models with death preceded by significant ataxia, ptosis, bradypnea, emesis, tremors, decreased activity and mydriasis [341, 342] . Bind with viral cell, and inhibit the viral entry and increase immune system -- [372, 376] J o u r n a l P r e -p r o o f

Nasal Drugs /Spray have been developed for disinfection and treatment for SARS-CoV-2. To the obvious fact that the viral loads are expelled out of nasal cavities from infected patients, disinfecting nasal cavities can help to decrease the risk of infection in uninfected person as well as to reduce the viral load in infected person [377] . Few of developed products are given in table 6 along with their working mechanism. J o u r n a l P r e -p r o o f

The rhACE2 is also known as APN01, can block the SARS-CoV-2 entry into the host cell by interfering with the interaction between S protein and the ACE2 receptor of host cells [385] . A recent report stated that SARS-CoV-2 infected human kidney and blood vessel organoids treated with rhACE2 could block early entery of SARS-CoV-2 infection in host cells by a factor of 1,000-5,000 times [386] . The rhACE2 could preclude further ACE2 receptor activation, thereby perpetuating pulmonary vascular integrity and inhibiting acute respiratory distress syndrome (ARDS) [387] .

Hydroxychloroquine (HCQ) and chloroquine (CQ) are long-standing oral drugs specifically used to treat malaria and chronic inflammation. These two drugs have unique properties such as lipophilic weak bases and superior diffusion into organelles membrane (e.g. cell membranes, lysosomes, endosomes and Golgi vesicles). Both drugs become protonated, trapped in the organelles and upsurging the pH in the cell interior [388] . It is postulated that the raise in endosomal pH prevents the viral particles fusion and their cellular entry [389] . Also, they are known to interfere in the glycosylation of ACE2. This can make spike protein-ACE2 binding less efficient and impedes the virus's entry into the cells [390] . HCQ and CQ can prevent the antigen processing, T-cell activation, TLR-cyclic GMP-AMP Synthase (cGAS), CD154 expression and downregulate the pro-inflammatory genes [391] . The EC 50 values for HCQ and CQ towards SARS-CoV-2 were estimated to be 6.14 and 23.90 μM, respectively [392] . However, both HCQ and QC trigger severe side effects, including neuropsychiatric effects, hypoglycemia, retinopathy and QTc prolongation [393, 394] .

Peptidomimetics are compounds with pharmacophore as an essential element that mimics natural compounds such as peptides and proteins to interact with biological targets. This alternative can overcome the limitations of naturally available peptides, i.e., and TMPRSS2 [137] . This type of study and other research reports could provide a fundamental outline for the development of therapeutics.

In this section, we have discussed few such therapeutic candidates and classified them based on their targets.

Recently, Xia et al. carried out a study related to derivatives of SARS-CoV-2 HR2

peptides [398] . 

Peptide-based inhibitors can prevent the SARS-CoV-2 initiation to host cell entry approaches and showed their interaction with SARS-CoV-2 [406] . Researchers have also remade the peptide designs using the structural bioinformatics and logo analyses to enhance the binding affinity to RBD of SARS-CoV-2 [404] . Thus, these computational approaches in combination with in-vitro and in-vivo experiments could lead to the design of appropriate therapeutics [407] .

Nafamostat, a serine protease inhibitor used for disseminated intravascular coagulation (DIC), has an ability to prevent SARS-CoV-2 host cell entry by preventing the pathway through TMPRSS2 [408] . used endosomal cathepsins for cell entry [410] . Camostat could also inhibit SARS-CoV-2 by 50 to 60% in TMPRSS2+ cell lines with no side effects, and the inhibition efficacy is J o u r n a l P r e -p r o o f increased to 100% by the addition of E64d [147] . Through animal studies, it was found that camostat mesylate controlled the viral entry by 10-fold in calu 3 airway epithelial cells and interestingly increased the mice's survival rate [411, 412] . Camostat is known to inhibit an in-vivo infection caused by a virus that utilizes TMPRSS2, and could be a suitable component of a drug combination against SARS-CoV-2.

Oxocarbazate inhibitor CID23631927 has revealed better anti-viral effect and selectivity toward CatL of SARS-CoV [413, 414] . It is noteworthy that oxocarbazate µM observed in human aortic endothelial cells [415] . Based on this, oxocarbazate inhibitor can be a potential therapeutic agent for treating SARS-CoV-2.

Most of the plants have the potential to mitigate the new SARS-CoV-2 infection.

person and enhanced patient health state with severe or mild symptoms [416] . Hence, a detailed investigation on the 3CLpro structure and its catalytic mechanism might provide more information for the anti-SARS-CoV-2 drug development. The RdRp, also named nsp12 is a conserved protein needs to form SARS-CoV-2 replication/transcription complex by catalyzing the RNA replication from a RNA template [174] . Therefore, nsp-12 has high potential for use as prominent therapeutic target. In other words, the S protein cleavage activation and its structural integrity performs a prominent role in SARS-CoV-2 virulence and invasion. Notably, the blocking of viral entry into host cells by targeting either S proteins or the host cell surface receptor is valuable for developing the suitable therapeutic strategies. Thus, these four structural and functional proteins make attractive targets for SARS-CoV-2 drug development [55] .

Recently, the molecule-protein docking was carried out between different people has shown an enhanced ability to induce the antibiotic response in human [430, 431] . Further, the VLPs developed with influenza virus have also demonstrated good biocompatibility, safety and efficacy in animal models and human clinical trials [432] .

The vaccine developed from tomato and low nicotine tobacco plants have also shown stable expression of S protein (S1) against SARS. Notably, it exhibited a significant increase in amount of SARS-CoV-specific antibodies after immunization in mice model.

It can be concluded that the plant based vaccines developed so for have shown promising results in pre-clinical trials [433, 434] . Hence, any continued efforts in this direction might result in plant based safe vaccines for SARS-CoV-2 in near future. Pre-clinical study [441] SARS-CoV S1 protein fusion Transient expression in N. benthamiana SARS-CoV S1-GFP fusion protein

Research [442] SARS-CoV S1 protein based vaccine Stable expression in tomato SARS-CoV S1 protein

Pre-clinical study [443] RBD -receptor binding domain (RBD), GFP -green fluorescent protein

Stem cells (SCs) have the ability to differentiate into a variety of diverse cell types in the body. Self-regenerative and differentiation ability of certain types stem cells (e.g.

mesenchymal stromal cells (MSCs)) plays an important role in stimulating the regeneration of alveolar epithelial type II cells by secreting vascular endothelial and hepatocyte growth factors [444 445 ]. Alternatively, various kinds of chemokines present at the site of Inflammation can also attract MSCs and its secretion of immunoregulatory cytokines to modify the functioning of various immunocytes such as dendritic cells, NK cells, T cells, B cells, macrophages and neutrophils [446] . Notably, the factors such as the transforming growth factor β, prostaglandin E2, Indoleamine 2,3-dioxygenase and human leukocyte antigen isoform have been recognized as the major effectors in the above-mentioned processes [447] . Thus, MSCs may provide a therapeutic alternative for patients with severe or critical COVID-19 either by repairing the lung damage or inhibiting the over-activated inflammatory response and influencing the progression of pulmonary fibrosis. The MSC therapy has been shown to minimise pulmonary lesions and limit the inflammatory response generated by influenza virus infection in both human and animal models [448, 449] . The efficacy and safety of MSC treatment in J o u r n a l P r e -p r o o f patients with acute respiratory distress syndrome (ARDS) have also been studied. The intravenous transfusion of MSCs in moderate or severe COVID-19 patients was proven to be safe and well tolerated in recent phase-1 clinical trials [451] . For the first time, the intravenous MSC therapy has improved the clinical outcome of COVID-19 patients while displaying good immunological tolerance in critically ill patients [451] . Similarly, menstrual blood-derived MSCs (MB-MSCs) were used in a clinical trial for severe patients, and it was discovered that MSC transplantation could help in treating COVID-19, particularly in ICU patients. In a recent study, the infusion of umbilical cord MSCs (UC-MSCs) into COVID-19 patients with moderate or severe disease was found to be safe in phase 2 and 3 studies with 96-week follow-up course [452] . When the influence of high dose of MSCs (upto 200x10 6 cells) and exosomes produced from allogeneic MSCs were tested for therapy efficacy, the treatment was found to be well tolerated and showed prospective improvement in some clinical measures [453] . Further, COVID-19

patients have also been treated using stem cells other than MSCs such as human embryonic stem cell-derived immunity-and matrix-regulatory cells (hESC-IMRCs) [450] .

The docking score was recently assessed between 3CLpro crystalline structure Table 8 [464].

The purified recombinant proteins from different etiologic agents are most prominent candidates under the investigation for vaccines. The protein-based vaccines are formulated by using the harmless protein fragment or protein shells that mimic the SARS-CoV-2 virus to stimulate the human immune response [459] . 

Nucleic acids such as DNA and RNA are inserted into human cells as a genetic instruction, which can induce an immune response [467] . DNA-based vaccines are nonreplicating, non-infectious and provide long term immunogenicity to the host. Further, they are stable, less expensive, prepared in short time duration and easily getting degraded in host models. However, it has poor immunogenicity when used in humans [466] . Due to this, RNA-based vaccines are preferred over DNA-based vaccines. Often, mRNA based vaccines are directly injected into the host cell and allowed for translation in the cytoplasm. Currently, two types of mRNA based vaccines are established, namely self-amplifying mRNA and non-amplifying mRNA based vaccines. The self-amplifying mRNA-based vaccine technology has the capability to ramp-up vaccine production to meet the increase in demand for vaccines [469] [470] [471] .

They are generally produced either by completely killing or inactivating the pathogen. When they are injected into the host, they induce protective antigen against epitopes that are present on the surface of real virus. However, these vaccines tend to produce the weaker immune response, thus it requires the adjuvants to provide an effective immune response [472, 473] . While the inactivated polio vaccine is the better example for the completely killed (whole) pathogen, the tetanus and diphtheria vaccination is the example for subunit formulation [474] . Sinopharm and Sinovac are among the manufacturers farthest along in the development of this type of vaccine.

They have also successfully completed phase 3 clinical trials for their vaccines and obtained international authorization for emergency use [466] .

J o u r n a l P r e -p r o o f 

Nasal vaccination is considered to be a reliable and influencing method to prevent SARS-CoV-2 infection as the viral invasion mainly occurs via nasal mucosa. Among the available vaccines, adenovirus vector-based vaccines are considered as reliable vectors of antigens to hosts owing to its potential to induce both adaptive and innate responses [476] . They are safer, less expensive and produced in higher quantities to meet the demands [475] . Alternatively, SARS-COV-2-M2sr categorized under M2SR is another type of vaccine which is produced upon deletion of M2 gene that activates the immune response (innate and cellular) in the host [481] [482] [483] . The advantage of such vaccine is that it J o u r n a l P r e -p r o o f [486] . Similarly, CovMOV developed by

Intravacc embeds viral S antigen in bacterial outer membrane vesicles and is in the preclinical trial [488] . AuraVax therapeutics has also proposed a liposomal stimulator of interferon genes or STING agonist to use as an adjuvant in vaccine for SARS-CoV-2 [489] . Notably, it triggers mucosal immune response and provides better protection against virus. The list of aforementioned vaccines along with their current state is given in Table 9 . J o u r n a l P r e -p r o o f

The introduction of the vaccine into the human body is described as vaccination that protects the body from specific infection by developing the resistance and strengthening the immune system against pathogens [490] . It is considered as a harmless and effective route to control or kill pathogens by triggering the immune cells to produce antibodies that react against the exposed disease. The immunization process saves several millions of people from more than 20 life-threatening diseases and makes them live longer and healthier by building resistance against specific diseases [491] . such as diabetes and heart disease [492] . It could also induce life-threatening allergies for people who are in treatment for chemotherapy and chronic illnesses as it severely affects the immune system. Interestingly, it is very safe and effective in people with underlying conditions such as liver or kidney disease, asthma, diabetes and hypertension. The vaccine ingredients may stabilize and control these diseases [493] . However, these impacts may differ for every vaccine.

The major ingredients of vaccines such as weakened or killed antigen, adjuvants, preservatives and stabilizers play a crucial role in encountering the virus and boosting the host immune response. For instance, the added preservatives ensure a vaccine stays effective, and stabilizers are protecting the vaccine during storage and transportation [494] . After satisfying the potential benefit of immunization, the approval for commercial use of vaccines will be obtained from study investigators, regulatory agencies and overseeing ethical committees. The 

Most vaccines for SARS-CoV-2 disease have been developed in a short time span (within 10-16 months) in order to control the rate of infection and casualties around the globe. Hence, the concerns over the safety, effectiveness and side effects of newly developed vaccines need to be addressed in detail [495] . For example, the Strategic Advisory Group of Experts (SAGE) announced that the developed the Pfizer-BioNTech COVID-19 mRNA vaccine is safe and effective to people, As of 14 th October 2021, 23 vaccines have been approved for emergency use across the globe, as shown in Table 10 . However, the vaccination is not recommended for some specific populations and it may be either due to lack of supply or limited data and contraindications [496] . Further, a certain population people who had received the COVID 19 vaccine developed severe headache, abdominal pain, leg pain, shortness of breath and severe type of blood clot called cerebral venous sinus thrombosis (or CVST) combined with low levels of blood platelets (thrombocytopenia) [497] . As a result, the regular medical assessments and post-approval clinical studies are urgently needed to confirm their safety and effectiveness. 

Given the fact that the long-time protection of vaccine from specific disease is the main thing in preventing the infections, their ability of long-term protection should be fully investigated for newly developed SARS-CoV-2 vaccines. At present, most SARS-CoV-2 vaccines are given to people in two dose regimens.

As reinfection of cases raise concerns over the immunity after vaccination, the additional studies need to be performed urgently to give further direction for the J o u r n a l P r e -p r o o f people who recuperate from SARS-CoV-2 disease in order to suppress the subsequent wave of infections. A detailed investigation on reinfections (even after vaccination) and the ability of vaccines against new mutations will shed more light on long-term protection of vaccines against SARS-CoV-2 [499] .

The storage and transportation mechanisms are also pose great challenges for the commercialization of vaccines as the existing installations are not able to cope up with the demands caused by larger vaccination schedules across the globe. The prepared vaccines are packed carefully in glass vials due to its ability to withstand extreme temperatures for safe cold vaccine storage and transport globally [500] . When a vaccine is too hot or cold, it becomes less effective or even inactive. If stored at the incorrect temperature, the vaccines can be ruined or unsafe for use. Most vaccines require refrigerated storage at temperature in the range between 2 and 8 °C [501] . Some vaccines even require ultra-cold temperature from -20 to -70 °C [502] . For frozen vaccines, the storage temperature is maintained at 2 -8 °C. Since the regular refrigerators cannot consistently maintain these low temperatures, specialized medical refrigerators are required for these precious products. The messenger RNA (mRNA) based vaccines (mRNA-1273-Moderna and BNT162b2-Pfizer-BioNTech) are developed using the strands of mRNA held together within lipid particles. The prepared vaccines are vulnerable to degradation at room temperature and need doses to be frozen for transportation, then thawed for the use [503] . Therefore, the concerns regarding the storage temperature could slow down the rollout of SARS-CoV-2 vaccines. Similarly, the mRNA-1273 vaccine is stored at temperature in the range between -25 and -15 °C. As it is stable and active at -20°C, it can be stored in standard -20°C freezers meant for hospitals and pharmacies [504] . The Indian vaccines developed can be stored at a temperature of -20 °C, hence they can be stored at normal hospital refrigerators. However, the efficacy and other temperature related data is yet to be declared officially. For instance, Pfizer-BioNTech announced that BNT162b2 vaccine displayed 90% efficacy when J o u r n a l P r e -p r o o f stored at -70 °C. Similarly, the Sputnik V vaccine liquid form must be stored at -18 °C or below to maintain its stated 92% efficacy [505] .

Up to 275 vaccines are being developed worldwide till date and 23 of them are being currently used in different countries. As most of the countries are facing frequent waves of infections and there is no sign for the end of Covid-19

pandemic, the need for vaccines along with syringes, needles and plastic vials for effective administration and storage of vaccines is growing with each passing day.

Based on the available data, the USA has ordered about 850 million of syringes and needles for their two doses of vaccination [506] . Hence, the requirement across the globe has to be taken care while a series of vaccines are being rolled out. In addition, further developments are required on the design and mechanical integrity of glass vials for efficient storage and transport of vaccines. For instance, the parameters such as mechanical integrity, resistant to breakage, chemical stability, mechanical durability, thermal stability and compact designs/dimensions are not only playing a key role in maintaining the activity of vaccines but also preventing the loss of doses during the transportation and handling of vaccines. It is worth noting that they should be stable in the temperature range between -196 °C to 121 °C while having the chemical stability to handle liquids with pH range of 3-14 [507] .

Worldwide acceptance of vaccine is necessary to prevent further spread of 

Currently, SARS-CoV-2 is spreading rapidly as the third severely contagious human disease and has caused serious threat globally. Beyond doubts, it has now been widely accepted that the prevention of public gatherings and following quarantine strategies and standard operating procedures is the way to move forward for controlling SARS-CoV-2 infections. As it has coexisted with people for a long time, it has developed a niche in human beings. As a result, continuous monitoring of the gene alterations in new SARS-CoV-2 infections is required to promptly recognize any deletion or insertion in the genomic sequence. 

Isothermal Amplification based Method ………………………………………………………

Microarray-based Method ….……………………………………………………………………45

Therapeutic targets for SARS-CoV-2 …………………………………………………………………….……...51 8.1 Therapeutic agents to target RNA-dependent RNA polymerase (RdRp)

Therapeutic Agents for Blocking the Virus-Cell Membrane Fusion …………………………

Plant-based Molecules for Targeting SARS-CoV-2 Proteins ………………………

Stem Cell therapy for COVID-19 ………………………………………………

Molecular molecular dock against 3CLpro

72 9.1 Vaccines administered via intramuscular routes………………………………

85 10.2 Long-Term protection ……………………………………………………………………………..88 10.3 Storage and Transportation of Vaccines …………………………………………

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

Features, Evaluation, and Treatment of Coronavirus

Coronavirus disease 2019 (COVID-19): current status and future perspectives

MERS, SARS and other coronaviruses as causes of pneumonia

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2): An Update

Characterization of the coronavirus M protein and nucleocapsid interaction in infected cells

The Coronaviruses of Animals and Birds: Their Zoonosis, Vaccines, and Models for SARS-CoV and SARS-CoV2

The Strengths of Scanning Electron Microscopy in Deciphering SARS-CoV-2 Infectious Cycle

Zoonotic origins of human coronaviruses

SARS-CoV-2 is an appropriate name for the new coronavirus

Origin and evolution of pathogenic coronaviruses

Analysing COVID-19 pandemic through cases, deaths, and recoveries

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

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges

SARS-COV-2 infection (coronavirus disease 2019) for the gastrointestinal consultant

COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned?

Transmission of COVID-19 virus by droplets and aerosols: A critical review on the unresolved dichotomy

Biological fluid dynamics of airborne COVID-19 infection

COVID-19 faecal-oral transmission: Are we asking the right questions?

COVID-19 and diabetes: Knowledge in progress

Incubation Period and Reproduction Number for novel coronavirus (COVID-19) infections in India

Pandemic preparedness of dentists against coronavirus disease: A Saudi Arabian experience

Conserving Supply of Personal Protective Equipment-A Call for Ideas

Human Coronavirus: Host-Pathogen Interaction

Efficiency of Treatments Involving Ultraviolet Irradiation for Decontaminating Packaging Board of Different Surface Compositions

Minimalistic coarse-grained modeling of viral capsid assembly

Design, Synthesis, and Mechanism Study of Benzenesulfonamide-Containing Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Improved Antiviral Activities

Dietary Intakes As Potential Risk Factors for COVID-19 Mortality: A Multicountry Ecological Bayesian Regression Analysis

Evaluation of an electrostatic spray disinfectant technology for rapid decontamination of portable equipment and large open areas in the era of SARS-CoV-2

Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus

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

SARS coronavirus replicase proteins in pathogenesis

Spiking Pandemic Potential: Structural and Immunological Aspects of SARS-CoV-2

Expression and Functions of SARS

The SARS-CoV-2 main protease as drug target

Crystal structures of SARS-CoV-2 ADP-ribose phosphatase (ADRP): from the apo form to ligand complexes

Genomic characterization of a novel SARS-CoV-2

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

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

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Assembly of coronavirus spike protein into trimers and its role in epitope expression

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Insights into SARS-CoV transcription and replication from the structure of the nsp7-nsp8 hexadecamer

Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine

A structural analysis of M protein in coronavirus assembly and morphology

Subcellular location and topology of severe acute respiratory syndrome coronavirus envelope protein

An overview of viral structure and host response

Biochemical characterization of SARS-CoV-2 nucleocapsid protein

Expanding our understanding of the role polyprotein conformation plays in the coronavirus life cycle

Coronaviruses: an overview of their replication and pathogenesis

Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists

Coronavirus disease 2019: What we know?

Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors

Structural and Biochemical Characterization of the nsp12-nsp7-nsp8 Core Polymerase Complex from SARS-CoV-2

A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus

The severe acute respiratory syndrome-coronavirus replicative protein nsp9 is a single-stranded RNA-binding subunit unique in the RNA virus world

Crystal structure and functional analysis of the SARS-coronavirus RNA cap 2′-o-methyltransferase nsp10/nsp16 complex

Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design

A map of SARS-CoV-2 and host cell interactions

Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5

Characterization of viral proteins encoded by the SARS-coronavirus genome

Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach

Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19

Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

The Nucleocapsid Protein of SARS-CoV-2: a Target for Vaccine Development

COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses

Cleavage and activation of the severe acute respiratory syndrome coronavirus spike protein by human airway trypsin-like protease

Cell entry mechanisms of SARS-CoV-2

Molecular biology of coronaviruses: current knowledge

An insight into SARS-CoV-2 membrane protein infection, present and challenges for target-based antiviral drug development

Mechanism and Complex Roles of HSC70 in Viral Infections

Structural Proteins in Severe Acute Respiratory Syndrome Coronavirus-2

In-silico approaches to detect inhibitors of the human severe acute respiratory syndrome coronavirus envelope protein ion channel

Coronavirus Proteins as Ion Channels: Current and Potential Research

The OC43 human coronavirus envelope protein is critical for infectious virus production and propagation in neuronal cells and is a determinant of neurovirulence and CNS pathology

Analyses of Coronavirus Assembly Interactions with Interspecies Membrane and Nucleocapsid Protein Chimeras

Host-membrane interacting interface of the SARS coronavirus envelope protein: Immense functional potential of C-terminal domain

Structural model of the SARS coronavirus E channel in LMPG micelles

Structure-Based Stabilization of Non-native Protein-Protein Interactions of

Coronavirus Nucleocapsid Proteins in Antiviral Drug Design

Structural Characterization of SARS-CoV-2 : Where We Are , and Where We Need to Be

Emerging coronaviruses: Genome structure, replication, and pathogenesis

Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody

Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites

Genotyping coronavirus SARS-CoV-2: methods and implications

Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC

A CRISPR-based yeast two-hybrid system for investigating RNA-protein interactions

Structure of replicating SARS-CoV-2 polymerase

Unique and conserved features of genome and proteome of SARScoronavirus, an early split-off from the coronavirus group 2 lineage

The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway

The Architecture of SARS-CoV-2 Transcriptome

A new coronavirus associated with human respiratory disease in China

Time series prediction of COVID-19 by mutation rate analysis using recurrent neural network-based LSTM model

Mechanisms of viral mutation

The genetic sequence, origin, and diagnosis of SARS-CoV-2

Structure of mouse coronavirus spike protein complexed with receptor reveals mechanism for viral entry

Prospect of SARS-CoV-2 spike protein: Potential role in vaccine and therapeutic development

Variant analysis of SARS-CoV-2 genomes

Geographic and Genomic Distribution of SARS-CoV-2

Spike mutation SARS-CoV-2," bioRxiv

Spike mutation D614G alters SARS-CoV-2 fitness

An emergent clade of SARS-CoV-2 linked to returned travellers from Iran

A genetic barcode of SARS-CoV-2 for monitoring global distribution of different clades during the COVID-19 pandemic

The proximal origin of SARS-CoV-2

Genomic variations in SARS-CoV-2 genomes from Gujarat: Underlying role of variants in disease epidemiology

Genomic variance of the 2019-nCoV coronavirus

Phylogenetic network analysis of SARS-CoV-2 genomes

Emergence of genomic diversity and recurrent mutations in SARS-CoV-2

A dynamic nomenclature proposal for SARS-CoV-2 to assist genomic epidemiology

Temporal signal and the phylodynamic threshold of

Recurrent emergence and transmission of a SARS-CoV-2 Spike deletion ΔH69/ΔV70

The high infectivity of SARS-CoV-2 B.1.1.7 is associated with increased interaction force between Spike-ACE2 caused by the viral N501Y mutation

Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England

The British variant of the new coronavirus-19 (Sars-Cov-2) should not create a vaccine problem

Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: Insights from linking epidemiological and genetic data

The SARS-CoV-2 S1 spike protein mutation N501Y alters the protein interactions with both hACE2 and human derived antibody: A Free energy of perturbation study

Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy

SARS-CoV-2 genome surveillance in Mainz, Germany, reveals convergent origin of the N501Y spike mutation in a hospital setting

Evidence of escape of SARS-CoV-2 variant B. 1.351 from natural and vaccine-induced sera

Antibody resistance of SARS-CoV-2 variants B. 1.351 and B. 1.1. 7. Nature

Understanding variants of SARS-CoV-2. The Lancet

Post-vaccination SARS-CoV-2 infections and incidence of the B. 1.427/B. 1.429 variant among healthcare personnel at a northern California academic medical center

Sequence analysis of 20,453 SARS-CoV-2 genomes from the Houston Metropolitan Area identifies the emergence and widespread distribution of multiple isolates of all major variants of concern

Circulating SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity

Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity

SARS-CoV-2 lineage B. 1.526 emerging in the New York region detected by software utility created to query the spike mutational landscape

The localized rise of a B. 1.526 variant containing an E484K mutation

Discovery of a SARS-CoV-2 variant 1 from the P.1 lineage harboring K417T/E484K/N501Y mutations in Kofu, Japan

Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil

Pr ep rin t n pe er re vie we d Pr ep rin t n ot pe er re vie we

Country in Focus New variant of SARS-CoV-2 in UK causes surge of COVID-19

SARS-CoV-2 and ORF3a: Non-Synonymous Mutations and Polyproline Regions

EBioMedicine A clade of SARS-CoV-2 viruses associated with lower viral loads in patient upper airways

Reporting two SARS-CoV-2 strains based on a unique trinucleotide-bloc mutation and their potential pathogenic difference Non-technical summary Through an extensive analysis of the SARS-CoV-2 whole-genome sequences , here I am reporting two strains of the

Spiking Pandemic Potential: Structural and Immunological Aspects of SARS-CoV-2

Articles Genomic characterisation and epidemiology of 2019 novel coronavirus : implications for virus origins and receptor binding

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

The SARS-CoV-2 Spike Glycoprotein Biosynthesis, Structure, Function, and Antigenicity: Implications for the Design of Spike-Based Vaccine Immunogens

Coronavirus membrane fusion mechanism offers a potential target for antiviral development

TMPRSS2 activates the human coronavirus 229E for cathepsinindependent host cell entry and is expressed in viral target cells in the respiratory epithelium

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is J o u r n a l P r e -p r o o f Blocked by a Clinically Proven Protease Inhibitor

The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade

Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects

Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes

Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection

A Novel Angiotensin-Converting Enzyme-Related Carboxypeptidase (ACE2) Converts Angiotensin I to Angiotensin 1-9

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

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

Sars-CoV-2 and black population: ACE2 as shield or blade?

The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

ACE2 of the heart: From angiotensin I to angiotensin

Role of the Angiotensin Type 2 Receptor in the Regulation of Blood Pressure and Renal Function

The ACE2/Angiotensin

SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2

SARS-COV-2 associated acute pancreatitis: Cause, consequence or epiphenomenon?

Review of Infectious Etiology of Acute Pancreatitis

SARS coronavirus entry into host cells through a novel clathrin-and caveolae-independent endocytic pathway

Topology and Membrane Anchoring of the Coronavirus Replication Complex: Not All Hydrophobic Domains of nsp3 and nsp6 Are Membrane Spanning

Molecular biology of severe acute respiratory syndrome coronavirus

SARS-Coronavirus Replication / Transcription Complexes Are Membrane-Protected and Need a Host Factor for Activity In Vitro

Evolutionary analysis of SARS-CoV-2: how mutation of Non-Structural Protein 6 (NSP6) could affect viral autophagy

Drug targets for corona virus: A systematic review

Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex

Structure of the RNA-dependent RNA polymerase from COVID-19 virus

Continuous and Discontinuous RNA Synthesis in Coronaviruses

Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting

Coronavirus nsp10/nsp16 Methyltransferase Can Be Targeted by nsp10-Derived Peptide In Vitro and In Vivo To Reduce Replication and Pathogenesis

Architecture and self-assembly of the SARS-CoV-2 nucleocapsid protein

Short peptides derived from the interaction domain of SARS coronavirus nonstructural protein nsp10 can suppress the 2'-O-methyltransferase activity of nsp10/nsp16 complex

Immuno-epidemiology and pathophysiology of coronavirus disease 2019 (COVID-19)

The chemokine system in innate immunity

Imiquimod -A toll like receptor 7 agonist -Is an ideal option for management of COVID 19

Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice

TLR signaling

Control of adaptive immunity by the innate immune system

The light and the dark sides of Interleukin-10 in immune-mediated diseases and cancer

Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients

Articles Clinical features of patients infected with 2019 novel coronavirus

Preventing COVID-19-induced pneumonia with anticytokine therapy

The laboratory tests and host immunity of COVID-19 patients with different severity of illness

The Science Underlying COVID-19: Implications for the Cardiovascular System

Increased Risk of Hospitalization and Death in Patients with COVID-19 and Pre-existing Noncommunicable Diseases and Modifiable Risk Factors in Mexico

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China

Neurological manifestations in COVID-19 : A narrative review

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

Myocardial injury is associated with higher mortality in patients with coronavirus disease 2019: a meta-analysis

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence

Coagulopathy of Coronavirus Disease

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

Coagulopathy in COVID-19: Focus on vascular thrombotic events

D-Dimer, Fibrinogen, and IL-6 in COVID-19 Patients with Suspected Venous Thromboembolism: A Narrative Review

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

An Atypical Case of COVID-19 induced Rhabdomyolysis and Acute Kidney Injury

Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19

Analysis clinical features of COVID-19 infection in secondary epidemic area and report potential biomarkers in evaluation

Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms

Platelet-to-lymphocyte ratio is associated with prognosis in patients with coronavirus disease-19

Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China

Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome

Immunological and inflammatory profiles in mild and severe cases of COVID-19

Virologic and clinical characteristics for prognosis of severe COVID-19: a retrospective observational study in Wuhan, China

Acute Myocardial Injury of Patients with Coronavirus Disease

Aberrant pathogenic GM-CSF<sup>+</sup> T cells and inflammatory CD14<sup>+</sup>CD16<sup>+</sup> monocytes in severe pulmonary syndrome patients of a new coronavirus

Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients

Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2

Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6 Level in Critically Ill Patients With Coronavirus Disease

Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia

Incidence, clinical characteristics and prognostic factor of patients with COVID-19: a systematic review and meta-analysis

Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese

Immune cell profiling of COVID-19 patients in the recovery stageby singlecell sequencing

SARS-CoV-2 infection: The role of cytokines in COVID-19 disease

Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection," medRxiv

May Mediate Disease Severity In COVID-19

Rhabdomyolysis in a Patient With Coronavirus Disease

Concomitant neurological symptoms observed in a patient diagnosed with coronavirus disease 2019

Neurological complications of coronavirus disease (COVID-19) Encephalopathy. Cureus

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

Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in

Thromboinflammation and hypercoagulability of COVID-19

Guillain-Barré syndrome related to COVID-19 infection

Guillain-Barré Syndrome associated with SARS-CoV-2 infection

Coronavirus in water environments: occurrence, persistence and concentration methods -a scoping review

The presence of SARS-CoV-2 RNA in the rfeces of COVID-19 patients

Diarrhea during COVID-19 infection: pathogenesis, epidemiology, prevention and management

Viral load of SARS-CoV-2 in clinical samples

Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents

Indirect virus transmission in cluster of COVID-19 cases

COVID-19: gastrointestinal manifestations and potential

Potential fecal transmission of SARS-CoV-2: current evidence and implications for public health

Computational analysis of SARS-CoV-2/COVID-19 surveillance by wastewater-based epidemiology locally and globally: feasibility, economy, opportunities and challenges

SARS-CoV-2 in wastewater: potential health risk, but also data source

COVID-19 faecal-oral transmission: are we asking the right questions?

The indispensable role of chest CT in the detection of coronavirus disease 2019 (COVID-19)

Clinical Characteristics of Coronavirus Disease 2019 in China

Recent advances and perspectives of nucleic acid detection for coronavirus

Chest CT Findings in Coronavirus Disease-19 (COVID-19): Relationship to Duration of Infection

COVID-19 pneumonia: what has CT taught us?

Computed tomography of the chest: I. Basic principles

Quantitative RT-PCR: pitfalls and potential

Broadly reactive and highly sensitive assay for Norwalk-like viruses based on real-time quantitative reverse transcription-PCR

Diagnosing COVID-19: The Disease and Tools for Detection

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

Patients with RT-PCR-confirmed COVID-19 and Normal Chest CT

Inactivating porcine coronavirus before nuclei acid isolation with the temperature higher than 56 °C damages its genome integrity seriously

Chest CT for Typical Coronavirus Disease 2019 (COVID-19) Pneumonia: Relationship to Negative RT-PCR Testing

Time Course of Lung Changes at Chest CT during Recovery from Coronavirus Disease 2019 (COVID-19)

Management of ground-glass opacities: should all pulmonary lesions with ground-glass opacity be surgically resected?

Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases

Isothermal nucleic acid amplification technologies for point-of-care diagnostics: a critical review

Rapid Detection of Novel

COVID-19) by Reverse Transcription-Loop-Mediated Isothermal Amplification

Rapid colorimetric detection of COVID-19 coronavirus using a reverse transcriptional loop-mediated isothermal amplification (RT-LAMP) diagnostic platform: iLACO

Rapid Molecular Detection of SARS-CoV-2 (COVID-19) Virus RNA Using Colorimetric LAMP

Rapid Detection of SARS-CoV-2 Using Reverse transcription RT-LAMP method

Detection of loop-mediated isothermal amplification reaction by turbidity derived from magnesium pyrophosphate formation

Loop-mediated isothermal amplification of DNA

Development of a single nucleotide polymorphism DNA microarray for the detection and genotyping of the SARS coronavirus

Generic Detection of Coronaviruses and Differentiation at the Prototype Strain Level by Reverse Transcription-PCR and Nonfluorescent Low-Density Microarray

Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19 . The COVID-19 resource centre is hosted on Elsevier Connect , the company ' s public news and information

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections

Antibody responses to SARS-CoV-2 in patients with COVID-19

CRISPR systems for COVID-19 diagnosis

EMT signaling: potential contribution of CRISPR/Cas gene editing

Mandegary, A. ZEB1 and ZEB2 gene editing mediated by CRISPR/Cas9 in A549 cell line

Harnessing nanoparticles for the efficient delivery of the CRISPR/Cas9 system

PCS: a powerful new approach to inducing multiple chromosome splitting in Saccharomyces cerevisiae

An updated evolutionary classification of CRISPR−Cas systems

Diversity and evolution of class 2 CRISPR−Cas systems

CRISPR-Cas12a target binding unleashes indiscriminate single-stranded DNase activity

Two distinct RNase activities ofCRISPR-C2c2 enable guide-RNA processing and RNA detection

Preparation of carbon dot as a potential CRISPR/Cas9 plasmid delivery system for lung cancer cells

SHERLOCK: nucleic acid detection with CRISPR nucleases

SHERLOCK: nucleic acid detection with CRISPR nucleases

Molecular Mechanisms of RNA Targeting by Cas13-containing Type VI CRISPR-Cas Systems

Multiplexed and portable nucleic acid detection platform with Cas13, Cas12a, and Csm6

Nucleic acid detection with CRISPR-Cas13a/C2c2

Evaluation of Enzyme-Linked Immunoassay and Colloidal Gold-Immunochromatographic Assay Kit for Detection of Novel Coronavirus

Causing an Outbreak of Pneumonia (COVID-19)," medRxiv

Microfluidic designs and techniques using lab-on-a-chip devices for pathogen detection for point-of-care diagnostics

A smartphone dongle for diagnosis of infectious diseases at the point of care

Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based Biosensor

Clustered Regularly Interspaced Short Palindromic Repeats/Cas9-Mediated Lateral Flow Nucleic Acid Assay

Rapid diagnosis of H5N1 avian influenza virus infection by newly developed influenza H5 hemagglutinin gene-specific loop-mediated isothermal amplification method

A new approach for diagnosis of bovine coronavirus using a reverse transcription recombinase polymerase amplification assay

The role of respiratory viruses in cystic fibrosis

Improved rolling circle amplification (RCA) of hepatitis B virus (HBV) relaxed-circular serum DNA (RC-DNA)

Diagnosis of human respiratory syncytial virus infection using reverse transcription loop-mediated isothermal amplification

Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays

Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations

Nanoparticle-based bio-barcode assay redefines 'undetectable' PSA and biochemical recurrence after radical prostatectomy

United States

Synergistic antiviral effects against SARS-CoV-2 by plant-based molecules

Immune-mediated approaches against COVID-19

A Structure-Function Diversity Survey of the RNA-Dependent RNA Polymerases From the Positive-Strand RNA Viruses

Homology-Based Identification of a Mutation in the Coronavirus RNA-Dependent RNA

Polymerase That Confers Resistance to Multiple Mutagens

Preventive Efficacy of Tenofovir/Emtricitabine Against Severe Acute Respiratory Syndrome Coronavirus 2 Among Pre-Exposure Prophylaxis Users

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

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

The ProTide Prodrug Technology: From the Concept to the Clinic

Late Ebola virus relapse causing meningoencephalitis: a case report

In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2

Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial

Remdesivir for the treatment of Covid-19-preliminary report

Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase

Mechanism of action of T-705 ribosyl triphosphate against influenza J o u r n a l P r e -p r o o f virus RNA polymerase

In vitro and in vivo activities of anti-influenza virus compound T-705

T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Role of favipiravir in the treatment of COVID-19

Efficacy of favipiravir for an end stage renal disease patient on maintenance hemodialysis infected with novel coronavirus disease 2019

Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase

Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study

Viral replication. Structural basis for RNA replication by the hepatitis C virus polymerase

Sofosbuvir as a potential alternative to treat the SARS-CoV-2 epidemic

Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study

Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import

Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

Multiple-dose versus single-dose ivermectin for Strongyloides stercoralis infection (Strong Treat 1 to 4): a multicentre, open-label, phase 3, randomised controlled superiority trial

Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus

Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin

Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease

HIV protease inhibitors: a review of molecular selectivity and toxicity

HIV-1 assembly, budding, and maturation

Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis?

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19

Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

Ribavirin therapy for severe COVID-19: a retrospective cohort study

Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019-nCoV Infection

Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis

Complex Immune Dysregulation in COVID-19

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review

Seroconversion and indolent course of COVID-19 in patients with multiple sclerosis treated with fingolimod and teriflunomide

Canakinumab in a subgroup of patients with COVID-19

Anakinra for severe forms of COVID-19

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

COVID19 coagulopathy in Caucasian patients

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

The Potential Role of Heparin in Patients With COVID-19: Beyond the Anticoagulant Effect. A Review

Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial

Umifenovir treatment is not associated with improved outcomes in patients with coronavirus disease 2019: a retrospective study

Pirfenidone: A novel hypothetical treatment for COVID-19

Camostat mesilate therapy for COVID-19

Antiviral activity and safety of darunavir/Cobicistat for the treatment of COVID-19

A clinical pilot study on the safety and efficacy of aerosol inhalation treatment of IFN-κ plus TFF2 in patients with moderate COVID-19

Is oseltamivir suitable for fighting against COVID-19: In silico assessment, in vitro and retrospective study

Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized

Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

3C-like protease (3CLpro) structure: Virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates

Intranasal vaccines for SARS-CoV-2: From challenges to potential in COVID-19

NORSTMas an upper airway 'disinfectant

APEPTICO's global survey on incidence of ARDS and outcomes in hospitalized patients with COVID-19 has been published by Critical Care. www.apeptico.com/index-news

Neurimmune and Ethris sign collaboration agreement to rapidly develop inhaled mRNA-based antibody therapy for the treatment of Covid-19

A Trial of ciclesonide in adults with mild-to-moderate COVID-19

Effect of an acute intranasal aerosol dose of PH94B on social and performance anxiety in women with social anxiety disorder

A randomized double-blind placebo-controlled trial 1266 to determine the safety and efficacy of inhaled SNG001 (IFNb-1a for 1267 nebulization) for confirmed SARS-CoV-2 1268 infection

Partner Therapeutics initiates patient enrollment in U.S. 1253 clinical trial evaluating Leukine (rhuGM-CSF, sargramostim) in COVID-19 1254 patients

Diagnosing COVID-19: The Disease and Tools for Detection

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

Patients with RT-PCR-confirmed COVID-19 and Normal Chest CT

Inactivating porcine coronavirus before nuclei acid isolation with the temperature higher than 56 °C damages its genome integrity seriously

Chest CT for Typical Coronavirus Disease 2019 (COVID-19) Pneumonia: Relationship to Negative RT-PCR Testing

Time Course of Lung Changes at Chest CT during Recovery from Coronavirus Disease 2019 (COVID-19)

Management of ground-glass opacities: should all pulmonary lesions with ground-glass opacity be surgically resected?

Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases

Isothermal nucleic acid amplification technologies for point-of-care diagnostics: a critical review

Rapid Detection of Novel Coronavirus (COVID-19) by Reverse Transcription-Loop-Mediated Isothermal Amplification

Rapid colorimetric detection of COVID-19 coronavirus using a reverse transcriptional loop-mediated isothermal amplification (RT-LAMP) diagnostic platform: iLACO

Rapid Molecular Detection of SARS-CoV-2 (COVID-19) Virus RNA Using Colorimetric LAMP

Rapid Detection of SARS-CoV-2 Using Reverse transcription RT-LAMP method

Detection of loop-mediated isothermal amplification reaction by turbidity derived from magnesium pyrophosphate formation

Loop-mediated isothermal amplification of DNA

Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics

Development of a single nucleotide polymorphism DNA microarray for the detection and genotyping of the SARS coronavirus

Generic Detection of Coronaviruses and Differentiation at the Prototype Strain Level by Reverse Transcription-PCR and Nonfluorescent Low-Density Microarray

Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19 . The COVID-19 resource centre is hosted on Elsevier Connect , the company ' s public news and information

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections

Antibody responses to SARS-CoV-2 in patients with COVID-19

SHERLOCK: nucleic acid detection with CRISPR nucleases

Molecular Mechanisms of RNA Targeting by Cas13-containing Type VI CRISPR-Cas Systems

Multiplexed and portable nucleic acid detection platform with Cas13, Cas12a, and Csm6

Nucleic acid detection with CRISPR-Cas13a/C2c2

Evaluation of Enzyme-Linked Immunoassay and Colloidal Gold-Immunochromatographic Assay Kit for Detection of Novel Coronavirus

Causing an Outbreak of Pneumonia (COVID-19)," medRxiv

Microfluidic designs and techniques using lab-on-a-chip devices for pathogen detection for point-of-care diagnostics

A smartphone dongle for diagnosis of infectious diseases at the point of care

Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based Biosensor

Clustered Regularly Interspaced Short Palindromic Repeats/Cas9-Mediated Lateral Flow Nucleic Acid Assay

Rapid diagnosis of H5N1 avian influenza virus infection by newly developed influenza H5 hemagglutinin gene-specific loop-mediated isothermal amplification method

A new approach for diagnosis of bovine coronavirus using a reverse transcription recombinase polymerase amplification assay

The role of respiratory viruses in cystic fibrosis

Improved rolling circle amplification (RCA) of hepatitis B virus (HBV) relaxed-circular serum DNA (RC-DNA)

Diagnosis of human respiratory syncytial virus infection using reverse transcription loop-mediated isothermal amplification

Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays

Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations

Phytochemicals containing biologically active polyphenols as an effective agent against Covid-19-inducing coronavirus

Essential oil composition, total phenolic, flavonoid contents, and antioxidant activity of Thymus species collected from different regions of Iran

Antiviral effects of plant-derived essential oils and their components: an updated review

Plant-based drugs and vaccines for COVID-19. Vaccines

Tobacco-Based Coronavirus Vaccine Poised for Human Tests Bloomberg

Tobacco Plants Contribute Key Ingredient For COVID-19 Vaccine

Potential for Developing Plant-Derived Candidate Vaccines and

Transient plant transformation mediated by Agrobacterium tumefaciens: Principles, methods and applications

What does plant-based vaccine technology offer to the fight against COVID-19?

Immunogenicity and safety of a quadrivalent plant-derived virus like particle influenza vaccine candidate-Two randomized Phase II clinical trials in 18 to 49 and≥ 50 years old adults

Potential for Developing Plant-Derived Candidate Vaccines and

Severe acute respiratory syndrome (SARS) S protein production in plants: development of recombinant vaccine

ClinicalTrial -KBP-201 COVID-19 Vaccine

Pilot production of SARS-CoV-2 related proteins in plants: a proof of concept for rapid repurposing of indoor farms into biomanufacturing facilities. Frontiers in plant science

Potential for Developing Plant-Derived Candidate Vaccines and

Boosted expression of the SARS-CoV nucleocapsid protein in tobacco and its immunogenicity in mice

Severe acute respiratory syndrome (SARS) S protein production in plants: development of recombinant vaccine

Accumulation of recombinant SARS-CoV spike protein in plant cytosol and chloroplasts indicate potential for development of plantderived oral vaccines

Mesenchymal stem cell perspective: cell biology to clinical progress

Secretion of immunoregulatory cytokines by mesenchymal stem cells

Growth factor gene-modified mesenchymal stem cells in tissue regeneration. Drug design, development and therapy

Current advance of immune evasion mechanisms and emerging immunotherapies in renal cell carcinoma

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Clinical Study of Mesenchymal Stem Cell Treatment for Acute Respiratory Distress Syndrome Induced by Epidemic Influenza A (H7N9) Infection: a Hint for COVID-19

Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomized phase 2a safety trial

Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19

Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial

Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series

Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants

Potential role of medicinal plants and their constituents in the mitigation of SARS-CoV-2: identifying related therapeutic targets using network pharmacology and molecular docking analyses

Antiviral activity of nucleoside analogues against SARS-coronavirus (SARS-coV)

A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19

Improved molecular diagnosis of COVID-19 by the novel, highly sensitive and specific COVID-19-RdRp/Hel real-time reverse transcription-PCR assay validated in vitro and with clinical specimens

What Are the Most Powerful Immunogen Design Vaccine Strategies? Reverse Vaccinology 2.0 Shows Great Promise

Advances in antiviral vaccine development

SARS-CoV-2 Vaccines: Status Report

Viruslike particles in vaccine development

Stress, the HPA axis, and nonhuman primate well-being: a review

Virus-like particle-based human vaccines: quality assessment based on structural and functional properties

COVID-19 vaccine: A recent update in pipeline vaccines, their design and development strategies

SARS-CoV-2 vaccines

Peptide-based synthetic vaccines

Pathogen recognition and innate immunity

DNA vaccines against influenza viruses. Vaccines for Pandemic Influenza

SARS-CoV-2 vaccines

Rapidly produced SAM® vaccine against H7N9 influenza is immunogenic in mice. Emerging microbes & infections

draft-landscape-of-covid-19-candidate-vaccines @ www.who.int

Novel platforms for the development of a universal influenza vaccine

Recombinant vaccines and the development of new vaccine strategies

Methods and clinical development of adenovirus-vectored vaccines against mucosal pathogens

Oxford to study nasal administration of COVID-19 vaccine

Intranasal vaccine For Covid-19. www.bharatbiotech.com/ 1104 intranasalvaccine.html

A randomized, double-blind, placebo-controlled Phase I/ II clinical trial to evaluate the safety and immunogenicity of Ad5-NCoV for 1112 inhalation in adults 18 years of age and older

Phase 2, double-blind, randomized, placebo-controlled study of 1120

NasoVAX in the prevention of clinical worsening in patients with early Coronavirus infectious disease 2019

FluGen Inc. Focused on efficacy -M2SR: the vaccine

M2SR, a single replication universal flu vaccine

A Phase 1, randomized, double-blinded, placebo-1135 controlled, dose-escalation and dose-expansion study to evaluate the safety and 1136 immunogenicity of DelNS1-NCoV-RBD LAIV for COVID-19 in Healthy Adults

Nasal spray vaccine for Covid-19

Phase 1, open-label, dose-escalation study to evaluate 1145 tolerability, safety, and immunogenicity of an intranasal live attenuate respiratory syncytial

Promising new COVID-19 treatment in 1150 development at Illinois Tech. www.iit.edu/news/promising-new-covid-19-1151 treatment-developmentillinois-tech

Intravacc announces positive pre-clinical data for its SARS-CoV-2 nose 1153 spray vaccine

Liposomal deliver enhances immune activation by STING agonists for cancer immunotherapy

Why are vaccines against many human viral diseases still unavailable; an historic perspective?

Viral Vaccines in India: An Overview

SARS-CoV-2 serosurvey in Health Care Workers of the Veneto Region

Vaccine manufacturing: challenges and solutions

Immunological mechanisms of vaccination

What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2

mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach

joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine @ www.fda.gov

Vaccines for COVID-19: The current state of play

Technologies to Improve Immunization

A systematic review of SARS-CoV-2 vaccine candidates

Visual inspection of vaccine storage conditions in general practices: A study of 75 vaccine refrigerators

Logistical challenges for potential SARS-CoV-2 vaccine and a call to research institutions, developers and manufacturers

COVID-19 vaccination campaigns take shape

Risk factors for improper vaccine storage and handling in private provider offices

Needle size for vaccination procedures in children and adolescents

Why aren't covid-19 vaccines being manufactured in standard prefilled J o u r n a l P r e -p r o o f syringes?

COVID-19 vaccine acceptance and hesitancy in low-and middle-income countries

Mapping global trends in vaccine confidence and investigating barriers to vaccine uptake: a large-scale retrospective temporal modelling study