SARS-CoV-2/COVID-19: Viral Genomics, Epidemiology, Vaccines, and Therapeutic Interventions
Abstract
:1. Introduction
2. Epidemiology and Transmission of SARS-CoV-2
- SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2
- COVID-19 or Covid-19: Corona virus disease, 2019. COVID-19 is the official name of the disease manifested by SARS-CoV-2.
- R0: Reproduction number that defines the number of secondary cases that will be produced by a single infectious index case in a population that is fully susceptible to the disease. For example, a R0 of 2 means that, on average, one primary index case would infect two other people, generating two secondary cases. Continuous horizontal (human-to-human) transmission will occur if R0 is above the critical threshold of one.
- Fomite Transmission: A fomite is any inanimate object (i.e., surface) when contaminated with or exposed to infectious agent, can serve as a source to transmit the agent into a new host.
- Non-Pharmacological Interventions (NPIs): NPIs are evidence based, non-invasive, mostly policy/regulation driven interventions on human health. NPIs (i.e., physical [“social”] distancing) can be very effective to contain viral shedding.
3. Genomics of SARS-CoV-2
4. Transcriptomic Map and SARS CoV-2-Human Protein–Protein Interactions to Identify Drug Targets
5. Diagnosis of COVID-19
6. Development of Vaccines and Experimental Therapeutic Interventions for SARS-CoV-2
6.1. Vaccine Development
6.2. Experimental Therapeutic Interventions
6.2.1. Convalescent Plasma (CP) Therapy
6.2.2. Soluble Human Angiotensin-Converting Enzyme 2 (ACE2)
7. Drug Repurposing for COVID-19
- Lopinavir (LPV)-Ritonavir (RTV) combination (Kaletra): This is an FDA-approved drug for HIV-1 treatment. Lopinavir is a protease inhibitor that inhibits virus particle maturation, a late step in HIV-1 replication, while ritonavir helps boost the activity of lopinavir by inhibiting CYP3A enzymes that slows down the rate at which lopinavir is broken down in the liver [69]. Findings from in vitro and animal studies against both SARS and MERS indicate its potential for COVID-19 treatment [69,70,71,72]. Lopinavir-Ritonavir has been used either on its own or in combination with either alpha interferon (China) or chloroquine/hydroxychloroquine (South Korea) for COVID-19 treatment with some success [73,74]. However, new data from China cast doubt on the beneficial effect in seriously ill COVID-19 patients [75]. Thus, results from additional clinical trials are needed to establish the efficacy of this treatment for COVID-19 which are currently underway.
- Favipiravir (Favilavir or Avigan): Favipiravir (FPV) is an RNA-dependent RNA polymerase inhibitor developed by Fujifilm Toyama Chemical in Japan that is safe and has been effective in other viral infections, including influenza [76,77]. It has now been shown to be useful against SARS-CoV-2 in initial clinical trials conducted in Wuhan and Shenzhen [78]. In this study, the effects of FPV versus LPV/RTV were compared during the treatment of COVID-19 patients. The FPV-treated patients demonstrated much better therapeutic response especially with regard to faster viral clearance and improvement rate in chest imaging. Based on these encouraging results, favipiravir has been approved by the National Medical Products Administration of China as the first anti-COVID-19 drug in the country [66].
- Chloroquine/Hydroxychloroquine: Chloroquine is an inexpensive drug for the treatment of malaria and features on the WHO list of essential medicines. It is also used as an anti-inflammatory agent for the treatment of autoimmune diseases. Chloroquine is thought to inhibit virus replication by increasing endosomal pH as many viruses such as Ebola and Marburg that require the acidic environment of the endosome for successful replication [79,80,81]. However, a recent study showed that the anti-inflammatory effects of chloroquine are mediated by upregulation of the cyclin-dependent kinase inhibitor, p21 [82]. In vitro studies have shown its potent antiviral effect against the SARS-CoV-2 [83]. A multicenter clinical trial in China has reported efficacy with amelioration of exacerbation of pneumonia and acceptable safety margin with use of chloroquine for treatment of COVID-19 [10]. Hydroxychloroquine is an analogue of chloroquine which is more stable with better clinical safety profile and has anti-SARS-CoV-2 activity. It has been shown to quicken recovery and clearance of the virus in COVID-19 patients and used successfully in combination with the macrolide antibiotic azithromycin [84]. A recent clinical trial, however, has shown disappointing results with the combination of azithromycin with hydroxychloroquine in critically-ill COVID-19 patients [85], suggesting that larger studies with controlled design are needed before conclusive recommendations can be made for chloroquine/hydroxychloroquine in the treatment of COVID-19. Interestingly, chloroquine and hydroxychloroquine are zinc ionophores and zinc has been shown to inhibit RNA-dependent RNA polymerase enzyme of coronaviruses [86,87]. Thus, one reason for the limited success of some of these clinical trials could be due to absence of zinc supplementation which may be necessary to observe the therapeutic effects of these drugs on SARS-CoV-2 and other RNA virus infections [88].
- Remdesivir (GS-5734): Remdesivir is a nucleotide analogue prodrug with broad spectrum antiviral activity against many RNA viruses [89]. Like Favipiravir, it blocks RNA-dependent RNA polymerase, an enzyme that replicates the viral genome, inhibiting an early step in virus replication, compared to protease inhibitors that target the late steps of virus replication [90,91]. It has also shown to inhibit replication of MERSCoV, SARS-CoV, and SARS-CoV-2 in animal models [83,89,92,93]. So far, it has been used as an investigational drug for the treatment of Ebola, MERS-CoV, and SARS-CoV2, and other RNA viruses, but has not been approved for any disease [83,89,92,93]. In a compassionate use of remdesivir in a cohort of patients hospitalized for severe COVID-19, the developers of the drug (Gilead Sciences, City, US State abbrev., USA) reported clinical improvement in 68% (36 of 53) of patients [94]. The first randomized, double-blind, placebo-controlled, multicenter clinical trial of remdesivir in 237 patients from Hubei, China, has just been published [95]. Unfortunately, it did not show statistically meaningful clinical benefits except for numerical reduction in time to clinical improvement [95]. Furthermore, treatment with remdesivir had to be stopped early in some patients because of undesirable effects in 12% patients versus 5% patients on placebo. Similar results have been announced from the first US clinical trial of the drug at the time of this writing, which are still unpublished. Further results are awaited on multiple clinical trials of remdesivir in several countries for more conclusive guidelines on its use in COVID-19 patients.
- SNG001: SNG001 is an inhaled experimental drug (interferon beta) developed by the UK biotech firm Synairgen. The ability to inhale the drug will allow the patients to “self-administer” it by using a small hand-held nebulizer. It was developed for the severe lung disease chronic-obstructive pulmonary disorder (COPD), but, due to the current COVID-19 crisis, it has been fast-tracked for use in a 100-patient phase II clinical trial (EudraCT2020-001023-14) in the UK (https://adisinsight.springer.com/drugs/800024480), the results of which are awaited.
- Tocilizumab: Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R) that is approved by FDA to treat patients with rheumatoid arthritis, systemic juvenile idiopathic arthritis, and giant cell arteritis [96]. IL-6 has been shown to be a key mediator of cytokine release storm (CRS) observed in critically ill COVID-19 [96]. Therefore, it has been proposed as a potential therapy to treat such patients [97]. Thus, Tocilizumab has recently been used as an immunosuppressive agent during CRS observed in severely ill COVID-19 patients in China and Italy with promising results [98,99]. COVID-19 patients treated with Tocilizumab in China showed marked improvement indicating that Tocilizumab potentially could be very effective in treating patients with severe infection. Consistent with this, administration of tocilizumab in a COVID-19 patient with pneumonia in Italy showed favorable changes of CT findings within 14 days of treatment [100]. It is turning out to be a promising therapy to treat severely ill COVID-19 patients.
- Kinases: p21-activated protein kinases (PAKs) are cytosolic serine/threonine protein kinases downstream of small (p21) GTPases, including members of the Cdc42 and Rac families. Multiple studies have shown that the major pathogenic kinase in this group, PAK1, plays an important role in the entry, replication and spread of several important viruses, including influenza and HIV [101,102]. Coronaviruses exploit macropinocytosis to gain entry into cells and this process has been shown to be dependent on PAK1 activity [103,104]. Targeting of PAK1 to prevent micropinocytosis has been implicated for therapeutic intervention [105]. This strongly suggests that PAK1-inhibitors could be valuable for the treatment of COVID-19 infection. PAK-1 inhibitors include caffeic acid and its ester, propolis, ketorolac, and triptolide. Unfortunately, all these have problems with solubility and cell penetration. However, newer PAK-1 inhibitors, such as 15K (the 1,2,3-triazolyl ester of ketorolac, that is 500 times more potent at inhibiting PAK1 than the parent compound [106], minnelide (in which a hydroxyl group of triptolide is phosphorylated, boosting its water-solubility over 3000 times [107], and frondoside A [108] are much more potent and may be of value in suppressing the effects of this virus.
8. Non-Pharmacological Interventions
9. Future Directions for COVID-19 Research
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Category | Data Type | Database |
---|---|---|
SARS-CoV-2 Genome Sequencing Data | DNA Sequencing Data | https://www.ncbi.nlm.nih.gov/genbank/sars-cov-2-seqs/ |
SARS-CoV-2 Transcriptomic Map | RNA Sequencing Data | Open Science Framework: accession number doi:10.17605/OSF.IO/8F6N9 |
SARS-CoV-2 and Human Protein Interactions | Mass Spectrometry Raw Data | http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD018117 |
SARS-CoV-2 Strains | Genomic Epidemiology | https://nextstrain.org/ncov https://www.gisaid.org/ |
The COVID-19 Host Genetics Initiative | Host Genetics Data (GWAS, WES, WGS) | https://www.covid19hg.org/ |
COVID-19 Cell Atlas | Single cell transcriptomics data | www.covid19cellatlas.org |
List of Clinical Trials | Clinical Trial Related Information | https://clinicaltrials.gov/ct2/home |
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Uddin, M.; Mustafa, F.; Rizvi, T.A.; Loney, T.; Al Suwaidi, H.; Al-Marzouqi, A.H.H.; Kamal Eldin, A.; Alsabeeha, N.; Adrian, T.E.; Stefanini, C.; et al. SARS-CoV-2/COVID-19: Viral Genomics, Epidemiology, Vaccines, and Therapeutic Interventions. Viruses 2020, 12, 526. https://doi.org/10.3390/v12050526
Uddin M, Mustafa F, Rizvi TA, Loney T, Al Suwaidi H, Al-Marzouqi AHH, Kamal Eldin A, Alsabeeha N, Adrian TE, Stefanini C, et al. SARS-CoV-2/COVID-19: Viral Genomics, Epidemiology, Vaccines, and Therapeutic Interventions. Viruses. 2020; 12(5):526. https://doi.org/10.3390/v12050526
Chicago/Turabian StyleUddin, Mohammed, Farah Mustafa, Tahir A. Rizvi, Tom Loney, Hanan Al Suwaidi, Ahmed H. Hassan Al-Marzouqi, Afaf Kamal Eldin, Nabeel Alsabeeha, Thomas E. Adrian, Cesare Stefanini, and et al. 2020. "SARS-CoV-2/COVID-19: Viral Genomics, Epidemiology, Vaccines, and Therapeutic Interventions" Viruses 12, no. 5: 526. https://doi.org/10.3390/v12050526