Remdesivir

Remdesivir (VEKLURY®) is an antiviral prodrug initially developed to treat RNA viruses, such as Ebola [107], and the first drug approved by the U.S. Food and Drug Administration (FDA) for SARS-CoV-2 [108]. Remdesivir is a broad-spectrum antiviral that was applied to SARS-CoV-2 given its success with previous coronaviruses. An adenosine nucleotide, it works by being metabolized into remdesivir triphosphate (RDV-TP) [109]. RDV-TP is a highly selective (3.65-fold) competitive inhibitor of adenosine triphosphate (ATP). It targets the RNA-dependent RNA polymerase (RdRp) enzyme of the SARS-CoV-2 virus, incorporating itself into the viral RNA chain during replication to prevent addition of further nucleotides.

Side-effects for Remdesivir are typically mild, but RDVTP also affects DNA and RNA polymerases in humans which risk injuries to organs. Intravenously administered Remdesivir may cause elevated liver enzymes, harmful for patients with liver conditions [110]. It may be used in renally-impaired patients with estimated globular filtration rates (eGFR) < 30 ml/min [111].

Both placebo and standard of care (SOC) trials show promising results. A 10 day Remdesivir treatment reduced median recovery time from 15 to 10 days in severely ill patients [112]. At the end of the trial, 46% of Remdesivir patients were not hospitalized compared to 36% of placebo. In SOC comparisons, patients treated with Remdesivir for 5 days showed significant improvement over SOC patients on Day 11, with 70% of Remdesivir patients not hospitalized compared to 60% of SOC [113, 114]. One significant trial measured the clinical status of outpatients at 28 Days, comparing a 3-day treatment to placebo [115]. 0.7% of Remdesivir patients had COVID-19, related hospitalizations or all-cause deaths compared to 5.4% of placebo. Remdesivir treatment reduced the rate of hospitalization or death due to COVID-19 by 87% [116].

Aerosolized nano-liposomal carriers of Remdesivir may improve direct drug delivering to lung cells, increase metabolization to RDV-TP and reduce side-effects [117]. Remdesivir nanoliposomes had minimal cytotoxicity in A549 lung carcinoma cells, sustained release up to 50 hours, and significant lung deposition [118]. This aerosol delivery is a future avenue for greater efficacy and self-administration.

Molnupiravir

Molnupiravir (EIDD-2801/MK-4482/Lagevrio®) is a widespectrum antiviral prodrug, originally tested against influenza A [119]. The FDA gave an EUA for Molnupiravir in December 2021 [120]. Molnupiravir is metabolized into the active form β-d-N4hydroxycytidine (NHC) triphosphate, leading to mutated RNA products [121]. In SARS-CoV-2, NHC triphosphate is incorporated into the RNA chain, where it induces errors in replication and mutations in the viral genome, limiting replication and spread.

Molnupiravir side effects include gastro-intestinal symptoms, dizziness and nausea. It has a clean safety profile in general [122, 123]. Molnupiravir has been found to significantly reduce SARS-CoV-2 load and disease transmission in ferret models [124]. In humans, a phase I trial found no significant increase in adverse effects compared to placebo [122, 123]. A phase II trial in hospitalized patients compared the efficacy of placebo treatment and 200 mg, 400 mg, and 800 mg dosages of Molnupiravir twice per day for a 5-day course [125, 126]. The trial found no significant increase in adverse effects, median recovery or all-cause mortality with higher dosages.

A phase III trial found that Molnupiravir (800mg over a 5-day course) significantly reduced percentage of all-cause hospitalization or death (7.3%) compared to placebo (14.1%) to placebo in non-hospitalized, non-vaccinated participants with mild-moderate COVID-19 [127, 128]. Treatment reduced risk of hospitalization or death by 31% compared to placebo.

Favipiravir

Favipiravir (Avigan®) is an broad-class antiviral initially approved for novel influenza [129]. In vitro and in vivo studies demonstrate its efficacy against Ebola, arenavirus, yellow fever virus and foot-and-mouth disease [130]. Favipiravir-RTP, the active form of this drug (a purine analogue), acts as a substrate for the viral RdRp, inhibiting its activity and ultimately terminating protein synthesis [130, 131]. Just like with other viruses, for SARS-CoV-2 it hinders replication of the virus and thus viral load in the patient.

Favipiravir has no optimal dosage established for SARSCoV-2 [130]. It’s oral administration allows for easy at-home treatment of mild-to-moderate COVID-19 [132]. Side effects are mild, including nausea, vomiting, diarrhea and reversible elevation of bilirubin and uric acid. Favipiravir is teratogenic so not administered to pregnant patients [130].

The limited Favipiravir trials for SARS-CoV-2 treatment show reasonable efficacy. One phase III trial showed reduction in median time to clinical cure from 5 to 3 days [133]. In a second trial, by day 10 98% of patients, compared to79% of control, returned negative PCR testing [134].

Ivermectin

Ivermectin (Stromectol®) is an antiparasitic, semisynthetic, anthelmintic agent with potent antiviral and anti-inflammatory properties. Derived from the soil bacterium Streptomyces avermitilis, it was originally used in animals for heartworm and parasites. It is WHO-approved for human treatment of river blindness, scabies and lice [135]. Ivermectin shows antiviral activity against a range of RNA and some DNA viruses, including Zika, dengue and yellow fever [136], though its exact mechanism is unclear. In parasites, ivermectin selectively binds to glutamategated chloride ion channels in invertebrate muscle and nerve cells, resulting in hyperpolarization and paralyzing the parasite. In viruses, it may have antiviral action via inhibition of IMPα/β1mediated nuclear import of viral proteins into host cells [136]. By disrupting this process, it may impede the virus’ ability to replicate and spread in the body.

Potential side effects including headache, muscle pain, or nausea [135, 137], as well as sudden drop in blood pressure and facial/limb swelling [138]. Laboratory test abnormalities include decrease in white cell count and elevated liver tests [138].

In vitro studies show that SARS-CoV-2 infected cells treated with 5 μM of Ivermectin result in a 99.98% reduction in viral RNA [137]. In a phase III trial, patients treated with Doxycycline and Ivermectin recovered more quickly (60.7% vs. 44.4%), were less likely to progress to more serious disease (8.7% vs. 17.8%), and were more likely to be COVID-19 negative by PCR on day 14 (7.7% vs. 20.0%) [139]. Also, topical Ivermectin and Carrageenan prevented COVID-19 spread in an observational trial, with 0% positive cases after 28 days compared to 11.2% in the control [140].

Following a trend of patients self-administering Ivermectin, the FDA advised against its usage and restricted prescriptions by general practitioners. Serious harm may occur in self-medicating without proper guidance [138]. However, reliable results from ongoing trials could lead to its repurposing in combination with other therapeutics for COVID-19 treatment, potentially changing public perception and usage.

Paxlovid

Pfizer’s Paxlovid was the first oral antiviral to receive an EUA, approved by the FDA in December 2021 [141]. It contains nirmatrelvir and ritonavir, co-packaged for oral use. Nirmatrelvir is a SARS-CoV-2 main proteases inhibitor, designed especially for SARS-CoV-2, which prevents the protease from cleaving viral polyproteins into functional components necessary for viral replication. Ritonavir is an HIV-1 protease inhibitor and CYP3A inhibitor, originally designed for treatment of HIV/AIDS. In Paxlovid, it increases the concentration and duration of nirmatrelvir in the body by inhibiting the enzyme responsible for metabolizing nirmatrelvir. Together, the two drugs work toward reducing viral replication and therefore viral load in patients. Side effects are typically mild, including nausea, fatigue and altered taste [142].

Treating high-risk patients with only nirmatrelvir showed a 67% reduction in hospitalizations and an 81% reduction in mortality in patients 65 years and above. No significant benefit in protection from severe COVID-19 was seen in younger adults [143]. Early administration of Paxlovid significant reduces risk of all-cause mortality and disease progression, and reduces viral burden faster than non-use [144]. A 2023 US study found that high-risk patients receiving Paxlovid within five days of a positive COVID-19 test had 26% lower risk of long COVID symptoms after 90 days compared to placebo [145]. It was initially aimed at those with moderate COVID-19 at extreme risk of severe disease progression [142], but is now indicated for non-hospitalized patients at risk of disease progression [144].

Immunotherapies

Monoclonal Antibodies

There are three main recombinant monoclonal antibodies (rMABs): Casirivimab/Imdevimab, Bamlanivimab/Etesevimab and Sotrovimab. The three rMABs therapies work in a similar manner, reducing a patient’s viral load to accelerate recovery. (Figure S3 explaining on neutralization of virus via monoclonal antibodies, in Supplementary Materials)

Figure S3: Neutralization of virus via monoclonal antibodies. When monoclonal antibodies are present, they attach to the spike protein of the virus, preventing them from binding to the receptor on the host cell, thus endocytosis is blocked, and the virus can no longer replicate in the cell. Graphic made with Biorender.com.

Casirivimab/Imdevimab is a combination of rMABs, sold under the name REGEN-COV^TM or Ronapreve^TM. Both Casirivimab and Imdevimab are immunoglobulin gamma-1 proteins which attach to the spike protein of SARS-CoV-2 [146]. REGEN-COV^TM is effective as both a preventative measure and a treatment. Of patients who had never been infected with SARSCoV-2, 4.8% of a REGEN-COV^TM treatment group developed COVID-19 after a 4 week period in comparison to 14.2% of the placebo [147]. As a treatment, REGEN-COV^TM significantly reduces hospitalization and death due to COVID-19 and results in a shorter recovery period (10 days compared to 14 days for placebo) [148]. REGEN-COV^TM is promising for both treating and preventing COVID-19 and could be an alternative to vaccination for immunocompromised and other unvaccinated people.

Bamlanivimab/Etesevimab are  similar rMABs which neutralize the virus, prevent binding to ACE2 receptors and entry to host cells (Graphic representation found in appendix under Figure 8 and 9) [149, 150]. Bamlanivimab/Etesevimab has reduced hospitalization and death by COVID-19 [151]. After 28 days, hospitalization was 2.1% in treatment group vs. 7.0% in placebo.  10 deaths occurred in placebo, while the treatment group also showed lower rates of high viral load (9.8% vs 29.5% in the placebo group). Bamlanivimab/Etesevimab reduced viral load but not recovery time, suggesting need for further research and trials.

Sotrovimab is another rMAB that was originally used against SARS-CoV-1 as well as other sarbecoviruses [152].  It binds to a highly conserved epitope of the SARS-CoV-2 spike protein. Sotrovimab contains two modifications in the Fc binding region to increase its half-life, therapeutic duration and concentration [153]. Sotrovimab shows promising trial results with hospitalization rates of 1% in the treatment group compared to 7% in placebo. Only 2% of the treatment group experienced serious adverse effects compared to 6% of placebo [152]. Sotrovimab shows promising results as broader therapy for all sarbecoviruses including SARSCoV-2.

Convalescent Plasma Therapy

Convalescent plasma (CP) therapy was recommended as a possible treatment early in the pandemic due to its antiviral properties and success in prior infection outbreaks, endemic situations like SARS-CoV-1, H1N1, and Ebola, when treatments were scarce [154]. The antibodies present in convalescent plasma, taken from a recovered patient for the target virus, recognize and bind to specific viral components, neutralizing the virus and triggering an immune response. Enhancing the antiviral response and reducing hyperinflammation are key in treating COVID-19 [21]. CP from recovered COVID-19 patients contains neutralizing IgM and IgG antibodies which limit viral growth [21]. It also encompasses immune-modulatory cytokines that regulate the cytokine storm.

The FDA authorized CP therapy for emergency use and allowed the use of high-titre COVID-19 CP based on a large observational study of hospitalized patients, which showed that the risk of death was 7% lower in a high-titre CP infusion subgroup compared to a low-titre group [155].

CP trials have yielded mixed results, due to factors such as therapy commencement, the quality and number of antibodies transfused, and donor characteristics. To properly select an appropriate donor, conduct serological tests via ELISA prior to trial to measure spike and RBD specific antibody present in the serum. The functionality and quality of these antibodies should be ascertained by neutralization assays [156].

The RECOVERY trial tested CP efficacy in patients that entered the hospital with COVID-19. CP had no influence on length of hospital stay while 24% of both groups died within 28 days. Thus, the largest clinical trials for CP concluded that hightitre CP was ineffective in improving survival or other clinical outcomes [157]. A Bayesian re-evaluation of the RECOVERY trial found that the subgroup of patients who had not yet developed anti-COVID-19 antibodies benefited from CP [158]. This was supported by a randomized, placebo-controlled trial of CP with high IgG titres given within 72 hours of mild symptoms onset. 3% of CP patients developed serious respiratory disease compared to 16% of placebo [159].

The PLACID trial had multiple limitations including bias due to its open label design and no pre-commencement computation of neutralizing antibody titre in donors and patients. It found that CP did not alleviate development of severe COVID-19 nor all deaths.

CP should clinically benefit COVID-19 patients; however, trials have yielded heterogenous results in reducing mortality and clinical improvement. Most CP data originates from uncontrolled cohort studies or case series, thus more controlled studies are needed.

CRISPR/Cas Technology for Elimination and Treatment

As various vaccine platforms were being developed and refined as preventive measures, other biotechnological tools to eliminate the virus were explored, with CRISPR on the forefront. The gene-editing technology, CRISPR/Cas showed promise in vitro and in vivo models, in preventing viral replication of SARSCoV-2 due to its high precision nature and versatility. Previous successful reprogramming of CRISPR-Cas13 to detect and inhibit RNA viruses suggest its potential against any virus, as demonstrated in studies performed by the Broad Institute (MIT) and Harvard University [160].

Reprogrammed CRISPR-Cas systems have shown promise in silencing the efficiency of SARS-CoV-2 [161]. Accessible regions of spike and nucleocapsid transcripts were targeted to suppress replication-component SARS-CoV-2 in Green African monkey kidney cells and human embryonic kidney cells, achieving levels of up to 95% efficiency.  The CRISPR-Cas system also inhibited nucleocapsid expression of the virus by 90% for both the ancestral virus and the Delta variant, achieved through CRISPR RNA (crRNA) redesign.

Furthermore, Prophylactic Antiviral CRISPR in huMAN cells (PAC-MAN) effectively degrades SARS-CoV-2 sequences in human lung epithelial cells [26]. This system uses repurposed Cas13d RNA-guided RNA endonuclease activity to target and inhibit viral replication by targeting specific genomic regions such as the RNA-dependent RNA polymerase (RdRP) and nucleocapsid proteins, which would halt viral replication.

CRISPR technology’s adaptability enables rapid cRNA design and production, making it extremely adaptable to ongoing SARS-CoV-2 mutations. PAC-MAN’s RNA-targeting approach suggests potential efficacy against all coronavirus strains. However, the success of CRISPR therapeutics depends on effective delivery to infected cells and minimizing off-target expression and cleavage in the host.

CRISPR-based Diagnosis

Fast and accurate diagnostics are crucial to controlling transmission of SARS-CoV-2. PCR testing, while accurate, can take up to 72 hours for result. Rapid antigen tests give results in 15 to 20 minutes but are less accurate and susceptible to user errors and inaccuracies [162] CRISPR-based assays for SARS-CoV-2 detection can take only 40 minutes while maintaining accuracy [163].

There are two main CRISPR-based diagnosis tools: DNA endonuclease-targeted CRISPR trans reporter (DETECTR), and STOPCovid (SHERLOCK Testing in One Pot) detection. DETECTR (Mammoth Biosciences) was first showcased in 2017, followed by SHERLOCK (SHERLOCK Biosciences) in 2018 [164].

DETECTR is a CRISPR/Cas12 based detection technique utilizing a lateral flow assay. For a COVID-positive patient, Cas12 accurately targets and cleaves a reporting molecule confirming the virus’ presence in the cell (Figure 6). This technology has several advantages over current PCR testing: rapid results, no need for intricate laboratory infrastructure, and the integration of simple, accessible reporting formats. CRISPR diagnosis is a cheaper, quicker option for viral detection [163]. The SHERLOCK (STOPCovid) test provides accurate results in under an hour with only two key steps: liquid handling and tube opening [165]. This makes testing simpler and decreases sample cross-contamination. Clinical trials show extremely high accuracy for both negative and through RT-PCR”, positive detection [163]. American trials involved 12 SARS-CoV-2 positive and 5 negative patients. Results successfully revealed SARS-CoV-2 detection in 3/3 trials for 11/12 patient samples with only one misrepresented answer in the three rounds. In negative patients, STOPCovid accurately provided negative results [165].

Figure 6: The SARS-CoV-2 DECTECTR diagnosis technique using CRISPR-Cas-12 Adapted from “COVID-19 Diagnostic Test Graphic made with BioRender.com.

In May 2020, SHERLOCK became the first CRISPR SARS-CoV-2 rapid diagnostic tool approved by the FDA [166], followed by Mammoth Bioscience’s DETECTR in August. These diagnostic tools outweigh all current competitors in SARS-CoV-2 detection. They will only be refined to be more cost-effective and accurate. Indeed, on January 21^st 2022, Mammoth Bioscience’s high-throughput assay, DETECTR Boost, was given emergency approval for laboratory use [167]. In January 2022, pharmaceutical giant Bayer paid Mammoth Biosciences $US 40 million to work on gene-editing technologies in four different diseases using their extensive CRISPR toolbox [168]. SARS-CoV-2 technologies based on alternative CRISPR-Cas systems are likely to lead to new and improved methods for diagnosis, treatment and prevention.

Conclusions

Global case numbers of SARS-CoV-2 infections have passed 765 million as recorded in May 2023.  The rapid advances in biotechnology during the pandemic has shown the power of global medical cooperation in combating SARS-CoV-2. Among the available treatment and management regiments, vaccination platforms such as mRNA, as well as pre-existing viral vectors, and inactivated vaccines were the best defence against severe illness and death caused by SARS-CoV-2 pandemic. Due to the ease of production and enormous efficacy, mRNA vaccines have been heralded as the future of vaccine technology. The success of mRNA platform in preventing the SARS-CoV-2 infection have led to further explorations and development of mRNA vaccines for other infectious diseases as well as cancer. Furthermore, in tandem with development of vaccine platforms, there is hope for alternative ways of administration of vaccines, transitioning from intramuscular (IM) to the non-invasive intranasal, which may ally fears for many. Unfortunately, at this time, only the viralreplicating platforms are using this approach in clinical trials.

At the height of the pandemic, while waiting for EUA and large-scale production of the various vaccines, healthcare returned to basics in treatment and management, that is, utilizing repurposed medications and monoclonal therapies. Most of these broad-class drugs were able to manage mild to moderate symptoms of SARSCoV-2 at home; however, combinatory use with immunotherapies improved their therapeutic efficacy. On the other hand, convalescent plasma may have potential but presented logistical challenges and mixed results.  Nevertheless, due to limited resources, infrastructure, and economics, not all were privy to these treatments.

Aside from the refinement of various vaccines platforms, one of the most significant biotechnological breakthroughs lie in the redesigning of CRISPR-technology for both detection and treatment purposes. Repurposing of CRISPR technology such as PAC-MAN would represent an additional treatment for combatting mutating variants. Current mRNA vaccines together with putative CRISPR technology, we should be able to mount an agile response not only to coronaviruses, but to other future viral threats. The remarkable scale of global cooperation seen during the SARSCoV-2 pandemic has reduced vast human suffering and mortality. Furthermore, biotechnological breakthroughs will continue to evolve, thus preparing us for the future pandemics. 

Disclosure

Author Contributions: Conceptualization, B.Y.C. and C.Y.W.; methodology, B.Y.C. C.Y.W. and C.S.; software, S.P.T.; validation, B.Y.C. C.Y.W. and C.S.; formal analysis, S.P.T., P.E.B., A.B., A.H., V.N. and A.S.; investigation, S.P.T., P.E.B., A.B., A.H., V.N. and A.S.; resources, S.P.T., P.E.B., A.B., A.H., V.N. and A.S.; data curation, B.Y.C. and C.Y.W.; writing—original draft preparation, S.P.T., P.E.B., A.B., A.H., V.N. and A.S.; writing—review and editing, S.P.T, B.Y.C and C.Y.W.; supervision, B.Y.C. C.Y.W. and C.S. All authors have read and agreed to the published version of the manuscript

Funding: This research was supported by the NUW Alliance

Malaysia Internship Program, which was funded by the Australian Government New Colombo Plan (NCP) scheme. Students from University of Newcastle, UNSW Sydney and University of Wollongong undertook virtual internships with International Medical University (IMU) faculty in Kuala Lumpur, Malaysia.

Funding for program delivery costs and research learning outcomes (such as publication costs) were covered by the NCP scholarships in order to deepen institutional partnerships and support student mobility in the Indo-Pacific. 

Institutional Review Board Statement: Not applicable.

Data Availability Statement: Not applicable.

Acknowledgments: Not applicable.

Conflicts of Interest: None.

References

1. Safarchi A, Fatima S, Ayati Z, Fatemeh Vafaee (2021) An update on novel approaches for diagnosis and treatment of SARS-CoV-2 infection. Cell & Bioscience 11: 164.
2. WHO announces COVID-19 outbreak a pandemic (2020)
3. WHO Coronavirus (COVID-19) Dashboard (2022).
4. Zhou P, Yang X-L, Wang X-G, Ben Hu, Lei Zhang, et al. (2020) A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579: 270-273.
5. Hoffmann M, Kleine-Weber H, Schroeder S, Nadine Krüger, Tanja Herrler, et al. (2020) SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181: 271-280.e278.
6. Plante JA, Liu Y, Liu J, Hongjie Xia, Bryan A Johnson, et al. (2020) Spike mutation D614G alters SARS-CoV-2 fitness. Nature 592: 116-121.
7. Korber B, Fischer WM, Gnanakaran S, Hyejin Yoon, James Theiler, et al. (2020) Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell 182: 812-827.e819.
8. Li Q, Wu J, Nie J, Li Zhang, Huan Hao, et al. (2020) The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity. Cell 182: 1284-1294.e1289.
9. Li B, Deng A, Li K, Yao Hu, Zhencui Li, et al. (2021) Viral infection and transmission in a large, well-traced outbreak caused by the SARS-CoV-2 Delta variant. Nat Commun 13: 460.
10. Update on Omicron (2021)
11. Classification of Omicron (B.1.1.529): SARS-CoV-2 Variant of Concern (2021)
12. Araf Y, Akter F, Tang Y-d, Rabeya Fatemi, Md Sorwer Alam Parvez, et al. (2022) Omicron variant of SARS-CoV-2: Genomics, transmissibility, and responses to current COVID-19 vaccines. J Med Virol 94: 1825-1832.
13. Torjesen I (2021) Covid-19: Omicron may be more transmissible than other variants and partly resistant to existing vaccines, scientists fear. BMJ 375: n2943.
14. CovGlobe Omicron Analysis Dashboard (2023).
15. Geddes L. Arcturus: WHO upgrades XBB.1.16 to a COVID-19 “variant of interest” (2023).
16. COVID19 Vaccines Tracker (2022).
17. Singh TU, Parida S, Lingaraju MC, Manickam Kesavan, Dinesh Kumar, et al. (2020) Drug repurposing approach to. Pharmacol Rep 72: 1479-1508.
18. Pushpakom S, Iorio F, Eyers PA, K Jane Escott, Shirley Hopper, et al. (2019) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18: 41-58.
19. Low ZY, Farouk IA and Lal SK. (2020) Drug Repositioning: New Approaches and Future Prospects for Life-Debilitating Diseases and the COVID-19 Pandemic Outbreak. Viruses 12: 1058.
20. Hammond J, Leister-Tebbe H, Gardner A, Paula Abreu, Weihang Bao, et al. (2022) Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med 386:1397-1408.
21. Esmaeilzadeh A, Elahi R (2021) Immunobiology and immunotherapy of COVID-19: A clinically updated overview. J Cell Physiol 236: 2519-2543.
22. Salasc F, Lahlali T, Laurent E, Manuel Rosa-Calatrava, Andrés Pizzorno, et al. (2022) Treatments for COVID-19: Lessons from 2020 and new therapeutic options. Curr Opin Pharmacol 62: 43-59.
23. Gadwal A, Roy D, Khokhar M, A Modi, P Sharma, et al. (2021) CRISPR/Cas-New Molecular Scissors in Diagnostics and Therapeutics of COVID-19. Indian J Clin Biochem 36: 459-467.
24. Jiang F, Doudna JA. (2017) CRISPR–Cas9 Structures and Mechanisms. Annu Rev Biophys 46: 505-529.
25. Gronowski AM (2018) Who or What is SHERLOCK? Ejifcc 29: 201-204.
26. Abbott TR, Dhamdhere G, Liu Y, X Lin, L Goudy, et al. (2020) Development of CRISPR as an Antiviral Strategy to Combat SARS-CoV-2 and Influenza. Cell 181: 865-876.e12.
27. WHO lists 9th COVID-19 vaccine for emergency use (2021).
28. WHO Target Product Profiles for COVID-19 Vaccines (2020).
29. The COVID-19 vaccine tracker and landscape compiles detailed information of each COVID-19 vaccine candidate in development by closely monitoring their progress through the pipeline (2022).
30. WHO issues its first emergency use validation for a COVID-19 vaccine and emphasizes need for equitable global access (2020).
31. Alharbi NK, Padron-Regalado E, Thompson CP, Alexandra Kupke, Daniel Wells, et al. (2017) ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice. Vaccine 35: 3780-3788.
32. Pfizer and BioNTech Initiate Study to Evaluate Omicron-Based COVID-19 Vaccine in Adults 18 to 55 Years of Age (2022).
33. Inc P Pfizer and BioNTech Announce Omicron-Adapted COVID-19 Vaccine Candidates Demonstrate High Immune Response Against Omicron (2022).
34. Arena CT (2022) Moderna doses first subject in Omicron-specific booster vaccine trial.
35. Chalkias S, Harper C, Vrbicky K, Stephen R Walsh, Brandon Essink, et al. (2022) A Bivalent Omicron-Containing Booster Vaccine against Covid-19. N Engl J Med 387: 1279-1291.
36. CureVac Provides Update on Phase 2b/3 Trial of First-Generation COVID-19 Vaccine Candidate, CVnCoV (2021).
37. Anand P, Stahel VP. (2021) The safety of Covid-19 mRNA vaccines: a review. Patient Saf Surg 15: 20.
38. Chen M, Yuan Y, Zhou Y, Zhaomin Deng, Jin Zhao, et al. (2021) Safety of SARS-CoV-2 vaccines: a systematic review and meta-analysis of randomized controlled trials. Infect Dis Poverty 10: 94.
39. COVID-19 advice for the public: Getting vaccinated (2022).
40. Walter EB, Talaat KR, Sabharwal C, A Gurtman, S Lockhart, et al. (2022) Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age. N Engl J Med 386: 35-46.
41. Ali K, Berman G, Zhou H, W Deng, V Faughnan, et al. (2021) Evaluation of mRNA-1273 SARS-CoV-2 Vaccine in Adolescents. N Engl J Med 385: 2241-2251.
42. Collie S, Champion J, Moultrie H, LG Bekker, G Gray, et al. (2021) Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa. N Engl J Med 386: 494-496.
43. Choi A, Koch M, Wu K, L Chu, L Ma, et al. (2021) Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis. Nature Medicine 27: 2025-2031
44. Health AGDo (2022).
45. Lin D-Y, Xu Y, Gu Y, D Zeng, B Wheeler, et al. (2023) Effectiveness of Bivalent Boosters against Severe Omicron Infection. N Engl J Med 388: 764-766.
46. Solis D LM, Porter-Morrison A, Hentenaar IT, Yamamoto F, Godbole S, et al. (2023) Neutralization against BA.2.75.2, BQ.1.1, and XBB from mRNA Bivalent Booster. N Engl J Med 388: 183-185.
47. Waltz E (2022) Omicron-targeted vaccines do no better than original jabs in early tests. Nature.
48. Matthew Gagne, Juan I Moliva, Kathryn E Foulds, Shayne F Andrew, Barbara J Flynn, et al. (2022) mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits comparable B cell expansion, neutralizing antibodies and protection against Omicron. Cell 185: 1556-1571.
49. Polack FP, Thomas SJ, Kitchin N, J Absalon, A Gurtman, et al. (2020) Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 383: 2603-2615.
50. Baden LR, El Sahly HM, Essink B, K Kotloff, S Frey, et al. (2021) Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 384: 403-416.
51. Park JW, Lagniton PNP, Liu Y, RH Xu (2021) mRNA vaccines for COVID-19: what, why and how. Int J Biol Sci 17: 1446-1460.
52. Okamura S, Ebina H (2021) Could live attenuated vaccines better control COVID-19? Vaccine 39: 5719-5726.
53. Zhu F-C, Guan X-H, Li Y-H, J-Y Huang, T Jiang, et al. (2020) Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet 396: 479-488.
54. COVID-19 Vaccine Janssen Consumer Medicine Information (CMI) summary. Department of Health and Aged Care's Health Products Regulation Group: Therapeutic Goods Association (2022).
55. Agency UKMHR. Summary of Product Characteristics for Vaxzevria (2023).
56. Organisation WH (2022) The Janssen Ad26.COV2.S COVID-19 vaccine: What you need to know.
57. Wu S, Huang J, Zhang Z, J Wu, J Zhang, et al. (2021) Safety, tolerability, and immunogenicity of an aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in adults: preliminary report of an open-label and randomised phase 1 clinical trial. The Lancet Infectious Diseases 21: 1654-1664.
58. Jeyanathan M, Fritz DK, Afkhami S, E Aguirre, KJ Howie, et al. (2022) Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans. JCI Insight 7: e155655.
59. Hassan AO, Kafai NM, Dmitriev IP, JM Fo, BK Smith, et al. (2020) A Single-Dose Intranasal ChAd Vaccine Protects Upper and Lower Respiratory Tracts against SARS-CoV-2. Cell 183: 169-184.e113.
60. Peacock TP, Brown JC, Zhou J, N Thakur, J Newman, et al. (2022) The SARS-CoV-2 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently uses the endosomal route of entry.
61. van Doremalen N, Lambe T, Spencer A, Sandra B-R, JN Purushotham, et al. (2020) ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature 586: 578-582
62. Logunov DY, Dolzhikova IV, Shcheblyakov DV, AI Tukhvatulin, OV Zubkova, et al. (2021) Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 397: 671-681.
63. Mahase E (2021) AstraZeneca vaccine: Blood clots are “extremely rare” and benefits outweigh risks, regulators conclude 373: n931.
64. Tobaiqy M, Elkout H, MacLure K (2021) Analysis of Thrombotic Adverse Reactions of COVID-19 AstraZeneca Vaccine Reported to EudraVigilance Database. Vaccines (Basel) 9:393
65. Eric Kowarz, Lea Krutzke, Marius Külp, Patrick Streb, Patrizia Larghero, et al. (2022) “Vaccine-Induced Covid-19 Mimicry” Syndrome: Splice reactions within the SARS-CoV-2 Spike open reading frame result in Spike protein variants that may cause thromboembolic events in patients immunized with vector-based vaccines. Elife 2022: e74974.
66. Malkevitch NV, Robert-Guroff M (2004) A call for replicating vector prime-protein boost strategies in HIV vaccine design. Expert Rev Vaccines 3: S105-117.
67. Cao W-C, Liu W, Zhang P-H, F Zhang, JH Richardus, et al. (2007) Disappearance of Antibodies to SARS-Associated Coronavirus after Recovery. N Engl J Med 357: 1162-1163.
68. Interim recommendations for use of the inactivated COVID-19 vaccine, CoronaVac, developed by Sinovac (2021).
69. McDonald I, Murray SM, Reynolds CJ, DM Altmann, RJ Boyton, et al. (2021) Comparative systematic review and meta-analysis of reactogenicity, immunogenicity and efficacy of vaccines against SARS-CoV-2. NPJ Vaccines 6: 74.
70. Schmidt T, Klemis V, Schub D, J Mihm, F Hielscher, et al. I(2021) Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination. Nat Med 27: 1530-1535.
71. Borobia AM, Carcas AJ, Pérez-Olmeda M, L Castaño, MJ Bertran, et al. (2021) Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet 398: 121-130.
72. Organisation WH. The Novavax vaccine against COVID-19: What you need to know (2022).
73. Evaluation of the Safety and Immunogenicity of a SARS-CoV-2 rS Nanoparticle Vaccine With/Without Matrix-M Adjuvant. Novavax Coalition for Epidemic Preparedness Innovations (2023).
74. Heath PT, Galiza EP, Baxter DN, M Boffito, D Browne, et al. (2021) Safety and Efficacy of NVX-CoV2373 Covid-19. N Engl J Med 385: 1172-1183.
75. World Health Organization Grants Second Emergency Use Listing for Novavax COVID-19 Vaccine (2021).
76. Administration ATG. Transporting, storing and handling COVID-19 vaccines (2023).
77. Say D and Crawford N. COVID-19 Vaccine Platforms (2022).
78. Robert-Guroff M (2007) Replicating and non-replicating viral vectors for vaccine development. Curr Opin Biotechnol 18: 546-556.
79. Santosuosso M, Mc Cormick S, Xing Z (2005) Adenoviral vectors for mucosal vaccination against infectious diseases. Viral Immunol 18: 283-291.
80. Phase 2b/3 Trial of VSV-ΔG SARS-CoV-2 Vaccine (BRILIFE) Against Approved Comparator Vaccine.
81. To Evaluate Safety & Immunogenicity of DelNS1-2019-nCoV-RBD-OPT1 for COVID-19 in Healthy Adults Received 2 Doses of BNT162b2.
82. Safety and Immunogenicity of COVI-VAC, a Live Attenuated Vaccine Against COVID-19. Identifier: NCT04619628.
83. Safety and Immunogenicity of an Intranasal RSV Vaccine Expressing SARS-CoV-2 Spike Protein (COVID-19 Vaccine) in Adults. Identifier: NCT04798001.
84. A Phase III Clinical Study of a SARS-CoV-2 Messenger Ribonucleic Acid (mRNA) Vaccine Candidate Against COVID-19 in Population Aged 18 Years and Above. Identifier: NCT04847102.
85. The ARCT-154 Self-Amplifying RNA Vaccine Efficacy Study (ARCT-154-01). Identifier: NCT05012943.
86. Dose-Confirmation Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of mRNA-1273 COVID-19 Vaccine in Adults Aged 18 Years and Older. ModernaTX Inc. Identifier: NCT04405076.
87. Safety and Immunogenicity Study of a SARS-CoV-2 (COVID-19) Variant Vaccine (mRNA-1273.351) in Naïve and Previously Vaccinated Adults. Identifier: NCT04785144.
88. Trials C. A Study to Evaluate the Immunogenicity and Safety of mRNA-1273.529 Vaccine for the COVID-19. Identifier: NCT05249829.
89. Study on Sequential Immunization of Inactivated SARS-CoV-2 Vaccine and Recombinant SARS-CoV-2 Vaccine (Ad5 Vector). Identifier: NCT04892459.
90. Study on Heterologous Prime-boost of Recombinant COVID-19 Vaccine (Ad5 Vector) and RBD-based Protein Subunit Vaccine. Identifier: NCT04833101.
91. Study on Sequential Immunization of Inactivated COVID-19 Vaccine and Recombinant COVID-19 Vaccine (Ad5 Vector) in Elderly Adults. Identifier: NCT04952727.
92. Study of Sputnik V COVID-19 Vaccination in Adults in Kazakhstan. Identifier: NCT04871841.
93. Study to Evaluate Efficacy, Immunogenicity and Safety of the Sputnik-Light. Identifier: NCT04741061.
94. An Open Study on the Safety, Tolerability, and Immunogenicity of "Sputnik Light" Vaccine. Identifier: NCT04713488.
95. Clinical Trial of Efficacy, Safety, and Immunogenicity of Gam-COVID-Vac Vaccine Against COVID-19. Identifier: NCT04530396.
96. Efficacy, Immunogenicity, and Safety of the Inactivated COVID-19 Vaccine (TURKOVAC) Versus the CoronaVac Vaccine. Identifier: NCT05230940.
97. Immunogenicity, Efficacy and Safety of QazCovid-in® COVID-19 Vaccine. Identifier: NCT04691908.
98. A Study to Evaluate The Efficacy, Safety and Immunogenicity of Inactivated SARS-CoV-2 Vaccines (Vero Cell) in Healthy Population Aged 18 Years Old and Above. Identifier: NCT04510207.
99. Efficacy, Safety and Immunogenicity of Inactivated SARS-CoV-2 Vaccines (Vero Cell) to Prevent COVID-19 in Healthy Adult Population In Peru Healthy Adult Population In Peru. Identifier: NCT04612972.
100. Phase III Clinical Trial of CinnaGen COVID-19 Vaccine (SpikoGen). Identifier: NCT05005559.
101. Immunogenicity and Safety of a Booster Dose of the SpikoGen COVID-19 Vaccine. Identifier: NCT05175625.
102. A Study to Evaluate MVC-COV1901 Vaccine Against COVID-19 in Adult. Identifier: NCT04695652.
103. A Study to Evaluate the Efficacy, Immune Response, and Safety of a COVID-19 Vaccine in Adults ≥ 18 Years With a Pediatric Expansion in Adolescents (12 to < 18 Years) at Risk for SARS-CoV-2. Identifier: NCT04611802.
104. A Study Looking at the Effectiveness, Immune Response, and Safety of a COVID-19 Vaccine in Adults in the United Kingdom. Identifier: NCT04583995.
105. Rando HM, Wellhausen N, Ghosh S, AJ Lee, AA Dattoli, et al. (2021) Identification and Development of Therapeutics for COVID-19. Msystems 6: e0023321.
106. Mohanty SS, Sahoo CR, Padhy RN (2021) Targeting Some Enzymes with Repurposing Approved Pharmaceutical Drugs for Expeditious Antiviral Approaches Against Newer Strains of COVID-19. AAPS PharmSciTech 22: 214
107. Tchesnokov EP, Feng JY, Porter DP, M Götte (2019) Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir. Viruses 11: 326.
108. FDA Approves First Treatment for COVID-19 (2020).
109. Veklury® (remdesivir) Prescribing Information (2021).
110. Aleem A, Mahadevaiah G, Shariff N, JP Kothadia, (2021) Hepatic manifestations of COVID-19 and effect of remdesivir on liver function in patients with COVID-19 illness. Proc (Bayl Univ Med Cent) 34: 473-477.
111. Wang S, Huynh C, Islam S, B Malone, N Masani, et al. (2021) Assessment of Safety of Remdesivir in Covid −19 Patients with Estimated Glomerular Filtration Rate (eGFR) < 30 ml/min per 1.73 m^2. J Intensive Care Med 37: 764-768.
112. Adaptive COVID-19 Treatment Trial (ACTT). Identifier: NCT04280705.
113. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment. Identifier: NCT04292730.
114. Spinner CD, Gottlieb RL, Criner GJ, JR Arribas López, AM Cattelan, et al. (2020) Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA 324: 1048-1057.
115. Study to Evaluate the Efficacy and Safety of Remdesivir (GS-5734™) Treatment of Coronavirus Disease 2019 (COVID-19) in an Outpatient Setting (2019). Identifier: NCT04501952.
116. Gottlieb RL, Vaca CE, Paredes R, J Mera, BJ Webb, et al. (2021) Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med 386: 305-315.
117. Li J, Zhang K, Wu D, L Ren, X Chu, et al. (2021) Liposomal remdesivir inhalation solution for targeted lung delivery as a novel therapeutic approach for COVID-19. Asian J Pharm Sci 16: 772-783.
118. Vartak R, Patil SM, Saraswat A, M Patki, NK Kunda, et al. (2021) Aerosolized nanoliposomal carrier of remdesivir: An effective alternative for COVID-19 treatment in vitro. Nanomedicine (Lond) 16: 1187-1202.
119. Toots M, Yoon J-J, Hart M, MG Natchus, GR Painter, et al. (2020) Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model. Transl Res 218: 16-28.
120. Administration UFaD. Coronavirus (COVID-19) Update: FDA Authorizes Additional Oral Antiviral for Treatment of COVID-19 in Certain Adults. (2021).
121. Kabinger F, Stiller C, Schmitzová J, C Dienemann, G Kokic, et al. (2021) Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol 28: 740-746.
122. Painter WP, Holman W, Bush JA, F Almazedi, H Malik, et al. (2021) Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2. Antimicrob Agents Chemother 65: e02428-20.
123. COVID-19 First In Human Study to Evaluate Safety, Tolerability, and Pharmacokinetics of EIDD-2801 in Healthy Volunteers. Identifier: NCT04392219.
124. Cox RM, Wolf JD, Plemper RK (2021)Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat Microbiol 6: 11-18
125. Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19 (MK-4482-001). Identifier: NCT04575584.
126. Arribas José R, Bhagani S, Lobo Suzana M, I Khaertynova, L Mateu, et al. (2022) Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19. NEJM Evidence 1
127. Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002). Identifier: NCT04575597.
128. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, E Kovalchuk, A Gonzalez, et al. (2021) MOVe-OUT Study Group. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med 386: 509-520.
129. Shiraki K, Daikoku T (2020) Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther 209: 107512
130. Agrawal U, Raju R, Udwadia ZF (2020) Favipiravir: A new and emerging antiviral option in COVID-19. Med J Armed Forces India 76: 370-376
131. Furuta Y, Gowen BB, Takahashi K, K Shiraki, DF Smee, et al. (2013) Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res 100: 446-454.
132. Udwadia ZF, Singh P, Barkate H, S Patil, S Rangwala, et al. (2021) Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int J Infect Dis 103: 62-71.
133. Ctri A Clinical Study on Favipiravir Compared to Standard Supportive Care in Patients With Mild to Moderate COVID-19 (2020).
134. Study of Favipiravir Compared to Standard of Care in Hospitalized Patients With COVID-19. Identifier: NCT04542694.
135. Bryant A, Lawrie TA, Dowswell T, EJ Fordham, S Mitchell, et al. (2021) Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. Am J Ther 28: e434-e460.
136. Yang SNY, Atkinson SC, Wang C, A Lee, MA Bogoyevitch, et al. (2020) The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res 177: 104760.
137. Caly L, Druce JD, Catton MG, DA Jans, KM Wagstaff, et al. (2020) The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 178: 104787.
138. FAQ: COVID-19 and Ivermectin Intended for Animals (2023).
139. Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19 Infection. Dhaka Medical College. Identifier: NCT04523831.
140. USEFULNESS of Topic Ivermectin and Carrageenan to Prevent Contagion of Covid 19. Identifier: NCT04425850.
141. Administration UFaD. Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19. (2021).
142. Administration UFaD. (2022) Fact Sheet for Healthcare Providers: Emergency Use Authorization for Paxlovid.
143. Arbel R, Sagy YW, Hoshen M, E Battat, G Lavie, et al. (2022) Oral Nirmatrelvir and Severe Covid-19 Outcomes During the Omicron Surge. N Engl J Med 387: 790-798.
144. Wong CKH, Au ICH, Lau KTK, EHY Lau, BJ Cowling, et al. (2022) Real-world effectiveness of early molnupiravir or nirmatrelvir–ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.2 wave: a retrospective cohort study. Lancet Infect Dis 22: 1681-1693.
145. Xie Y, Choi T, Al-Aly Z (2023) Association of Treatment With Nirmatrelvir and the Risk of Post–COVID-19 Condition. JAMA Intern Med e230743.
146. Deeks ED (2021) Casirivimab/Imdevimab: First Approval. Drugs 81: 2047-2055.
147. COVID-19 Study Assessing the Efficacy and Safety of Anti-Spike SARS CoV-2 Monoclonal Antibodies for Prevention of SARS CoV-2 Infection Asymptomatic in Healthy Adults and Adolescents Who Are Household Contacts to an Individual With a Positive SARS-CoV-2 RT-PCR Assay. Identifier: NCT04452318.
148. Weinreich DM, Sivapalasingam S, S Ali, H Gao, Norton T, et al. (2021) REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. N Engl J Med 385: e81.
149. Chigutsa E, O’Brien L, Ferguson-Sells L, A Long, J Chien, et al. (2021) Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID-19 Infection. Clin Pharmacol Ther 110: 1302-1310.
150. FDA authorizes bamlanivimab and etesevimab monoclonal antibody therapy for post-exposure prophylaxis (prevention) for COVID-19 (2021).
151. Dougan M, Nirula A, Azizad M, B Mocherla, RL Gottlieb, et al. (2021) Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N Engl J Med 385: 1382-1392.
152. Gupta A, Gonzalez-Rojas Y, Juarez E, MC Casal, J Moya, et al. (2021) Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N Engl J Med 385: 1941-1950.
153. TGA provisionally approves GlaxoSmithKline's COVID-19 treatment: sotrovimab (XEVUDY) (2021).
154. Salazar E, Christensen PA, Graviss EA, DT Nguyen, B Castillo, et al. (2020) Treatment of Coronavirus Disease 2019 Patients with Convalescent Plasma Reveals a Signal of Significantly Decreased Mortality. Am J Pathol 190: 2290-2303.
155. Korley FK, Durkalski-Mauldin V, Yeatts SD, K Schulman, RD Davenport, et al. (2021) Early convalescent plasma for high-risk outpatients with Covid-19. N Engl J Med 385:1951-1960.
156. Gupta SL, Jaiswal RK (2022) Neutralizing antibody: a savior in the Covid-19 disease. Mol Biol Rep 49: 2465-2474.
157. Abani O, Abbas A, Abbas F (2021) Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet 397: 2049-2059.
158. Hamilton FW, Lee T, Arnold DT, Lilford R, Hemming K, et al. (2021) Is convalescent plasma futile in COVID-19? A Bayesian re-analysis of the RECOVERY randomized controlled trial. Int J Infect Dis 109: 114-117.
159. Libster R, Pérez Marc G, Wappner D, S Coviello, A Bianchi, et al. (2021) Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med 384: 610-618.
160. Freije CA, Myhrvold C, Boehm CK, AE Lin, NL Welch, et al. (2019) Programmable Inhibition and Detection of RNA Viruses Using Cas13. Mol Cell 76: 826-837.e11.
161. Fareh M, Zhao W, Hu W, JML Casan, A Kumar, et al. (2021) Reprogrammed CRISPR-Cas13b suppresses SARS-CoV-2 replication and circumvents its mutational escape through mismatch tolerance. Nat Commun 12: 4270.
162. Routsias JG, Mavrouli M, Tsoplou P, K Dioikitopoulou, A Tsakris, et al. (2021) Diagnostic performance of rapid antigen tests (RATs) for SARS-CoV-2 and their efficacy in monitoring the infectiousness of COVID-19 patients. Sci Rep 11: 22863.
163. Broughton JP, Deng X, Yu G, CL Fasching, V Servellita, et al. (2020) CRISPR–Cas12-based detection of SARS-CoV-2. Nat Biotechnology 38: 870-874.
164. Mustafa MI, Makhawi AM, Kraft CS (2021) SHERLOCK and DETECTR: CRISPR-Cas Systems as Potential Rapid Diagnostic Tools for Emerging Infectious Diseases. J Clin Microbiol 59: e00745-20.
165. Joung J, Ladha A, Saito M, R Bruneau, M-L W Huang, et al (2020) Point-of-care testing for COVID-19 using SHERLOCK diagnostics. medRxiv 20091231.
166. Sherlock Biosciences Receives FDA Emergency Use Authorization for CRISPR SARS-CoV-2 Rapid Diagnostic (2020).
167. In Vitro Diagnostics EUAs - Molecular Diagnostic Tests for SARS-CoV-2 (2022).
168. Liu A. JPM 2022: Bayer taps CRISPR science from Doudna's lab in $1B biobucks Mammoth gene therapy deal (2022).

References (for supplementary materials)

S1.    WHO lists Moderna vaccine for emergency use, https://www.who.int/news/item/30-04-2021-who-lists-moderna-vaccine-for-emergency-use (2021).

S2.    WHO issues its first emergency use validation for a COVID-19 vaccine and emphasizes need for equitable global access, https://www.who.int/news/item/31-12-2020-who-issues-its-first-emergency-use-validation-for-a-covid-19-vaccine-and-emphasizes-need-for-equitable-global-access (2020).

S3.    Statement of the COVID-19 subcommittee of the WHO Global Advisory Committee on Vaccine Safety (GACVS) on safety signals related to the Johnson & Johnson/Janssen COVID-19 vaccine, https://www.who.int/news/item/19-05-2021-statement-gacvs-safety-johnson-johnson-janssen-covid-19-vaccine (2021).

S4.    WHO recommendation AstraZeneca/EU approved sites COVID-19 Vaccine (ChAdOx1-S) [recombinant]), (2021).

S5.    WHO lists two additional COVID-19 vaccines for emergency use and COVAX roll-out, https://www.who.int/news/item/15-02-2021-who-lists-two-additional-covid-19-vaccines-for-emergency-use-and-covax-roll-out (2021).

S6.    Organisation WH. WHO validates 11th vaccine for COVID-19. WHO2022.

S7.    WHO issues emergency use listing for eighth COVID-19 vaccine, https://www.who.int/news/item/03-11-2021-who-issues-emergency-use-listing-for-eighth-covid-19-vaccine (2021).

S8.    WHO lists additional COVID-19 vaccine for emergency use and issues interim policy recommendations, https://www.who.int/news/item/07-05-2021-who-lists-additional-covid-19-vaccine-for-emergency-use-and-issues-interim-policy-recommendations (2021).

S9.    WHO validates Sinovac COVID-19 vaccine for emergency use and issues interim policy recommendations, https://www.who.int/news/item/01-06-2021-who-validates-sinovac-covid-19-vaccine-for-emergency-use-and-issues-interim-policy-recommendations (2021).

S10.  WHO lists 10th COVID-19 vaccine for emergency use : Nuvaxovid, https://www.who.int/news/item/21-12-2021-who-lists-10th-covid-19-vaccine-for-emergency-use-nuvaxovid (2021)

S11.  World Health Organization Grants Second Emergency Use Listing for Novavax COVID-19 Vaccine, https://ir.novavax.com/2021-12-20-World-Health-Organization-Grants-Second-Emergency-Use-Listing-for-Novavax-COVID-19-Vaccine (2021).

S12.  Fight COVID-19 Trial. https://ClinicalTrials.gov/show/NCT04303299.

S13.  Trial of Early Therapies During Non-hospitalized Outpatient Window for COVID-19. https://ClinicalTrials.gov/show/NCT04372628.

S14.  Lopinavir/ Ritonavir, Ribavirin and IFN-beta Combination for nCoV Treatment. https://ClinicalTrials.gov/show/NCT04276688.

S15.  Clinical Study of Arbidol Hydrochloride Tablets in the Treatment of Pneumonia Caused by Novel Coronavirus. https://ClinicalTrials.gov/show/NCT04260594

S16.  A Prospective/Retrospective,Randomized Controlled Clinical Study of Antiviral Therapy in the 2019-nCoV Pneumonia. https://ClinicalTrials.gov/show/NCT04255017

S17.  Darunavir/Cobicistat vs. Lopinavir/Ritonavir in COVID-19 Pneumonia in Qatar. https://ClinicalTrials.gov/show/NCT04425382

S18.  Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe Coronavirus Disease (COVID-19). https://ClinicalTrials.gov/show/NCT04292899

S19.  Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment. https://ClinicalTrials.gov/show/NCT04292730

S20.  Study to Evaluate the Efficacy and Safety of Remdesivir (GS-5734™) Treatment of Coronavirus Disease 2019 (COVID-19) in an Outpatient Setting. https://ClinicalTrials.gov/show/NCT04501952

S21.  Adaptive COVID-19 Treatment Trial 2 (ACTT-2). https://ClinicalTrials.gov/show/NCT04401579

S22.  Adaptive COVID-19 Treatment Trial (ACTT). https://ClinicalTrials.gov/show/NCT04280705

S23.  Adaptive COVID-19 Treatment Trial 3 (ACTT-3). https://ClinicalTrials.gov/show/NCT04492475

S24.  Study of Favipiravir Compared to Standard of Care in Hospitalized Patients With COVID-19. https://ClinicalTrials.gov/show/NCT04542694

S25.  Evaluation of Sofosbuvir and Daclatasvir Combo in COIVD-19 Patients in Egypt. https://ClinicalTrials.gov/show/NCT04773756

S26.  Sofosbuvir/Ledipasvir and Nitazoxanide for Treatment of COVID-19. https://ClinicalTrials.gov/show/NCT04498936

S27.  Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002). https://ClinicalTrials.gov/show/NCT04575597

S28.  Study of MK-4482 for Prevention of Coronavirus Disease 2019 (COVID-19) in Adults (MK-4482-013). https://ClinicalTrials.gov/show/NCT04939428

S29.  The Safety of Molnupiravir (EIDD-2801) and Its Effect on Viral Shedding of SARS-CoV-2 (END-COVID). https://ClinicalTrials.gov/show/NCT04405739

S30.  A Safety, Tolerability and Efficacy of Molnupiravir (EIDD-2801) to Eliminate Infectious Virus Detection in Persons With COVID-19. https://ClinicalTrials.gov/show/NCT04405570

S31.  Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19 (MK-4482-001). https://ClinicalTrials.gov/show/NCT04575584

S32.  Clinical Trial of Ivermectin Plus Doxycycline for the Treatment of Confirmed Covid-19 Infection. https://ClinicalTrials.gov/show/NCT04523831

S33.  USEFULNESS of Topic Ivermectin and Carrageenan to Prevent Contagion of Covid 19. https://ClinicalTrials.gov/show/NCT04425850

S34.  A Multicentre Open-label Two-arm Randomised Superiority Clinical Trial of Azithromycin Versus Usual Care In Ambulatory COVID19 (ATOMIC2). https://ClinicalTrials.gov/show/NCT04381962

S35.  Hydroxychloroquine vs. Azithromycin for Outpatients in Utah With COVID-19. https://ClinicalTrials.gov/show/NCT04334382.