COVID-19 (Novel Coronavirus 2019) And The Ongoing Clinical Trials

Coronaviruses are enveloped, positive-sense single stranded viruses ((+)ssRNA virus) belonging to the family Coronaviridae. Most coronaviruses have 8-10 open reading frames (ORFs). ORF1a and ORF1b are translated into polyprotein 1a (pp1a) and pp1ab, which are processed by viral proteases to produce 16 non-structural proteins containing RNA-dependent RNA polymerase enzyme (RdRp). The viral RNA is replicated through transcription of a minus-strand template by RdRp. During replication, coronaviruses generate 6-9 subgenomic mRNAs (sgmRNAs), which lead to translation of accessory and structural proteins from downstream ORFs. Spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins, necessary for completion of a viral replication cycle, are translated from sgmRNAs. At present, comprehensive surveillance remains critical so as to isolate the source of infection, eliminate the routes of transmission, accelerate diagnosis and treatment of suspected cases, and actively research and take measures to deal with the risks of infection and transmission that may result from the scheduled return to work and school.

COVID-19 has triggered enormous human casualties and serious economic loss posing global threat, an understanding of the ongoing situation and the development of strategies to contain the virus’s spread are urgently needed. Currently, various diagnostic kits to test for COVID-19 are available and several repurposing therapeutics for COVID-19 have shown to be clinically effective. In addition, global institutions and companies have begun to develop vaccines for the prevention of COVID-19. Whereas the trials on SARS-CoV-2 genome-based specific vaccines and therapeutic antibodies are currently being tested, this solution is more long-term, as they require thorough testing of their safety. On the other hand, the repurposing of the existing therapeutic agents previously designed for other virus infections and pathologies happens to be the only practical approach as a rapid response measure to the emergent pandemic, as most of these agents have already been tested for their safety. Individuals of any age are susceptible to infection, including neonates and pregnant women. Most patients present with mild to moderate symptoms. The most common symptoms are fever, dry cough, fatigue; upper respiratory tract symptoms can include pharyngalgia, headaches, and myalgia. There is also one report describing patients with gastrointestinal symptoms, including abdominal pain and diarrhea in children and adolescents. These agents can be divided into two broad categories, those that can directly target the virus replication cycle, and those based on immunotherapy approaches either aimed to boost innate antiviral immune responses or alleviate damage induced by dysregulated inflammatory responses. The initial clinical studies revealed the promising therapeutic potential of several of such drugs, including favipiravir, a broad-spectrum antiviral drug that interferes with the viral replication, and hydroxychloroquine, the repurposed antimalarial drug that interferes with the virus endosomal entry pathway. We speculate that the current pandemic emergency will be a trigger for more systematic drug repurposing design approaches based on big data analysis.

Rapid complete genome analysis of SARS-CoV-2 and international sharing of the information have so far allowed us to produce faster and more accurate diagnostic tools. Currently, most of the developed diagnostic tools are qRTPCR-based diagnostic tools, which require longer sample preparation and analysis time, delaying necessary actions for COVID-19 patients in the field. As COVID-19 spreads continuously all over the world, the development of rapid diagnostic methods, which can be tested in the field, is urgently required. It has been reported that some drugs are known to be effective for the treatment of COVID-19 patients. However, the lack of clinical evidence may lead to unpredictable clinical prognosis. At the moment, quick screening of therapeutic agents for the repurposing of FDA-approved and well-characterized drugs may be a more practical approach in epidemics. Vaccines are typically divided into different types, including inactivated vaccines, live attenuated vaccines, vectored vaccines, nucleic acid-based vaccines, and recombinant subunit vaccines.  Considering the seriousness of the recent outbreaks of zoonotic coronaviruses, therapeutic agents for pan-coronaviruses should be developed to cope with future outbreaks.

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Vaccines are the most effective strategy for preventing infectious disease since they are more cost-effective than treatment, and reduce morbidity and mortality without long-lasting effects. Preventive and therapeutic vaccines will be of fundamental value as the most obvious way to protect global health. Over the past two decades, three human coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) emerged worldwide, causing considerable threat to global health. However, there is still no approved vaccines for human coronaviruses. A combination of glucocorticoid together with the antiviral immunomodulatory agent, interferon-α (IFN-α), was also evaluated. Researchers reported that glucocorticoids together with IFN-α can quickly reverse pulmonary imaging abnormalities and improve blood oxygen saturation in patients with SARS. Research groups around the world are accelerating the development of COVID-19 vaccines using various approaches. Precise recognition mechanisms between the virus surface proteins and the host receptors are important for understanding of cross-species transmission and host tropism and for the establishment of animal models for vaccine development. The spike (S) protein of coronaviruses is an important target for vaccine development because it mediates the infection mechanism through receptor binding of host cells. So far there are no specific antiviral measures available to treat COVID-19. Most of the typical options guiding drug manufacture take years of development and are obviously inadequate for the ongoing outbreak. In this situation, studies are often conducted on compassionate use of unproven therapies and clinical trial approvals expedited. In spite of our limited knowledge, there are several treatment options that could be pursued as first-line therapy for COVID-19. These modalities could be tested rapidly on patients currently diagnosed with SARS-CoV-2 infection.

Further research is needed so that we will have a clearer understanding of diagnosis and treatment, prognosis, as well as efforts toward vaccine and drug development. Any solution will be of great significance for overcoming COVID-19 and for preparations for any recurrence.

British Bio Medicine.

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