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Biotech In The Fight With Coronavirus, 2019-nCoV

February 09, 2020

Biotech company Gilead Science is testing antiviral drug remdesivir which is currently underway in China in hopes that it will be...

Biotech company Gilead Science is testing antiviral drug remdesivir which is currently underway in China in hopes that it will be an effective treatment for the 2019 Novel Coronavirus (2019-nCoV).
There is no cure for the deadly Wuhan coronavirus, but several big biotech companies are hoping they can treat the symptoms with existing antiviral medications. Gilead Sciences, a biopharmaceutical firm with an experimental drug called remdesivir that is used to treat the Ebola virus, said late Friday it is working with Chinese health authorities to see if the medication can combat the symptoms of coronavirus.

The company said in a statement that remdesivir has demonstrated some success in treating MERS and SARS, two viruses similar to the Wuhan coronavirus, in animals. Remdesivir has also been used for emergency treatment of patients with Ebola. But the drug has not yet been officially licensed or approved for treatment by any global health organization, Gilead added. Investors were nonetheless encouraged. Shares of Gilead (GILD) rose more than 5% Monday.
A randomized, controlled trial of Gilead’s antiviral drug remdesivir is currently underway in China in hopes that it will be an effective treatment for the 2019 Novel Coronavirus (2019-nCoV).
Gilead is not the only drug firm hoping to find a successful treatment for the coronavirus. Big Pharma, rivals Johnson & Johnson (JNJ) and GlaxoSmithKline (GSK) are also working on vaccines. Biotech company AbbVie (ABBV) has said that they have seen promising results for treating the Wuhan coronavirus with a mixture of two of its HIV medications and Tamiflu, which is produced in a joint venture by Swiss pharma giant Roche (RHHBF) and Japan's Chugai Pharmaceutical Co (CHGCY)

Intro
  • A recent cluster of pneumonia cases in Wuhan, China was caused by a novel beta coronavirus, the 2019 novel coronavirus ( 2019-nCoV ).
  • Data collected and analyzed from patients using Real-time PCR and Next Generation Sequencing identified it to be a virus of the family of coronaviridiae, genus, coronavirus, a novel beta coronavirus, 2019-nCoV.
  • Its occurrence has raised questions into the genetic relationship and similarity to SARS-CoV of 2003 considering that they both occurred in China and in areas that are of close proximity. SARS-CoV was first reported in Guangdong province, which borders Hong Kong, and 2019-nCoV in Wahun, Town of China as well.
  • From data and reports by various organizations including the CDC and WHO indicate that the difference between these two infections is the severity and contagiousness rates, with SARS-CoV being severe as compared to the 2019-nCoV, but 2019-nCoV being more contagious with high rates of infectivity and spread (https://www.pulselive.co.ke/bi/tech/the-wuhan-coronavirus-and-sars-belong-to-the-same-family-but-experts-say-there-are/mhb8zw9) as compared to SARS-CoV.
  • Factors like a transmission from an animal to person and person-to-person and nosocomial spread have been the routes of consideration with more reports leaning to an animal to person transmission considering first sight of infectivity was a wet market and person-person transmissions, but yet to be verified.
  • Traveling has enhanced the spread of the virus to various countries including Korea, Japan, Taiwan Malaysia, USA, and Australia with great concern about an epidemic outbreak of this specific virus.
  • This occurrence comes after reported cases of the same virus occurrence in Research that has been done from 31st Dec 2019 to 4th Jan 2020 has revealed new data into the pathology of the virus.
  • In the past two decades, we have seen three variants of coronavirus emerging causing serious epidemic diseases of the respiratory tract system and this an indication that this virus continues to impose continuous threats to human health and affecting the economy as they continue to emerge unexpectedly, spread easily with catastrophic consequences.
What is Coronavirus?
  • Coronaviruses belong to the family coronaviridae and are enveloped, positive-sense, single-stranded RNA viruses. they are round and sometimes pleiomorphic with 80-120nm diameter
  • The coronavirus genome is approximately 31 kb, making these viruses the largest known RNA viruses yet identified.
  • They are respiratory viruses classified under family: Coronaviridae and Coronavirus as the genus name.
  • There are now 7 types of coronaviruses that have been identified by the CDC,  which includes:
    Common human coronaviruses
    1. 229E (alpha coronavirus)
    2. NL63 (alpha coronavirus)
    3. OC43 (beta coronavirus)
    4. HKU1 (beta coronavirus)
      Other human coronaviruses
      1. MERS-CoV (the beta coronavirus that causes Middle East Respiratory Syndrome, or MERS)
      2.  SARS-CoV (the beta coronavirus that causes a severe acute respiratory syndrome, or SARS)
      3. 2019 Novel Coronavirus (2019-nCoV)
      • The most common coronaviruses among humans are 229E, NL63, OC43, and HKU1 and some can evolve and cause human diseases, becoming new human coronaviruses.
      • Three recent examples of these are 2019-nCoV, SARS-CoV, and MERS-CoV.
      • 2019 Novel Coronavirus (2019-nCoV) is a virus (more specifically, a coronavirus) identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China (https://www.cdc.gov/coronavirus/2019-ncov/about/index.html).
      • Similarities of clinical features between 2019-nCoV and previous betacoronavirus infections have been noted with most patients presented with fever, dry cough, dyspnoea, and bilateral ground-glass opacities on chest CT scans.
      • These features of 2019-nCoV infection bear some resemblance to SARS-CoV and MERS-CoV infections, in their routes of transmission, pathologies, and manifestations, and even in the forms of treatment that have initially been used to reduce the symptoms of patients.
      • The virus has been noted to have a long incubation period of 1-14 days, with patients remaining asymptomatic until the occurrence of the disease, producing severe upper and lower respiratory tract infections.
      • The virus though has been greatly associated with SARS-CoV since it has a range of similarities in symptom manifestations and the initial steps taken in detecting and identifying the virus involved those applied during the SARS-CoV outbreak in 2003.
      • This is a major factor because the virus is novel and a lot more research is yet to uncover its pathologies, including the immunological responses that increased the hyperproduction of cytokines into the patients’ plasma.
      • Cases of patients presented with this viral infection have symptoms ranging from acute illness to progressively severe respiratory illnesses associated with pneumonia.
      Epidemiology of 2019-nCoV
      • Total Confirmed Cases14,557
        • There were 14,557 confirmed cases of 2019-nCoV as of February 2, 2020 (Source: WHO).
        • There were 305 deaths due to 2019-nCoV as of February 2, 2020 (Source: WHO).
          • China- 304
          • Philippines- 1
        • 443 people have recovered from 2019-nCoV as of February 2, 2020 (1:30 pm EST) (Source: Johns Hopkins University).
      Risk Factors of 2019-nCoV
        From the data collected by the CDC, the persons at risk are
        1. Elderly persons above the age of 50 persons with underlying diseases like diabetes, Parkinson’s disease, cardiovascular diseases.
        2. Demographically, it can also be stated that the persons living in China around Wahun town are most at risk, especially those working and shopping from Animal markets within the localities; and persons traveling into and out of Wahun.
        3. Hospital-acquired infection- Health care workers caring for patients with the 2019-nCoV (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext)
        Clinical Features (Symptoms) of 2019-nCoV

        Manifestations are mild and/or progressive in some cases to severe symptoms that can eventually lead to death. These include
        1. Fever associated with flu-like symptoms of coughing, headache
        2. Upper or/and lower respiratory tract symptoms associated with shortness of breath and breathing difficulties
        3. Diarrhea after the virus colonizes the epithelial lining of the gastrointestinal tract
        4. General body weakness and myalgia (fatigue)
        5. In severe cases, individuals elicit symptoms of pneumonia with abnormal chest CT, hemoptysis, lymphopenia, associated with complications of severe acute respiratory distress syndrome, acute cardiac injury, kidney failure and eventually, death.
        Incubation Period of 2019-nCoV
        • 1-14  days after exposure (Most cases remain asymptomatic during this period)
        • Animal to Human transmission (Examples: camels, cattle, cats, and bats)
        • Human to Human transmission (Via blood, stool, urine, saliva, semen, etc.)
        • Nosocomial transmission from infected patients to caregivers and health care workers
        NOTE: The exact way the virus is spread is not fully known. With similar coronaviruses (MERS and SARS) person-to-person spread is thought to have happened mainly via respiratory droplets produced when an infected person coughs or sneezes, similar to how influenza and other viruses that cause respiratory illness spread. There also may be some spread when a person touches a surface or object that has a virus on it and then touches his or her own mouth, nose, or possibly their eyes (www.cdc.gov).

        Pathophysiology of 2019-nCoV
        • Initially, coronaviruses remained obscure primarily because there were no severe human diseases that were attributed to it since it was known to cause the common cold.
        • But since 2003, after the occurrence of SARS-CoV in 2003, in China and MERS-CoV, in 2012 in Saudi Arabia, and now the outbreak of Pneumonial clustered Novel Coronavirus (2019-nCoV), has put this virus on the map, significantly labeling coronavirus as an ‘Emerging Pathogen’.
        • The coronavirus envelope, under an electron microscope, appears to be crowned by a characteristic ring of small bulbous structures.
        • This morphology is formed by the viral spike (S) peplomers, which are type 1 glycoproteins that populate the surface of the virus and determine host tropisms, and other structures like the Membrane (M), a protein that spans the membrane three times and has a short N-terminal ectodomain and a cytoplasmic tail; and envelope protein (E), a highly hydrophobic protein and the nucleocapsid.
        • These viral spike proteins are known to play a role in the pathogenesis of coronaviruses by inducing neutralizing antibodies and mediating viral fusion of the vial cell envelope with the host cell membrane.
        • They are also capable of hemagglutination. this immensely contributes to the infectivity and progressiveness of the virus which spirals to Severe Respiratory illnesses and pneumonia.
        • Also, considering the virus’s long incubation period of 1-14 days (according to China’s National Health Commission), the period is contagious thus enhancing the rate of spread and infection to other individuals through contact and exposure to infected aerosols.
        • During the incubation period, the virus remains asymptomatic upon which the host immune system responds by activating antibody production which induces cytokine production, causing severe inflammation of the lungs causing inflammatory-lung injury with severe pneumonia and other upper and lower respiratory infections associated with fever, headaches, coughing, hemoptysis, myalgia, and renal failure.
        • This increases rapidly the mechanisms of immunopathogenesis and, unfortunately, causes pulmonary tissue damage, functional impairment, and reduced lung capacity.
        • Early investigations into the 2019-nCoV, indicated a cascade of cytokines present in plasma of most patients i.e production of cytokines or chemokines in the acute phase of the illness, plasma cytokines and chemokines (IL1B, IL1RA, IL2, IL4, IL5, IL6, IL7, IL8 (also known as CXCL8), IL9, IL10, IL12p70, IL13, IL15, IL17A, Eotaxin (also known as CCL11), basic FGF2, GCSF (CSF3), GMCSF (CSF2), IFNγ, IP10 (CXCL10), MCP1 (CCL2), MIP1A (CCL3), MIP1B (CCL4), PDGFB, RANTES (CCL5), TNFα, and VEGFA, which were measured using Human Cytokine Standard 27-Plex Assays panel and the Bio-Plex 200 system (Bio-Rad, Hercules, CA, USA).
        • The pathophysiology of this novel virus(2019-nCoV) along with that of SARS-CoV and MERS-CoV are all yet to be understood.
        Diagnosis of 2019-nCoV
        Specimens as per the WHO recommendation:
        1. Respiratory materials including Nasopharyngeal and oropharyngeal swabs, sputum and/or endotracheal aspirate or bronchoalveolar lavage in patients with more severe respiratory disease.
        2. Tissue from biopsies or autopsy including those from the lungs
        3. Whole blood
        4. Urine samples
        5. Serum for serological testing, acute sample and convalescent sample (2-4 weeks after acute phase)
        NB: Collection of the samples should be done with CAUTION and all samples regarded as potentially infectious with regard to strict adherence to Infection Prevention and Control guidelines.

        Clinical diagnosis: 

        Observing patient symptoms. This includes; fever, headaches, myalgia, sneezing, and coughing. If the patients meet the case definition of the suspected 2019-nCoV, he/she should be screened for the virus with PCR.

        Laboratory Diagnosis:

         Currently, the diagnostic tests available are aiming at conventionally detecting the causes of pneumonia early, to support disease control activities and to work with reference Labs that can perform pan coronavirus detection and directed sequencing. (WHO/2019-nCoV/laboratory/2020.3). The recommended diagnostic methods include;
        1. Isolation of the virus in human airway epithelial cells.
        2. Use of pan-coronavirus assay for amplification
        3. followed by, Real-time Reverse Transcription (RT)-PCR assay has been designed to detect sequences of the virus
        4. Whole-genome sequencing and genome analysis by bioinformatics including phylogenic tree construction to distinguish the characteristics of 2019-nCoV from other coronaviruses.
        5. Serological testing to confirm immunological responses to the specific virus, 2019-nCoV for example, cytokine identification, measurement, and quantification.
        Treatment and Prophylaxis of 2019-nCoV
        • Symptomatic treatment of the disease.
        • The virus currently has no specific drug of choice for treatment but the first cases reported with severe illnesses were administered with corticosteroids ((methylprednisolone 40–120 mg per day))to reduce inflammatory induced lung injury, low-to-moderate quantities to patients with Acute Respiratory Syndrome (thelancet.com).
        • For severe cases, treatment should include care to support vital organ functions.
        • Currently, there are no antiviral drugs that have effective treatment for Coronaviruses.
        Prevention and Control of 2019-nCoV
        • Maintaining basic hand and respiratory hygiene.
        • Avoid close contact, with anyone showing symptoms such as coughing and sneezing.
        • Avoid contact with farm or wild animals such as bats.
        • The consumption of raw or undercooked animal products should be avoided.
        • People can stay at home if they are sick.
        • Cleaning and disinfecting frequently touched objects and surfaces.
        NOTE WITH CAUTION: Detection of a possible case of an emerging pathogen causing severe acute respiratory disease should be reported immediately to local, sub local and national health care authorities for immediate action. This includes animal and human infections.
        Also, handling of such patients should be done with high precaution with safe clothing including gloves and face masks, and possible quarantine and exclusion protocols followed, immediately.

        References

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