Coronavirus COVID-19 (SARS-CoV-2): Facts & Drug Discovery Updates (formerly 2019-nCoV)
Scientific Facts to Understand and Respond to the COVID-19 Pandemic
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Originally Authored by Barry Bunin, PhD on January 28th, 2020,
Last Updated by Jason Bret Harris, PhD on [wpbb post:modified_date format='F j, Y'].
As news about COVID-19 and Coronavirus dominates the headlines, it is easy to get emotional and react to every latest development. However, we believe it is helpful to examine the facts and take a broader view on this outbreak. Here is what we know about the new virus so far, and how the scientific community is working to counter it.
What is the Coronavirus 2019 (COVID-19), formerly 2019-nCoV, and SARS-COV-2?
2019-nCoV is a Coronavirus, the family of viruses traditionally associated with the common and mild cold. It is genetically most related to, yet distinct from, the Severe Acute Respiratory Syndrome (SARS) and the Middle East respiratory syndrome (MERS) Coronaviruses. It was named temporarily as the novel Coronavirus-2019 (2019-nCoV) and later formerly named to COVID-19 (disease name) and SARS-COV-2 (virus name). We are learning as the disease unfolds daily in front of our eyes:The NIAID provided a balanced summary of the current state of affairs with regards to 2019-nCoV:
"The emergence of yet another outbreak of human disease caused by a pathogen from a viral family formerly thought to be relatively benign underscores the perpetual challenge of emerging infectious diseases and the importance of sustained preparedness. 2"
NPR has a list of key medical terminologies and definitions commonly used in media coverage of the outbreak. Late November 2019, origin of COVID-19 suspected from bat to human crossover in Wuhan, China. Genetic variation studies seem to suggest the main host reservoir in nature for 2019-nCoV likely is the bat. Possible recombination and transmission may have involved snake hosts based on genetic glycoprotein analyses. On December 31st of 2019, the Wuhan Municipal Health Commission in Wuhan City, Hubei province, China reported a cluster of pneumonia cases of unknown aetiology, with a common reported link to Wuhan's Huanan Seafood Wholesale Market (a wholesale fish and live animal market selling different animal species). On January 10th, sequencing data for the 2019-nCoV virus were released. The causative agent of the mystery pneumonia was identified as a novel coronavirus by deep sequencing and etiological investigations by at least 5 independent laboratories of China. The Wuhan seafood market pneumonia virus isolate Wuhan-Hu-1 complete genome is now deposited online in Genbank. On January 12th, the World Health Organization temporarily named the new virus as 2019 novel coronavirus (2019-nCoV). In a paper titled "Coronaviruses: genome structure, replication, and pathogenesis" the genetic details were shared:
"The genome of CoVs is a single-stranded positive-sense RNA (+ssRNA) (~30kb) with 5'-cap structure and 3'-poly-A tail." and "The genome size of CoV (~30kb) is the largest among all RNA viruses, which is almost two times larger than that of the second largest RNA viruses. The maintenance of the giant genome size of CoVs might be related to special features of the CoV RTC, which contains several RNA processing enzymes such as the 3'-5' exoribonuclease of nsp14. The 3'-5' exoribonuclease is unique to CoVs among all RNA viruses, and proved to function as a proofreading part of the RTC [12-14]. Sequence analysis showed that the 2019-nCoV possesses a typical genome structure of coronavirus and belongs to the cluster of betacoronaviruses that includes Bat-SARS-like (SL)-ZC45, Bat-SL ZXC21, SARS-CoV and MERS-CoV. Based on the phylogenetic tree of CoVs, 2019-nCov is more closely related to bat-SL-CoV ZC45 and bat-SL-CoV ZXC21 and more distantly related to SARS-CoV. 1"
On February 11th, WHO announces official names for the virus responsible for COVID-19 (previously known as "2019 novel coronavirus") and the disease it causes. The official names are: Disease coronavirus disease (COVID-19) Virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On February 14th, Biologist John D. Loike wrote an opinion on scientists' ethical obligation to provide factual information to educate the general public about the coronavirus. On March 17th, Scripps completes a study and finds that COVID-19 has natural origins and was not engineered in a lab as rumored.
Where and how is COVID-19 spreading (epidemiology)?
The original cases in humans appeared around the city of Wuhan, in central Hubei province in China, where 2019-nCoV was first identified. In November 2015, study predicts a potential threat of humans contracting the circulating bat SARS-like CoV SHC014. Late November 2019, origin of COVID-19 suspected from bat to human crossover in Wuhan, China. Genetic variation studies seem to suggest the main host reservoir in nature for 2019-nCoV likely is the bat. Possible recombination and transmission may have involved snake hosts based on genetic glycoprotein analyses. On December 30th, 2019, three bronchoalveolar lavage samples were collected from a patient with pneumonia of unknown etiology which was sequenced and determined to be a novel coronavirus (COVID-19), reported by WHO. On December 31st of 2019, the Wuhan Municipal Health Commission in Wuhan City, Hubei province, China reported a cluster of pneumonia cases of unknown aetiology, with a common reported link to Wuhan's Huanan Seafood Wholesale Market (a wholesale fish and live animal market selling different animal species). On January 9th, sequencing data for the 2019-nCoV virus were released. The causative agent of the mystery pneumonia was identified as a novel coronavirus by deep sequencing and etiological investigations by at least 5 independent laboratories of China. A number of cases were also been confirmed in Thailand, Japan, Taiwan, South Korea, USA, and Europe over the next few months.
- See Live Data, WorldOMeter provides Coronavirus Testing: Criteria and Numbers by Country.
- See Live Data, OurWorldInData provides Interactive Charts by Country.
- See Live Data, Johns Hopkins University has a useful dashboard that tracks the total number of known cases of COVID-19 globally.
- See Live Data, CDC tracks U.S. Cases.
- See Live Data. Mutation/Evolution of the Virus Strain (slow rates of change at about 2 mutations/month).
Although it was believed to be transmitted initially from animal to human (with the origin beginning at a now closed, specific marketplace in Wuhan City where live animals are routinely sold), there are now multiple examples of human-to-human 2019-nCoV transmission.
On January 24th, there were 830 reported cases and twenty six confirmed deaths from 2019-nCoV, of course not all cases are necessarily reported so these should be considered the minimal numbers. On January 25th, the WHO has posted 5 Situational Reports on 2019-nCoV. The 5th WHO report included 1320 confirmed cases for 2019-nCoV. Human to human transmission has been reported, however the vast majority of cases are related to travel history to Wuhan City, China. On January 26th, Some models suggest there may be 30,000 - 200,000 humans with 2019-nCoV. On February 21st, COVID-19 thought to primarily transmit from person to person via respiratory droplets, and there is no definitive evidence for fecal or airborne transmission. Asymptomatic carrier transmission has been suspected. On March 3rd, WHO published a 40-page report of the WHO-China Joint Mission on COVID-19, with detailed findings on the virus and the disease, assessment of current situation, and recommendations for global communities. On March 11th, WHO Characterizes COVID-19 as a pandemic. As of March 27th, at least 8 Strains of SARS-CoV-2 are making their way around the globe. As of July, 3rd, Evidence of higher infectivity from mutation, D614G, in SARS-COV-2 and decreased S1 shedding. Although the deaths are obviously significant to those directly and indirectly involved, the novelty and unknown trajectory of the outbreak is what makes it newsworthy. Given there are orders of magnitude more deaths from common flu, scientists have discussed perhaps rebranding Influenza. "We should rename influenza; call it XZ-47 virus, or something scarier," said Dr. Paul Offit, director of the Vaccine Education Center at Children's Hospital of Philadelphia.The World Health Organization said that the preliminary R0 (reproduction number) estimate is 1.4 to 2.5, meaning that every person infected could infect between 1.4 and 2.5 people. So it is being transmitted, but currently it is not spreading relatively fast. The exact reproduction number is of course unknown, since all cases are not reported and there is a lag between infection, noticing, and reporting. Social Distancing has been the general response to control the disease. It used to slow the spread of the disease in order to maintain critical care capacity for the sickest of patients. Social distancing is hard to implement and a common question is how much and for how long to implement it. This is further discussed in an article: "How Long Should Social Distancing Last. Predicting Time to Moderation, Control, and Containment of COVID-19?"
What is COVID-19 similar to?
2019-nCoV is part of a family of coronaviruses that includes the common cold, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). Since first identified in Saudi Arabia in 2012 around 34% of people reported as infected with MERS have died (858 of 2494 cases). MERS R0 is less than one. The SARS outbreak led to 8098 identified cases and 774 deaths (9.6%). SARS had an R0 of 2-5. SARS disappeared as quickly as it appeared in 2002-03. If we are honest about it, we don't always entirely know why contagious infections grow or decline. Often we are better at determining correlation, rather than causation. This is not surprising, as contagious infections are by definition, evolving phenomena. Researchers are evaluating countermeasures for 2019-nCoV using SARS-CoV and MERS-CoV as prototypes. For example, platform diagnostics are being rapidly adapted to include 2019-nCoV, allowing early recognition and isolation of cases. Broad-spectrum antivirals, such as remdesivir, an RNA polymerase inhibitor, as well as lopinavir/ritonavir and interferon beta have shown promise against MERS-CoV in animal models and are being assessed versus 2019-nCoV. Vaccines, with nucleic acid vaccine platform approaches used for SARS-CoV or MERS-CoV, are being pursued at the National Institute of Allergy and Infectious Diseases Vaccine Research Center. "During SARS, researchers moved from obtaining the genomic sequence of SARS-CoV to a phase 1 clinical trial of a DNA vaccine in 20 months and have since compressed that timeline to 3.25 months for other viral diseases. For 2019-nCoV, they hope to move even faster, using messenger RNA (mRNA) vaccine technology. Other researchers are similarly poised to construct viral vectors and subunit vaccines.2" On March 11th, Cleveland Clinic summarizes current data about symptoms of Covid-19 compared to Common Cold and Flu.
COVID-19 Vaccine Development
Vaccine (and antibody) development makes sense, given the potentially faster timeline than de novo small molecule drug discovery, although other antivirals have been used in SARS and MERS. The Wall Street Journal reported several drugmakers are racing to develop vaccines that could protect against the new respiratory virus originating in China. Moderna Inc., Inovio Pharmaceuticals Inc. and Novavax Inc. all plan to develop vaccines against the newly identified viral strain. Researchers at the University of Queensland in Australia are also trying to develop a vaccine against the strain. More recently, FierceBiotech reported that both JNJ and Gilead have jumped into the accelerated Coronavirus Vaccine race. Year 2020 On January 10th, Inovio scientists race to manufacture INO-4800 vaccine and begin
preclinical testing. Human clinical trials are planned for April with 30 healthy volunteers in the U.S. and China and South Korea shortly thereafter. If successful there will be 1 million does planned by end of 2020. On February 11th, Johnson & Johnson announced a collaboration with US Department of Health & Human Services (BARDA) to accelerate the development of a vaccine, using their vaccine platform technology, which was used for the developing an experimental Ebola vaccine in 2009, On January 13th, NIH and Moderna finalized sequence for mRNA-1273, the Company's vaccine against the novel coronavirus. The NIH disclosed their intent to run a Phase 1 study.On February 23rd, GSK announces using their pandemic vaccine adjuvant platform to target COVID-19, a technology used to develop HPV and flu vaccines in the past.On February 24th, Dr. James Hamblin discussed the outlook for vaccine development and how the low fatality rate of COVID-19 makes it hard to contain.On March 16, the NIH announced that the first participant in its Phase 1 study for mRNA-1273 was dosed, a total of 63 days from sequence selection to first human dosing. The open-label trial is expected to enroll 45 healthy adult volunteers ages 18 to 55 years over approximately six weeks. mRNA-1273 is an mRNA vaccine against SARS-CoV-2 that encodes for a prefusion stabilized form of the Spike (S) protein. On April 23rd, Second round of dosing for mRNA-1273 announced by Moderna. On May 18th, Moderna releases early results, demonstrating that vaccination with mRNA-1273 elicits an immune response of the magnitude caused by natural infection starting with a dose as low as 25 µg.On May 20th, Prototype DNA vaccine protects against SARS-CoV-2 in rhesus macaques.On May 20th, SARS-CoV-2 infection protects against rechallenge in rhesus macaques. On May 29th, Phase 2 study, being conducted by Moderna will evaluate the safety, reactogenicity and immunogenicity of two vaccinations of mRNA-1273 given 28 days apart with 600 healthy participants across two cohorts of adults ages 18-55 years (n=300) and older adults ages 55 years and above (n=300). On June 11th, Moderna Advances Late-Stage Development of its Vaccine (mRNA-1273) Against COVID-19 with Phase 3 study of 30,000 subjects expected to begin in July 2020 at 100 μg dose level.On July 1st, Phase 1/2 Study to Describe the Safety and Immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in Adults 18 to 55 Years of Age: Interim Report released with positive results to move the vaccine further along.On July 2nd, SARS-CoV-2 Vaccine (BNT162b1) Shows Signs of Activity in Phase 1/2 Study. On July 13th, FDA grants fast track status for 2 vaccine candidates (NT162b1 and BNT162b1) in 1/2 phase trials from Pfizer and Biopharmaceutical New Technologies (BioNTech).On July 14th, Moderna's vaccine candidate (mRNA-1273) for COVID-19 Induces Immune response in all Phase 1 participants. On July 27th, Moderna and NIH Begin Phase 3 Trial for COVID-19 V vaccine candidate (mRNA-1273).On August 11th, Russia Approves First COVID-19 Vaccine from Gamaleya Institute which was not assessed in any phase 3 testing. On September 4th, Russia Investigators Release Data for New COVID-19 Vaccine. On September 8th, AstraZeneca Covid-19 vaccine study put on hold due to suspected adverse reaction in participant in the U.K. On September 8th, SARS-CoV-2 Vaccine Developers Sign Safety Pledge. On September 11th. Positive Phase 1-2 Results for the Novavax COVID-19 Vaccine. On September 12th. AstraZeneca, Oxford Resume COVID-19 Vaccine Trial After Safety Review. On September 23rd, Johnson & Johnson initiates pivotal global phase 3 clinical trial of Janssen's COVID-19 vaccine candidate JNJ-78436735 which unlike the other COVID-19 vaccines in clinical trials it does not require a booster shot.On September 24th, Sinovac announced yesterday it had been approved to begin a phase1/2 Trial for adolescents and children for its CoronaVac vaccine. On October 16th, Covaxx's investigational vaccine, UB-612, becomes the first multitope peptide-based vaccine activating both B and T cells. On October 16th, Pfizer, BioNTech COVID-19 vaccine, BNT-162. planned for late November FDA submission.On November 9th, Pfizer COVID-19 vaccine reports 90% efficacy in preliminary, non-reviewed data.On November 9th, FDA grants Novavax fast track status for its investigational COVID-19 vaccine, NVX-CoV2373.On November 16th, Moderna's vaccine in a preliminary analysis shows nearly 95 percent effectiveness at preventing illness, including severe cases.On November 19th, AstraZeneca/Oxford COVID-19 vaccine, ChAdOx1 nCoV-19, was found to be safe and invoke an immune response in phase 2 clinical trial.On November 23rd, AstraZeneca's investigational COVID-19 vaccine, AZD1222, was 90% efficacious in 1 of their 2 dosing regimens.On December 2nd, United Kingdom's Medicines & Healthcare Products Regulatory Agency (MHRA) granted a temporary authorization for emergency use for Pfizer and BioNtech's COVID-19 vaccine.On December 9th, Canada approves Pfizer's vaccine for emergency use authorization.On December 9th, United Arab Emirates said that it had approved a China vaccine showing 86% effectiveness.On December 10th, FDA advisory panel votes to support Pfizer's vaccine.On December 11th, US Food and Drug Administration (FDA) grants Emergency Use Authorization (EUA) to Pfizer vaccine, BNT162b2, as the first vaccine for the prevention of coronavirus 2019 (COVID-19) in the United States.On December 17th, FDA advisory panel votes to support Moderna's vaccine.On December 18th, US Food and Drug Administration (FDA) grants Emergency Use Authorization (EUA) to Moderna vaccine, mRNA-1273, as the second vaccine for the prevention of coronavirus 2019 (COVID-19) in the United States.On December 30th, United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) grants emergency authorization of the AstraZeneca and Oxford COVID-19 vaccine, AZD1222, for individuals 18 years and older.On January 7th, 2021, European Commission has grants a conditional marketing authorization (CMA) to Moderna's vaccine, mRNA1273.On January 7th, 2021, Chinese vaccine company Sinovac's investigational COVID-19 vaccine, CoronaVac, was said to be 78% effective according to Brazilian investigators in phase 3 trial.On January 8th, 2021, In vitro data from Pfizer and the University of Texas Medical Branch indicate vaccine BNT162b2 is effective in preventing the pandemic virus' highly transmissible mutated variants currently spreading globally.On January 14th, 2021, Johnson & Johnson's (J&J) JNJ-78436735 COVID-19 vaccine showed neutralizing antibodies against COVID-19 in over 90 percent of study participants at Day 29 and 100% of participants aged 18-55 years at Day 57.On January 15th, 2021, Moderna announces that their vaccine, mRNA-1273, does produce neutralizing titers against the B.1.1.7 (UK variant) and B.1.351 (South Africa variant).On January 15th, 2021, Merk discontinues vaccine candidates V590 and V591 and shifts to focus on vaccine production efforts.On January 28th, 2021, Protein-based vaccine candidate NVX-CoV2373, from Novavax, has phase 3 findings showing 89.3% efficacy in prevention of COVID-19 in participants from the UK.On January 29th, 2021, Johnson & Johnson (J&J) vaccine, JNJ-78436735, shows as 85% effective in preventing severe disease across all regions studied-28 days after vaccination.On February 2nd, 2021, Russian vaccine, Gam-COVID-Vac, demonstrates 91.6% efficacy, according to new phase 3 findings. On February 8th, 2021, South Africa pauses rollout of two-dose AstraZeneca vaccine after findings that it is not as effective against the regionally-borne 501Y.V2 variant. On February 18th, 2021, Both the Pfizer/BioNTech and Moderna vaccines show reduced efficacy against South African variant. On February 19th, 2021, CDC shows relatively low rates of adverse events for Both the Pfizer/BioNTech and Moderna vaccines. On February 24th, 2021, Janssen one-shot vaccine, Ad26.COV2.S, shows 66.1% efficacy (95% CI, 55.0 - 74.8) in preventing COVID-19 versus placebo ≥28 days after administration. On February 26th, 2021, Canada authorizes AstraZeneca's vaccine. On February 27th, 2021, US Food and Drug Administration (FDA) has granted Emergency Use Authorization (EUA) to Johnson & Johnson's Janssen Pharmaceuticals one-shot vaccine, Ad26.COV2.S, becoming the third vaccine approved for the prevention of COVID-19 in the United States.
COVID-19 Drug Development
The rapidly generated 2019-nCoV sequence and diagnostic information are both now publicly available on Virological.org.On January 10th, sequencing data for the 2019-nCoV virus were released in GenBank. On January 16th, a laboratory assay had been developed by researchers at the German Centre for Infection Research at the Charité university hospital in Berlin.On January 25th, five PCR protocols and primers for diagnosis of the Wuhan City 2019-nCoV strains are available from the World Health Organization (WHO). Additional information on real time RT-PCR protocols for laboratories are available online from the CDC.On January 29th, RNA Primer Designs from WHO Protocol & Publication: Real-time RT-PCR assays for the detection of SARS-CoV-2.On February 3rd, Doctors in Thailand reported promising results in treating infected patients with a combination of flu and HIV medications which included large doses of the flu drug oseltamivir combined with HIV drugs lopinavir and ritonavir, improved the conditions of several patients at the Rajavithi Hospital in BangkokOn February 4th, Crystal Structure(6LU7)of COVID-19 main protease in complex with an inhibitor N3.On February 4th, Nature article discusses in vitro study looking at repurposing antiviral drugs, with two compounds remdesivir (EC50 = 0.77 μM; CC50 > 100 μM; SI > 129.87) and chloroquine (EC50 = 1.13 μM; CC50 > 100 μM, SI > 88.50) potently blocked virus infection at low-micromolar concentration and showed high SI.By February 18th, More than 100 clinical trials underway in China, Japan, Thailand, and UK to treat COVID-19 (the illness caused by SARS-CoV-2) under WHO monitoring.On February 25th, Gilead Sciences Initiates Two Phase 3 Clincical Trials of open-label Investigational Antiviral Remdesivir for the Treatment of COVID-19 to begin in March, which follows FDA's rapid review and acceptance of their IND (Investigational New Drug). NIH announces clinical trials which will involve 1,000 patients across Asia and other countries.On March 12, COVID-19 virus isolated in laboratory.On March 16, COVID-19 Open Research Dataset (CORD-19) created by White House call-to-action and answered by Allen Institute for AI, Chan Zuckerberg Initiative (CZI), Georgetown University's Center for Security and Emerging Technology (CSET), Microsoft, and the National Library of Medicine (NLM) at the National Institutes of Health.On March 17th, Hydroxychloroquine, a repurposed Malaria drug, shows clinical signs of effective after initial limited testing in February with COVID-19 patients.On March 17th, Open-label and non-randomized clinical study of Hydroxychloroquine (repurposed Malaria antiviral) and azithromycin (well-known antibacterial) as a treatment of COVID-19: results of an open-label and non-randomized clinical trial. Combining both drugs showed better results.On March 18th, Bayer prepares to donate chloroquine, a 70-year old Malaria drug, to U.S. for likely treatment of COVID-19.On March 18th, Trial of Kaletra (Lopinavir-Ritonavir), a potential repurposed HIV antiviral, showed no benefit and adverse events in Adults Hospitalized with Severe Covid-19.On March 18th, Medical authorities in China have said a drug used in Japan to treat new strains of influenza, Avigan (favipiravir), appeared to be effective in coronavirus patients. The drug acts as an RNA Polymerase inhibitor with a good safety profile.On March 19th, Teva to Donate Hydroxychloroquine Sulfate Tablets to Hospitals Nationwide for Potential COVID-19 Treatment, On March 19th, Mylan Ramps Manufacturing of Hydroxychloroquine Sulfate Tablets to Meet Potential COVID-19 U.S. Patient Needs.On March 20th, Novartis commits to donate up to 130 million doses of hydroxychloroquine to support the global COVID-19 pandemic responseOn March 20th, New crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors (6Y2E (unliganded Mpro), 6Y2F (complex with 13b in space group C2), and 6Y2G (complex with 13b in space group P212121). The plasmid encoding the SARS-CoV-2 Mpro will be freely available.On March 23rd, AbbVie will not enforce global patent rights on all formulations of HIV med Kaletra (Aluvia) as the drug is being evaluated to treat severe COVID-19 in several clinical trials.On March 23rd, Report about Institute Pasteur Korea (IPK) confirmed the efficacy repurposing of Alvesco (ciclesonide), a type of steroid in asthma treatment, in treating COVID-19.On March 24th, Roche announced that the FDA has approved its phase 3 trial of Actemra, an interleukin-6 inhibitor - has already been approved in China, in severely ill COVID-19 patients, who have been hospitalized with pneumonia.On March 24th, FDA plans to facilitate emergency access for convalescent plasma, derived from patients who have already recovered from the disease, and the FDA said they will help provide access to it for patients with serious or immediately life-threatening COVID-19 infectionsOn March 25th, Vir Biotechnology indicated it has identified several human monoclonal antibody (mAb) candidates against SARS-CoV-2. In the interest of saving time, the company's lead development was transferred to WuXi Biologics and Biogen several weeks ago with human trials likely in the next 3-5 months.On March 25th, The COVID-19 Therapeutics Accelerator-launched by the Gates Foundation, Wellcome, and Mastercard. Companies participating in the collaboration include BD, bioMérieux, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Eli Lilly, Gilead, GSK, Johnson & Johnson, Merck (known as MSD outside the U.S. and Canada), Merck KGaA, Novartis, Pfizer, and Sanofi. Companies have agreed to share their proprietary libraries of molecular compounds that already have some degree of safety and activity dataOn March 28th, Collaborative Drug Discovery (CDD) publishes COVID-19 main protease (Mpro) Active Fragments data set in CDD Vault. Here is a Video Preview and instructions on how to access it. These are active molecular fragments against Mpro/COVID-19 crystal structure which are made available from Diamond Light Source, the UK's national synchotron science facility in collaboration with Dectris.On April 4th, Initial results from a placebo-controlled trial of hydroxychloroquine with 62 patients for mild COVID-19 indicate a more quick recovery compared to placebo.On April 10th, Report released of using Remdesivir for compassionate care in patients with Severe Covid-19.On April 10th, Cryo-EM Structure available of COVID-19 Virus RNA-dependent RNA polymerase (RdRp, also named nsp12).On April 15th, Clinical study shows benefit of remdesivir in rhesus macaques (monkey) infected with SARS-CoV-2. Human trials expected soon.On April 29th, Gilead results from Phase 3 Trial of Remdesivir (no control group) in patients with severe COVID-19 demonstrated that a 5-day dose is as effective as a 10-day dose.On April 29th, First study of Remdesivir in adults with severe COVID-19 using a randomised, double-blind, placebo-controlled, multicentre trial shows no statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.On April 29th, NIH study of Remdesivir, in a randomized placebo-controlled trial with over 1,000 hospitalized patients and in multiple countries, showed that patients recovered 31% faster. The results also suggest a slightly lower mortality rate, but this significance is unclear until the complete results are analyzed.On May 1st, Remdesivir receives FDA Emergency Use Authorization for the treatment of COVID-19.On May 12th, Nafamostat shows ∼ 600-fold more potency than Remdesivir and other FDA approved drug candidates in an antiviral screening assay with human lung cells.On May 14th, Abivax SA announced preliminary results of its drug candidate ABX464 against SARS-CoV-2 in in vitro reconstituted human respiratory epithelium model.On May 15th, Sorrento Therapeutics announced Friday its anti-SARS-CoV-2 antibody STI-1499 completely neutralized virus infectivity at a very low antibody dose, indicating its candidacy for further assessment and development.On May 15th, Phase 2 Trial suggests combination antiviral therapy speeds recovery in COVID-19 patients using interferon beta-1b, lopinavir-ritonavir, and ribavirin which appears to be safe and superior compared to lopinavir-ritonavir monotherapy.On May 27th, Remdesivir trial Inconclusive on 5 or 10 day treatment duration for COVID-19.On May 29th, Review finds that ACE Inhibitors, ARBs do not worsen COVID-19 risk.On June 3rd, Hydroxychloroquine Fails to Show Efficacy for COVID-19 Prophylaxis.On June 15th, FDA withdraws emergency use authorization for Hydroxychloroquine.On June 15th, Pepcide (Famotidine) for heartburn is being studied for its observed clinical benefit for COVID-19 patients.On June 17th, Dexamethasone, a well-studied steroid, appears to help severe cases of COVID-19 by suppressing over an active immune response.On June 29th, UK Regulators Approve Phase 2/3 Study of Opaganib for COVID-19, as a first-in-class SK2 selective inhibitor intended for exploration in multiple indications.On July 30th, BMJ releases a "Regularly updated drug treatments for covid-19: living systematic review and network meta-analysis".On September 3rd, Phase 3 Trial of Remdesivir for Moderate COVID-19 Shows Modest Results, Uncertainties.On September 14th, Baricitinib Plus Remdesivir Improves Hospitalized COVID-19 in double-blind, randomized, controlled trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).On September 30th, Regeneron's investigational antibody cocktail, REGN-COV2, showing it reduced viral load and the time to alleviate symptoms in non-hospitalized patients with COVID-19.On October 7th, Eli Lilly and Company's investigational antibodies, Bamlanivimab (LY-CoV555) and Etesevimab (LY-CoV016), linked to less viral load, hospital risk, in Covid-19 patients.On October 8th, ACTT-1 trial show antiviral agent remdesivir was superior to placebo in reduced time to recovery (5-day reduction) and lesser evidenced lower respiratory tract infections among adults hospitalized with coronavirus 2019.On October 9th, Remdesivir plus Baricitinib reduces hospitalized COVID-19 mortality by 35% in new ACTT-2 trial finding.On October 22nd, First fully FDA-Approved COVID-19 Tteatment in US is Gilead Sciences' remdesivir (Veklury®) for the treatment of coronavirus disease 2019.On November 9th, FDA grants emergency use authorization (EUA) to Eli Lilly for bamlanivimab (LY-CoV555), an investigational neutralizing antibody for the treatment of coronavirus.On February 9th, 2021, US Food and Drug Administration (FDA) has issued an emergency use authorization (EUA) for combination bamlanivimab and etesavimab for the treatment of mild to moderate coronavirus 2019 (COVID-19) in adults and children aged 12 years and older (weighing at least 40 kg).
Lessons for Drug Discovery Collaboration?
As shared in a timely NIH JAMA Viewpoint from Catharine I. Paules, MD; Hilary D. Marston, MD, MPH; Anthony S. Fauci, MD we know 2019-nCoV is similar to MERS and SARS thanks to rapid data sharing and international collaboration:
"While MERS has not caused the international panic seen with SARS, the emergence of this second, highly pathogenic zoonotic HCoV illustrates the threat posed by this viral family. In 2017, the WHO placed SARS-CoV and MERS-CoV on its Priority Pathogen list, hoping to galvanize research and the development of countermeasures against CoVs. The action of the WHO proved prescient. On December 31, 2019, Chinese authorities reported a cluster of pneumonia cases in Wuhan, China, most of which included patients who reported exposure to a large seafood market selling many species of live animals. Emergence of another pathogenic zoonotic HCoV was suspected, and by January 10, 2020, researchers from the Shanghai Public Health Clinical Center & School of Public Health and their collaborators released a full genomic sequence of 2019-nCoV to public databases, exemplifying prompt data sharing in outbreak response."
Publishers like the British Medical Journal (and in a moment of solidarity other publishers like Wiley and Elsevier) are providing information on the Coronavirus freely on the internet to spur short-term global response efforts and support long-term research, in contrast to their usual paid-content business models. The British Medical Journal has also made information freely available on MERS and SARS.Shared Resources:
- On March 16, COVID-19 Open Research Dataset (CORD-19) created by White House call-to-action and answered by Allen Institute for AI, Chan Zuckerberg Initiative (CZI), Georgetown University's Center for Security and Emerging Technology (CSET), Microsoft, and the National Library of Medicine (NLM) at the National Institutes of Health.
- On March 25th, The COVID-19 Therapeutics Accelerator-launched by the Gates Foundation, Wellcome, and Mastercard. Companies participating in the collaboration include BD, bioMérieux, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Eli Lilly, Gilead, GSK, Johnson & Johnson, Merck (known as MSD outside the U.S. and Canada), Merck KGaA, Novartis, Pfizer, and Sanofi. Companies have agreed to share their proprietary libraries of molecular compounds that already have some degree of safety and activity data.
- On March 28th, Collaborative Drug Discovery (CDD) publishes COVID-19 main protease (Mpro) Active Fragments data set in CDD Vault. Here is a Video Preview and instructions on how to access it. These are active molecular fragments against Mpro/COVID-19 crystal structure which are made available from Diamond Light Source, the UK's national synchotron science facility in collaboration with Dectris.
- STM has a list of freely available research data related to Coronavirus from major publishers.
- opencovid-19: A repository dedicated for to sharing all things COVID-19, including APIs for data streams for WEB AND APP DEVELOPERS.
- NIH Resource to Analyze COVID-19 Literature: The COVID-19 Portfolio Tool
- Consortia of National Labs, companies, and Universities fast tracks proposals for computing time.
One of the unique ways we can combat epidemics, not available to previous generations, is to leverage the free, global, instantaneous access to everyone across our species via the Internet. We have only scratched the surface of the full potential of this mechanism for both response and research.An example of sharing and data reuse: commentary from Certara D360 seeks to share some key insights relevant to optimizing posology of COVID19 candidate therapeutics that were learned from attempts to optimize anti-infective posology in settings where quality and timely availability of data is challenging, with particular focus on influenza PK/PD, including experiences from H5N1 and pH1N1 outbreaks.Collaboration can range from two scientists sharing data privately to publicly shared data with the international scientific community. Quantity has a quality all its own. In the case of an outbreak, publicly shared information allows the conversation to co-evolve with many brains (and technologies) rapidly in parallel - when additional data, analyses, and insights are also shared in a timely manner.When a timely response is needed, collaboratively sharing data allows the rate of learning to accelerate.Within the commercial drug discovery arena, there are two counterbalances to immediate sharing. First, the data from diverse drug discovery assays are heterogeneous, complex, and may require metadata from procedures to understand. Second, the data sharing, due to this heterogeneity requires sophisticated tools (i.e. sharing structure activity relationships from a series of primary and secondary high-throughout put screens run on hundreds of thousands of compounds, at nine concentrations, in triplicate is not as trivial as say sharing a like on Facebook). Nonetheless, collaboration may be the key to quantum leaps in efficiency in drug discovery.Open data (and idea) sharing is the purpose of the scientific literature. Scientific literature became a more global phenomena with the advent of the printing press.We take the Internet for granted today, however the ability to instantaneously share information around the world is arguably the most fundamental paradigm shift for our species. We are no longer ants, but an ant colony. We can learn from the art of emergent, collective intelligence. Our memes traveling at the speed of the www to coordinate our collective thinking is our competitive advantage vs the ancient relentless mechanisms of mutation, selection, and horizontal gene transfer. The ace in our pocket is the ability to collectively learn and instantaneously share collective learnings. Prokaryotes have a fixed velocity of learning and information transfer (different in every case, but metaphorically speaking in general). Humans combining our intelligence with the Internet have the potential for uncapped, accelerated learning.The next level of accelerated learning is integrating computers and algorithms together, via web-based platforms. Not only our own CDD Vault which balances protecting intellectual property through secure data sharing while promoting maximum collaboration...but all the connecting web-based scientific data sharing platforms (with the majority sponsored by our publicly funded, government coordinated efforts such as PubMed, GenBank, ChEMBL, KEGG, and PubChem, to mention just a handful of many impactful, web-based scientific data sharinig platforms). And there are highly impactful, community based efforts such as, well, Wikipedia (and it's equally important cousin DBpedia). We can and will collaborate better over time.There is a need for accelerated data sharing and discovery for a number of viral diseases, including 2019-nCoV:
"As there is no effective therapeutics or vaccines, the best way to deal with severe infections of CoVs is to control the source of infection, early diagnosis, reporting, isolation, supportive treatments, and timely publishing epidemic information to avoid unnecessary panic. For individuals, good personal hygiene, fitted mask, ventilation and avoiding crowded places will help preventing CoVs infection. 1"
It is worth mentioning the rapid development of 2019-nCoV Diagnostic kits, a number of which are already now available.As with the response to the last Ebola epidemic and after this 2019-nCoV epidemic, we will need to consider general solutions to surveillance and response. The only thing we know for sure is that next time will be slightly different. In response our tactics and tools can get better with each new epidemic via greater, web-coordinated collaboration.In the near future, it is not difficult to imagine a time when emerging data and protocols are represented in FAIR (Findable, Accessible, Interoperable, Reusable) standardized formats for parallel computer analyses.3 Bioportal already has standardized, precisely defined terms for the new Coronavirus. Future generations will be able to collaborate better, faster, longer term, and smarter.4 We're all in this together.On February 28th, Bill Gates wrote an opinion on what actions world leaders should take in response to the threat of COVID-19.
Symptoms, Diagnostics, & Treatments for COVID-19
The rapidly generated 2019-nCoV sequence and diagnostic information are both now publicly available on Virological.org.On January 24th, the clinical features of 41 ICU patients infected with 2019-nCoV in Wuhan China were published. The patients had pneumonia with abnormal findings on chest CT and a "cytokine storm" with higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MP1A and TNFα. These data are from just the patient in the ICU, obviously the majority of people infected are not in the ICU.On January 29th, Analysis of the first 425 patients in Wuhan showed that the median age was 59, the mean incubation period was 5.2 days, and the R0 was estimated at 2.2.On January 31st, The New England Journal of Medicine published a report detailing the identification, diagnosis, clinical course, and management of the first US case of 2019-nCoV.On February 3rd, Doctors in Thailand reported promising results in treating infected patients with a combination of flu and HIV medications.On February 6th, JAMA published an article with important information for clinicians including criteria to guide the evaluation of Patients Under Investigation (PUI) in the US.On March 11th, Cleveland Clinic summarizes current data about symptoms of Covid-19 compared to Common Cold and Flu.On March 18th, study in China demonstrates that digestive symptoms are an indicator of recovery outcomes. Study suggests digestive symptoms can be used as an earlier alert for at-risk patients before developing respiratory symptoms.On March 19th, A 15-minute antibody test (CoronaCheck ™) from blood droplet without laboratory equipment or personnel required is available from 20/20 GeneSystems, Inc. The test is intended to identify persons having an immune response against SARS-CoV-2.On March 21st, FDA issued the first emergency use authorization for a point-of-care COVID-19 diagnostic for the Cepheid Xpert Xpress SARS-CoV-2 test which will provide results within hours, rather than days like the existing tests, and the company plans to roll it out by March 30.On March 23rd, FDA eases laboratory testing and imaging requirements for drugs with risk evaluation and mitigation strategies (REMS) that require such measures in an effort to ensure patient access to certain drugs during the COVID-19 pandemic.On March 28th, A new 5-minute COVID-19 test from Abbott's ID Now Platform that can be run in a doctor's office was approved for emergency use by the FDA.On April 1st, FDA approves emergency use of a 15 minute antibody immunity test from Cellex described as qSARS-CoV-2 IgG/IgM Rapid Test.On April 21st, LabCorp's Home Self-test kit for COVID-19 approved by FDA.On May 3rd, Roche's COVID-19 antibody test, with high precision, receives FDA Emergency Use.On May 18th, FDA authorizes emergency use authorization for at-home Coronavirus test collection kit to Everlywell and is the first that is not associated with a specific laboratory.On June 25th, FDA Authorizes 15-Minute Antibody Testing Kit.On August 15th, FDA Grants Emergency COVID-19 Authorization to Yale's Open Source Method of Saliva Testing.
- Coronaviruses: genome structure, replication, and pathogenesis. Chen Y, Liu Q, Guo D. J Med Virol. 2020 Jan 22. doi: 10.1002/jmv.25681. Review. PMID: 31967327
- Coronavirus Infections-More Than Just the Common Cold. Paules CI, Marston HD, Fauci AS. JAMA. 2020 Jan 23. doi: 10.1001/jama.2020.0757. PMID: 31971553.
- The FAIR Guiding Principles for scientific data management and stewardship. Wilkinson, M., Dumontier, M., Aalbersberg, I. et al. Sci Data 3, 160018 (2016). https://doi.org/10.1038/sdata.2016.18
- The Long Now Foundation suggests we use the date 02020 to think longer term, rather than the more conventional 2020 (http://longnow.org/).
This blog is authored by members of the CDD Vault community. CDD Vault is a hosted drug discovery informatics platform that securely manages both private and external biological and chemical data. It provides core functionality including chemical registration, structure activity relationship, chemical inventory, and electronic lab notebook capabilities.