CORONAVIRUS (2019-NCOV): THE FACTS

Author: Barry Bunin, PhD

As news about the Wuhan 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 holistic 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. For updated information on the epidemic, see the original post:

https://www.collaborativedrug.com/coronavirus-2019-ncov-facts/

Here are some public health updates, followed by the original article in full:

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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.

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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.

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, 2020, 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

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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.

On February 4th, Crystal Structure 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 Studies of 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 17th, hydroxychloroquine, a repurposed Malaria drug, shows clinical signs of effective after initial limited testing in February with COVID-19 patients.

On March 18th, Bayer prepares to donate chloroquine, their 70-year old Malaria drug, to U.S. for likely treatment of COVID-19.

On March 18th, Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19 as a repurposed HIV antiviral.

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Early COVID-19 News From the Initial Start of the Pandemic

February 5th: JAMA published an article with important information for clinicians including criteria to guide the evaluation of Patients Under Investigation (PUI) in the US.

February 3rd: Doctors in Thailand reported promising results in treating infected patients with a combination of flu and HIV medications.

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.

January 30th: WHO declared the 2019-nCoV outbreak a Public Health Emergency of International Concern (PHEIC), while noting that "China quickly identified the virus and shared its sequence...which has resulted in the rapid development of diagnostic tools."

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.

NPR has a list of key medical terminologies and definitions commonly used in media coverage of the outbreak.

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What is the Coronavirus (2019-nCoV)?

• 2019-nCoV is a Coronavirus, the family of viruses traditionally associated with the common 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. We are learning as it unfolds daily in front of our eyes:
• 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 (reference 1).”

• 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 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 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.
• The rapidly generated 2019-nCoV sequence and diagnostic information are both now publicly available on Virological.org.
• 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.
• 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 (reference 2).”

Where and how is it spreading?

• The majority of cases in humans are around the city of Wuhan, in central Hubei province in China, where 2019-nCoV was first identified. A limited number of cases have also been confirmed in Thailand, Japan, Taiwan, South Korea, USA, and Europe. 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 which can be found online here:
• https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
• The 5th WHO report included 1320 confirmed cases reported 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.
• 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. Some models suggest there may be 30,000 - 200,000 humans with 2019-nCoV.

What is it 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, and 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 (reference 2).”

Coronavirus 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.

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 is freely on the internet to spurn 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.
• 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.
• 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. (reference 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 analyses3. Bioportal already has standardized, precisely defined terms for the new Coronavirus. Future generations will be able to collaborate better, faster, longer term, and smarter (reference 4). We’re all in this together.

References

1. 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
2. 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.
3. 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
4. The Long Now Foundation suggests we use the date 02020 to think longer term, rather than the more conventional 2020 (https://longnow.org/).