Chloroquine Remdesivir, Lopinavir Ribavirin or Ritonavir, Galidesivir [2R,3S,5R)-5-(4-amino-5H-pyrrolo[3,2-d]pyrimidin- 7-yl)-3-hydroxy-2-pyrrolidinemethanol], favipiravir have shown efficacy to inhibit coronavirus in vitro. More than 500 patents that disclose the use of four biologics classes such as therapeutic antibodies, cytokines, RNA therapies, and vaccines to treat and prevent SARS and MERS have been analyzed for this study.

An additional 38 patents contained information pertaining to other types of antiviral antibodies that were useful for SARS and MERS therapies.

These included

• Neutralizing antibodies or antibodies designed to target proteins such as IL-6/IL-6R, TLR3 (Toll-like receptor 3), CD16,
• ITAM (immunoreceptor tyrosine-based activation motif),
• DC-SIGN (dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin),
• ICAM-3 (intercellular adhesion molecule 3),
• IP-10/ CXCL10 (interferon γ-inducible protein 10).

Cytokine storm has been reported to correlate with disease severity in SARSCoV-2 infection. Patients admitted to an ICU had higher concentrations of proinflammatory cytokines and chemokines, particularly G-CSF, IP-10/CXCL10, MCP1 (monocyte chemoattractant protein 1), and TNFα, as well as elevated cytokines from T helper 2 cells such as IL-4 and IL-10.

Pathophysiology and virulence mechanisms of CoVs, and SARS-CoV-2 have links to the function of the nsps and structural proteins. For instance, research underlined that multi-domain non-structural protein 3 (Nsp3), a 200 KD protein is able to block the host innate immune response. Among functions of structural proteins, the envelope has a crucial role in virus pathogenicity as it promotes viral assembly and release (Cascella, et al 2020). However, 8 domains of Nsp3 exist in all known CoVs:

1. The ubiquitin-like domain 1 (Ubl1),
   1. the Glu-rich acidic domain (also called “hypervariable region”),
   2. a macrodomain (also named “X domain”),
   3. the ubiquitin-like domain 2 (Ubl2),
   4. the papain-like protease 2 (PL2pro),
   5. the Nsp3 ectodomain (3Ecto, also called “zinc-finger domain”),
   6. Y1
   7. CoV-Y (unknown functions).

In addition, the two transmembrane regions, TM1 and TM2, exist in all CoVs. The three-dimensional structures of domains in the N-terminal two thirds of Nsp3 have been investigated by X-ray crystallography and/or nuclear magnetic resonance (NMR) spectroscopy since the outbreaks of SARS-CoV in 2003 as well as MERS-CoV in 2012 (Lei et. al 2018)

Researchers had proposed some 20 years ago to systematically test chloroquine in viral infections because it had been shown to be effective in vitro against a broad range of viruses. This drug has multiple activities, one of which is to alkalize the phagolysosome, which hampers the low-pH-dependent steps of viral

replication, including fusion and uncoating. Other mechanisms of antiviral activity are poorly explained (Baron et. al. 2020; Colson et.al 2020). Teicoplanin, an antibiotic used to treat staphylococci infection, previously showed efficacy to inhibit the first stage of MERS-coronarivus viral cycle in human cells. This activity is conserved on the SARS-Cov-2, thus placing teicoplanin as a potential treatment for patients with this virus.

It highlights antiviral strategies involving small molecules and biologics targeting complex molecular interactions involved in coronavirus infection and replication. The drug-repurposing effort documented herein focuses primarily on agents known to be effective against other RNA viruses including SARS-CoV and MERS-CoV. The patent analysis of coronavirus-related biologics includes therapeutic antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. More than 500 patents disclose methodologies of these four biologics with the potential for treating and preventing coronavirus infections, which may be applicable to COVID-19. The information included in this report provides a strong intellectual groundwork for the ongoing development of therapeutic agents and vaccines.

Global research and innovation forum: towards a research roadmap

On 30 Jan 2020, following the recommendations of the Emergency Committee, the WHO Director-General declared that the outbreak constitutes a Public Health Emergency of International Concern (PHEIC).

World scientists on COVID-19 met at the World Health Organization’s Geneva headquarters from 11 to 12 Feb 2020 to assess the current level of knowledge about the new virus, agree on critical research questions that need to be answered urgently, and

ways to work together to accelerate and fund priority research that can contribute to curtail this outbreak and prepare for future outbreaks.

WHO – Eight immediate research actions were agreed as part of this Forum [2]

1. Mobilize research on rapid point of care diagnostics for use at the community level – this is critical to be able to quickly identify sick people, treat them and better estimate how widely the virus has spread.
2. Immediately assess available data to learn what standard of care approaches from China and elsewhere are the most effective – there is an imperative to optimize standard of care given to patients at different stages of the disease and take advantages of all available technological innovations to improve survival and recovery.
3. Evaluate as fast as possible the effect of adjunctive and supportive therapies. The global research community need to understand what other adjunctive treatments than currently being used we currently have at our disposal that may help with the standard of care provided to patients, including the quick evaluation of interventions such as steroids and high flow oxygen.
4. Optimize use of protective equipment and other infection prevention and control measures in health care and community settings – It is critical to protect health care workers and the community from transmission and create a safe working environment.
5. Review all evidence available to identify animal host(s), to prevent continued spill over and to better understand the virus transmissibility in different contexts over time, the severity of disease and who is more susceptible to infection- Understanding transmission dynamics would help us appreciate the full spectrum of the disease, in terms of at risk groups, and conditions that make the disease more severe as well as the effectiveness of certain public health interventions.
6. Accelerate the evaluation of investigational therapeutics and vaccines by using “Master Protocols”- Rapidly developing master protocols for clinical trials will accelerate the potential to assess what works and what does not, improve collaboration and comparison across different studies, streamline ethics review and optimize the evaluation of new investigational drugs, vaccines and diagnostics.
7. Maintain a high degree of communication and interaction among funders so that critical research is implemented – Funders reiterated their current financial commitments to tackling this outbreak and agreed that the priorities agreed at the Forum would help to coordinate existing investments and inform mobilization of additional resources in the coming days, weeks and months.
8. Broadly and rapidly share virus materials, clinical samples and data for immediate public health purposes–It was agreed that virus materials, clinical samples and associated data should be rapidly shared for immediate public health purposes and that fair and equitable access to any medical products or innovations that are developed using the materials must be part of such sharing.

Controversies over the Terminology

”Coronavirus may have origins in China’s biological warfare lab in Wuhan”

• Lethal animal virus epidemic coronavirus, which has sent panic waves across the world, may have its origins at the epicenter of the epidemic, Wuhan, in a laboratory which has been linked to China’s covert biological weapons program.
• The Washington Times reported the link with China’s biological weapons quoting Dany Shoham, a former Israeli military intelligence officer, expert in bioweapons and who has studied Chinese bio warfare. The biosafety lab is located about 20 miles from the Hunan Seaford Market that reports from China say may have been origin point of the virus.
  • According to the report, Radio Free Asia this week rebroadcast a local Wuhan television report from 2015 showing China’s most advanced virus research laboratory known as the Wuhan Institute of Virology.
  • The laboratory is the only declared site in China capable of working with deadly viruses.
  • “Certain laboratories in the institute have probably been engaged, in terms of research and development, in Chinese (biological weapons), at least collaterally, yet not as a principal facility of the Chinese BW alignment,” Shoham told The Washington Times.
  • However, he didn’t confirmed but didn’t refused possibilities. Asked if the new coronavirus may have leaked, he said: “In principle, outward virus infiltration might take place either as leakage or as an indoor unnoticed infection of a person that normally went out of the concerned facility. This could have been the case with the Wuhan Institute of Virology, but so far there isn’t evidence or indication for such incident.”
  • He also added, that suspicions were raised about the institute when a group of Chinese virologists working in Canada improperly sent samples to China of what he said were some of the deadliest viruses on earth, including the Ebola virus.
  • The Wuhan virology institute is under the Chinese Academy of Sciences. But certain laboratories within it “have linkage with the PLA or BW-related elements within the Chinese defense establishment,” he said.
• Rutgers University microbiologist Richard Ebright told London”s Daily Mail that “at this point there’s no reason to harbor suspicions” that the lab may be linked to the virus outbreak.
• In 1993, China declared a second facility, the Wuhan Institute of Biological Products, as one of eight biological warfare research facilities covered by the Biological Weapons Convention (BWC) which China joined in 1985.
• China in the past has denied having any offensive biological weapons. The State Department, in a report last year, said it suspects that China has engaged in covert biological warfare work and its origin yet not known.
  • Later, Chinese Foreign Min. later claimed that some Americans working in Wuhan, were first found infected. This came after tweet of US President Trump who termed it as “Chines Virus’.
• While, Gao Fu, Director of Chinese Center for Disease Control and Prevention, told state-controlled media that initial signs as of Thursday indicated that the virus originated from wild animals sold at a seafood market in Wuhan.
• As per the Washington Times, one ominous sign, said a US official, is that false rumors since the outbreak began several weeks ago are being circulated on the Chinese internet claiming the virus is part of a US conspiracy to spread germ weapons.
  • That could indicate that China is preparing propaganda outlets to counter future charges the new virus escaped from one of Wuhan’s civilian or defense research laboratories.
• The WHO is calling the microbe novel coronavirus 2019-nCoV. At a meeting in Geneva on Jan 23^rd, the organization stopped short of declaring a Public Health Emergency of International Concern.
  • The virus outbreak causes pneumonia-like symptoms and prompted China to deploy military forces to Wuhan this week in a bid to halt the spread. All travel out of the city of 11 million people was halted.
  • The Wuhan site has studied coronaviruses in the past, including the strain that causes Severe Acute Respiratory Syndrome, (SARS), H5N1 influenza virus, Japanese encephalitis, and dengue. Researchers at the institute also studied the germ that causes anthrax- a biological agent once developed in Russia.
• “The US has compliance concerns with respect to Chinese military medical institutions” toxin research and development because of the potential dual-use applications and their potential as a biological threat,” the report added.
• The recent outbreak of a new and potentially deadly coronavirus in China has, unsurprisingly, kicked off a deluge of misinformation and conspiracy theories. – Foreign Policy
  • The Toronto Sun columnist Candice Malcolm pumped the theory on her YouTube show, asking: “Why isn’t the mainstream media talking about the origins of this deadly virus? Could it be linked to China’s biological warfare program?”
  • GreatGameIndia, a small conspiracy website (?)—which, among other things, has reported that British intelligence was responsible for the downing of Malaysia Airlines Flight 17 over Ukraine in 2014—began publishing reports last week claiming that Canadian researchers had sold this strain of coronavirus to China.
  • The website pointed blame at Xiangguo Qiu, a former researcher with the National Microbiology Laboratory in Winnipeg, Manitoba, a government-run lab that has pioneered vaccines and treatments for various infectious diseases, including Ebola. While it’s true she was escorted from the lab last year by the Royal Canadian Mounted Police, there does not appear to be a national security element to the incident. Charges have not been laid, and those familiar with the case say it is likely a matter of paperwork and protocol. Qiu, in fact, worked extensively with labs in China to create treatments for deadly and infectious diseases.
• Inevitably there is an Israeli story that just might shed some light on what has been going on in China. Scientists at Israel’s Galilee Research Institute are now claiming that they will have a vaccine against coronavirus in a few weeks which will be ready for distribution and use within 90 days.
  • The institute is claiming that it has been engaged in 4 years of research on avian coronavirus funded by Israel’s Ministries of Science & Technology and Agriculture.
  • They are claiming that the virus is similar to the version that has infected humans, which has led to breakthroughs in development through genetic manipulation, but some scientists are skeptical that a new vaccine could be produced so quickly to prevent a virus that existed only recently.
  • They also have warned that even if a vaccine is developed it would normally have to be tested for side effects, a process that normally takes over a year and includes using it on infected humans.
• If one even considers it possible that the US had a hand in creating the coronavirus at what remains of its once extensive biological weapons research center in Ft Detrick Maryland, it is very likely that Israel was a partner in the project.
• Helping to develop the virus would also explain how Israeli scientists have been able to claim success at creating a vaccine so quickly, possibly because the virus and a treatment for it were developed simultaneously.
• The US President Trump is already being blamed for lying about the virus and there are various scenarios in mainstream publications speculating over the possible impact on the election in 2020.
• If the economy sinks together with the stock market, it will reflect badly on Trump whether or not he is actually at fault.
• If containment and treatment of the disease itself in the US does not go well, there could also be a considerable backlash, particularly as the Democrats have been promoting improving health care, which seems somewhat right.
• One pundit argues, however, that disease and a sinking economy will not matter as long as there is a turnaround before the election, but a lot can happen in the next eight months.