U Missouri researcher identifies four possible treatments for COVID-19

A researcher at the University of Missouri has found that four antiviral drugs, including remdesivir, a drug originally developed to treat Ebola, are effective in inhibiting the replication of the coronavirus causing COVID-19.
Kamlendra Singh, an associate professor in the College of Veterinary Medicine, and his team used computer-aided drug design to examine the effectiveness of remdesivir, 5-fluorouracil, ribavirin and favipiravir in treating COVID-19. Singh found that all four drugs were effective in inhibiting, or blocking, the coronavirus’ RNA proteins from making genomic copies of the virus.
“As researchers, we have an obligation to search for possible treatments given that so many people are dying from this virus,” Singh said. “These antiviral drugs, if they turn out to be effective, all have some limitations. But in the midst of a global pandemic, they are worth taking a deeper look at because based on our research, we have reason to believe that all of these drugs could potentially be effective in treating COVID-19.”
The coronavirus (SARS-CoV-2) that causes COVID-19, like all viruses, can mutate and develop resistance to antiviral drugs. Therefore, further testing in a laboratory setting and in patients is needed to better evaluate how the proposed treatments interact with the virus’ RNA polymerase.
“Our goal is to help doctors by providing options for possible treatments of COVID-19, and to ultimately contribute in improving the health outcomes of patients suffering from the infectious disease,” Singh said. “As researchers, we are simply playing our part in the fight against the pandemic.”
Singh’s research is an example of translational medicine, a key component of the University of Missouri System’s NextGen Precision Health Initiative. The NextGen initiative aims to improve large-scale interdisciplinary collaboration in pursuit of life-changing precision health advancements and research.

###

“Feasibility of Known RNA Polymerase Inhibitors as Anti-SARS-CoV-2 Drugs,” was recently published in Pathogens.
https://www.eurekalert.org/pub_releases/2020-05/uom-mri050420.php

Two drugs show promise against COVID-19

Korean researchers have screened 48 FDA-approved drugs against SARS-CoV-2, and found that two, that are already FDA-approved for other illnesses, seem promising. The FDA approval for other uses would greatly reduce the time needed to gain FDA approval of use in COVID-19. The research is published in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.
The investigators tested the drugs in Vero cells, a cell line developed from kidney cells of the African Green Monkey, which are commonly used to grow viruses for vaccine production.
An anti-helminthic drug called niclosamide demonstrated “very potent” antiviral activity against SARS-CoV-2, according to coauthors Sangeun Jeon, Meehyun Ko, and their collaborators, of the Zoonotic Virus Laboratory, Institut Pasteur Korea, Seongnam, Korea. “Not surprisingly, its broad-spectrum antiviral effect has been well documented in the literature, including antiviral properties against SARS- and MERS-CoV,” they write.
A downside of niclosamide is low absorption, which undercuts the drug’s power by reducing the dose that reaches the target tissue. However, “Further development or drug formulation could enable an effective delivery of this drug to the target tissue,” according to the report.
Despite substantially lower antiviral potency, ciclesonide, an inhaled corticosteroid used to treat asthma and allergic rhinitis, also showed promise against SARS-CoV-2. Intriguingly, the investigators note that a study published earlier this year ( by Matsuyama et al.) a treatment report of 3 patients infected by SARS-CoV-2, demonstrated antiviral activity and revealed the drug’s molecular target to be a viral protein called Nsp15.
“With its proven anti-inflammatory activity, ciclesonide may represent as a potent drug which can manifest [the] dual roles [of antiviral and anti-inflammatory] for the control of SARS-CoV-2 infection,” the investigators conclude. The anti-inflammatory activity might play a critical role in dampening or preventing the cytokine storms, an immune inflammatory overreaction that can kill COVID-19 patients.
https://www.eurekalert.org/pub_releases/2020-05/asfm-tds050420.php

Recently recovered COVID-19 patients produce varying virus-specific antibodies

Most newly discharged patients who recently recovered from COVID-19 produce virus-specific antibodies and T cells, suggests a study published on May 3rd in the journal Immunity, but the responses of different patients are not all the same. While the 14 patients examined in the study showed wide-ranging immune responses, results from the 6 of them that were assessed at two weeks after discharge suggest that antibodies were maintained for at least that long. Additional results from the study indicate which parts of the virus are most effective at triggering these immune responses and should therefore be targeted by potential vaccines.
It is not clear why immune responses varied widely across the patients. The authors say this variability may be related to the initial quantities of virus that the patients encountered, their physical states, or their microbiota. Other open questions include whether these immune responses protect against COVID-19 upon re-exposure to SARS-CoV-2, as well as which types of T cells are activated by infection with the virus. It is also important to note that the laboratory tests that are used to detect antibodies to SARS-CoV-2 in humans still need further validation to determine their accuracy and reliability.
“These findings suggest both B and T cells participate in immune-mediated protection against the viral infection,” says co-senior study author Chen Dong of Tsinghua University. “Our work has provided a basis for further analysis of protective immunity and for understanding the mechanism underlying the development of COVID-19, especially in severe cases. It also has implications for designing an effective vaccine to protect against infection.”
Relatively little is known about the protective immune responses induced by the disease-causing virus, SARS-CoV-2, and addressing this gap in knowledge may accelerate the development of an effective vaccine, adds co-senior study author Cheng-Feng Qin of the Academy of Military Medical Sciences in Beijing, China.
With this goal in mind, the researchers compared the immune responses of 14 COVID-19 patients who had recently become virus-free to those of six healthy donors. Eight of the patients were newly discharged, and the remaining six were follow-up patients who were discharged two weeks prior to the analyses. Specifically, the researchers collected blood samples and assessed the levels of immunoglobulin M (IgM) antibodies, which are the first to appear in response to an infection, as well as immunoglobulin G (IgG) antibodies, which are the most common type found in blood circulation.
Compared to healthy controls, both newly discharged and follow-up patients showed higher levels of IgM and IgG antibodies that bind to the SARS-CoV-2 nucleocapsid protein, which encapsulates the viral genomic RNA, as well as the S protein’s receptor-binding domain (S-RBD), which binds to receptors on host cells during the process of viral entry. Taken together, these findings show that COVID-19 patients can mount antibody responses to SARS-CoV-2 proteins and suggest that these antibodies are maintained for at least two weeks after discharge.
In addition, five newly discharged patients had high concentrations of neutralizing antibodies that bind to a pseudovirus expressing the SARS-CoV-2 S protein. Neutralizing antibodies prevent infectious particles from interacting with host cells. In addition, all except one follow-up patient had detectable neutralizing antibodies against the pseudovirus.
Compared to healthy controls, five newly discharged patients had higher concentrations of T cells that secrete interferon gamma (IFNγ) – a signaling molecule that plays a critical role in immunity – in response to the SARS-CoV-2 nucleocapsid protein. These are the same patients who had high concentrations of neutralizing antibodies. In addition, three newly discharged patients showed detectable levels of IFNγ-secreting T cells specific to the SARS-CoV-2 main protease – a protein that plays a critical role in viral replication. Meanwhile, seven newly discharged patients showed detectable levels of IFNγ-secreting T cells specific to the S-RBD of SARS-CoV-2. By contrast, only one follow-up patient had a high concentration of IFNγ-secreting T cells responsive to the nucleocapsid protein, the main protease, and S-RBD.
One finding with potential clinical relevance is that the amount of neutralizing antibodies was positively associated with IgG antibodies against S-RBD, but not with those that bind to the nucleocapsid protein. Moreover, S-RBD induced both antibody and T cell responses. “Our results suggest that S-RBD is a promising target for SARS-CoV-2 vaccines,” says co-senior study author Fang Chen of Chui Yang Liu Hospital affiliated to Tsinghua University. “But our findings need further confirmation in a large cohort of COVID-19 patients.”

###

This work was supported by from the National Key Research and Development Program of China, Natural Science Foundation of China, Beijing Municipal Science and Technology, Zhejiang University Foundation, and Tsinghua University. L.N., Y.F., W.P., and C.D. have filed a provisional patent on the methodology of detecting SARS-CoV-2-specific antibody responses.
Immunity, Ni, Ye, and Cheng et al.: “Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals” https://www.cell.com/immunity/fulltext/S1074-7613(20)30181-3
https://www.eurekalert.org/pub_releases/2020-05/cp-rrc050420.php

How COVID-19 spread has been contained by travel bans

Millions more people across the EU could have contracted COVID-19 had strict international travel bans not been implemented, shows a new report by computer modelling experts at Stanford University.
Using a newly developed mathematical epidemiology simulation, the study, published in Computer Methods in Biomechanics and Biomedical Engineering, predicts the huge impact that limiting air travel across the 27 EU nations had on restricting the spread of the disease.
The simulation can show live estimated figures for the growth of spread for each country if we were to remove travel bans today. The images above show how 0.2% of some populations could have become infected by 20th April (when the study was written, 5 April), however these figures change daily.
This new model could now play a vital part in establishing politicians’ exit strategies, with the team able to virtually lift travel restrictions between individual communities, states, or countries, to explore the potential gradual changes in spreading patterns and outbreak dynamics.
“There is a well-reasoned fear that easing of current (travel restriction) measures, even slightly, could trigger a new outbreak and accelerate the spread to an unmanageable degree,” lead author Ellen Kuhl, Professor of Mechanical Engineering at Standford University comments.
“Global network mobility models, combined with local epidemiology models, can provide valuable insight into different exit strategies. Our results demonstrate that mathematical modelling can provide guidelines for political decision making with the ultimate goal to gradually return to normal while keeping the rate of new COVID-19 infections steady and manageable,” says Kevin Linka, lead author and postdoctoral researcher in Dr. Kuhl’s group.
From its European origin in Italy, the novel coronavirus spread rapidly via the strongest network connections to Germany, Spain, and France, while slowly reaching the less connected countries, Estonia, Slovakia, and Slovenia.
Currently the levels of population known to be infected with the disease varies from country to country, however as of April 18, with flight being reduced by 89% in Germany, 93% in France, 94% in Italy, and 95% in Spain (Eurostat 2020), the graphs in this study show how the spread has been contained.
“Strikingly, our results suggest that the emerging pattern of the COVID-19 outbreak closely followed global mobility patterns of air passenger travel,” confirms Professor Kuhl, whose model can also predict the emerging global diffusion pattern of a pandemic at the early stages of the outbreak.
“Our results suggest that an unconstrained mobility would have significantly accelerated the spreading of COVID-19, especially in Central Europe, Spain, and France.”
Unfortunately, the model also confirms how travel bans were introduced too late to stop the Europe-wide outbreak altogether.
“A recent study based on a global metapopulation disease transmission model for the COVID-19 outbreak in China has shown that the Wuhan travel ban essentially came too late, at a point where most Chinese cities had already received many infected travellers (Chinazzi et al. 2020). Our study shows a similar trend for Europe, where travel restrictions were only implemented a week after every country had reported cases of COVID-19 (European Centre for Disease Prevention and Control 2020).
“As a natural consequence, unfortunately, no European country was protected from the outbreak,” Professor Kuhl, who is the Robert Bosch Chair of Mechanical Engineering at Standford added.
The first official case of COVID-19 in Europe was reported in France on January 24, 2020, followed by Germany and Finland only three and five days later. Within only six weeks, all 27 countries of the European Union were affected, with the last cases reported in Malta, Bulgaria, and Cyprus on March 9, 2020. At this point, there were 13,944 active cases within the European Union and the number of active cases doubled every three to four days (European Centre for Disease Prevention and Control 2020).
Dr Kuhl adds that although air travel is certainly not the only determinant of the outbreak dynamics, their findings indicate that “mobility is a strong contributor to the global spreading of COVID-19”. This is becoming especially important now that many countries are beginning to lift their travel restrictions in an attempt to gradually return to normal.
Other limitations highlighted – like any infectious disease model – include the simulation being subject to data uncertainties from differences in testing, inconsistent diagnostics, incomplete counting, and delayed reporting across all countries.
https://www.eurekalert.org/pub_releases/2020-05/tfg-hcs050420.php

What Will Re-Entry Look Like? 300 HR Execs’ Answers

The possibility of reopening nonessential businesses looms large. In Georgia, Mississippi and Texas, reopening is underway as early as this week.

Nationwide, company leaders who have only just gotten their teams acclimatized to working remotely are scrambling to plan for how and when to safely resume “business as usual” — though, moving forward, that may mean something quite different than it did before the coronavirus.

Employees, office tenants, property owners and managers can review some of those possible plans in an April 20 Challenger, Gray & Christmas Inc. survey of companies across the U.S. More than 300 HR executives from 23 industries, including manufacturing, construction, financial services, technology and real estate, provided preliminary insights on how their companies plan to get back to work. The findings, while falling short of any one-size-fits-all solution, do seem to confirm a great deal of the speculation that this pandemic will mean “the end of the office as we know it.”

Social Distancing And PPE

89% of employers are planning to provide sanitizing products.

86% will maintain social distancing protocols of 6 feet.

85% will regularly deep-clean workstations and work sites.

84% of employers plan to provide some personal protective equipment either to all workers or upon request.

79% are planning to limit or prohibit gatherings in shared spaces.

Nearly 60% are planning to limit or exclude visitors.

More than half are planning to provide or require workers to wear masks.

Monitoring Employee Health

45% are surveying workers to see if they had or have had any risk of exposure.

Two in five employers say they are planning on taking workers’ temperatures upon their return to work, per new guidelines from the U.S. Equal Employment Opportunity Commission about employee-managed temperature checks and symptoms screening.

When An Employee Tests Positive For COVID-19

77% of companies said they will require a two-week quarantine for anyone potentially exposed.

71% said they will deep-clean the entire office.

40% said they will return to crisis protocols.

More than one in 10 companies said they would shut down the entire work site if one employee tested positive.

Working From Home

More than half will make work-from-home accommodations permanent for some or allow people to work remotely until they feel safe enough to return.

15% will return to previous work-from-home policies.

9% plan to require all workers to return to the office environment “after the crisis is passed.”

When Are Companies Expecting To Return To The Office?

62% of companies surveyed are committed to keeping their coronavirus crisis plans in place until experts declare it is safe.

24% are planning to maintain their current precautions for one to three months.

7% are planning to keep their current precautions in place for three to six months.

5% expect the crisis to last through the end of 2020 or into 2021 and to continue under their pandemic operations plan until that time.

2% believed as of mid-April that they could remove precautions in a matter of weeks. Depending on the outcome of reopening efforts in the aforementioned Southern states, more will be revealed about whether that 2% were right.https://www.bisnow.com/national/news/top-talent/what-will-re-entry-look-like-300-hr-execs-answers-104090

HHS doling out $12B in CARES funds to 395 hospitals in COVID-19 hot spots

The American Hospital Association applauded the HHS announcement and said it “continues to urge remaining emergency funds be sent as soon as possible to hospitals and health systems on the front lines.”
The Greater New York Hospital Association praised the funding to hot spots in particular. “The remarkable self-sacrifice and dedication of our health care workers took place in an environment that was oftentimes likened to wartime conditions,” the group said in a statement.

• HHS said Friday it will begin distributing funds from the Coronavirus Aid, Relief, and Economic Security Act for hospitals in COVID-19 hot spots as well as those in rural areas.
• The department is sending $12 billion across 395 hospitals that provided inpatient treatment to 100 or more COVID-19 patients through April 10. The formula uses a fixed amount per admission plus additional funds based on Medicare and Medicaid disproportionate share and uncompensated care payments.
• Another $10 billion is being directed toward nearly 8,000 rural hospitals, which will receive a minimum base payment and a percentage of their annual expenses. Providers will received the money “in the coming days via direct deposit,” according to HHS.

The $100 billion CARES Act funding Congress approved for hospitals in late March has been allocated in a variety of ways in an attempt to reach hospitals quickly and equitably as they hemorrhage money during the pandemic.
“HHS has put these funds out as quickly as possible, after gathering data to ensure that they are going to the providers who need them the most,” Secretary Alex Azar said in a statement.
Most facilities have halted revenue-driving elective procedures to free up resources for COVID-19 patients, all the while seeing increased expenses to stay stocked and staffed up for any patient surges. A few states have recently started resuming those services.
The first round of CARES funding — $30 billion — was distributed broadly based on Medicare fee-for-service reimbursement. The second wave included $20 billion to be sent based on 2018 net patient service revenue and earmarks a portion for treating uninsured COVID-19 patients. A portal for providers to apply for that reimbursement launched Monday.
The nearly 400 hard-hit hospitals accounted for 71% of COVID-19 inpatient admission reported to HHS, the department said. The state with the most hospitals receiving this funding is New York at 90. New Jersey is next on the list at 53, followed by Illinois at 33 and Michigan at 30.
Hospitals in rural areas are at some of the highest risk of closing during the pandemic, and those geographies are facing increased rates of infection.
Rural hospitals are often the closest point of care for millions of Americans living in isolated regions. Local health systems power economies, oftentimes as an area’s largest employer, and drive other businesses and jobs to those communities.
But the smaller systems are budget-strapped, and many have been unable to keep up with technological trends, lacking capital to invest in updated, innovative technology, such as EHRs, telehealth and advanced imaging platforms.
https://www.healthcaredive.com/news/hhs-starts-doling-out-12b-in-cares-funds-to-395-hospitals-in-covid-19-hot/577226/

7 states team up to buy $5B in medical equipment, supplies for COVID-19

• Seven Northeast states are creating a buying consortium to purchase roughly $5 billion worth of medical equipment and supplies, including ventilators and personal protective equipment, to try to make up for a lack of centralized procurement infrastructure during the COVID-19 pandemic.
• New York, New Jersey, Connecticut, Pennsylvania, Delaware, Rhode Island and Massachusetts are aiming to use their combined purchasing power to drive down prices for the in-demand supplies for their combined 53.6 million residents. The group will also coordinate planning on gradually lifting social distancing requirements as the number of confirmed U.S. deaths from the novel coronavirus passed 67,000 on Sunday.
• Along with the Northeastern states, the Democratic governors of California, Oregon and Washington are working together to reopen their economies, as are Midwestern governors in Illinois, Indiana, Ohio, Wisconsin, Minnesota and Michigan.

States have been caught in a bidding war against each other, the federal government and private entities for medical equipment as the coronavirus continues to spread in the U.S. Fierce competition for supplies like masks, isolation gowns, nasopharyngeal swabs, ventilators and more has led states to shell out prices far above market rates. For example, the price tag of a single ventilator has snowballed from $12,000 to $65,000, according to the comptroller of Illinois.
The new regional supply chain is an attempt to tamp down on those skyrocketing prices as demand is unlikely to let up anytime soon, with some public health experts forecasting a return of the coronavirus in the fall.
“When you put all those hospitals together, all that public health capacity together — which will make us more competitive in the international marketplace — I believe it will save taxpayers money,” New York Gov. Andrew Cuomo said in a press conference Sunday.
“I also believe it will help us actually get the equipment because we have trouble still getting the equipment and just buying the equipment because these vendors on the other side they’re are dealing with countries, they’re dealing with the federal government — why should they do business with one state when they can do business with an entire country?”
Tensions have swirled between President Donald Trump and embattled states that have called on the federal government to quarterback the COVID-19 response. A handful of governors have asked the administration to centralize procurement through the Federal Emergency Management Agency, to take point in ordering equipment and disbursing it to areas of greatest need.
However, Trump has taken a backseat approach, putting the onus on states as governors report losing equipment negotiations to FEMA, which can pay higher prices.
States have few avenues for relief among the widespread shortages. The Strategic National Stockpile of emergency medical supplies has been largely depleted since April. Trump has invoked the Defense Production Act, a wartime authority allowing the president to force manufacturers to ramp up production of critical supplies, to mitigate some supply chain issues for ventilators and N95 masks, but marked deficits remain.
The problem partially stems from the U.S. reliance on global sources for medical equipment, as the country traditionally takes advantage of low-cost manufacturing abroad.
But despite the lack of equipment, protective gear and COVID-19 tests, a hodgepodge of red states have begun reopening their businesses and public spaces, including Georgia, Florida and Texas.
In a bright spot for the state, New York’s hospitalization rate dipped below 10,000 people on Sunday for the first time since mid-March as the number of new cases declined, and the state reported its lowest single-day death rate in weeks. However, more than 19,000 people have died in New York from COVID-19 to date, though officials say the real figure is likely much higher.
Moving forward, New York is requiring hospitals have a 90-day supply of PPE and other key medical supplies at a “rate of use during the worst of this crisis” to ensure enough masks and equipment in event of a resurgence, Cuomo said.
https://www.healthcaredive.com/news/7-states-team-up-to-buy-5b-in-medical-equipment-supplies-for-covid-19/577263/