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Dear Colleagues,

As part of our continuing coverage of COVID-19 and SARS-CoV-2, we are sharing five new articles. Commentary is provided by Drs. Ted Rosen, Sheila Fallon-Friedlander, Albert Yan, James Treat, and Hensin Tsao.

With aloha,
Dr. George Martin

1.

SARS-CoV-2 (COVID-19) By The Numbers
published March 31, 2020 with continual updates


https://elifesciences.org/articles/57309
This overview of COVID-19 is one of the most valuable "at a glance" articles that have come across my computer screen. I refer to it constantly. Developed by a high level scientific collaborative group, this article examines the basic science of SARS-CoV-2 and its practical implications such as: how do N95 masks block SARS-CoV-2?; how stable and infectious is the virus on surfaces?; how similar is SARS-CoV-2 to the common cold and flu viruses?; etc.  Their answers are supported by peer reviewed evidence when available. Definitely take a look.
We asked Dr. Hensin Tsao to weigh in on the information regarding the genetic evolution and stability of the SARS-CoV-2 virus and its implications. 

Hensin Tsao, MD, PhD Commentary:

In terms of lineage tracing, no different than evolutionary tracing of humans based on sequence diversification:  if you trace back far enough, we all evolved from a common ancestor and diverged.  If you trace the virus back far enough, it probably all started in the Wuhan area with a primordial virus and then diverged.  I'm not a viral ID geneticist but I would imagine the rate of diversification is a combination of at least several factors- mutation rate and selection. There may be other forces out there too. 

The next steps are potentially to do more precise genotype/phenotype studies. This has probably already been done but sub-strains may have different behavior (more aggressive, less aggressive, more likely to bind ACE2, etc.) that could explain local differences in outcome (e.g. Italy vs US).  Long term prospects for more precision, variant-specific medicine and a better understanding how we disperse pandemics for the future.

Asymptomatic carriage is an interesting idea - perhaps they have a polymorphism in the ACE2 gene that disallows entry or polymorphisms in other parts of human genome that disrupts the viral lifecycle.... Also, the virus may have mutated into benignity.  It is also not out of the question that some of us have been exposed to a cousin of this virus and may have some innate immunity.  

In terms of bio-engineering deadly viruses, nature does a much better job than the lab. Scientists have been collecting novel viruses in China for a while. There was a single scientist who identified 2,000 novel viruses in bats around the Wuhan area. Ostensibly, it was their hope to "better understand" these novel viruses to prevent future SARS-like outbreaks (https://www.washingtontimes.com/news/2020/mar/30/china-researchers-isolated-bat-coronaviruses-near-/).  But think about it:  2,000 viruses just like SARS-CoV-2 sitting around in animals in the wild. It's probably much more likely that one of these thousands of novel coronaviruses jumped the animal-man bridge than to think that a lab has the technology to introduce a mutation so precisely that it does this level of damage.

2.

Why Don’t We Have A Vaccine For Covid-19? 
Two Missed Vaccine Opportunities:


By George Martin, MD

They say opportunity knocks only once.  Well, it knocked twice and no one answered in 2003 and 2012 . 
 
Dr. Tony Fauci said something profound the other day on TV that struck me (paraphrasing here):  "We didn’t make a vaccine against SARS in 2003 when we had the chance."
 
We are battling COVID-19 using 50-year old medicines (HCQ) and treatments (plasma transfer), the anti-viral remdesivir is locked in clinical trials and we are repurposing a rheumatology drug that inhibits an inflammatory cytokine IL-6 to halt the progression of ARDS that results in an approximately 70% mortality in the US and 80+% worldwide.
 
Why don’t we have a vaccine against SARS-CoV-2?
 
Here is part of the timeline from CDC.gov on the emergence of SARS in Asia in 2003:
  • March 12, 2003. The World Health Organization (WHO) issues a global alert for a severe form of pneumonia of unknown origin in persons from China, Vietnam, and Hong Kong.
     
  • March 29, 2003 CDC extended its travel advisory for SARS to include all of mainland China and added Singapore. CDC quarantine staff began meeting planes, cargo ships and cruise ships coming either directly or indirectly to the United States from China, Singapore and Vietnam and also begins distributing health alert cards to travelers.
     
  • April 4, 2003 The number of suspected U.S. SARS cases was 115; reported from 29 states. There were no deaths among these suspect cases of SARS in the United States.
     
  • May 6, 2003 In the United States, no new probable cases were reported in the last 24 hours, and there was no evidence of ongoing transmission beyond the initial case reports in travelers for more than 20 days. The containment in the United States has been successful.
You can see why SARS in 2003 was taken so lightly then and more recently in December of 2019 by everyone (including me). SARS in 2003 was contained in 3 months basically by implementing a travel ban screening imports from endemic areas as well as screening imports (see below). The number of SARS cases in the US was 115 from 29 states and no reported deaths among suspect cases. By all criteria, the virus SARS-CoV-1 in 2003 was not a threat. With the threat of other pandemic viruses in 2003,  a vaccine against SARS-CoV-1 was not pursued.

The time course, rapid containment, and limited mortality rates in the US (no deaths in 115 reported cases) hardly raised an eyebrow. The virus was gone from the public eye in a blink. However, the SARS of 2003 was not the same SARS-CoV-2 that we are currently dealing with. The SARS-CoV-2 that we now deal with has only 50% of its genome in common with SARS-CoV-1 from 2003. The mutations that have taken place in the intervening time have created a more durable and lethal virus.
 
(Click here for the Core Document.)
 
Opportunity knocked a 2nd time in 2012:
 
This accounting came from an interview by Mike Hixenbaugh (NBC national investigative reporter):
 
According to Dr. Peter Hotez and other vaccine scientists, who argue that SARS, and the Middle East respiratory syndrome, or MERS, of 2012, should have triggered major federal and global investments to develop vaccines in anticipation of future epidemics.
 
Instead, the SARS vaccine that Hotez's team created in collaboration with scientists at the University of Texas Medical Branch at Galveston is sitting in a freezer, no closer to commercial production than it was four years ago.
 
"We could have had this ready to go and been testing the vaccine's efficacy at the start of this new outbreak in China," said Hotez, who believes the vaccine could provide cross-protection against the new coronavirus, which causes a respiratory disease known as COVID-19. "There is a problem with the ecosystem in vaccine development, and we've got to fix this."
 
Hotez took that message to Congress on Thursday while testifying before the House Committee on Science, Space and Technology. He argued that the new coronavirus should trigger changes in the way the government funds vaccine development.
 
"It's tragic that we won't have a vaccine ready for this epidemic," Hotez wrote in prepared remarks. "Practically speaking, we'll be fighting these outbreaks with one hand tied behind our backs."
This sad story is corroborated in an interview contained in an article from the Washington Post By Carolyn Y. Johnson:
 
When a mysterious new illness emerges and public alarm is at its peak, there’s a race to develop a way to prevent or treat the disease. But by the time a promising candidate is ready, it’s often too late to be helpful against the outbreak that triggered the rush. Public interest, funding and the urgency that drove the early vaccine development can quickly taper.
 
“We were getting candidate vaccines, the epidemics would die down, and they’d get put back on the shelf,” said Jacqueline Shea, chief scientific officer of Inovio, a biotech company that has been developing vaccines for ZikaEbola and Middle East respiratory syndrome.
 
That’s what happened with severe acute respiratory syndrome (SARS), to the dismay of Peter Jay Hotez, co-director of the Texas Children’s Hospital Center for Vaccine Development. Eight years ago, he and his co-director, Maria Elena Bottazzi, won federal funding to create a vaccine against SARS, a coronavirus that emerged in 2002 and infected 8,000 people and killed nearly 800. By 2016, they had manufactured enough of the potential vaccine to get through toxicology tests and human safety trials.
 
But the team tried and failed to win various grants to bring their experimental vaccine through further testing. They say about $2 million could have funded essential and time-consuming toxicology studies and ready it for phase 1 trials — the technical term for the first-in-humans studies that typically determine the dosing and safety of a drug. Although the threat of SARS has receded, it was becoming increasingly clear that coronaviruses, long thought to cause mild illness, were able to cause serious pandemics.
 
When the new coronavirus genome sequence was posted to an online genetic databank in early January, Hotez immediately saw the close similarity to SARS and realized the samples sitting in storage had the potential to defend against the new virus.
 
“Had we been able to secure the investment, we could have done all the phase 1 trials. We could have potentially been ready to vaccinate in China, now,” Hotez said. “This is the problem with the whole vaccine infrastructure — it’s reactive, not anticipatory enough. ‘Oh, SARS is gone now, let’s move on.’"

“The actual technical feat of making a vaccine against this virus is probably not going to be that hard,” Hotez said. “The problem is you can’t avoid or even compress the timelines very much for safety testing.”
 
That means scientists are flooded with public interest in their vaccine efforts right now and must temper their excitement with the reality that there will be a months-long wait, at minimum, for a vaccine that’s ready for its first tests in people.

“What is the value of a vaccine if development takes a year in the context of the current situation, which seems to be moving very rapidly? The value of a vaccine is we don’t actually know what the trajectory of the epidemic could be,” said Richard Hatchett, chief executive of the Coalition for Epidemic Preparedness Innovations, a global alliance that is funding the Inovio and Moderna efforts and another vaccine being created by researchers at the University of Queensland in Australia.

For example, if the outbreak is still raging after initial safety tests, it is possible experimental vaccines could be used to protect people on the front lines of treating the disease or in emergency situations before they are approved for the general population, as happened with Ebola. When Ebola devastated West Africa in 2014, a vaccine was not ready. But when the virus resurfaced in 2019 in Congo, more than 200,000 people were vaccinated.

If the infections have begun to subside by the time vaccines are through the first round of safety testing, getting a vaccine approved would still be useful in case the virus flares again — but showing it is safe for healthy people in the general population will take time and continued effort.
In the meantime, researchers are also looking at ways of quickly repurposing existing antiviral drugs to see whether any might work against the coronavirus. Paul Stoffels, chief scientific officer of Johnson & Johnson, said the company has donated 100 boxes of an HIV medication, Prezcobix, to clinicians in Shanghai to see whether it showed any efficacy against the illness. Purdue University researchers hope to test experimental drugs that were initially developed to fight SARS. At the University of North Carolina at Chapel Hill, researchers have been gearing up to test remdesivir, an experimental antiviral drug that has shown promise against other coronaviruses but failed against Ebola.

But every step takes time. Even having the right laboratory tests, ingredients and animal models of the disease are crucial and time-consuming steps. Laboratories have been waiting for the viral genome to be synthesized by companies and are anxious to get samples of the actual virus.
A decade after SARS, another coronavirus emerged that caused Middle East respiratory syndrome (MERS). Many say the coronavirus in China is a lesson that this family of viruses will continue to cross from animals into humans and cause potential pandemics. That means scientists would like to be prepared, with vaccine platforms that can be readily adapted to new infections and antiviral drugs that work broadly for multiple diseases.

Ted Rosen, MD commentary:

Ever since Jenner's bold work in vaccination conclusively proved efficacy, humanity has relied on this technique for protection against a host of microbes. To think, however, that the universe of pathogens is static, and that we no longer require new vaccines, is sheer folly. Both bacteria and viruses, born of the same progenitor some three billion years ago, continue to mutate, evolve, refine and infect. We must be ever vigilant for new harmful organisms that can spread - due to a lack of herd immunity - rapidly through susceptible human populations. 

While it is true that a golden opportunity to commercialize a coronavirus vaccine was missed, not once but twice, in the same decade, all is not lost. First, we do not know for sure that any vaccine developed in response to a different coronavirus (SARS-CoV-1 and Mers-CoV) would confer adequate and lasting immunity to the current COVID-19 organism. The current virus shares only about 80-90% of genetic material with the older scourges. Second, even if a vaccine had been fully developed years ago, there certainly wouldn't have been enough available to mass vaccinate the entire country, let alone the planet. The question then remains, would it have been deployed quickly enough to secure a vaccinated "ring" around contacts of all initial cases, and thereby circumvent local spread and eventually nationwide infection? This is hardly a sure assumption. Finally, the techniques for developing vaccines have improved since 2003-2012. This has broadened our ability to develop different types of vaccines to determine the optimal one. We already have an mRNA-based vaccine in clinical trials. A scalable needle-free patch vaccine directed against the spike protein has been developed at the University of Pittsburgh. Over 30 additional potential vaccines, many using novel technologies, are in various stages of development. 

One might say, a vaccine developed and commercialized and stockpiled between 2003 and 2012 would have been nice. The “Something is better than nothing” philosophy. But perhaps the ultimately successful vaccine(s) will be preferable, both due to specificity, durability and means of delivery.

3.

Could Indomethacin Be An Adjunctive Therapy Along With HCQ/Azithromycin In Early COVID-19 infections?

Abstract:  Indomethacin has a potent antiviral activity against SARS coronavirus. https://www.ncbi.nlm.nih.gov/pubmed/17302372

Severe acute respiratory syndrome (SARS) is a newly emerging, highly transmissible and fatal disease caused by a previously unknown coronavirus (SARS-CoV). Existing in non-identified animal reservoirs, SARS-CoV continues to represent a threat to humans because there is no effective specific antiviral therapy for coronavirus infections.

OBJECTIVES:
Starting from the observation that cyclopentenone cyclooxygenase (COX) metabolites are active against several RNA viruses, we investigated the effect of the COX inhibitor indomethacin on coronavirus replication.

METHODS:
Work involving infectious SARS-CoV was performed in biosafety level 3 facilities. SARS-CoV was grown in monkey VERO cells and human lung epithelial A549 cells, while canine coronavirus (CCoV) was grown in A72 canine cells. Antiviral activity was analysed by determining infective virus titres by TCID50, viral RNA synthesis by Northern blot analysis and real-time RT-PCR, and viral protein synthesis by SDS-PAGE analysis after 35S-methionine-labelling. Antiviral efficacy in vivo was determined by evaluating virus titres in CCoV-infected dogs treated orally with 1 mg/kg body weight indomethacin (INDO).

RESULTS:
Unexpectedly, we found that INDO has a potent direct antiviral activity against the coronaviruses SARS-CoV and CCoV. INDO does not affect coronavirus binding or entry into host cells, but acts by blocking viral RNA synthesis at cytoprotective doses. This effect is independent of cyclooxygenase inhibition. INDO's potent antiviral activity (>1,000-fold reduction in virus yield) was confirmed in vivo in CCoV-infected dogs.

CONCLUSIONS:
The results identify INDO as a potent inhibitor of coronavirus replication and suggest that, having both anti-inflammatory and antiviral activity, INDO could be beneficial in SARS therapy.

George Martin, MD commentary:

In my research examining the impact of NSAIDs on the outcome of COVID-19 patients, I came across this article. I had also been looking for a readily available, inexpensive drug with a reasonable safety profile that possessed potential anti-viral activity against SARS-CoV-2. 
Research on SARS-CoV-1 would likely have been done following the 2003 localized SARS epidemic and be required to be done in a biosafety level 3 lab, which would limit the number of studies on the virus. I did not expect to find many studies but what I found shows great promise.

It might be worthwhile taking a close look at indomethacin in much the same way we have looked at HCQ and azithromycin.  In addition to its potential anti-viral effects which could be used as an adjunctive therapy along with HCQ/azithromycin in early stage COVID-19, it should be effective in relieving some of the  COVID-19 related symptoms such as fever, myalgia and other symptoms.  
 

4.

Forecasting COVID-19 impact on hospital bed-days, ICU-days, ventilator days and deaths by US state in the next 4 months

This study presents the first set of estimates of predicted health service utilization and deaths due to COVID-19 by day for the next 4 months for each state in the US.

OBJECTIVE

To determine the extent and timing of deaths and excess demand for hospital services due to COVID-19 in the US.

DESIGN, SETTING, AND PARTICIPANTS

This study used data on confirmed COVID-19 deaths by day from WHO websites and local and national governments; data on hospital capacity and utilization for US states; and observed COVID-19 utilization data from select locations to develop a statistical model forecasting deaths and hospital utilization against capacity by state for the US over the next 4 months.

EXPOSURE(S)

COVID-19.

MAIN OUTCOME(S) AND MEASURE(S)

Deaths, bed and ICU occupancy, and ventilator use.

RESULTS

Compared to licensed capacity and average annual occupancy rates, excess demand from COVID-19 at the peak of the pandemic in the second week of April is predicted to be 64,175 (95% UI 7,977 to 251,059) total beds and 17,309 (95% UI 2,432 to 57,584) ICU beds. At the peak of the pandemic, ventilator use is predicted to be 19,481 (95% UI 9,767 to 39,674). The date of peak excess demand by state varies from the second week of April through May. We estimate that there will be a total of 81,114 deaths (95% UI 38,242 to 162,106) from COVID-19 over the next 4 months in the US. Deaths from COVID-19 are estimated to drop below 10 deaths per day between May 31 and June 6.

CONCLUSIONS AND RELEVANCE

In addition to a large number of deaths from COVID-19, the epidemic in the US will place a load well beyond the current capacity of hospitals to manage, especially for ICU care. These estimates can help inform the development and implementation of strategies to mitigate this gap, including reducing non-COVID-19 demand for services and temporarily increasing system capacity. These are urgently needed given that peak volumes are estimated to be only three weeks away. The estimated excess demand on hospital systems is predicated on the enactment of social distancing measures in all states that have not done so already within the next week and maintenance of these measures throughout the epidemic, emphasizing the importance of implementing, enforcing, and maintaining these measures to mitigate hospital system overload and prevent deaths.

George Martin, MD commentary:

This is a comprehensive epidemiology modeling and forecasting of the current COVID-19 pandemic as it pertains to hospital bed stays, ICU-days, ventilator days and deaths by US states over the next 4 months.  The model allows you to click on specific states to look at the projections over the next 4 months. If accurate, it could facilitate preparation and allocation of resources that include materials and manpower for the peak of the epidemic in each state. An example of how it many affect resource allocation is NY state. Gov. Cuomo was recently quoted in the media (March 27th NPR.org; Author Bobby Allyn) as needing 30,000 ventilators in the next 21 days. According to data in this model, NY state should only need 4,141 ventilators. This disparity hopefully can be resolved by careful communication with regard to resource management. The model also projects shortages and surpluses in ICU and hospital beds on a state by state basis.
 
Please be sure to visit the model and select your state. It is eye opening.

View the Interactive Model
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