August 11, 2020
Without reliable information, we rely on fear or luck.
A. Numbers & Trends
1. Cases & Tests
3. Top 5 States in Cases, Deaths, Hospitalizations, and Positivity
B. New Scientific Findings & Research
C. Improved & Potential Treatments
2. Interleukin-6 inhibitors may be an effective treatment
D. Concerns & Unknowns
E. The Road Back?
F. Back to School!?
1. US Children & Schools
H. Practical Tips & Other Useful Information
I. Johns Hopkins COVID-19 Update (8/10)
J. Links to Other Stories
- Researchers See Promising Results Using Cannabis Terpenes To Treat C19 A recent study examining the use of cannabis terpene formulation – NT-VRL on inflammatory conditions has had some promising results in treating cytokine storm syndrome caused by C19.
- NIH ‘Shark Tank’ on track to produce quick, inexpensive C19 tests by fall Easier to use inexpensive tests with quick results are the surest path back toward normal until we have a vaccine — and thanks to a National Institutes of Health project called the “Shark Tank,” scientists are transforming C19 diagnostic testing.
- American tragedy: Number of people dying alone in hospitals skyrockets due to C19 A recent study finds a dramatic shift in where Americans are spending their final moments. Patients with C19 this year are 12 times more likely to die in a medical facility than patients dying of any cause in 2018. Researchers add that many of these patients are tragically dying alone.
- Broad neutralization of SARS-related viruses by human monoclonal antibodies A summary from a recent study in Science that suggests a large proportion of the non-neutralizing antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of preexisting memory B cells elicited by prior HCoV infections
A. Numbers & Trends
Note: Unless otherwise noted, (i) all cases/deaths are confirmed cases/deaths that have been reported, and (ii) all numbers reported in this update are as of the end of the most recent reporting period. Green highlights indicate a decrease or no change and yellow highlights indicate an increase.
1. Cases & Tests (8/10)
- Total Cases = 20,245,420 (+1.1%)
- New Cases = 216,297 (-8,227) (-3.7%)
- New Cases (7 day average) = 257,997 (+2,314) (+0.9%)
- Number of new cases is 16,205 higher than last week
- 1,000,000+ new cases every 4 days (based on 7 day average)
- 7 day average of new cases is slightly less than the peak on 8/1, but has increased during the last 2 days
US Cases & Testing:
- Total Cases = 5,251,446 (+1.0%)
- New Cases = 49,800 (+1,821) (+3.8%)
- Percentage of New Global Cases = 23%
- New Cases (7 day average) = 55,142 (+155) (+0.3%)
- Total Number of Tests = 66,178,615
- Percentage of positive tests (7 day average) = 7.4%
- 7 day average of new cases increased 155, the first increase since the second peak on 7/25
- Total Deaths = 738,116 (0.6%)
- New Deaths = 4,558 (-256) (-5.3%)
- New Deaths (7 day average) = 5,863 (+27) (+0.5%)
- Number of new deaths is 185 higher than one week ago
- 7 day average of new deaths is highest since 4/29
- 7 day average of new deaths has been trending higher since 5/26
- Total Deaths = 166,192 (+0.3%)
- New Deaths = 569 (+44)
- Percentage of Global New Deaths = 12.5%
- New Deaths (7 day average) = 1,038 (+1) (+0.1%)
- 7 day average of new deaths is 92 less than the second peak on 8/2
- 7 day average of new deaths increased slightly since yesterday (+1)
3. Top 5 States in Cases, Deaths, Hospitalizations, and Positivity (8/10)
B. New Scientific Findings & Research
1. Cutting edge synthetic peptides block C19
- Researchers at Ligandal Inc., the University of California San Francisco and Toyota Technological Institute at Chicago, have designed novel synthetic peptides that potently inhibit the ability of the coronavirus to infect host cells.
- The team’s SARS-BLOCK™ peptides competitively inhibit the receptor-binding domain (RBD) on the coronavirus spike protein – the surface structure that binds the host cell angiotensin-converting enzyme 2 (ACE2) receptor, to gain viral entry.
- As well as blocking this viral entry pathway, the peptides are also designed to bind to the neutralizing antibodies generated against the coronavirus following infection, with the aim of inducing a specific neutralizing antibody response.
- “In contrast to neutralizing antibody therapies and other approaches that seek to target the virus, we developed a biomimetic virus decoy peptide technology that would compete for viral binding to cells, and expose the virus for binding to neutralizing antibodies,” write Dr. Andre Watson and colleagues.
- The researchers say they also discovered that ACE2 prevents the binding of RBD to neutralizing antibodies and that the SARS-BLOCK™ peptides can reverse this immune-evasive mechanism of the virus.
- A pre-print version of the paper is available in the server bioRxiv, while the article undergoes peer review.
The challenges faced in developing treatments
- The long-term health effects of the coronavirus infection are not yet known but are thought to involve outcomes ranging from respiratory, neurological, and vascular to renal, respiratory, and even autoimmune.
- Although various vaccines are in different stages of development, the long-term immune responses to vaccination and infection remain unclear, and the alternative “herd immunity” approach would significantly compromise global health and pose a significant burden in terms of the long-term associated health problems.
- One potential treatment approach is the administration of neutralizing antibodies as a way of halting disease progression, but the transient nature of this therapy leaves the patient vulnerable to reinfection.
- “An ideal therapeutic strategy must take into account the root cause of infection, rather than attempting to treat specific downstream symptoms, given the measurable effects of various portions of the virus on extensive and specific cascades of physiological, intracellular, and biological systems,” said Watson and team.
Mimicking the RBD of the viral spike protein
- The researchers used computational techniques to design, simulate, and synthesize model peptides that mimic the coronavirus spike RBD for ACE2 and exhibit neutralizing antibody binding motifs.
- Next, the team conducted binding and competitive association assays and infected ACE2-expressing cells with pseudotyped lentivirions displaying the coronavirus spike protein.
- After modeling the key interacting motifs of the spike protein and its RBD, the team was able to design and synthesize SARS-BLOCK™ peptides that potently and competitively inhibited the binding of ACE2 to the RBD, which reduced cellular infection by as much as 95 to 100%, without causing any toxicity.
- As well as preventing this RBD-ACE2 binding, the peptides bound neutralizing antibodies with micromolar affinity, says the team.
|Peptides simulated via RaptorX were aligned with the coronavirus binding interface of ACE2 (ACE2 in red, with PDBePISA-predicted binding interfaces in green). Shown from left to right (top) are SARS-BLOCK™ Peptides 1 (a), 4 (b), 5 (c), and 6 (d) bound to ACE2. Of note, all peptides exhibited two mutations introducing a disulfide bond to recreate the beta sheet structure of the SARS-CoV-2 receptor binding motif (RBM). Otherwise, Peptides 1 and 4 utilized the wildtype sequence, while Peptide 5 utilized MHC-I and MHC-II epitopes, and Peptide 6 utilized a GSGSG linker (white) in one of its non-ACE2-interfacing loop regions. Peptides 4, 5 and 6 exhibited additional, proprietary modifications to their sequences to facilitate appropriate folding, while Peptide 1 lacked this modification. Taking into account the 9 possible folded states generated for each peptide, we utilized PyMOL align commands which take into account multiple potential conformations of each peptide and may serve as a basis for future studies exploring more advanced molecular dynamics approaches for relaxing and simulating intramolecular interactions at the binding interface (e). In essence, the overlay of many possible folded states represents an electron distribution cloud of possible states that can be simulated for the minimal interfacial free energy of binding, and this approach requires vastly fewer computational resources than typically required for modeling binding pockets of de novo peptides or protein-protein interfaces without existing interfacial structures.|
ACE2 stopped spike being recognized by the immune system
- The researchers also discovered that soluble ACE2 blocks the binding of neutralizing antibodies by forming an “immune cloak” on the spike RBD, thereby preventing the RBD from being recognized by the adaptive immune system.
- The researchers found that the spike RBD bound to ACE2 with an approximate 2.3nM affinity and that ACE2 could stop a neutralizing antibody binding with the RBD that would otherwise have a bound with an affinity of around 6nM.
- Next, the team showed that the SARS-BLOCK™ peptides were able to “uncloak” the ACE2 viral coating mechanism, thereby reversing this immune-evasive property and stimulating an immune response by enabling the binding of neutralizing antibodies to the viral surface.
- “In contrast to neutralizing antibody therapies and other approaches that seek to target the virus, we developed a biomimetic virus decoy peptide technology that would compete for viral binding to cells, and expose the virus for binding to neutralizing antibodies,” writes the team.
The peptides could provide a new generation of antivirals
- The researchers say the synthetic nature, in silico screening, and precise conformation of the peptides enable their rapid production, without the limitations that are associated with other antiviral approaches or vaccine approaches.
- The team says the SARS-BLOCK™ peptides are a promising C19 antidote that effectively provides a new generation of prophylactic and reactive antiviral therapeutics.
- “Because SARS-BLOCK™ mimics the virus, rather than binding to it, and also due its ability to displace ACE2 from cloaking the virus spike protein, we believe that these multifunctional peptides will prove to be an effective immune-enhancing strategy in infected patients, with additional potential to serve as a prophylactic vaccine,” concludes the team.
2. A never-before-seen image of the coronavirus copy machine
|Two essential enzymes coordinate to read and copy SARS-CoV-2 genetic material (shown as blue spheres). Credit: Rockefeller University|
- Exactly how viruses replicate is a complex puzzle with many missing pieces. And in the age of the pandemic, solving it has become a matter of acute urgency.
- Figuring out the details of the fundamental copy operations that make one virus into thousands more could give scientists a significant leg up in discovering novel drugs that smother the coronavirus and stop infection in its tracks.
- In a new study published in Cell, Rockefeller scientists provide a crucial piece of the puzzle: an atomic-level resolution view of the coronavirus’ replication system. “We now have an additional structural template that can be really helpful for drug developers trying to find new compounds that could get into this molecular machine and make it stop,” says Elizabeth Campbell, a research associate professor at Rockefeller.
- Like many other viruses, the coronavirus copies its genetic material with the help of an enzyme as complex as what its name may suggest: the RNA-dependent RNA polymerase, or RdRp. Because it is absolutely essential to viral replication, this machinery is thought to be a promising target for antiviral drugs. In fact, some existing antivirals, as well as several new candidates under investigation specifically for C19 act on RdRp—including remdesivir, which is currently being used in several countries for treatment of severe cases.
- These antiviral drugs try to lodge into nooks and crannies of the giant RdRp molecule, like clogs inside its gears, bringing the machine to a halt. To pull this off, a compound needs to be exceptionally precise—which means that scientists trying to design a successful compound need the most detailed picture of the RdRp they can possibly get.
- Further complicating matters is the fact that RdRp doesn’t work alone. It joins hands with a number of other proteins, including another crucial enzyme called the helicase, which in its own right is a promising target for C19 drug discovery. This tight cluster of RdRp and associated proteins is “likely what the enzyme looks like outside the lab and in its native environment, inside an infected cell,” says James Chen, a postdoctoral associate in Seth Darst’s lab and one of the study’s first authors.
- Using a powerful imaging technique called cryo-electron microscopy, Darst and Campbell’s team, and their collaborators in the labs of Brian Chait and Tarun Kapoor, were able to show what exactly this multipart machine looks like. One piece of good news: Even when they form a complex, the cavities of the RdRp or the helicase don’t change shape, so molecules designed to inhibit these enzymes in isolation may still work on the duo. What’s more, the image reveals several previously unknown sites in the machine that may be vulnerable to drugs—including one spot at the interface between the two enzymes, a joint that could be potentially dismantled by an interfering molecule.
Cracking the coronavirus and more
- The new findings could improve human health in a number of ways. In the case of C19, as scientists around the world are racing to find antiviral molecules, the new data might significantly speed up their work. In particular, the unprecedented resolution at which the team produced their 3-D map of the RdRp-helicase complex will aid computational studies in which researchers explore the function of drug candidates “virtually,” based on their knowledge of the chemical structure of the molecules.
- “When one is looking for molecules that can lodge into a particular binding pocket, having a detailed picture of what that pocket looks like greatly improves the computational docking precision,” says Brandon Malone, a graduate student at Rockefeller and the study’s co-author.
- Beyond C19, the new findings might also help scientists narrow down their ideas about how exactly the two enzymes read and copy genetic material in all so-called RNA viruses, a vast group of pathogens including everything from coronaviruses to dengue, Ebola, and the common flu.
- “Now we’ll be able to not only propose models for the mechanics of viral replication, but also actually test those models.” says Chen.
3. Decoys could trick C19, keep humans safe from infection
- The coronavirus that causes C19 infects cells by plugging into a receptor on their surface. Now, by crafting a “decoy” of that receptor, scientists aim to foil the virus’s attack.
- In a new study, published Aug. 4 in the journal Science, researchers engineered such a decoy and found that the coronavirus bound tightly to the imposter receptor, and once attached, the virus couldn’t infect primate cells in a lab dish. The decoy binds to the virus as tightly as a neutralizing antibody, a Y-shaped molecule generated by the immune system to grab the virus and prevent it from infecting cells.
- Neutralizing antibodies are the “best that the human body makes … so that’s our target” — to have a decoy receptor that sticks to the coronavirus just as snuggly, study author Erik Procko, an assistant professor of biochemistry at the University of Illinois at Urbana-Champaign, told Live Science. The team found that their newly designed decoy, known as sACE2.v2.4, tightly binds both the novel coronavirus and SARS-CoV, a related virus that caused outbreaks of severe acute respiratory syndrome in the early 2000s.
- If the decoy works in animals as it does in cell culture, it could be developed into a C19 treatment and preventative therapy for humans. That said, the research is still in very early stages and no decoy receptor has ever been approved as a treatment for an infectious disease, Procko said.
- “This would be something new, if it is successful,” being that it would be the first decoy approved as an antiviral, he said.
Designing a decoy
- A few decoy receptors have been approved by the FDA for the treatment of inflammatory- and immune system-related diseases, such as the rare “familial cold autoinflammatory syndrome” that causes recurrent fevers, joint pain and inflammation of the eyes, according to a 2013 report in the journal Frontiers in Immunology. However, decoy receptors developed as antiviral treatments have historically hit roadblocks on their way to approval.
- The first decoy designed to thwart a virus mimicked a natural receptor found on immune cells called CD4, which binds to HIV, according to a 2008 report in the journal Current Opinion in Biotechnology. While promising in studies that used lab-grown HIV strains, CD4 decoys did not bind effectively to strains isolated from HIV/AIDS patients, according to the report. To this day, no CD4 decoys have graduated from clinical trials and been approved for use in patients. The same is true of the decoys designed to treat rhinovirus, foot-and-mouth disease virus, hepatitis A and SARS-CoV.
- Procko noted that, to be a successful antiviral, a decoy receptor must meet two major criteria:
- First, it must not disrupt important bodily functions, given that natural receptors often play multiple roles in the body. For example, the ACE2 receptor, which C19 exploits as a gateway into cells, also helps control blood volume and lower blood pressure, he said. By infecting cells with ACE2 receptors, C19 actually interferes with ACE2 activity in the body — a decoy ACE2 receptor could potentially “rescue” some of this lost activity by leaving natural receptors open for business, rather than bound to the coronavirus, Procko said.
- However, decoy ACE2 receptors could cause unanticipated side effects, so the researchers need to monitor for these in animal studies and early clinical trials, he added.
- In addition to being safe to administer, a decoy receptor must show high affinity for the virus it targets, meaning it binds tightly to the virus in human cells.
- “To be a good binder, with high affinity, you need to bind on your target quickly and you need to come off your target slowly,” Procko said. To find a decoy that binds well to the coronavirus, Procko and his colleagues ruled out thousands of inadequate ACE2 copycats using an experimental technique known as “deep mutagenesis.”
- So what is deep mutagenesis? Think of a Vegas slot machine — a mix of three different fruits equals a certain payout (or not). DNA is similar: a set of three letters code for a single amino acid, or protein building block. In this case, the team scrambled the three-letter segments in 117 spots in human DNA that past studies suggested affected how tightly coronavirus bound to the ACE2 receptor. This allowed the researchers to essentially “pull the slot machine lever” over and over to study how swapping out each amino acid (a single spin of the slot machine) for another affected the ACE2 receptor’s coronavirus binding. In this case, the scrambled DNA was expressed in different versions of human cells in a lab dish.
- “You can exhaustively test many, many thousands of mutations, to see which are relevant,” Procko said.
- After producing cells with mutant ACE2 receptors — ones based on scrambled DNA segments — the researchers exposed the cells to the portion of the coronavirus that locks into the ACE2 receptor, known as the receptor-binding domain. They found that sACE2.v2.4 showed the highest affinity for the virus; the researchers then developed a version of the decoy that can exist in the body without being attached to a cell, as the detached receptor is all that would be needed for a future drug.
The next steps
- Compared with an unmodified ACE2 receptor, “less than 1% of the entire protein sequence has been changed” to craft the decoy, Proko noted. If fully developed as a treatment for humans, the decoy receptor would likely be delivered into the body through an injection or inhaled as a mist, he said. Drugs derived from living things, like the decoy receptor, are “frequently long-lived,” and can persist in the body for a week or more, he said.
- A decoy receptor would serve a similar purpose to antibody cocktails designed to treat C19, which would include multiple antibodies that bind in different ways to the coronavirus. However, a report published June 15 in the journal Science suggests that the virus can mutate to escape the grasp of specific antibodies — a decoy receptor might be more reliable in the long run, as the virus would be less likely to mutate in such a way that it no longer binds to ACE2, Procko said. The fact that sACE2.v2.4 tightly binds both the coronavirus and its predecessor SARS-CoV supports this notion, given that both viruses use ACE2 to break into cells.
- Procko founded a start-up called Orthogonal Biologics to continue work on the ACE2 decoy earlier this year, along with study author Kui Chan who serves as Chief Operating Officer. The next step is to do animal studies, and should the treatment advance to human studies, they have to show the decoy can be manufactured reliably at large scales.
- Interestingly, an ACE2 decoy that was developed by researchers tied to Apeiron Biologics is already being tested in clinical trials for the treatment of C19, and so far, appears safe in both healthy people and those with lung disease, according to a statement from the company. The major difference is that the existing decoy closely resembles the natural ACE2 receptor, and has not been mutated to bind as tightly as possible to the coronavirus, while sACE2.v2.4 has. (Procko and his colleagues were not involved in the design of the Apeiron decoy.)
- Apeiron developed the existing decoy following the SARS epidemic as a treatment for the coronavirus, but has also tested the drug for the treatment of various lung conditions, including acute respiratory distress syndrome (ARDS) and pulmonary arterial hypertension. Based on early data, patients appear to tolerate the treatment well, without major side effects. Though the Apeiron product is different from the decoy Procko and his colleagues developed, the early results are encouraging, Procko said. “We know that you can inject [the Apeiron decoy] into people and it doesn’t hurt them,” which gives hope for their mutated ACE2 decoy, Procko said.
- Procko’s team has begun testing their decoy in mice infected with C19 and has “not yet observed any toxicity,” he noted.
4. C19 Patients Exhibit Early Antibody Signatures Potentially Predictive of Death or Recovery
- Researchers at the Ragon Institute of MGH, MIT and Harvard, and the University of Washington (UW) School of Medicine, have identified five immune response markers that, collectively, were able to distinguish between those C19 patients who convalesced from the infection, and those who didn’t survive the disease. The researchers used a systems serology technique to generate a detailed profile of coronavirus-specific humoral—antibody generating—responses in hospitalized patients, which they validated in a second patient cohort. The findings indicated that individuals who survived C19 infection and those who died exhibited antibody responses that were primarily directed against different coronavirus proteins.
- “Any given feature tells only a small part of the story,” said co-lead scientist Galit Alter, PhD, group leader at the Ragon Institute and professor of medicine at Harvard Medical School. “By looking at the overall profile of the immune response, we can begin to truly understand how the immune system responds to C19 and then use that knowledge to prevent the worst outcomes of this disease.”
- The results could help in the development of C19 vaccine candidates, suggested co-lead researcher Helen Chu, MD, associate professor of medicine, division of allergy and infectious diseases, and UW Medicine physician. “Finding these early antibody signatures may have implications for assessing C19 vaccine candidates to ensure they produce an immune response similar to that of individuals who survive natural infection.”
- The investigators reported on their study in Immunity, in a paper titled, “Distinct early serological signatures track with SARS-CoV-2 survival.”
- It’s still not clear why some individuals infected with coronavirus recover from infection and others die, the authors noted. “While the rapid spread of the coronavirus, even during the asymptomatic phase of this infection, is alarming, more harrowing is our inability to predict disease trajectories among symptomatic individuals.” And without any therapeutics or vaccines as countermeasures, there is “an urgent need” to start mapping how immunity to the virus starts to develop. This knowledge will not only help to guide patient care, but could help to direct the development of future immune-based strategies against the disorder.
- For their study, the researchers profiled how the immune responses of hospitalized coronavirus infected patients evolved, to see if they could define antibody features that were predictive of disease outcome. A team headed by Chu collected samples from a cohort of 22 hospitalized coronavirus patients, 12 of whom recovered, and 10 of whom died.
- Alter’s team then applied her systems serology technique—which is an approach that relies on more than 60 assays to create a detailed profile of the immune response—to compare the immune responses of those individuals who had survived, with the responses of individuals who died from C19.
- Coronavirus has two main proteins that trigger humoral immune system responses. They are the spike (S) protein and the nucleocapsid (N) protein. The N protein is produced at significantly higher levels in the virus than the S protein is, but previous studies have shown that an immune response to the N protein does not provide protection against coronaviruses related to SARS-CoV-2.
- Using her systems serology technique, which creates a detailed profile of the humoral immune response, Alter’s lab compared the immune responses from the recovered individuals to those of deceased patients. They found that those who had recovered exhibited a humoral immune response that responded mostly to S protein, while deceased individuals had a shift in immunodominance such that they had a stronger immune response to the N protein. “The shift in immunodominance was only apparent after comparing robust, detailed profiles of the immune response from different groups of patients,” Alter said.
- This immunodominance shift could be detected by measuring five immune response markers: IgM and IgA1 responses to S protein and antibody-dependent complement deposit, IgM, and IgA2 response to N protein. Using these five markers, researchers were able to build a model that could correctly classify clinical samples as belonging to deceased or convalesced individuals.
- “Despite inter-individual heterogeneity, distinct antibody signatures resolved individuals with different outcomes,” the investigators wrote. “While no differences in coronavirus -specific IgG levels were observed, spike–specific humoral responses were enriched among convalescent individuals, whereas functional antibody responses to the nucleocapsid were elevated in deceased individuals. These data point to early diverging humoral immune responses that may mark more effective immunity and suggest that functional antibodies directed against S protein might be beneficial for coronavirus disease trajectory.”
- In order to verify this model, another 40 clinical C19 samples—20 from convalesced individuals and 20 from deceased patients—from a different hospital were evaluated. The results showed the same S protein to N protein shift in immunodominance in samples from the deceased individuals, compared with those from convalesced patients.
- Importantly, in the samples analyzed, this immunodominance shift was more predictive of recovery or death than were demographic factors, such as age or sex. “Thus, a minimal set of coronavirus humoral profiles, rather than demographic information, appear to significantly resolve individuals who later went on to die from those who recover,” the team noted. “… these findings suggest that a consistent overall shift in S:N immunity early in coronavirus infection may have a protective role and aid in recovery from severe disease.”
- How these predictive immune markers may be influenced by risk factors of C19, time course of infection, or severity of disease isn’t yet known. However, the study provides a potential approach to identifying at-risk patients, based on individual immune responses, and may help in the design and development of anti-C19 vaccines, the scientists suggested. “Whereas this study only attempted to understand the humoral disparities between convalescent and deceased individuals in a cohort of severely infected individuals, further studies may attempt to define humoral profiles able to further classify individuals across the clinical trajectory spectrum ranging from asymptomatic to severe disease.”
- And while the team noted several limitations to their studies, they concluded, “These results demonstrate that early antigen-specific and qualitative features of coronavirus-specific antibodies, point to differences in disease trajectory, highlighting the potential importance of functional antigen-specific humoral immunity to guide patient care and vaccine development.
C. Improved & Potential Treatments
1. Israeli company says close to putting out ‘new Remdesivir’
- A new anti-viral, anti-inflammatory drug against coronavirus might be soon offered to patients all over the world by Israeli pharmaceutical company RedHill.
- The treatment, based on a chemical compound called Opaganib, has already shown very promising result in compassionate use carried out a the Shaarei Zedek Medical Center in Jerusalem, as Gilead Raday, RedHill’s Chief Operating Officer, told The Jerusalem Post.
- Now, two new studies carried out in the US and in several countries in the world, might be able to soon provide the additional data required for emergency authorization – the same received by the renowned Remdesivir.
- Headquartered in Israel, Redhill Biopharma was established in 2009 and is listed in the Nasdaq. Most of its activities are US focused and specialized on gastro-intestinal drugs, both developed in-house and acquired.
- However, among the pipeline of products the company features, Opaganib presented anti-viral effects long before C19 appeared.
- “Even before the pandemic erupted, we had already noticed that this new chemical entity was able to target a very unique component in the cells that is involved in multiple activities, activities with oncology implications, but also with anti-viral functions,” Raday said. “Viruses need this element in order to replicate within the cell and Opaganib proved to be effective in inhibiting it.”
- Research on the potential of the compound was carried out in connection with the Ebola pandemic.
- “Strong evidence emerged that Opaganib provided inhibition of the virus replication. However, by the time we got that data, the epidemic had subsided so we did not continue with the process,” he recalled.
- Other tests showed that the product seemed relevant against the influenza virus and other virus close to the coronavirus.
- By the time C19 emerged therefore, RedHill was already aware of its potential.
- “We are very ready to use this compound and evaluate it quickly,” Raday said. “We are very developing rapidly and are currently among the most advanced products in the fight against C19: ours is a frontrunner among the investigational products which have shown safety to a wide extent and effectiveness against the virus.”
- “It is important to highlight that this product has not only anti-viral but also anti-inflammatory effects, which is very relevant for this disease,” he added.
- Opaganib showed very promising results on patients hospitalized at Shaarei Zedek.
- “The compassionate use provided very encouraging clinical backing to all the data that we had previously,” Raday pointed out. “Researchers compared the impact of giving Opaganib to patients hospitalized in severe conditions who required oxygen supplementation to outcome of patients in similar conditions who were not given the treatment. They found that while a third of the latter progressed to require mechanical ventilation, none of the former did. In addition, the patients who received the treatment improved much faster and had a better inflammatory response.”
- Redhill is also conducting a small randomized control study in the US, involving around 40 patients.
- “We hope it will help confirm what we saw from the compassionate use, even if might be too small to have statistical significance. The goal is to have the data as early as the end of September,” the manager said.
- “In parallel we have designed a rigorous global study in countries where the epidemic is still peaking,” he added. “We are hoping to complete it by the end of the year to have the final required statistical proof to receive the emergency authorization, like Remdesivir has.”
- Up to 270 patients in several countries including Brazil and Russia are currently been recruited.
- Once recruitment is completed, the study involves two weeks of treatment – with a pill taken orally twice a day mornings and evenings – followed by a month of observation to see how each patient responds.
- “The fact that the pill is taken orally is important because, while at the moment we are looking at hospitalized patients, if we get good results we might be able to expand its use to those in milder conditions, even before they get to the hospital,” Raday concluded.
2. Interleukin-6 inhibitors may be effective treatment
- The immune systems of people with severe C19 can go into overdrive, causing excessive inflammation that worsens their breathing difficulties.
- This “cytokine release syndrome,” or “cytokine storm,” can lead to potentially fatal respiratory distress syndrome.
- During the pandemic, healthcare professionals have been using immune-modifying drugs called interleukin-6 (IL-6) receptor inhibitors “off label” in an attempt to prevent this from happening.
- These drugs, which are monoclonal antibodies, work by targeting receptors for an immune signaling molecule, or cytokine, called IL-6. This dampens the excessive immune response.
- Healthcare professionals usually prescribe these drugs for rheumatoid arthritis, which is an autoimmune condition in which the immune system attacks the joints.
- An earlier observational study, by researchers at the University of Michigan in Ann Arbor, found that an IL-6 receptor inhibitor called tocilizumab improved the survival of C19 patients on ventilators.
- Other observational studies have also shown benefits, but the optimal timing for giving IL-6 receptor inhibitors remained unclear.
- If a patient receives the drug too early, it may impair the body’s antiviral response. If they receive it too late, after the cytokine-mediated immune response has started to damage tissues, it may be ineffective.
Supplementary oxygen requirement
- The new study, which took place at Boston Medical Center in Massachusetts, divided 255 patients into two groups according to their need for supplementary oxygen.
- One group comprised 106 patients who were critically ill but had not yet undergone intubation, while the other group comprised 149 patients who were at an earlier stage of the disease.
- All the patients received tocilizumab or another IL-6 receptor inhibitor called sarilumab.
- Over the study period, those who received treatment at the earlier stage of the disease were less likely to die, less likely to require intubation, and more likely to be discharged from the hospital.
- There were no significant differences between the groups in terms of preexisting risk factors that are known to worsen outcomes in C19. These include age, coronary artery disease, and high blood pressure.
- Of the 255 patients, 34 (13.3%) developed bacterial infections after receiving the drugs. However, these infections were not associated with an increased risk of mortality, the researchers point out.
- Dr. Pranay Sinha, who led the study, explains that it showed that patients who received IL-6 receptor inhibitors at an earlier stage of the disease — before critical respiratory decompensation — fared better. This highlights the importance of prompt testing and treatment, he says.
- “We hope these findings can help guide physicians as we seek solutions to reduce mortality, increase extubation, reduce length of stay in the hospital, and have more patients discharged from the hospital alive,” he adds.
3. Rogue immune system reactions hint at an early treatment for C19
- In severe cases of C19, a person’s immune system throws everything it has at the coronavirus, but some of the weapons it lobs end up hurting the patient instead of fighting the virus.
- Now researchers have new clues for getting the immune system back on target, before the disease becomes severe. One of the most comprehensive looks to date at the immune system of C19 patients pinpoints where things go awry. The findings suggest that bolstering the body’s first line of defense against the virus using drugs known as interferons may help prevent severe illness.
- In a study of 113 patients admitted to Yale New Haven Hospital from May 18 to May 27, researchers monitored immune system chemicals and cells in two groups: severely ill C19 patients who needed intensive care and moderately ill patients who were hospitalized but didn’t end up in the ICU. For comparison, the team also looked at healthy health-care workers.
- This study characterized the nuances of the immune response and “characterizes the inflammation at its nittiest, grittiest level,” says Michal Tal, an immunologist at Stanford University who was not involved in the study.
- Moderately ill patients had an initial spurt of immune chemicals that fight viruses and fungi, then those levels gradually went back to normal, Akiko Iwasaki, an immunologist at Yale University, and colleagues found. But in the severely ill patients, levels of those chemicals remained high, the researchers report July 27 in Nature. In addition, allergy-producing antibodies and immune chemicals and cells usually dedicated to expelling parasitic worms got enlisted against the virus. As in other studies, the severely ill patients also had low levels of T cells, immune cells involved in recognizing and killing viruses.
- That catalog of all the different ways the immune system misfires is striking, Tal says. “The immune system is just throwing the whole kitchen sink at this [virus],” she says. That desperation may end up hurting patients with tissue-damaging inflammation.
- One of those weapons is interferon alpha, normally one of the body’s first defenses against viruses. Those chemicals are usually produced in the first couple of days of an infection, then wane as other parts of the immune system take over the fight. But in people with severe disease, levels of interferon either don’t dip as they should, or become part of the kitchen sink of immune chemicals that can end up being harmful, the researchers discovered.
- If a patient comes into the hospital after 10 days of being sick, Iwasaki says, “and their blood levels of interferon alpha are sky high, that’s probably an indication that that person needs more attention and [will] potentially need mechanical ventilators.” People in the study with high levels of interferon alpha had a 4.5 times greater risk of being admitted to the ICU or dying than people with normal levels.
- Interferon alpha itself may not be making the illness worse, says Eleanor Fish, an immunologist at the University of Toronto. Instead, it may be an issue of timing. In severely ill C19 patients, elevated levels of interferon may be a consequence of extreme inflammation, rather than the cause, she says. These interferons come “too little, too late, but whether it’s exacerbating disease needs to be teased out,” she says. “What we know is that absence of interferon early on in disease is not a good thing.”
- Normally, interferons are produced when cells’ virus alarms are tripped. Interferons flood into the infected area, signal uninfected cells to raise their defenses, and help kill infected cells. “It both removes the viral factory and prevents new infections,” Iwasaki says. With most viruses, “if you generate a robust interferon response within a few minutes of exposure to the virus, you’re likely going to be fine.”
- But, says Iwasaki, “in the case of COVID, this well-orchestrated line of events isn’t happening.” The virus shuts down the interferon response early on. That allows the virus to invade the lungs and do damage without setting off early intruder alarms. Other immune chemicals, called cytokines and chemokines, flood the damaged area attempting to expel invaders and heal the tissue, but can set off a “cytokine storm” that further batters tissues. The high levels of interferon alpha seen in severely ill patients may be produced by cells that don’t normally make those chemicals in a last-ditch effort to combat the virus, Iwasaki says.
- “The earlier you can control the virus, the less damage you’re going to get,” Iwasaki says. And one promising way of potentially controlling the virus early is by giving people interferons.
- Fish and others have already compiled data suggesting that two forms of the drug, interferon alpha and interferon beta, may help fight the coronavirus. In a small study of 77 people with C19, Fish and colleagues found that interferon alpha helped clear viral infections almost seven days sooner on average than people given arbidol hydrochloride, a drug thought to block viral entry to cells.
- What’s more, ramping up interferon didn’t lead to an overzealous immune response, as feared. In fact, people taking interferon had lower levels of an inflammatory protein called IL-6 in their blood than those taking the other drug, the researchers reported May 15 in Frontiers in Immunology. Another study of interferon beta, given in combination with anti-HIV drugs, suggested that interferon speeds recovery from C19 (SN: 5/8/20). And the U.K.-based drug company Synairgen reported July 20 in a news release that inhaled interferon beta reduced the risk of developing severe disease among patients enrolled in a small trial compared with those taking a placebo.
- More trials of interferon alpha, beta and of interferon lambda are in the works. The U.S. National Institute of Allergy and Infectious Diseases announced August 5 that it has begun a clinical trial of about 1,000 hospitalized people with C19 that will test interferon beta 1a in combination with the antiviral drug remdesivir (SN: 7/13/20). But Iwasaki’s study hints that it may be too late to give interferons once a person is already sick enough to be hospitalized.
- Giving interferons as soon as possible after detecting a coronavirus infection may prevent severe illness and speed recovery, Fish and other scientists say. Interferons might also be given as a preventative for people at high risk of contracting coronavirus. Some trials of the early use of interferons are also under way or in the planning stage.
D. Concerns & Unknowns
1. Average C19 incubation period may be longer than first thought
- The incubation period for C19 might be longer than first thought, according to a new study involving people from Wuhan, the central China city where the coronavirus was first detected.
- While the common wisdom among health authorities is that the average incubation period is about five days, rising to a maximum of about two weeks, researchers from the Chinese Centre for Disease Control and Prevention, US National Institute of Allergy and Infectious Diseases and Peking University, say the mean value could be higher.
- In their study, which used probability modelling and clinical data of more than 1,000 C19 patients who left Wuhan before the city went into lockdown on January 23, the researchers found the mean incubation time was 8.29 days, while the median value was 7.76 days.
- “Precise knowledge of the incubation period would help to provide an optimal quarantine period for disease control purposes, and is essential in the investigation of the mechanism of transmission and development of treatment,” the researchers said.
- “Despite the importance of the incubation period, it is often poorly estimated based on limited data.”
- While the research, which was published on Friday in the American journal Science Advances, supported the thinking that the incubation period for most patients is not more than 14 days – the typical quarantine period set by most countries – it estimated 10 per cent of people may develop symptoms more than two weeks after becoming infected.
- That could be a public health concern with regards to quarantine periods, the report said, though added that the limitations of the study could have affected the estimate.
- The researchers said that as their findings were based on cases from earlier in the year, they might not apply to later cases, if the virus had mutated.
- The results were based on a probability model that avoided “recall bias” and other inaccuracies that may occur when collecting data, the study said.
- The method used the travel history and symptom onset data of confirmed cases who left Wuhan between January 19-23. The later date is when the city was put under lockdown to control the spread of the disease.
- Understanding the incubation period can help authorities make their disease control plans, as people can transmit the virus before they show symptoms.
2. Why coronavirus occurs less in children than adults
- The human cell receptor that the novel coronavirus latches onto in its victims is less prevalent in children than adults, which is likely why children may not be as susceptible to C19, according to a new study.
- In the recent report published in JAMA, the study authors stated that children account for less than two percent of reported C19 cases. The researchers hypothesized that this may be due to the gene expression of a specific cell receptor called angiotensin-converting enzyme 2(ACE2).
- The virus enters the human body through the ACE2 receptor, which is located on the surface of certain human cells, according to the study.
- “ACE2 is known to be present in our airway, kidneys, heart, and gut,” stated lead author Dr. Supinda Bunyavanich in a news release provided to Fox News.
- ACE2 is typically known for its role in regulating blood pressure, according to health experts. The retrospective analysis involved examining the nasal passage tissues of 305 patients aged 4 through 60.
- “The nasal passages are usually the first point of contact for SARS-CoV-2 and the human body,” the lead author explained in the study.
- The researchers at Mount Sinai Hospital in New York City discovered children had lower levels of ACE2 gene expression than adults, according to the researchers. “The coronavirus uses ACE2 to enter the human body, where it spreads,” Bunyavanich said.
- Bunyavanich, a professor of genetics, genomic sciences and pediatrics at Icahn School of Medicine at Mount Sinai, said that the ACE2 expression may be linked to a person’s susceptibility to getting the novel coronavirus. According to the physician, the researchers found that “there are low levels of ACE2 expression in the nasal passages of younger children, and this ACE2 level increases with age into adulthood. This might explain why children have been largely spared in the pandemic.”
- Bunyavanich’s study is one of only a few examining the relationship between ACE2 in the airway and age, according to the release. These findings could lead to a potential indicator of susceptibility to the novel coronavirus, the researchers said.
E. The Road Back?
1. Here’s How to Crush the Virus Until Vaccines Arrive
Opinion by Michael T. Osterholm, a professor and director of the Center for Infectious Disease Research and Policy at the University of Minnesota and Neel Kashkari, president of the Federal Reserve Bank of Minneapolis.
- In just weeks we could almost stop the viral fire that has swept across this country over the past six months and continues to rage out of control. It will require sacrifice but save many thousands of lives.
- We believe the choice is clear. We can continue to allow the coronavirus to spread rapidly throughout the country or we can commit to a more restrictive lockdown, state by state, for up to six weeks to crush the spread of the virus to less than one new case per 100,000 people per day.
- That’s the point at which we will be able to limit the increase in new cases through aggressive public health measures, just as other countries have done. But we’re a long way from there right now.
- The imperative for this is clear because as a nation what we have done so far hasn’t worked. Some 160,000 people have died, and in recent days, roughly a thousand have died a day. An estimated 30 million Americans are collecting unemployment.
- On Jan. 30, when the World Health Organization declared C19 a public health emergency, there were 9,439 reported cases worldwide, most in China, and only six reported cases in the United States.
- On July 30, six months later, there were 17 million cases reported worldwide, including 676,000 deaths. The United States had four million reported cases and 155,000 deaths. More than a third of all U.S. cases occurred during July alone.
- And the next six months could make what we have experienced so far seem like just a warm-up to a greater catastrophe. With many schools and colleges starting, stores and businesses reopening, and the beginning of the indoor heating season, new case numbers will grow quickly.
- Why did the United States’ C19 containment response fail, particularly compared with the successful results of so many nations in Asia, Europe and even our neighbor Canada?
- Simply, we gave up on our lockdown efforts to control virus transmission well before the virus was under control. Many other countries didn’t let up until the number of cases was greatly reduced, even in places that had extensive outbreaks in March and April. Once the number of new cases in those areas was driven to less than one per 100,000 people per day as a result of their lockdowns, limiting the increase of new cases was possible with a combination of testing, contact tracing, case isolation and extensive monitoring of positive tests.
- The United States recorded its lowest seven-day average since March 31 on May 28, when it was 21,000 cases, or 6.4 new cases per 100,000 people per day. This rate was seven to 10 times higher than the rates in countries that successfully contained their new infections. While many countries are now experiencing modest flare-ups of the virus, their case loads are in the hundreds or low thousands of infections per day, not tens of thousands, and small enough that public health officials can largely control the spread.
- In contrast, the United States reopened too quickly and is now experiencing around 50,000 or more new cases per day.
- While cases are falling in the hard-hit areas of Arizona, California, Florida and Texas because of the imposition of some physical-distancing measures, they are rapidly increasing in a few of Midwestern states. In Minnesota, we just documented the most new cases in a one-week period since the pandemic began.
- At this level of national cases — 17 new cases per 100,000 people per day — we simply don’t have the public health tools to bring the pandemic under control. Our testing capacity is overwhelmed in many areas, resulting in delays that make contact tracing and other measures to control the virus virtually impossible.
- Don’t confuse short-term case reductions in some states as permanent. We made that mistake before. Some have claimed that the widespread use of masks is enough to control the pandemic, but let us face reality: Gov. Gavin Newsom of California issued a public masking mandate on June 18, a day when 3,700 cases were reported in the state. On July 25, the seven-day daily case average was 10,231. We support the wearing of masks by all Americans, but masking mandates and soft limitations on indoor crowds in places such as bars and restaurants are not enough to control this pandemic.
- To successfully drive down our case rate to less than one per 100,000 people per day, we should mandate sheltering in place for everyone but the truly essential workers. By that, we mean people must stay at home and leave only for essential reasons: food shopping and visits to doctors and pharmacies while wearing masks and washing hands frequently. According to the Economic Policy Institute, 39% of workers in the United States are in essential categories. The problem with the March-to-May lockdown was that it was not uniformly stringent across the country. For example, Minnesota deemed 78% of its workers essential. To be effective, the lockdown has to be as comprehensive and strict as possible.
- If we aren’t willing to take this action, millions more cases with many more deaths are likely before a vaccine might be available. In addition, the economic recovery will be much slower, with far more business failures and high unemployment for the next year or two. The path of the virus will determine the path of the economy. There won’t be a robust economic recovery until we get control of the virus.
- If we do this aggressively, the testing and tracing capacity we’ve built will support reopening the economy as other countries have done, allow children to go back to school and citizens to vote in person in November. All of this will lead to a stronger, faster economic recovery, moving people from unemployment to work.
- We know that a stringent lockdown can have serious health consequences for patients who can’t get access to routine care. But over the past six months, medical professionals have learned how to protect patients and staffs from spreading the coronavirus; therefore we should be able to maintain access to regular medical care during any new lockdown.
- This pandemic is deeply unfair. Millions of low-wage, front-line service workers have lost their jobs or been put in harm’s way, while most higher-wage, white-collar workers have been spared. But it is even more unfair than that; those of us who’ve kept our jobs are actually saving more money because we aren’t going out to restaurants or movies, or on vacations. Unlike in prior recessions, remarkably, the personal savings rate has soared to 20 percent from around 8 percent in January.
- Because we are saving more, we have the resources to support those who have been laid off. Typically when the government runs deficits, it must rely on foreign investors to buy the debt because Americans aren’t generating enough savings to fund it. But we can finance the added deficits for C19 relief from our own domestic savings. Those savings end up funding investment in the economy. That’s why traditional concerns about racking up too much government debt do not apply in this situation. It is much safer for a country to fund its deficits domestically than from abroad.
- Congress should be aggressive in supporting people who’ve lost jobs because of C19. It’s not only the right thing to do but also vital for our economic recovery. If people can’t pay their bills, it will ripple through the economy and make the downturn much worse, with many more bankruptcies, and the national recovery much slower.
- There is no trade-off between health and the economy. Both require aggressively getting control of the virus. History will judge us harshly if we miss this life- and economy-saving opportunity to get it right this time.
F. Back to School!?
1. US Children & Schools
- The beginning of the 2020-21 school year continues to be tumultuous with some schools conducting classes in-person, some only teaching remotely, and others utilizing hybrid approaches. Plans also continue to change rapidly in many school districts, particularly in those that have been forced to implement quarantine, to varying degrees, or even suspend in-person classes entirely following positive coronavirus tests among students or staff. Schools in multiple states—including Georgia, Indiana, Mississippi, North Carolina, and Tennessee—have had to adapt existing plans in response to C19 cases.
- A study published jointly by the American Academy of Pediatrics and the Children’s Hospital Association found that 97,078 new confirmed infections among children were reported in the last 2 weeks of July, representing a 40% increase in overall reported infections among children.
- By the end of July, there were 338,982 total infections by children in the US, equivalent to 447 cases per 100,000 children and making up 8.8% of total US cases. Notably, the study found that 0.6%-8.9% of all cases among children—across 20 states and New York City—were hospitalized. Additionally, states reported C19 mortality in children as high as 0.3%, although 20 of 44 states reported zero pediatric C19 deaths.
- Two studies published in the US CDC’s Morbidity and Mortality Weekly Report (MMWR) address C19 disease and associated conditions in pediatric cases. The first study describes clinical manifestations and characteristics of multisystem inflammatory syndrome in children (MIS-C), a rare but serious condition among pediatric C19 patients that has thus far affected at least 570 children across 40 states and Washington, DC. The second study describes characteristics of hospitalized pediatric C19 patients in the US from March to July.
- The researchers noted that hospitalization rates were higher among racial and ethnic minorities, consistent with data reported among adult C19 cases. The hospitalization rate was 4-8 times higher among Black and Hispanic and Latino children than among non-Hispanic White children.
- Notably, one-third of all hospitalized children were ultimately admitted to an intensive care unit (ICU), clearly illustrating that, while children are at lower risk for severe disease than adults, pediatric patients can experience severe C19 disease. Among hospitalized children, 42% had an underlying medical condition, with obesity being the most common. In the US, 1 in 5 children are obese, which further highlights the risk of severe C19 disease among pediatric patients.
Source: Johns Hopkins COVID-19 Update
1. Scientists tested 14 types of masks — here are the ones that worked and didn’t
- Bandannas, gaiters and knitted masks are some of the least effective face coverings for preventing the spread of coronavirus, according to a new study.
- Researchers at Duke University made the discovery while testing 14 different types of masks, according to the study published Friday.
- N95 masks, often used by health care professionals, worked best to stop the transmission of respiratory droplets during regular speech.
- Other good performers at stopping leakage were three-layer surgical masks and cotton masks, which can be made at home, the researchers with Duke’s physics department found.
- But while bandannas and knitted face coverings may be a unique look, they did not offer much protection, according to the study.
- The scientists also discovered that neck fleeces, or neck gaiters, often worn by runners, were the least effective and actually allowed more respiratory droplets to escape than not wearing a mask at all.
- That’s because they were shown to break down larger droplets into smaller particles, allowing them to slip out the sides of the covering more easily.
- “We were extremely surprised to find that the number of particles measured with the fleece actually exceeded the number of particles measured without wearing any mask,” Martin Fischer, one of the study’s authors, told CNN.
- “We want to emphasize that we really encourage people to wear masks, but we want them to wear masks that actually work.”
- To test the masks, the scientists made use of a black box outfitted with a laser and a cellphone camera.
- Someone wearing a face mask would speak in the direction of the laser beam inside the box. Then the amount of respiratory droplets scattered by the beam were recorded by the camera in the back of the box.
- A computer algorithm counted the droplets seen in the video to determine how many had leaked through.
- The researchers said this was a low-cost, effective method to test which face coverings worked and which didn’t.
- “This is a very powerful visual tool to raise awareness that very simple masks, like these homemade cotton masks, do really well to stop the majority of these respiratory droplets,” Fischer told CNN.
2. Avoid wearing coronavirus face masks with vents, valves, CDC says in updated guidance
- Valves make masks a bit more breathable but ‘don’t do anything in terms of filtering’
- The Centers for Disease Control and Prevention (CDC) recently updated its guidelines advising Americans to avoid such face masks, as they aren’t as effective in preventing the spread of C19.
- “The purpose of masks is to keep respiratory droplets from reaching others to aid with source control. Masks with one-way valves or vents allow exhaled air to be expelled out through holes in the material. This can allow exhaled respiratory droplets to reach others and potentially spread the C19 virus,” the federal agency states in its guidance.
- “Therefore, CDC does not recommend using masks if they have an exhalation valve or vent.”
- “Although there is some feeling that any type of mask is better than none, it’s really not that helpful when one isn’t wearing a mask correctly or wearing one that is ineffective, and may not even realize it. These recent guidelines from the CDC are helpful in helping people choose masks,” Dr. John Whyte, the chief medical officer of the health care website WebMD, told Fox News in an email.
- “I know everyone wants comfort when wearing a mask. The key for protection is a good seal — thereby keeping as many infectious particles that we can from affecting other people. Sometimes that seal makes our glasses foggy or causes humidity. The problem with the valves is that although the prevent particles from coming in, they allow particles to come out — defeating the purpose of infection control. Masks with vent decrease the effectiveness of the seal,” he continued.
- Indeed: Though valves make masks a bit more breathable, “they don’t do anything in terms of filtering out anything the wearer is exhaling,” Dr. Ali Raj, executive vice chairman of the department of medicine at Mass. General Hospital, told the Boston Globe in May.
- “When you’ve got people coming out and businesses opening back up, you might as well have people not wearing masks at all if they’ve got a one-way valve because they’re just breathing everything right out into the air without any filtration,” he added.
- The CDC’s guidance comes after N95 respirators with small valves on the front became the target of a similar warning from a local health department in May.
- At the time, the San Francisco Department of Public Health took to Twitter to remind residents that if they are choosing to wear an N95 (which should ideally be reserved for medical workers on the frontline, officials have stressed), they should ensure it doesn’t have the front valve.
- Valved N95 masks are not typically used in a medical setting, though they are said to make breathing easier, according to a 2008 study on the masks. In general, N95s help to “reduce the wearer’s exposure to airborne particles, from small particle aerosols to large droplets,” according to the CDC.
H. Practical Tips & Other Useful Information
1. Why Are Some Groceries Still So Hard to Find During Covid?
- At the beginning of the pandemic, it was nearly impossible to find toilet paper, cleaning supplies or canned soup. Five months later, supplies of those goods are recovering, according to data from market-research firm IRI. But shelves remain generally emptier than they were before the pandemic, and it could get worse before it gets better.
- As C19 cases continue to rise in certain states, grocers are reporting a new increase in staples purchases that could lead to scarcity. The even-stronger demand for items such as baking ingredients and paper towels has made it tough for manufacturers to produce the items fast enough to keep shelves full.
- “In-stock conditions at retailers are much better than two months ago but not anywhere where we would like them to be,” said Kellogg Co. Chief Executive Steve Cahillane.
- Manufacturers of food, beverages, paper products and cleaning supplies ramped up production in the spring to help grocers get back in shape. During the peak shopping spree at the end of March, stores ran out of 13% of their items on average. Now, roughly 10% of items remain out of stock, compared with a normal range of 5% to 7% before the pandemic.
- That might not seem significant, but leaving shelves 90% full for half a year would cost the supermarket industry some $10 billion in lost revenue, according to research from trade associations.
- For grocery shoppers, it means that someone with 20 items on their list would be out of luck on two of them. Shopper surveys have shown that if people can’t find what they are looking for, they will try a different store, and the retailer risks losing that customer for good.
- Manufacturers and retailers are focused on making, delivering and stocking their top-selling items. That can lead to out-of-stocks of niche or seasonal items, such as barbecue tools.
- Other aisles have less stock because the sector simply can’t make enough. For instance, flour mills are behind on deliveries despite boosting production by as much as 40%.
- As increases in C19 cases cause states to pull back their reopening plans, grocery makers and retailers say demand is ticking up and they have little extra stock to spare.
- “As soon as you saw that big states were having an issue, we absolutely saw an increase in orders immediately,” B&G Foods Inc. Chief Executive Ken Romanzi said.
- B&G Foods, which makes Green Giant canned and frozen vegetables, said it blew through its inventory in the spring and is making as much as possible but hasn’t been able to stock up on extras to prepare for another wave of shutdowns. Other manufacturers such as Kimberly-Clark Corp., Campbell Soup Co. and General Mills Inc. have also said they haven’t been able to rebuild inventories because of the strong demand.
- Prices for food and household goods also surged during the hardest-hit months of the pandemic because manufacturers and retailers dramatically cut back on discounts. Instead of 2-for-1 deals to encourage people to buy more, they implemented purchase limits on hot items such as pasta and paper towels.
- Retailers say promotions have picked up again this summer, helping average price increases slow from May, according to IRI data.
- Overall, store prices remain about 5% higher on average than a year ago, IRI says. Typically, inflation would result in a roughly 2% increase.
- A few categories are offering more discounts than usual. Grooming-supply companies, for instance, are trying to boost sales because people have stopped prioritizing their appearance regularly as they aren’t going to work or many social events. Sports and energy drinks also upped their deals during the peak of the pandemic when gyms were closed and people weren’t going to convenience stores as much.
Down at the Factory
- Total U.S. manufacturing slowed during the pandemic as nonessential businesses were shut down. Factories making food and other items for grocery stores increased their capacity by anywhere from 10% to 40%. However, those producing large quantities for restaurants, schools and hotels reduced their output if they couldn’t switch to making retail-sized products.
- In the end, factories making food, paper products and cleaning supplies reported significantly less disruption because of the pandemic than industries such as autos and appliances.
I. Johns Hopkins COVID-19 Update
August 10, 2020
1. Numbers & Trends
- The WHO C19 Situation Report for August 9 reports 19.46 million cases (273,552 new) and 722,285 deaths (6,207 new). The global cumulative incidence could potentially reach 20 million cases by tomorrow or Wednesday’s Situation Report, and the global mortality could reach 750,000 deaths by the end of this week.
Central & South America
- Central and South America continues to be the major global C19 hot spot, with 5 of the top 10 countries in terms of both total and per capita daily incidence. Brazil surpassed 3 million cumulative C19 cases, and it is currently reporting 43,106 new cases per day. Brazil remains #3 globally in terms of daily incidence. Colombia is reporting 9,976 new cases per day, and its daily incidence appears to be leveling off. Columbia remains #4 globally in terms of daily incidence, but it is well behind the top 3 countries. Peru has reported steadily increasing daily incidence since late June. It is now reporting 7,025 new cases per day, surpassing its first peak in early June. Peru climbed to #5 globally in daily incidence. Argentina’s C19 epidemic continues to accelerate steadily, up to 6,467 new cases per day. Argentina is currently #7 globally in terms of daily incidence. Mexico has reported decreased daily incidence over the past week or so, down from a high of 7,022 on August 2 to 5,890 today. Mexico fell to #8 globally in terms of daily incidence. Multiple other countries in the region are also reporting more than 1,000 new cases per day. In terms of per capita daily incidence, Panama is #1, Peru is #3, Brazil is #5, Colombia is #6, and Argentina is #9. Bolivia fell out of the top 10, but it and several other countries are reporting more than 100 new daily cases per million population.
- India has reported more than 2 million cumulative C19 cases. India is now #1 globally with respect to daily incidence, surpassing the US, with 58,768 new cases per day and still increasing. The global record for average daily incidence is 67,374, set by the US on July 23, and India could soon surpass this mark if it continues along its current trajectory.
- The Philippines’s daily incidence fell to 3,818 new cases per day, down from a high of 4,356 on August 6. The Philippines remains #10 in terms of daily incidence, but it could soon fall out of the top 10.
- South Africa has reported steadily decreasing daily incidence since its peak on July 20 (12,584 new cases per day), and it is down to 6,910 new cases per day. South Africa fell to #6 in terms of daily incidence, and it fell out of the top 10 for per capita daily incidence.
- After consistent decreases in daily incidence since late June, Bahrain reported increasing daily totals over the past several days. At #4 it remains the only country in the Eastern Mediterranean region in the global top 10 in terms of per capita daily incidence. Kuwait is the only other country in the region reporting more than 100 new daily cases per million population. Nearby Israel (#7), in the WHO’s European region, remains among the top countries globally as well.
- The US CDC reported 4.97 million total cases (54,590 new) and 161,284 deaths (1,064 new). We expect the US to surpass 5 million cases in this afternoon’s update. In total, 15 states (increase of 2) are reporting more than 100,000 cases, and Ohio and South Carolina should surpass this benchmark in the coming days. California and Florida are reporting more than 500,000 cases; Texas more than 450,000; New York* more than 400,000; and Georgia more than 200,000.
- *The CDC removed New York City from its list of jurisdictions, but it did not combine the total state incidence for New York on this list. The CDC reports New York as having 192,761 cases, but the New York State Department of Health reports 420,860 cases. It does not appear that this impacts the cumulative national incidence reported by the CDC.
- The US fell to #2 in terms of total daily incidence, behind India, and also fell to #8 in terms of per capita daily incidence.
- The Johns Hopkins CSSE dashboard reported 5.06 million US cases and 163,156 deaths as of 1:30pm on August 10.
2. US C19 Stimulus Package
- On Saturday, US President Donald Trump signed an executive order and 3 memoranda that aim to provide economic relief from the effects of the US C19 epidemic. The decision to take executive action followed continued struggles in negotiations in the Congress to finalize a “Phase 5” spending package. The executive order addresses the risk of an “abnormally large wave of evictions” after protections under the CARES Act expired, directing the Secretaries of Health and Human Services (and the CDC Director), Treasury, and Housing and Urban Development (HUD) to evaluate the need to provide protection for individuals at risk for eviction and associated options for doing so. The individual memoranda direct the deferral of payroll taxes, suspension of student loan repayment and interest accrual, and extension of expanded unemployment benefits through the end of 2020.
- Opponents of President Trump’s efforts have highlighted several notable issues with the executive actions that could limit their effect. With respect to eviction protections, the executive order does not appear to actually extend the federal moratorium on evictions that expired several weeks ago, but rather, it directs senior government leadership to evaluate further options. The memorandum on payroll taxes postpones the payments until 2021, which temporarily increases paychecks but could force taxpayers to pay back the difference later, unless the Congress authorizes an associated tax cut. Payroll taxes fund federal programs such as social security and Medicare/Medicaid, so a future payroll tax cut could ultimately impact national programs that support millions of Americans.
- The expanded unemployment benefits total US$400 per week, which is down from US$600 under the CARES Act. Additionally, they require the Federal Emergency Management Agency (FEMA) to redirect funding from the Disaster Relief Fund (DRF) to state governments to cover US$300 per week, and it requires states to supply another US$100 per week using funds previously allocated to support C19 response operations. Notably, the DRF is used to provide federal support for disasters like hurricanes, and the US is just entering the 2020 hurricane season. Additionally, some elected officials, Democrat and Republican, and experts have highlighted specific concerns about policies in the orders that may be unconstitutional, including allocating federal funding. Others have noted that executive action is not sufficient to fix these problems and that Congressional action is needed to address them, particularly with respect to identifying long-term solutions.
3. Antigen Tests
- Since the onset of the US epidemic, the response has been hampered by testing delays, with tests often taking more than 48 hours—or in some cases, more than a week—to process. These lengthy delays make successful contact tracing difficult or impossible in many cases, which allows community transmission to continue. Rapid, point-of-care tests could potentially provide a solution to testing delays. These antigen tests detect the presence of virus in the sample by looking specifically for molecular structures on the outside of viral particles, as opposed to the presence of viral RNA. These same antigens are what the immune system uses to detect viral particles and initiate an immune response.
- While these tests can be conducted more quickly, potentially on the order of 15-30 minutes, they may not be as accurate as the standard PCR diagnostic tests currently in use for SARS-CoV-2.
- With the aim of supplementing existing SARS-CoV-2 testing capacity and reducing delays, 7 governors are arranging to purchase 3.5 million rapid tests, including antigen tests. The governors acknowledged that antigen tests are more likely to produce inaccurate results, but these tests could provide the capacity needed to implement community-wide screening programs. Additionally, the US government is working to procure antigen tests to supplement national testing capacity. The federal government reportedly hopes to obtain 20 million tests per month by September, but some experts believe that the US may need more than 4 times that many tests to implement an effective testing/screening program. As with existing tests, including diagnostic and serological, antigen tests are not a universal solution; however, they can provide valuable information, particularly if utilized in conjunction with other testing products and strategies.
4. India Mortality
- India’s C19 case fatality ratio has been declining steadily since mid-June, and it is poised to cross below 2%. But as India becomes the third country to surpass 2 million C19 cases, there is concern that its C19 mortality could be artificially low. With only 44,386 cumulative deaths nationwide and case fatality ratio at 2%, India appears to be in much better shape than most other countries, particularly those that have reported high incidence. As we discussed previously, case fatality is notoriously difficult to estimate in the midst of an epidemic, and there are a number of factors that could be contributing to India’s low reported mortality.
- One report from 2019 found that only 22% of deaths nationwide are “medically certified”—and much lower in some parts of the country—including rural areas where local populations do not have easy access to medical care. It is possible that C19 victims without an official cause of death may not be accounted for or may be under reported in the national totals. It is unclear if or how this may have changed as a result of the C19 pandemic. Additionally, the average age of India’s population is lower than some other countries that have been severely affected, which could be contributing to lower mortality. From this perspective, India’s case fatality aligns relatively closely with countries with similar population age. In contrast, countries like France, Italy, Spain, and the UK have much older populations (mean age of 40 years and older, compared to 26.7 years in India) and much higher case fatality (9% and higher).
5. New Zealand
- On Sunday, New Zealand marked 100 days since its last domestic SARS-CoV-2 transmission. New Zealand implemented a robust screening, testing, and contact tracing response, complemented by national social distancing policies, that ultimately led to eliminating the virus in early June. While domestic transmission has been successfully interrupted, there is still concern that imported cases could ignite new transmission chains within the island nation. The WHO has not established formal criteria for C19 elimination, but New Zealand is currently demonstrating its ability to maintain zero domestic transmission, including through effective border screening and quarantine policies. In total, New Zealand has reported 1,219 confirmed cases of C19 and 22 deaths since the beginning of the pandemic.
6. Mask Efficacy
- Researchers from Duke University (US) evaluated various types of face masks to compare their ability to filter respiratory droplets. Mask use has become popular in many countries, and mandatory in some countries or regions, since the onset of the pandemic, and many types of mask construction are available, ranging from medical-grade respirators and surgical masks to homemade cloth masks and bandanas. With many options available, this study provides insight into how effective various types can be in terms of reducing exposure to respiratory droplets. The study, published in Science: Advances, evaluated 14 types of mask construction, including a fit-tested (non-valved) N95 respirator, a valved N95 respirator, a surgical mask, a bandana, a neck gaiter, and various examples of cloth masks using different designs and materials. Individuals wore the masks and spoke aloud into the test chamber. The experimental setup was designed to be low cost, utilizing a cell phone camera to record laser light reflected and refracted by the respiratory droplets, and an automated algorithm calculated the droplet count based on the recorded video. The results for each mask were compared against a control using no mask.
- The majority of the masks tested reduced the number of expelled droplets by more than 60%, and 10 of the masks reduced droplets by approximately 80% or more. Not surprisingly, the most effective options were the fitted N95 respirator and surgical mask, which contained nearly all of the droplets. Also not surprisingly, the fitted, non-valved N95 respirator was “far superior” to the valved respirator, as the valve allows exhaled air to pass through unfiltered. The mask constructed of knit material (ie, as opposed to woven) was only 65% effective, and the bandana was only 35-40% effective. Notably, the neck gaiter actually increased the number of expelled droplets. The researchers believe this resulted from the material separating larger droplets into numerous smaller droplets. Considering that smaller droplets remain aloft longer than larger droplets, this could indicate that this type of mask may be less effective in reducing transmission, or even “counterproductive.”
- Using a low-tech option (ie, cell phone camera) for data collection could limit the size and quantity of droplets counted in the study compared to more sensitive cameras and sensors designed for this purpose; however, the study does provide a high-level overview of the relative performance of certain types of masks. Additionally, the study specified that the bandanna material was folded over to provide a second layer, but it does not address whether the neck gaiter was folded as well. Some mask policies recommend or require at least 2 layers of material for a mask, so this could potentially provide improved efficiency over a single layer. The study does not make any assessment of the role of masks in protecting the wearer from exposure.