November 6, 2020
Without reliable information, we rely on fear or luck.
“There’s a risk that this mutated coronavirus is so different from the others that we’d have to put new things in a vaccine and therefore [the mutation] would slam us all in the whole world back to the start.”Professor Kare Molbak, a vaccine expert and director of infectious diseases at Denmark’s State Serum Institute (see story below)
Factors Contributing to Spread of C19 (see full story below):
- Taking Trips 34%
- Spending Time From Home 26%
- Size of Population 23%
- Urban Density 13%
- Weather/Humidity 3%
1. Cases & Tests
3. Top 5 States in Cases, Deaths, Hospitalizations & Positivity
L. Linked Stories
- C19 Transmission: Tracking Flight Trajectory of Evaporating Cough Droplets
- New Research Provides Clues on Restraining the Aggressive Nature of the COVID Coronavirus
- C19 is making tinnitus worse — new study
- Coronavirus uses ‘genome origami’ to infect and replicate inside host cells
- Algorithm to Contain Pandemic: Testing Sewage to Home In on C19
- Investigators Find Subset of C19 Patients Who Recover Quickly and Sustain Antibodies
- Visualization Tool: See How Your Congressional District Has Handled C19
- Rapid Method Finds Potent C19 Antibody Among a Trillion Possibilities
- Case study details leukemia patient who shed infectious coronavirus for at least 70 days
- Delirium could be an early marker of C19
- Understanding the spread of infectious diseases
- Using AI to Track the C19 Pandemic’s Impact on Mental Health
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A. The Pandemic As Seen Through Headlines
(In no particular order)
- A second day with more than 100,000 cases in US
- The coming months look grim
- US supply of N95 masks dwindles amid surge in COVID-19 cases
- COVID-19 hospitalizations in US hit three-month high
- TSA sees spike in positive coronavirus cases among airport workers
- Coronavirus cases at U.S. colleges have hit a quarter million
- Midwestern States Thrive With Fewer Virus Rules As Second Wave Arrives
- AstraZeneca expects COVID-19 vaccine results by year’s end
- The first U.S. criminal negligence case over the spread of the virus in a nursing home moves forward
- Two areas in Staten Island are reporting a concerning rise in cases, NYC mayor says
- UK National Healthcare System placed on highest alert level as intensive care beds fill up
- The virus is surging again in the Northeastern US — Maine, Rhode Island and Connecticut have reported records for new daily cases in the past week
- The prime minister of Greece announced a three-week nationwide lockdown, starting Saturday, after a sharp spike in infections.
- Officials in France warned that the country’s intensive care units could be overwhelmed by mid-November
- England began a four-week national lockdown today as Europe confronts a growing wave of coronavirus infections
- Pennslyvania suffers daily covid record
- Italy sees new record
- Regeneron working on to distribute antibody drug to the poor
- New record or near-record numbers seen in Greece, Italy, Poland and the Czech Republic
- 7-day average for 5 main European countries hits new record
- Greece expands lockdown nationwide
- Germany cases come roaring back
- Poland, Czech Republic see record numbers
- India reports just 50,000 new infections
- China halted the entry of almost anyone traveling from Bangladesh, Belgium, Britain, India or the Philippines, the latest move by Beijing to keep out anyone with even a slight chance of being infected with the virus
- Study finds 1.7 million New Yorkers have been infected with coronavirus and virus was in NYC earlier than reported
- Kenya, where cases are rising, extended a curfew and banned political gatherings.
- France, facing a backlash from small businesses closed during a second national lockdown, has ordered big retailers to stop selling books, clothes, toys, flowers and other nonessential items. The order set off chaos and confusion.
- A surge in daily infections is forcing a reckoning in the Netherlands, which has long prided itself on efficient government — some say to the point of smugness.
- British woman arrested trying to take elderly mother out of nursing home before lockdown
- El Paso counted 3,100 cases, a record high, and its hospitals are reaching a breaking point, the El Paso Times reports.
- Missouri poll worker with COVID-19 still worked shift, died after election
- North Dakota state legislative candidate who died of COVID-19 wins election
- A mutation in the virus has prompted Denmark to kill millions of infected mink.
- In Utah, nearly 10,000 mink at nine fur farms have died from the virus.
- PETA slams Denmark’s planned COVID-19 mink massacre
- Cinemark posts huge loss as COVID-19 pummels movie theaters
- American Airlines cuts 100,000 December flights amid COVID-19
- Dogs can detect COVID-19 quicker and more accurately than nasal swabs, study finds
- You can now buy a $28,000 socially distant ‘Wedding in the Sky’
- Elevator etiquette has New Yorkers at each other’s throats
- Look closely at your medical bill, and you just might find a ‘Covid fee’
B. Numbers & Trends
Note: Unless otherwise noted, (i) all cases/deaths are confirmed cases/deaths that have been reported, (ii) all numbers reported in this update are as of the end of the most recent reporting period, and (iii) all changes reflect changes since the preceding day.
1. Cases & Tests
- Worldwide Cases:
- Total Cases = 49,011,024
- New Cases = 604,689
- New Cases (7 day average) = 522,793 (+8,832) (+1.7%)
- Record high number of new cases
- Record high 7 day average of new cases
- 1,000,000+ cases every 2 days (based on 7 day average)
- US Cases & Testing:
- Total Cases = 9,919,522
- New Cases = 118,204
- New Cases (7 day average) = 96,437 (+3,740) (4.0%)
- Percentage of New Global Cases = 16%
- Total Number of Tests = 153,593,809
- Percentage of positive tests (7 day average) = 8.8%
- Record high number of new cases
- Record high 7 day average of new cases
- 7 day average of new cases is 294% higher than 1st peak on 4/10
- 7 day average of new cases increasing at a very high rate
- 7 day average of percentage of positive tests are increasing at a high rate
- Worldwide Deaths:
- Total Deaths = 1,238,825
- New Deaths = 8,717
- New Deaths (7 day average) = 7,330 (+220) (+3.1%)
- Record high number of new deaths on 11/4 (9,056)
- Record high 7 day average
- 7 day average is increasing at a high rate
- Rapid increase in new cases indicates that new deaths will continue to increase
- Total Deaths = 240,953
- New Deaths = 1,125
- New Deaths (7 day average) = 905 (+11) (1.2%)
- Percentage of Global New Deaths = 12.3%
- 7 day average of new deaths continue to rise
- Since 10/15, the 7 day average has increased from 713 to 905, and increase of 192, or 26.9%
- Increases in new cases and positive rate indicate that new deaths will continue to increase
- 7 day average is 40.4% of 1st peak on 4/21
- Although new cases are 243% higher than 1st peak, the confirmed case fatality rate has declined by 86.4%
3. Top 5 States in Cases, Deaths, Hospitalizations & Positivity (11/5)
- The positivity rate continues to rise across the country
- Nationally, the average 7-day positivity rate was 8.8% — up from 6.6% as of 10/22.
- More than 60% of all tests are now positive in ND, 50% in SD, and 40% in IA.
- Four states (NE, KS, ID, WI) 7-day positivity rates greater than 30%
- Seven states (MO, IN, WY, UT, NV, MN, MT) had 7-day positivity rates greater than 20%.
- In total, 42 states have 7-day positivity rates greater than 5% (+3 states since 10/22)
- Hospitalizations in the US increased to 53,322, up 30% since 10/22.
- 40 states have had increases of hospitalized patients of more than 10% since 10/22
- 19 states have more than 1,000 hospitalized patients.
- 6 states (HI, MA, MS, NC, SC, VA) recorded a decline in the number of hospitalized patients compared to 10/22
4. U.S. Daily C19 Cases Top 100,000 for First Time
What to Know
- The U.S. reported more than 100,000 new coronavirus cases in a single day for the first time.
- Hospitalizations hit new highs in the Midwest.
- Deaths in the U.S. and Europe are edging higher.
- Infections rose to record highs in several states as the U.S. reported more than 100,000 new coronavirus cases in a single day for the first time.
- Seven states in the U.S.—Colorado, Idaho, Indiana, Iowa, Maine, Minnesota and Nebraska—hit new highs for confirmed cases Wednesday, according to a Wall Street Journal analysis of Johns Hopkins University data. Pennsylvania also reported more than 2,800 new cases for the third day in a row Wednesday after setting a record Tuesday.
- Those new records come as the nation recorded more than 102,800 new cases for Wednesday, surpassing a high of more than 99,000 set Oct. 30, according to data compiled by Johns Hopkins University. Since the pandemic began, more than 9.5 million cases have been reported in the U.S.
- Speaking at a press conference Thursday, Ohio Gov. Mike DeWine, a Republican, said the state had 4,961 new cases of Covid-19, an all-time high for the state. The state also hit a new record for hospitalizations with 2,075 patients, a 55% increase compared with two weeks ago. A record number—541 people—are in hospital intensive care units, he said.
- Across the state there are more visits to doctors’ offices and to emergency departments, an early indication of more trouble to come, he said. Every county in the state has a high-incidence of cases, he said, including communities that were previously untouched by the disease.
- “This should scare you that you have this much spread in your hometown,” said Mr. DeWine.
- The dramatic increases in cases have been fueled by residents not adhering to social-distancing guidance and the use of face-coverings, he said, adding that weddings, funerals and parties inside homes are where health officials are seeing cases.
- “It comes back to people’s individual decisions. A lot of this we can’t micromanage and we can’t control, but the public can,” said Mr. DeWine.
- In Mississippi there were 1,612 new cases, a high not seen since July and a jump from the previous day’s total of 657 new cases, according to data from the state’s Department of Health.
- Maine Gov. Janet Mills, a Democrat, issued an executive order Thursday requiring people to wear face masks in public regardless of whether they can maintain social distance. The order comes as the New England state reported 183 new Covid-19 cases, a record single-day increase there. Nirav Shah, director of Maine’s Center for Disease Control and Prevention, said the state is experiencing “widespread community transmission.”
- In Wisconsin, where nearly 6,000 new cases were reported Wednesday, Department of Health Services Secretary-Designee Andrea Palm urged residents on Wednesday to stay home as much as possible.
- “We should not be having contact with other human beings that we do not live with. Hard stop,” said Ms. Palm.
- In New York, health officials were setting up additional testing sites and ramping up contact tracing in Staten Island after the borough recorded an uptick in cases.
- “We see the kind of increase that makes us concerned,” New York City Mayor Bill de Blasio said Thursday of the rate of people testing positive for Covid-19 in the borough.
- The nation reported more than 1,000 deaths from Covid-19 for the second day in a row on Wednesday. The figure was slightly lower than the more than 1,100 fatalities reported Tuesday, but higher than the 991 deaths reported a week earlier, according to Johns Hopkins. The overall death toll on Thursday surpassed 234,000.
5. About 20% of New Yorkers Have Had C19
- About one-fifth of New York City’s population has already had C19, new research shows.
- Researchers at the Icahn School of Medicine at Mount Sinai found that the new coronavirus was in New York City long before March 1, when the city’s first official case was confirmed, according to Mount Sinai Health System.
- The study, publishing Tuesday in the journal Nature, looked at more than 10,000 blood plasma samples from Mount Sinai Health System patients, taken between Feb. 9 to July 5 from both urgent care patients and those seeing routine health care. Antibody tests use blood samples to detect whether people have been previously infected with the coronavirus and have developed antibodies to it.
- C19 antibodies were found in plasma samples from New Yorkers as early as mid-February, they said, signaling that the virus may have been introduced in the region earlier than previously thought. A previous study, released in July, found that some New Yorkers had antibodies during the week ending Feb. 23.
- “We show that the infection rate was relatively high during the first wave in New York,” said Florian Krammer, corresponding author of the paper and Mount Sinai vaccinology professor at the Icahn School of Medicine. He added that the prevalence of antibodies was still far from a figure that might indicate herd immunity.
- The percentage of New Yorkers testing positive for C19 antibodies has remained at around the same level since July, according to data from the New York City Department of Health and Mental Hygiene.
- Researchers also found that C19’s infection fatality rate is near 1%, or 10 times deadlier than the flu.
C. New Scientific Findings & Research
1. Hot or Cold, Weather Has Little Effect on C19 Spread
- The link between weather and C19 is complicated. Weather influences the environment in which the coronavirus must survive before infecting a new host. But it also influences human behavior, which moves the virus from one host to another.
- Research led by The University of Texas at Austin is adding some clarity on weather’s role in C19 infection, with a new study finding that temperature and humidity do not play a significant role in coronavirus spread.
- That means whether it’s hot or cold outside, the transmission of C19 from one person to the next depends almost entirely on human behavior.
- “The effect of weather is low and other features such as mobility have more impact than weather,” said Dev Niyogi, a professor at UT Austin’s Jackson School of Geosciences and Cockrell School of Engineering who led the research. “In terms of relative importance, weather is one of the last parameters.”
- The research was published on October 26, 2020, in the International Journal of Environmental Research and Public Health.
- The study defined weather as “equivalent air temperature,” which combines temperature and humidity into a single value. The scientists than analyzed how this value tracked with coronavirus spread in different areas from March to July 2020, with their scale ranging from U.S. states and counties, to countries, regions and the world at large.
- At the county and state scale, the researchers also investigated the relationship between coronavirus infection and human behavior, using cellphone data to study travel habits.
- The study examined human behavior in a general sense and did not attempt to connect it to how the weather may have influenced it. At each scale, the researchers adjusted their analyses so that population differences did not skew results.
- Across scales, the scientists found that the weather had nearly no influence. When it was compared with other factors using a statistical metric that breaks down the relative contribution of each factor toward a particular outcome, the weather’s relative importance at the county scale was less than 3%, with no indication that a specific type of weather promoted spread over another.
- In contrast, the data showed the clear influence of human behavior — and the outsized influence of individual behaviors. Taking trips and spending time away from home were the top two contributing factors to C19 growth, with a relative importance of about 34% and 26% respectively. The next two important factors were population and urban density, with a relative importance of about 23% and 13% respectively.
- “We shouldn’t think of the problem as something driven by weather and climate,” Jamshidi said. “We should take personal precautions, be aware of the factors in urban exposure.”
- Baniasad, a biochemist and pharmacist, said that assumptions about how coronavirus would respond with weather are largely informed by studies conducted in laboratory settings on related viruses. She said that this study illustrates the importance of studies that analyze how the coronavirus spreads through human communities.
- “When you study something in lab, it’s a supervised environment. It’s hard to scale up to society,” she said. “This was our first motivation to do a more broad study.”
- Marshall Shepherd, an atmospheric sciences professor at the University of Georgia who was not part of the study, said that the research offers important insights about weather and coronavirus across scales.
- “This important work clarifies some of the innuendo about weather-C19 connections and highlights the need to address science challenges at the appropriate scales,” Shepherd said.
- Niyogi said that one of the key lessons of the coronavirus pandemic is the importance of analyzing phenomena at the “human scale”— the scale at which humans live their day-to-day lives. He said that this research is an example of this type of perspective.
- “COVID, it is claimed, could change everything,” Niyogi said. “We have been looking at weather and climate outlooks as a system that we scale down, down, down and then seeing how it might affect humans. Now, we are flipping the case and upscaling, starting at human exposure scale and then going outwards. This is a new paradigm we will need for studying virus exposure and human environmental modeling systems involving new sensing and AI-like techniques.”
2. Being in treatment with statins reduces C19 mortality by 22% to 25%
- Coronavirus has infected more than 40 million people around the world and has caused more than a million deaths in less than a year. Moreover, it is still not clear why some people who contract the virus show no symptoms whereas others may die or suffer very severe consequences. Although age, illnesses and previous treatments can be used to give a prognosis in some cases, it is still not possible to state for certain how each case of coronavirus will evolve.
- One of the treatments that have been discussed in regard to their role in the evolution of C19 has been statins. This drug helps to reduce cholesterol in the blood and thus prevent cardiovascular diseases. It is currently taken by one in four people and is the most widely used medicine among the general public. Now, a research by the Universitat Rovira i Virgili (URV) and Pere Virgili Institut (IISPV) led by Lluís Masana has found that people who are being treated with statins have a 22% to 25% lower risk of dying from C19. The research results have been published in the European Heart Journal – Cardiovascular Pharmacotherapy.
- The study was carried out through the Network of Lipid and Arteriosclerosis Units of Catalonia and collected information from 2,159 patients infected with the coronavirus (SARS-COv-2) from 19 hospitals in Catalonia during the first wave of the pandemic from March to May. The researchers evaluated one hundred clinical variables per patient such as age, sex, previous illnesses, cholesterol levels, evolution of the virus, treatments used for C19, and so on. The researchers then compared death rates of patients being treated with statins with death rates among those who were not and they also analyzed the effect of withdrawing statins when the patient was admitted to hospital. “In our comparison, we adjusted the groups so that they were comparable in terms of age, sex and the existence of earlier illnesses”, explained Masana, who has coordinated the study from the Lipid and Arteriosclerosis Research Unit at the URV’s Department of Medicine and Surgery, which is a member of the CIBERDEM Network bringing together research groups working on diabetes and metabolism in Spain. Masana is also a researcher at the Sant Joan University Hospital in Reus.
- The percentage of patients who died in the group not treated with statins was 25.4%, whereas it was 19.8% among those who were, that is to say 22% lower. “The data indicate that treatment with statins prevents one in five deaths“, indicated Masana. Furthermore, if treatment with this medicine continued during hospitalization, mortality fell by up to 25%, thus preventing one in four deaths.
- Consequently, Lluís Masana went on to say that “not only do these findings demonstrate that treatment with statins has no negative on the evolution of C19, they also show that it significantly reduces patient mortality”.
- One of the indirect effects of the pandemic is that some people have stopped taking preventive measures aimed at combatting chronic diseases or maintaining general health, and this has been the case with statins. “Some health professionals have even advised their withdrawal in the belief that they could worsen the effects of C19”, said Masana. In this regard, in addition the virus to directly causing death in some patients, complications and overall mortality can increase due to the withdrawal of these drugs and regular monitoring of the use of this medicine. “In the case of statins, we have demonstrated that fear of the pandemic should never be used as an excuse to suspend treatment”, concluded the researcher.
- Although the research was never intended to demonstrate that administering statins to C19 patients would reduce the risk of death, it does open the way for studies that may confirm this finding.
3. Almost 20% of C19 patients only show gastrointestinal symptoms
- Almost 20% of patients with C19 may only show gastrointestinal symptoms, according to a review of academic studies published in the journal Abdominal Radiology. The findings of the review suggest abdominal radiologists need to remain vigilant during the pandemic while imaging patients.
- Gastrointestinal symptoms associated with C19 vary widely but can include loss of appetite, nausea, vomiting, diarrhea and generalized abdominal pain. The researchers who conducted the review report that 18% of patients presented with such symptoms, while 16% of C19 cases may only present with gastrointestinal symptoms.
- “There’s a growing amount of literature showing that abdominal symptomatology is a common presentation for C19,” said Mitch Wilson, a radiologist and clinical lecturer in the University of Alberta’s Faculty of Medicine & Dentistry.
- The researchers, who also included Gavin Low, associate professor of radiology and diagnostic imaging, and medical student Kevin Lui, examined findings from 36 studies published through July 15 to reach their conclusions.
- In addition to gastrointestinal symptoms, they also determined potential signs radiologists should look for while conducting abdominal imaging that could be evidence of C19 infection. Those signs include inflammation of the small and large bowel, air within the bowel wall (pneumatosis) and bowel perforation (pneumoperitoneum). The signs are quite rare, said the researchers, and could indicate patients with advanced disease.
- “Seeing these things is not necessarily telling us a patient has C19,” said Wilson. “It could be from a variety of potential causes. But one of those potential causes is infection from the virus, and in an environment where C19 is very prevalent, it’s something to consider and potentially raise as a possibility to the referring physician.”
4. C19 “super-spreading” events play outsized role in overall disease transmission
- There have been many documented cases of C19 “super-spreading” events, in which one person infected with the coronavirus (SARS-CoV-2) infects many other people. But how much of a role do these events play in the overall spread of the disease? A new study from MIT suggests that they have a much larger impact than expected.
- The study of about 60 super-spreading events shows that events where one person infects more than six other people are much more common than would be expected if the range of transmission rates followed statistical distributions commonly used in epidemiology.
- Based on their findings, the researchers also developed a mathematical model of C19 transmission, which they used to show that limiting gatherings to 10 or fewer people could significantly reduce the number of super-spreading events and lower the overall number of infections.
- “Super-spreading events are likely more important than most of us had initially realized. Even though they are extreme events, they are probable and thus are likely occurring at a higher frequency than we thought. If we can control the super-spreading events, we have a much greater chance of getting this pandemic under control,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering and the senior author of the new study.
- MIT postdoc Felix Wong is the lead author of the paper, which appears this week in the Proceedings of the National Academy of Sciences.
- For the SARS-CoV-2 virus, the “basic reproduction number” is around 3, meaning that on average, each person infected with the virus will spread it to about three other people. However, this number varies widely from person to person. Some individuals don’t spread the disease to anyone else, while “super-spreaders” can infect dozens of people. Wong and Collins set out to analyze the statistics of these super-spreading events.
- “We figured that an analysis that’s rooted in looking at super-spreading events and how they happened in the past can inform how we should propose strategies of dealing with, and better controlling, the outbreak,” Wong says.
- The researchers defined super-spreaders as individuals who passed the virus to more than six other people. Using this definition, they identified 45 super-spreading events from the current SARS-CoV-2 pandemic and 15 additional events from the 2003 SARS-CoV outbreak, all documented in scientific journal articles. During most of these events, between 10 and 55 people were infected, but two of them, both from the 2003 outbreak, involved more than 100 people.
- Given commonly used statistical distributions in which the typical patient infects three others, events in which the disease spreads to dozens of people would be considered very unlikely. For instance, a normal distribution would resemble a bell jar with a peak around three, with a rapidly-tapering tail in both directions. In this scenario, the probability of an extreme event declines exponentially as the number of infections moves farther from the average of three.
- However, the MIT team found that this was not the case for coronavirus super-spreading events. To perform their analysis, the researchers used mathematical tools from the field of extreme value theory, which is used to quantify the risk of so-called “fat-tail” events. Extreme value theory is used to model situations in which extreme events form a large tail instead of a tapering tail. This theory is often applied in fields such as finance and insurance to model the risk of extreme events, and it is also used to model the frequency of catastrophic weather events such as tornadoes.
- Using these mathematical tools, the researchers found that the distribution of coronavirus transmissions has a large tail, implying that even though super-spreading events are extreme, they are still likely to occur.
- “This means that the probability of extreme events decays more slowly than one would have expected,” Wong says. “These really large super-spreading events, with between 10 and 100 people infected, are much more common than we had anticipated.”
Stopping the spread
- Many factors may contribute to making someone a super-spreader, including their viral load and other biological factors. The researchers did not address those in this study, but they did model the role of connectivity, defined as the number of people that an infected person comes into contact with.
- To study the effects of connectivity, the researchers created and compared two mathematical network models of disease transmission. In each model, the average number of contacts per person was 10. However, they designed one model to have an exponentially declining distribution of contacts, while the other model had a fat tail in which some people had many contacts. In that model, many more people became infected through super-spreader events. Transmission stopped, however, when people with more than 10 contacts were taken out of the network and assumed to be unable to catch the virus.
- The findings suggest that preventing super-spreading events could have a significant impact on the overall transmission of C19, the researchers say.
- “It gives us a handle as to how we could control the ongoing pandemic, which is by identifying strategies that target super-spreaders,” Wong says. “One way to do that would be to, for instance, prevent anyone from interacting with over 10 people at a large gathering.”
- The researchers now hope to study how biological factors might also contribute to super-spreading.
5. Rapid changes in biomarker of inflammation may be a key predictor of C19 outcomes
- Predicting the course of a C19 patient’s disease after hospital admission is essential to improving treatment. Brigham and Women’s Hospital researchers analyzed patients’ levels of inflammation, known to be associated with severity of illness, by looking at C-reactive protein (CRP) trends in 100 C19 patients admitted to the hospital. They found that a rapid rise in CRP levels during the first 48-to-72 hours of hospitalization was predictive of subsequent respiratory deterioration and intubation, while steadier CRP levels were observed in patients whose condition remained stable. Findings were published in Cell Reports Medicine.
- “We realized that whereas a single CRP lab value from hospital admission wasn’t very practical as a predictor of who might get sicker, tracking the rate of change from Day 1 to Day 2 or 3 was a very powerful and very clinically predictive test,” said corresponding author Edy Yong Kim, MD, PhD, of the Division of Pulmonary and Critical Care Medicine at the Brigham. “Even though all of these patients looked clinically similar upon admission, as early as 24 hours after hospitalization, the immune systems of patients who would go on to the ICU multiple days later were already inflamed, as measured by these biomarkers.”
- Inflammation is a broad term that describes the release of chemicals involved in immune responses. CRP tests integrate signals from a number of different proteins involved in inflammation, called cytokines, to provide physicians with a snapshot of a patient’s inflammatory activity within a matter of hours. Other tests, like cytokine assays, can provide more specific information about which proteins may be active in inflammatory pathways, but these tests can take one to two days to process, and C19 patients’ conditions can worsen before the results are received. CRP tests can therefore serve as a practical addition to standard protocols for assessing the anticipated clinical trajectories of C19 patients.
- “Because of our findings, we changed our guidelines at the Brigham to mandate CRP tracking every day for the first three days of hospitalization so that we could try to identify vulnerable patients and keep a close eye on their inflammation,” said Kim, who stressed the importance of putting findings into practice as early as possible amid the current uptick of positive cases.
- The results, from a study population of 100 Brigham patients, also provide insight into the underlying mechanisms at play in C19 infections. In particular, an increase in a cytokine called IL-6 during the first 24-48 hours was correlated to CRP levels and the progression of the disease. Fifteen patients treated during this acute period with the drug tocilizumab, an IL-6 receptor, had rapid, sustained reductions in their CRP levels. In larger, randomized trials, tocilizumab was not shown to provide benefits to C19 patients, but Kim states that this could be because the drug was not administered early enough to the subset of patients who stand to benefit most. Alternatively, while CRP is associated with IL-6, CRP can reflect other inflammatory pathways besides IL-6, so targeting other inflammatory cytokines or pathways besides IL-6 could be considered.
- “Even if you gave immunomodulatory drugs, which reduce rising inflammation, as early as Day 3 — which is pretty early for a clinical trial — that may already be too late,” Kim said. “But here we have some evidence that a rise in inflammation directly drives respiratory failure, which implies that the immunomodulatory drugs might be able to prevent respiratory failure if given very, very early — as early as hospital Day 1 and 2.”
- Ultimately, Kim hopes that the findings will help front-line workers better understand the volatility of C19 patients’ conditions. “Doctors’ and nurses’ clinical instincts about C19 are not fully developed because the disease is still so new,” Kim said.
- “But when we showed these results to frontline doctors and nurses at the Brigham, they felt like it matched what they intuitively saw in the spring. It’s always nice to hear that what you do in the lab reflects what goes on in the real world, too.”
6. Children produce different antibodies in response to C19
- Children and adults produce different types and amounts of antibodies in response to infection with the coronavirus (SARS-CoV-2), a new study from researchers at Columbia University Vagelos College of Physicians and Surgeons has found.
- The differences in antibodies suggest the course of the infection and immune response is distinct in children and most children easily clear the virus from their bodies.
- “Our study provides an in-depth examination of SARS-CoV-2 antibodies in kids, revealing a stark contrast with adults,” says Columbia University immunologist Donna Farber, PhD, the George H. Humphreys II Professor of Surgical Sciences in the Department of Surgery, who led the study with Matteo Porotto, PhD, associate professor of viral molecular pathogenesis in Columbia’s Department of Pediatrics. The first authors, Stuart Weisberg, MD, PhD, assistant professor of pathology & cell biology, and Thomas Connors, MD, assistant professor of pediatrics, enrolled patients into the study and conducted the data analysis.
- “In kids, the infectious course is much shorter and probably not as disseminated as in adults,” Porotto adds. “Kids may clear this virus more efficiently than adults and they may not need a strong antibody immune response to get rid of it.”
Children Less Affected by SARS-CoV-2
- One of the striking manifestations of the C19 pandemic is that the majority of children cope well with the virus while older people struggle.
- “This is a new infection for everybody,” Farber says, “but children are uniquely adapted to see pathogens for the first time. That’s what their immune system is designed to do. Children have a lot of naive T cells that are able to recognize all sorts of new pathogens, whereas older people depend more on our immunological memories. We’re not as able to respond to a new pathogen like children can.”
Children Make Fewer SARS-CoV-2 Neutralizing Antibodies
- Among the 47 children in the study, 16 were treated at Columbia University Irving Medical Center for MIS-C and 31 children of similar ages had tested positive for the virus after visiting the medical center for the treatment of other conditions. Half of the children without MIS-C had no C19 symptoms. The 32 adults in the study ranged from severely affected patients admitted to the hospital to those with milder disease who recovered at home.
- Both groups of children produced the same antibody profile, the study found, which differed from that of adults.
- Compared with adults, children produced fewer antibodies against the virus’s spike protein–which the virus uses to infect human cells. The children’s antibodies had the least neutralizing activity, while all adults, including young adults in their 20s, produced neutralizing antibodies. The sickest adults had the most neutralizing activity.
- Though it may seem counterintuitive that the sickest patients produce antibodies with the greatest neutralizing activity, Farber says that likely reflects the amount of time the virus is present in the sickest patients.
- “There is a connection between the magnitude of your immune response and the magnitude of the infection: The more severe the infection, the more robust the immune response, because you need to have more immune cells and immune reactions to clear a higher dose of a pathogen.”
Other Antibody Differences Show Children’s Infections Are Limited
- In contrast to adults, children also produced very few antibodies against a viral protein that is only visible to the immune system after the virus infects human cells.
- “That suggests that in kids, the infection doesn’t really spread a lot and doesn’t kill a lot of their cells,” Farber says.
- “Because children clear the natural virus rapidly, they do not have a widespread infection and they do not need a strong antibody response,” Porotto says.
- The reduced course of infection in children may signify that they are infectious for a shorter period of time compared with adults and therefore less likely to spread the virus, although the researchers did not measure viral load in the children.
- “Current studies in other countries indicate that younger school-age children are not vectors for the new coronavirus, so our data are consistent with those findings,” Farber says.
Children Should Respond Well to Vaccine
- The antibody responses found in children do not suggest that children will have a weaker response to a vaccine, the researchers say.
- Vaccines under development for SARS-CoV-2 contain pieces of the virus and do not mimic the normal route of infection.
- “Even though children don’t produce neutralizing antibodies in response to a natural infection with SARS-CoV-2, vaccines are designed to generate a protective immune response in the absence of an infection,” Farber says. “Children respond very well to vaccines, and I think they will develop good neutralizing antibody responses to a SARS-CoV-2 vaccine, and they’ll probably be better protected than the adults.
- “That said, very few vaccine studies are currently enrolling children and we will need this data to really understand how well the vaccines work in children.”
What Does the Adult Immune System Lack?
- Though the findings suggest the course of infection in children and adults is different, it’s still not known how the children are able to clear the virus more easily–and what the adult immune system lacks.
- Farber, Porotto, and their colleagues at Columbia are now looking for differences in T-cell response (antibodies are produced by the immune system’s B cells), especially T cells that reside in the lung. [Previous research from Farber’s lab has shown these “stay-at-home” T cells are more important in fighting lung infections than T cells that travel through the body via the bloodstream].
- Children infected with SARS-CoV-2 also may generate a stronger response from the innate immune system, which deploys interferon and cells called macrophages to indiscriminately attack cells infected by pathogens. Earlier studies suggest that the innate immune response may be delayed in adults infected with SARS-CoV-2.
- “If the innate response is really strong, that can reduce the viral load in the lungs, and the antibodies and T cells of the adaptive response have less to clear up,” Farber says.
- It’s also possible that the virus is less able to infect children’s cells, possibly because children’s cells express fewer proteins the virus needs to infect human cells.
- The Columbia researchers are now testing these possibilities with cells from children versus adults.
- “There are still all these issues that we have very little information about,” Porotto says. “The interaction between the virus and the host is the reason why we see so much diversity in responses to this virus, but we don’t understand enough about this virus yet to really determine what leads to severe disease and what leads to mild disease.”
7. Tissue in The Human Eye Appears Resistant to C19
- As the coronavirus pandemic spread across the world this year to such devastating effect, many of us were asking the same questions. How does the virus spread? How do I protect myself from the infection?
- The truth is, we’re still learning how the coronavirus (SARS-CoV-2) works. Official guidance from the CDC suggests the main way the virus spreads is through respiratory droplets or small particles, ejected from the mouth or nose of infected people, and then inhaled by others.
- But that’s not the only way the virus circulates. The same infectious droplets and particles can land on surfaces and be transferred by touch – meaning infection could result if you touch something with virus particles on it, and then touch your mouth, nose, or eyes, the CDC says.
- While this general advice is repeated by health authorities the world over, there’s still a lot we don’t know about how the coronavirus might enter the body through the eyes, although scientists suggest it’s “biologically plausible”.
- However, new evidence suggests at least some of the eye may in fact be resistant to SARS-CoV-2 – even while it’s susceptible to other kinds of viruses.
- In a new study, researchers at Washington University in St. Louis found that the cornea – the transparent dome at the front of the eye, which covers the iris and pupil – appeared to be resistant to coronavirus infection in experiments, although they’re eager to emphasise the findings are only preliminary.
- “Our findings do not prove that all corneas are resistant,” says molecular microbiologist Jonathan J. Miner, the first author of the study.
- “But every donor cornea we tested was resistant to the novel coronavirus. It’s still possible a subset of people may have corneas that support growth of the virus, but none of the corneas we studied supported growth of SARS-CoV-2.”
- In experiments using corneal tissue from 25 human donors and also mice corneas, the researchers exposed the eye tissue to three separate viruses: SARS-CoV-2, Zika virus, and herpes simplex virus 1 (HSV-1, which produces cold sores).
- In the human cornea explants tested (which also contained some conjunctiva tissue, the membrane that covers the rest of the front of the eye), the experiment showed that herpes and Zika virus were able to replicate in the tissue – but tests showed no sign of SARS-CoV-2 replication.
- “The cornea and conjunctiva are known to have receptors for the novel coronavirus, but in our studies, we found that the virus did not replicate in the cornea,” says senior author and ophthalmologist Rajendra S. Apte.
- “Our data suggest that the novel coronavirus does not seem to be able to penetrate the cornea.”
- As for how the human cornea and conjunctiva might be capable of resisting SARS-CoV-2, the team isn’t entirely sure. A potential molecular inhibitor of viruses in the eye – called interferon lambda – was able to limit virus growth in the human cornea for HSV-1 and Zika virus, but blocking the protein didn’t seem to boost SARS-CoV-2’s ability to replicate.
- Without more to go on, the researchers’ best guess for now is that the human cornea’s resistance to coronavirus is “likely regulated by a distinct antiviral pathway”. Quite what that pathway is we still don’t know, and the team says further study is needed to confirm these findings.
- In other words, health professionals shouldn’t ditch their protective eyewear yet, and until we know otherwise, nobody should assume coronavirus can’t get into the body via the eyes, despite the cornea’s seeming resistance.
- “It’s important to respect what this virus is capable of and take appropriate precautions,” Miner says.
- “We may learn that eye coverings are not necessary to protect against infection in the general community, but our studies really are just the beginning.”
- The findings are reported in Cell Reports.
8. Tiny variants in genes may dictate severity of coronavirus
- It has been one of the most baffling aspects of the C19 pandemic. Healthy young men and women have become infected with the virus and developed life-threatening side effects. But at the same time, many of their contemporaries have simply shrugged off the condition.
- Unknown factors are clearly leaving some people vulnerable to the pandemic’s worst effects even though some of them are young, are not overweight and do not suffer from other obvious health problems. Scientists think that tiny genetic differences are causing some to be struck down while many others are spared.
- And these differences in DNA are now being tracked by researchers who believe they offer a route to developing new drugs that could halt many of the worst consequences of suffering from C19.
- Key developments include research which indicates that interferon – a molecular messenger that stimulates immune defences against invading viruses – may play a vital role in defending the body. Scientists have found that rare mutations in some people may leave them unable to make adequate supplies of the interferon they need to trigger effective immune responses to Covid. Trials using interferon as Covid treatments are now under way at several centres.
- “These genetic findings give us very clear insights,” said Martin Hibberd, professor of emerging infectious diseases at the London School of Hygiene and Tropical Medicine. “They are natural biological experiments which suggest that people who make more interferon when infected have a better response to the disease. And that in turn tells us that patients could well benefit from treatment with interferon.”
- Research is also focusing on a gene known as TYK2. Some variants of this gene are involved in triggering some auto-immune diseases such as rheumatoid arthritis (RA) and also seems to be involved in causing severe Covid. A drug developed to treat RA, baricitinib, has a genetic common denominator with Covid and this has led to it being used in clinical trails against the virus. Last month the pharmaceutical company Eli Lilly announced that early results showed the drug helped Covid patients recover.
- “The crucial point is that by understanding the impact of gene variants in the body we can now think about finding drugs that could block their pathways and help patients,” said Jeffrey Barrett, of the Wellcome Sanger Institute’s C19 genomic surveillance programme. “The bad news is that it can take years of experiments to find treatments this way. The good news is that there are now so many scientists working on this kind of thing that we might still some quick answers.”
- Other research – pioneered by Kenneth Baillie, of Edinburgh University, and outlined in a recent issue of Science – has uncovered several other genes that appear to be important. These include OAS genes that are triggered by interferon and which code for proteins that are involved in breaking down viral RNA, from which the C19 virus is made. Baillie’s research has yet to be peer reviewed and he has counselled caution in interpreting this work. Nevertheless, he told Science that he hoped his results would speed the development of treatments “because the epidemic is progressing at such an alarming rate, even a few months of time saved will save lots of lives”.
- In addition, other researchers point out that there are other ways of using genetics to combat Covid. Dr Dipender Gill of Imperial College London has, with colleagues, used genetic data to predict how different interventions could affect disease reactions.
- Gill said: “We looked at five traits that have been linked to increased risk of getting severe C19: obesity, high blood pressure, poor cholesterol, smoking and diabetes. Then we looked to see if these traits could be modified in order to reduce that risk of severe infection.”
- To do that, Gill – working with a team of British, Norwegian and American scientists – analysed data from thousands of patients, using genetic variants that increase individuals’ risk of acquiring these conditions. They were then able to carry out studies that would show if action taken to modify these traits would reduce susceptibility to severe C19. The team made two key discoveries. “We found there is a causal link between obesity and the risk of having a severe C19 [reaction]. We also found the same effect for smoking. This indicates that losing weight and giving up smoking will have a direct impact in improving your chances of surviving C19. That is the power of genetic studies like these.”
D. Vaccines & Immunity
1. Will a small, long-shot U.S. company end up producing the best coronavirus vaccine?
- Eighteen months ago, a small vaccinemaker here called Novavax faced an existential threat: delisting by the NASDAQ stock index. On the heels of a second failed vaccine trial in less than 3 years, the firm’s shares had plunged to less than $1 for 30 straight days, triggering a warning by NASDAQ. Frantic to conserve cash, the company sold its two Maryland manufacturing facilities, slicing its payroll by more than 100 employees. By January, it employed only 166 people.
- “Good ideas. Bad management. … The company will probably die soon,” a former Novavax manager wrote on Glassdoor.com in October 2019.
- What a difference a year—and a pandemic—make. Today, Novavax is slated to receive up to $2 billion from the U.S. government and a nonprofit organization to develop and manufacture a coronavirus vaccine. The company’s stock closed at $80.71 per share on 30 October, it has hired more than 300 new employees, and this month it plans to launch a pivotal clinical trial of its coronavirus vaccine in the United States and Mexico. Made by moth cells harnessed to crank out the virus’ spike protein—which the pathogen uses to invade human cells—Novavax’s vaccine outshone major competitors on key measures in monkey and early human tests.
- The company is one of just seven vaccinemakers to win funding so far from Operation Warp Speed, the giant multiagency U.S. government effort aiming to quickly produce at least 300 million doses of C19 vaccines. But most Warp Speed–backed companies are giant pharmaceutical firms, and most have already launched late-stage clinical trials in the United States. Tiny Novavax is rushing to keep pace with its larger rivals because companies that win the first approvals from regulators will have big market advantages. Still, some observers say Novavax’s technology gives it an edge.
- “They are incredibly well positioned,” says Andrew Ward, a structural biologist at Scripps Research. Ward, who receives no payments from the company but owns some stock, led a team that last month published a paper in Science describing the structure of Novavax’s tailormade spike protein, the heart of its vaccine. He was impressed by its stability and conformation, as well as the vigorous antibody responses it has elicited in humans and animals. “They have the know-how,” he says. “And they obviously, as we confirmed, make a good product.”
- But other people are skeptical. They note that Novavax has focused on making vaccines for more than 20 years but has never brought one to market, and that its senior executives have sold tens of millions of dollars of company stock since its share price began to soar this summer.
- Most significantly, the company has an Achilles’ heel. Novavax must rely mostly on contract manufacturers to meet its ambitious goal for 2021: producing enough vaccine to give 1 billion people two shots each. If manufacturing problems crop up—and the company last week said manufacturing delays had slowed launch of its late stage North American trial—competing vaccines may surge ahead. “That’s concerning,” says David Maris, a veteran drug industry analyst and managing director at Phalanx Investment Partners. Where small companies such as Novavax are concerned, he adds, “people do want to believe in fairy tales.”
- On January10, researchers in China published the genome sequence of the virus ravaging the city of Wuhan. Three days later, Gregory Glenn, president of R&D at Novavax, asked his staff to order from a supplier the gene for the virus’ spike protein.
- Glenn and other Novavax scientists had spent years developing “protein subunit” vaccines, so named because they employ a protein (or part of one) from the targeted virus, plus an immune-boosting compound called an adjuvant, to provoke an immune response. The company hadn’t had a commercial success—its vaccine against a serious respiratory illness failed in clinical trials. But it had produced a promising flu vaccine aimed at older adults, which was nearing the end of a pivotal trial. The company had also created protein subunit vaccines against two close cousins of the pandemic virus—the coronaviruses that cause severe acute respiratory syndrome and Middle East respiratory syndrome, using those viruses’ spike proteins. Those vaccines hadn’t made it to market, but Novavax had plenty of experience with the coronavirus family. Glenn believed it was his company’s moment.
- The gene for the spike protein was slow to arrive, however. Finally, at 6 a.m. on 3 February, a vice president from the supplier hand-delivered a red-capped vial bearing the gene to Novavax’s beige brick building here. The virus still hadn’t been officially named—the vial was labeled “Cov/Wuhan”—but Novavax was now out of the gate and in the race to tame it.
- The company’s scientists started to work “with frenetic pace,” Glenn says. Some of their competitors were already a lap ahead, working on their own vaccines. “There’s no question [that we’re] behind” several companies that also won Warp Speed funds, Glenn said on the morning of 24 September, the day Novavax launched its first phase III trial, of 15,000 volunteers in the United Kingdom.
- Most of Novavax’s key competitors—Moderna, Pfizer, Johnson & Johnson subsidiary Janssen, and AstraZeneca—had launched phase III trials by then. To make their vaccines, all four of those firms use new technologies based on genetic material that directs protein production, rather than delivering proteins directly. Those platforms rely on DNA loaded in disabled viruses or on messenger RNA to carry genetic instructions for building the spike protein. Cells within a vaccinated person then churn out the protein, alerting the immune system.
- Developers of protein vaccines must develop their own version of the spike protein—one that closely mimics the naturally occurring spike and is stable enough to retain its immunological punch during manufacturing, packaging, and distribution. Most such vaccines include an additional compound called an adjuvant to help stimulate a strong, protective immune response. Those extra steps make protein vaccines slower to develop than those that deliver genetic instructions.
- But protein-based vaccines also have a long track record of effectiveness, in contrast with the newer, largely unproven approaches. The successful hepatitis B vaccine licensed in 1986 and recommended for all U.S. babies in their first day of life is a protein subunit vaccine. So are a flu vaccine approved in 2013 and the human papillomavirus vaccines that have sent rates of cervical cancer plunging since the first ones were licensed in the 2000s.
- Perhaps because the technology is tried and true, scores of other companies are also racing to develop protein subunit vaccines. Novavax is the only one to have launched a phase III trial. Of the other firms, the huge vaccinemaker Sanofi Pasteur is likely Novavax’s biggest rival. It “is going to be formidable competition to the Novavax vaccine,” says Vijay Samant, a former head of vaccine manufacturing at Merck and now a consultant to vaccine companies. (Novavax is not a client.) Sanofi Pasteur has deep pockets, infrastructure, and experience, and markets vaccines against 19 infectious diseases.
- But Novavax scientists say they’re ready for the competition. “We’ve been getting ready for this our whole lives,” says Gale Smith, Novavax’s chief scientist.
- Once the pandemic coronavirus gene arrived in Gaithersburg, Maryland, on 3 February, the company spent weeks making more than 20 versions of the spike protein, aiming for a product as immunologically potent as possible. The winner was the most stable antibody-inducing protein, one that mimicked the energy-packed state of the spike just before it fuses with the host cell membrane.
- In March, a team led by Nita Patel, a senior director in the vaccine development department (see sidebar, below), confirmed in lab tests that the engineered protein bound tightly to its human cell-surface receptor. The results strongly suggested antibodies to Novavax’s protein would interfere with the virus’ own spike protein as it tried to fuse with cells.
- Patel’s boss, Smith, next enlisted Ward to verify the protein’s structure and stability with electron microscopy. Other tests showed the Novavax spike is stable for many weeks at 2°C to 8°C—a key advantage over the Moderna and Pfizer vaccines, which need to be stored at –20°C and –70°C, respectively, and once thawed, last only days in the refrigerator.
- Now, the challenge was to make the protein in the vast quantities that the world would need. Novavax had a system to do that, co-invented by Smith decades earlier and since used by the company to develop its other vaccine candidates: moth cells.
- To make their vaccine, Novavax scientists first used a baculovirus to insert the gene for the SARS-CoV-2 spike protein into moth cells, which produced the spikes on their cell membranes. Scientists then harvested the spike proteins and mixed them with a synthetic soaplike particle in which the spikes embed. A compound derived from trees serves as an immune-boosting adjuvant.
- As a 34-year-old graduate student at Texas A&M University in 1983, Smith, with colleagues, had developed a system that could produce proteins in big quantities. The researchers started with an insect-infecting virus called a baculovirus, which had the virtue of a roomy genome that can accommodate large chunks of foreign DNA. The researchers inserted a gene for a human immune protein, interferon, into the virus and then used it to infect cells from the caterpillar form of a pest called the fall armyworm moth. The virus transferred the gene to the moth cells, which duly secreted human interferon.
- Back then, editors of major journals had little interest in the discovery and repeatedly rejected Smith’s paper, which found a home in an obscure new journal, Molecular and Cellular Biology. But today the system is widely used in biotechnology. Now, it is at work producing the Novavax vaccine at a plant owned by a contractor in Morrisville, North Carolina, and soon, it’s expected, at other plants owned or contracted by Novavax in Europe, the United States, and Asia.
- In North Carolina, countless baculoviruses loaded with the gene for the coronavirus spike protein are invading moth cells in 2000-liter bioreactors. The moth cells then express the coronavirus spikes on their cell membranes. Scientists harvest the proteins and mix them with a delivery vehicle: synthetic particles, on average 30 to 40 nanometers across. Each “nanoparticle” ends up studded with up to 14 spike proteins. The finished particles are only slightly smaller than the coronavirus itself, helping the immune system “see” them as a danger, Smith says. Then Novavax adds its adjuvant, based on saponin, a compound found in soap bark trees that stimulates the immune system (see graphic, above).
- To crank up production in the spring, Novavax had to cope with a harsh reality. “What we didn’t have—what we’d lost by downsizing last year—is taking [the vaccine] right over to a manufacturing facility,” Glenn says. “We could have been much earlier had we had that strategic asset.” Instead, the company “had to beg” he says, turning to Gaithersburg-based contract manufacturer Emergent BioSolutions to produce vaccine for the first human trials. It was “not ideal,” Glenn says. “We’re sprinters … [but] it’s hard to get someone else to sprint.”
- A vital piece of good news came on 24 March, boosting the company’s search for cash. The phase III clinical trial of Novavax’s flu vaccine in older adults, also made using the moth cell system, returned excellent results. For Novavax, which was now asking funders for major dollars for its pandemic coronavirus vaccine, the proof of its capabilities came at a fortuitous time.
- Three days later, senior Novavax scientists met with decision-makers from a key funder—the nonprofit, international Coalition for Epidemic Preparedness Innovations (CEPI)—in a crucial Zoom call. Novavax scientists were used to dealing with skeptics. “Most people don’t think [our nanoparticles] work,” Smith says. “We’ve been accused that [they] aren’t even real, which is ridiculous.” Then Ward’s new high-resolution images—showing tiny particles studded with spike proteins, with honeycomblike saponins floating beside them—flashed on dozens of people’s screens. It was “one of those precious moments,” recalls Nick Jackson, CEPI’s head of vaccine programs. “The excitement was palpable.”
- Six weeks later, CEPI awarded Novavax up to $384 million for trials and manufacturing of its vaccine.
- Ward’s work won over some scientific doubters. John Moore, an immunologist at Weill Cornell Medicine, had been skeptical of Novavax’s moth cell system because in the 1990s it had conspicuously failed to produce an HIV spike protein with the right characteristics to make an AIDS vaccine. But in August, when Ward’s work was posted as a preprint, “I looked at that paper and was impressed,” Moore says. “It changed my perception of the quality of the protein. The concerns I had were eliminated by data, which is as it should be.”
- By late May, Novavax had launched its first human safety trial in 131 volunteers in Australia and used the CEPI funding to buy, for $167 million in cash, a state-of-the-art vaccine manufacturing facility in the Czech Republic that the company said would deliver more than 1 billion doses in 2021. And in early July, Operation Warp Speed granted the company up to $1.6 billion, with $800 million available immediately, for a phase III clinical trial and for manufacturing 100 million doses of vaccine.
- In early August, the big investors in the tiny company won an initial vindication when Novavax announced strong results from the Australian trial. After two injections, “the antibody responses in the Novavax paper were markedly stronger than any of the other vaccines that have been reported,” and participants had experienced no severe adverse events, says Moore, who recently published a Journal of Virology review of the leading vaccine candidates. Moore says he intends to volunteer for a Novavax trial if eligible. “I’m going, ‘Yes, I’ll have that [vaccine].’”
- The government of the United Kingdom soon signed up to buy 60 million doses of Novavax’s vaccine, and the big drugmaker Takeda licensed it to manufacture at scale with funding from the Japanese government. Other scientists noted strong results in a dozen monkeys injected with various doses of Novavax’s vaccine and then infected with live coronavirus. The virus failed entirely to multiply in the animals’ noses and replicated in the lungs of just one monkey that received the lowest dose; that animal shut down the infection after 4 days.
- “It’s the only vaccine I’ve seen out of all the candidates that are further down the pipeline that actually had no viral replication in the nasal swabs of vaccinated animals,” says Angela Rasmussen, a virologist at Columbia University. That’s important, she says, because stopping viral replication in the nose can reduce the spread of infection among people who may be unaware they are sick. But she cautions that monkeys are not people. “We can’t really conclude that this vaccine is going to be better in practice until we have some reliable safety and efficacy data in people.”
- That’s why researchers will be eager to see results from Novavax’s phase III trials. In the one in progress in the United Kingdom, volunteers get either placebo or vaccine in two injections, 21 days apart. Researchers will evaluate whether vaccinated volunteers have fewer symptomatic coronavirus infections than placebo recipients. They’ll also keep monitoring safety, including any reactions to the adjuvant, because this will be the first time huge numbers of younger people with vigorous immune systems receive it.
- Vaccine trials need volunteers who are exposed to the virus, so skyrocketing infections in the United Kingdom are likely working in Novavax’s favor. The company estimates there will be enough infections among participants to allow a first look at the data early in 2021—and says it expects the U.K. data will be enough to drive approval of its vaccine.
- In the United States and Mexico, the company aims to enroll 30,000 volunteers—about 90% of them in the United States—in a trial expected to launch this month. Keeping volunteers in that trial may be challenging if other vaccine contenders win U.S. marketing approval in coming weeks. But Glenn argues that this scenario is “not very realistic” given the time required for U.S. Food and Drug Administration (FDA) action and widespread distribution of a vaccine.
- Observers also note that more than one vaccine will probably be needed to quell the pandemic. The first round of vaccine doses promised by Pfizer and Moderna combined would only cover 100 million people. Experts add that the first vaccine approved won’t necessarily be the best. “Especially when we are talking about vaccinating millions of people, you have just got to follow the science,” says Mayank Mamtani, a senior biotechnology analyst at B. Riley Securities. In the long run, “being first to market is just not, in my opinion, important.”
- Some observers raised their eyebrows when Novavax won Warp Speed funding, given that the firm was on life support last year. Maris bemoans the “complete lack of transparency as to how the funding decisions of Warp Speed were made.” (Journalists and investors have tried unsuccessfully to obtain Novavax’s Warp Speed contract.) “I would like to see the fundamental or deep analysis, if any, done prior to these funding decisions,” Maris says. “I’m not certain whether it exists.”
- In early 2019, Novavax’s share price fell so low that NASDAQ threatened to delist the company. Its candidate coronavirus vaccine has turned the small firm’s fortunes around, although its stock lost value in the fall.
- Novavax says it will release the contract next week as part of its quarterly financial reporting.
- Other critics noted that since the pandemic began, Novavax top managers have made tens of millions of dollars by exercising options to buy their company’s stock at earlier, lower prices and sell it at this year’s high prices. Such options are a common way to pay biotech executives, but against the background of a pandemic, the sales led to an unwelcome spotlight on Capitol Hill in September. At a hearing, the chair of the House of Representatives Financial Services Subcommittee on Investor Protection, Entrepreneurship, and Capital Markets raised the examples of Novavax and other companies by name. And in a stinging memo that Democratic lawmakers issued under the heading “Corporate Integrity and Profiteering in the COVID-19 Pandemic,” they reported that three senior executives at Novavax and two board members had pocketed nearly $17 million in August alone.
- Maris notes that executives who are bullish on their own companies tend to keep their stock. “So it’s interesting that they decided to sell.”
- Even if Novavax’s phase III trials succeed, vaccine watchers say the company’s biggest vulnerability will remain: the manufacturing process. “I think the vaccine is going to be efficacious,” Samant says. “But you put that 2 billion–dose task in front of a small company, it’s a huge uphill task.”
- Ward concurs. “It’s like trying to cook a really good quiche. You can make one for your family, but if you try to make 50 of them for a wedding, that’s actually very difficult to do, to get them all the same and equivalent.”
- “The [moth cell system] is not like the flu vaccine and eggs,” adds vaccine expert and FDA veteran Luciana Borio, an admirer of Novavax who is a vice president at In-Q-Tel, a technology investment firm. “It’s untested.”
- Novavax counters that the company’s manufacturing partners are deeply experienced in making vaccines at scale. For instance, the Serum Institute of India, a veteran vaccinemaker that is the world’s largest, is helping Novavax expand production at the 14,000-square-meter Czech facility, plus manufacturing an additional billion doses itself, in India, for low- and middle-income countries. That brings the total doses the company now says it can manufacture in 2021 to 2 billion, the promised number.
- The fact that world-class manufacturers such as the Serum Institute “didn’t even blink before wanting to work with them and helping them scale up” speaks highly of the company, Mamtani says.
- “It’s going to be a dark horse,” he predicts. “A dark horse helping us to get out of this darkness.”
2. C19 immune response faster and stronger post-infection
- Scientists have found the strongest evidence yet that people who recover from Covid may mount a much faster and more effective defence against the infection if they encounter the virus again.
- Researchers at Rockefeller University in New York found that the immune system not only remembered the virus but improved the quality of protective antibodies after an infection had passed, equipping the body to unleash a swift and potent attack if the virus invaded a second time.
- “It’s very good news,” said Michel Nussenzweig, the head of molecular immunology at Rockerfeller and a senior author of the study. “The expectation is that people should be able to produce a rapid antibody response and resist infection in a large number of cases.”
- It is unclear how long the immune system’s memory might last, but Nussenzweig said it could potentially provide some protection for years. The discovery may explain why verified re-infections from the virus are so far quite rare.
- When people are infected with coronavirus, the immune system launches a multi-pronged attack. One form of protection comes from T cells, which seek and destroy infected cells, and so prevent the virus from spreading. A second front involves B cells, which release antibodies into the blood. Antibodies latch on to the virus and stop it from invading cells in the first place.
- Once the infection has passed, the immune system stands down, but it remembers the virus by storing so-called memory T cells and memory B cells. Should the virus return, these are immediately called to action.
- Many studies have shown that the first wave of antibodies to coronavirus wane after a few months, raising concerns that people may lose immunity quickly. In their study of 87 coronavirus patients, the US researchers confirmed that antibodies wane, falling to about a fifth of their peak level over six months, but this may not matter too much, they believe.
- When the researchers examined the immune system’s memory, they noticed that six months after infection the antibodies made by memory B cells had evolved to become more potent. These highly honed antibodies could be unleashed within days of re-infection, rather than taking a couple of weeks to build up, as seen in primary infections.
- The scientists went on to show that tiny amounts of coronavirus, or protein fragments from inactive virus particles, lurked in patients’ intestines and apparently helped to maintain the immune system’s memory. The remnants of the virus are not thought to be harmful.
- “The take-home lessons are that people who have been infected, six months later have persistent B cell memory responses with antibodies that can neutralise the virus and can do it very well,” Nussenzweig said. That could mean wiping out the virus before it takes hold, he added. “We don’t know how long any protection will last, but it might be a really long time. It could be years.”
- The study is preliminary and has not been peer-reviewed or published in a journal.
- Charles Bangham, a professor of immunology at Imperial College London, who was not involved in the study, said the work suggested there was “a very good chance that if you’re re-exposed, you’ll make a brisker immune response” to the virus. “It remains to be proved that it’s protective, but you would be reasonably confident it would have some beneficial effect,” he said.
- Arne Akbar, a professor of immunology at University College London, said: “This is good news for everybody who has been sick with coronavirus.” He said the immune system was like an army that stands down once the threat is over, but remains prepared for a future invasion. “You want the army to be generated again very quickly, and this is what these researchers have found.”
E. Improved & Potential Treatments
1. Remdesivir for the Treatment of C19 — Final Report
- Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (C19), no antiviral agents have yet been shown to be efficacious.
- We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.
- A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test).
- In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity).
- The Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03).
- Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).
- Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.
2. WHO-led COVID drug scheme doubles down on antibodies, steroids and shuns remdesivir
- A World Health Organization-led scheme to supply C19 drugs to poor countries is betting on experimental monoclonal antibody treatments and steroids but shunning Gilead’s remdesivir therapy, an internal document shows.
- The Oct. 30 WHO draft document seen by Reuters says priorities are to secure monoclonal antibodies in a tight market and to boost distribution of cheap steroid dexamethasone, of which it has already booked nearly 3 million courses of treatment for poorer countries.
- Monoclonal antibodies are manufactured copies of antibodies created by the body to fight an infection, and drugmakers including Roche and Novartis confirmed initial contact with the WHO scheme.
- The paper, which for the first time outlines how the scheme would spend donors’ money, does not cite remdesivir among priority drugs – a significant omission as the antiviral is the only other medication alongside dexamethasone approved across the world for treating C19.
- Gilead Science said the WHO scheme had not funded its C19 trials and had never approached the firm for the possible inclusion of remdesivir in its portfolio.
- The drug-supply scheme is one of the four pillars of the so-called ACT Accelerator, a WHO-led project which also seeks to secure C19 vaccines, diagnostics and protective gear for poorer countries by raising more than $38 billion by the beginning of 2022.
- “Immediate priorities for the (therapeutics) pillar are intensifying efforts on monoclonal antibodies while scaling up dexamethasone use,” says the document, which is subject to change but due for publication as soon as Friday.
- The scheme, co-led by the Wellcome Trust, a charity, and Unitaid, a health partnership hosted by the WHO, urgently needs $6.1 billion, $750 million of which by February, out of a total ask of $7.2 billion.
- More than half the cash would be used to procure and distribute monoclonal antibodies, the document shows, calling these therapeutics “game-changing” but in short supply.
- No monoclonal antibody has, so far, been approved against C19, but the WHO scheme has already invested in research and secured production capacity at a Fujifilm Diosynth Biotechnologies plant in Denmark.
- Fujifilm didn’t immediately comment.
- The scheme wants $320 million to make antibodies in that facility, the document says, estimating that would be enough to secure 4 million antibody courses, at about $80 per course.
- A spokeswoman for Unitaid confirmed that it wanted to raise and invest $320 million in securing monoclonal antibodies but said commercial deals were confidential.
- Another $110 million would be used for regulatory approval and other market preparation procedures for monoclonal antibodies in poorer countries, the document shows, while $220 million would fund clinical trials.
- Among companies developing experimental monoclonal antibodies against C19 are U.S. firms Eli Lilly and Regeneron. U.S. President Donald Trump got their antibodies in October after testing C19 positive.
- Eli Lilly has already agreed to produce antibodies at the Fujifilm plant from April and make them available at “an affordable price” to poorer countries, a company spokeswoman said.
- A U.S. government-run trial of Lilly’s drug was paused in mid-October over safety concerns, but other trials continue and the U.S. administration last week sealed a $375-million supply deal.
- It is unclear how and whether the WHO scheme will raise the money needed for the antibody project.
- Roche, which has partnered with Regeneron to make up to 2 million doses of the so-called REGN-COV2 antibody annually by 2021, has had “preliminary discussions” with the ACT Accelerator over an access plan.
- “These discussions were in the context of development and production,” a Roche spokesman said in an email. “It is too early to speculate on future decisions, but we will continue working with them and other groups regarding REGN-COV2.”
- Novartis, which expects results soon from a trial of its arthritis treatment canakinumab against C19, said on Thursday it received a request several days ago from the WHO scheme seeking information about medicines to tackle the coronavirus. Novartis also makes dexamethasone.
- Despite being short of funds, the WHO drugs-supply scheme aims to distribute hundreds of millions of courses of C19 drugs to poorer countries by 2022.
- Apart from monoclonal antibodies and dexamethasone, it is also eyeing other experimental drugs, including new antivirals and repurposed drugs.
- The scheme would spend another $100 million to seal deals with unspecified drugmakers from mid-2021, the document says, and next year plans to invest another $4.4 billion on drugs that succeed in clinical trials.
- The Unitaid spokeswoman said dexamethasone and its alternative, hydrocortisone, were the most promising among repurposed drugs.
- Unitaid confirmed the scheme had not procured or funded remdesivir, which was initially trialled against Ebola. It did not comment on why remdesivir did not appear among priority treatments in the document.
- Remdesivir has been authorized in multiple countries to treat C19. However, preliminary findings of a WHO-sponsored trial conluded the antiviral had little or no benefit, contradicting previous positive trials.
- Governments however continue to buy it, with Germany this week announcing a 150,000-plus dose purchase.
3. Llama nanobodies could be a powerful weapon against C19
- Today in Science, researchers at the University of Pittsburgh School of Medicine describe a new method to extract tiny but extremely powerful coronavirus (SARS-CoV-2) antibody fragments from llamas, which could be fashioned into inhalable therapeutics with the potential to prevent and treat C19.
- These special llama antibodies, called “nanobodies,” are much smaller than human antibodies and many times more effective at neutralizing the SARS-CoV-2 virus. They’re also much more stable.
- “Nature is our best inventor,” said senior author Yi Shi, Ph.D., assistant professor of cell biology at Pitt. “The technology we developed surveys SARS-CoV-2 neutralizing nanobodies at an unprecedented scale, which allowed us to quickly discover thousands of nanobodies with unrivaled affinity and specificity.”
- To generate these nanobodies, Shi turned to a black llama named Wally–who resembles and therefore shares his moniker with Shi’s black Labrador.
- Shi and colleagues immunized the llama with a piece of the SARS-CoV-2 spike protein and, after about two months, the animal’s immune system produced mature nanobodies against the virus.
- Using a mass spectrometry-based technique that Shi has been perfecting for the past three years, lead author Yufei Xiang, a research assistant in Shi’s lab, identified the nanobodies in Wally’s blood that bind to SARS-CoV-2 most strongly.
- Then, with the help of Pitt’s Center for Vaccine Research (CVR), the scientists exposed their nanobodies to live SARS-CoV-2 virus and found that just a fraction of a nanogram could neutralize enough virus to spare a million cells from being infected.
- These nanobodies represent some of the most effective therapeutic antibody candidates for SARS-CoV-2, hundreds to thousands of times more effective than other llama nanobodies discovered through the same phage display methods used for decades to fish for human monoclonal antibodies.
- Shi’s nanobodies can sit at room temperature for six weeks and tolerate being fashioned into an inhalable mist to deliver antiviral therapy directly into the lungs where they’re most needed. Since SARS-CoV-2 is a respiratory virus, the nanobodies could find and latch onto it in the respiratory system, before it even has a chance to do damage.
- In contrast, traditional SARS-CoV-2 antibodies require an IV, which dilutes the product throughout the body, necessitating a much larger dose and costing patients and insurers around $100,000 per treatment .
- “Nanobodies could potentially cost much less,” said Shi. “They’re ideal for addressing the urgency and magnitude of the current crisis.”
- In collaboration with Cheng Zhang, Ph.D., at Pitt, and Dina Schneidman-Duhovny, Ph.D., at the Hebrew University of Jerusalem, the team found that their nanobodies use a variety of mechanisms to block SARS-CoV-2 infection. This makes nanobodies ripe for bioengineering. For instance, nanobodies that bind to different regions on the SARS-CoV-2 virus can be linked together, like a Swiss army knife, in case one part of the virus mutates and becomes drug-resistant.
- “As a virologist, it’s incredible to see how harnessing the quirkiness of llama antibody generation can be translated into the creation of a potent nanoweapon against clinical isolates of SARS-CoV-2,” said study coauthor and CVR Director Paul Duprex, Ph.D.
4. Protein decoys block C19 infection in vitro and protect animals in vivo
- Neoleukin Therapeutics, Inc., “Neoleukin” (NASDAQ:NLTX), a biopharmaceutical company utilizing sophisticated computational methods to design de novo protein therapeutics, today announced the publication in Science of research describing novel molecules designed to treat or prevent infection by the coronavirus (SARS-CoV-2). This report details the creation of de novo protein decoys that were specifically designed to bind the SARS-CoV-2 spike protein with high affinity, preventing its association with the viral receptor hACE2, which is required for infection. The manuscript titled “De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2” is available online here1 via Science First Release.
- As reported, the optimized, hyperstable proteins act as decoys that bind to the virus and block cellular entry. The lead molecule, NL-CVX1 (CTC-445.2d), is shown to prevent infection of multiple human cell lines and to protect hamsters from serious consequences of SARS-CoV-2 infection. Prophylactic intranasal administration of the protein decoy led to survival of all hamsters challenged with a lethal dose of SARS-CoV-2.
- “Our de novo proteins are designed to mimic the natural SARS-CoV-2 receptor, making them intrinsically resistant to viral mutation,” said Daniel-Adriano Silva, Ph.D., Vice President Head of Research, who led the discovery effort at Neoleukin. “We believe the development of NL-CVX1 is the fastest development of a therapeutic de novo protein from concept to preclinical validation, and it represents our most sophisticated design to date.”
- “The rapid development of this targeted protein demonstrates the potential of our de novo protein design platform and our team of scientists to address a broad spectrum of important biological problems,” said Jonathan Drachman, M.D., Chief Executive Officer of Neoleukin. “NL-CVX1 is designed to be stable and could potentially be administered by intranasal spray or inhalation to prevent and treat infection in the lungs and upper airways by SARS-CoV-2. We are currently evaluating the possibility of advancing this molecule to clinical trials in humans.”
5. Synthetic Mini-Antibody Identified to Combat C19
- The ability of the coronavirus (SARS-CoV-2) to infect cells depends on interactions between the viral spike protein and the human cell surface protein ACE2. To enable the virus to hook onto the cell surface, the spike protein binds ACE2 using three finger-like protrusions, called the receptor binding domains (RBDs). Blocking the RBDs therefore has the potential to stop the virus from entering human cells. This can be done using antibodies.
- Nanobodies, small antibodies found in camels and llamas, are promising as tools against viruses due to their high stability and small size. Although obtaining them from animals is time consuming, technological advances now allow for rapid selection of synthetic nanobodies, called sybodies. A technology platform to select sybodies from large synthetic libraries was recently developed in the lab of Markus Seeger at the University of Zurich, and made available for this study.
In search of the best sybody against SARS-CoV-2
- EMBL Hamburg’s Christian Löw group searched through the existing libraries to find sybodies that could block SARS-CoV-2 from infecting human cells. First, they used the viral spike protein’s RBDs as bait to select those sybodies that bind to them. Next, they tested the selected sybodies according to their stability, effectiveness, and the precision of binding. Among the best binders, one called sybody 23 turned out to be particularly effective in blocking the RBDs.
- To learn exactly how sybody 23 interacts with the viral RBDs, researchers in the group of Dmitri Svergun at EMBL Hamburg analyzed the binding of sybody 23 to the RBDs by small-angle X-ray scattering. In addition, Martin Hällberg at CSSB and Karolinska Institutet used cryo-EM to determine the structure of the full SARS-CoV-2 spike bound to sybody 23. The RBDs switch between two positions: in the ‘up’ position the RBDs poke out, ready to bind ACE2; in the ‘down’ position they are furled to hide from the human immune system. The molecular structures revealed that sybody 23 binds RBDs in both ‘up’ and ‘down’ positions, and blocks the areas where ACE2 would normally bind. This ability to block RBDs regardless of their position might explain why sybody 23 is so effective.
- Finally, to test if sybody 23 can neutralize a virus, the group of Ben Murrell at Karolinska Institutet used a different virus, called a lentivirus, modified such that it carried SARS-CoV-2’s spike protein on its surface. They observed that sybody 23 successfully disabled the modified virus in vitro. Additional tests will be necessary to confirm whether this sybody could stop SARS-CoV-2 infection in the human body.
Scientific collaboration during lockdown
- “The collaborative spirit has been enormous in these times, and everybody was motivated to contribute,” says Christian Löw, one of the lead scientists in the study. The researchers started the project as soon as they received approval from EMBL leadership to reopen their laboratories during the C19 lockdown. They managed to select the candidate sybodies and perform the analyses in just a few weeks.
- “Getting the results so quickly was only possible because the methodologies we used had already been established for other research projects unrelated to SARS-CoV-2. Developing these tools would have taken significantly more time and resources,” says Löw.
- The results of this project hold out the promise of a potential way to treat C19. In future work, the scientists will perform further analyses to confirm whether sybody 23 could be an effective C19 treatment.
6. Anti-inflammatory drug may improve outcomes for C19
- An enzyme that helps the coronavirus infect the body also plays a role in inflammation and patient outcomes in inflammatory bowel disease (IBD), according to a new study led by Cedars-Sinai. The findings raise the possibility that anti-inflammatory drug therapies for IBD may aid recovery from coronavirus.
- The multisite study, led by Cedars-Sinai and published today in the journal Gastroenterology, focused on angiotensin-converting enzyme 2 (ACE2), which normally plays a crucial health role by activating a hormone that helps regulate blood pressure. But in C19 infections, the SARS-CoV-2 virus binds to ACE2 and uses it to invade and infect cells, “hijacking” them to spread the virus.
- To learn more about how ACE2 affects the body, investigators examined its role in Crohn’s disease and ulcerative colitis – two types of IBD that can cause inflammation and scarring (fibrosis) in the digestive tract along with diarrhea, cramping and loss of appetite.
- “We chose these disorders because C19, while known for attacking the lungs, frequently causes gastrointestinal symptoms,” said Dermot P. McGovern, MD, PhD, the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics and senior author of the new study. “It was important for us to understand how C19 might affect IBD patients who are treated with anti-inflammatory medications. Also, there is increasing evidence that the GI tract may serve as an alternate route for uptake of SARS-COV-2 in general.”
- By examining records of nearly 1,000 patients at Cedars-Sinai, Washington University in St. Louis, Missouri, and multiple other centers across North America, the team found that levels of ACE2 in the small bowel were lower in Crohn’s patients and higher in the colons of ulcerative colitis patients than they were in patients without IBD. The differing ACE2 levels were associated with poorer outcomes and more severe disease in the IBD patients.
- “We saw that the effect of ACE2 depended on both its specific location in the gastrointestinal tract and the specific disease involved,” said McGovern, professor of Medicine and Biomedical Sciences. “So, this enzyme was a double-edged sword.”
- In both types of IBD, treatment with infliximab, an anti-inflammatory drug, normalized the levels of ACE2 and was associated with improved disease outcomes in patients. This finding suggests these drugs, commonly used in autoimmune diseases, also might improve outcomes in C19, the investigators said, “Overall, our study supports the potential paradoxical function of ACE2 in inflammation and C19,” McGovern explained. “Individuals with higher ACE2 expression may be at increased risk of infection with the coronavirus (SARS-CoV-2). But judging from our discoveries of how ACE2 works in IBD, this enzyme likely has anti-inflammatory and anti-fibrotic functions that also could help certain C19 patients recover from the virus.”
7. Cancer treatment could be used to treat C19
- Beta-blockers could potentially be used to treat C19, according to a new international study by Italian and Australian scientists.
- University of South Australia cancer researcher, Dr Nirmal Robinson, working with a team in Naples, has found evidence in animal models that the beta-blocker Propranolol helps suppress the spread of cancer in the lung which has an inflammatory profile very similar to C19.
- The scientists have presented their findings in a paper published in Frontiers in Immunology, calling for clinical trials to support their research.
- Dr Robinson, Head of the Cellular-Stress and Immune Response Laboratory at the Centre for Cancer Biology, says Propranolol is commonly used to treat heart conditions, anxiety and migraine. Recent clinical trials have shown its effectiveness for other conditions, including cancer.
- “Patients with C19 suffer from many abnormalities, including inflammation, because the the coronavirus (SARS-CoV-2) disrupts the body’s immune system. Beta-2 blockers could potentially reduce this inflammation and help rebalance the immune system,” Dr Robinson says.
- Beta-blockers including Propranolol are medicines that work by temporarily stopping or reducing the body’s natural ‘fight-or-flight’ response. In return, they reduce stress on certain parts of the body, such as the heart and blood vessels in the brain.
- They have also been suggested as a treatment option for autoimmune diseases such as rheumatoid arthritis.
- “SARS-Cov-2 enters the human cells through the protein ACE2, infecting the lower respiratory tract, causing profound inflammation and multi-organ failure.
- “Patients with comorbidities, such as high blood pressure, diabetes and heart disease, are at much higher risk,” he says.
- Other inflammation suppressors, including Tocilizumab (an immunosuppressive drug prescribed for arthritis) and Ruxolitinib (a drug used to treat the rare bone marrow blood cancer, myelofibrosis) have already been used to treat the more serious C19 cases, the researchers say.
- “We believe the beta-2-adrenergic pathway should be more deeply investigated as a possible target to reduce the inflammatory symptoms related to C19. The next step is to perform clinical trials to explore an alternative therapy to treat C19, based on the lessons we have learned from cancer,” Dr Robinson says.
8. A nasal spray blocked infection in lab animals, raising hopes for a new weapon against the virus
- A nasal spray that blocks the absorption of the coronavirus completely protected ferrets it was tested on, according to a small study released Thursday by an international team of scientists. The study, which was limited to animals and has not yet been peer-reviewed, was assessed by several health experts at the request of The New York Times.
- If the spray, which the scientists described as nontoxic and stable, is proved to work in humans, it could provide a new way to fight the pandemic, with a daily spritz up the nose acting like a vaccine.
- “Having something new that works against the coronavirus is exciting,” said Dr. Arturo Casadevall, the chairman of immunology at the Johns Hopkins Bloomberg School of Public Health, who was not involved in the study. “I could imagine this being part of the arsenal.”
- The work has been underway for months by scientists from Columbia University Medical Center in New York, Erasmus Medical Center in the Netherlands, Cornell University and the University of Campania in Italy. The study was funded by the National Institutes of Health and the Columbia University Medical Center.
- The spray, which attacks the virus directly, contains a lipopeptide, a cholesterol particle linked to a chain of amino acids, the building blocks of proteins. This particular lipopeptide exactly matches a stretch of amino acids in the spike protein of the virus, which the pathogen uses to attach to a human airway or lung cell.
- Before a virus can inject its RNA into a cell, the spike must effectively unzip, exposing two chains of amino acids, in order to fuse to the cell wall. As the spike zips back up to complete the process, the lipopeptide in the spray inserts itself, latching on to one of the spike’s amino acid chains and preventing the virus from attaching.
- “It is like you are zipping a zipper but you put another zipper inside, so the two sides cannot meet,” said Matteo Porotto, a microbiologist at Columbia University and one of the paper’s authors.
- The work was described in a paper posted to the preprint server bioRxiv Thursday morning, and has been submitted to the journal Science for peer review.
- Ferrets are used by scientists studying flu, SARS and other respiratory diseases because they can catch viruses through the nose much as humans do, although they also infect each other by contact with feces or by scratching and biting.
- The protective spray attaches to cells in the nose and lungs and lasts about 24 hours, Dr. Anne Moscona, a pediatrician and microbiologist at Columbia and co-author of the study.
- “If it works this well in humans,” she said, “you could sleep in a bed with someone infected or be with your infected kids and still be safe.”
Source: New York Times Coronavirus Update
F. Concerns & Unknowns
1. Mutant C19 strain in Denmark’s mink could cause ‘new pandemic
- The coronavirus mutation discovered in Denmark’s mink could spark a new wave of the illness in the country, scientists warn.
- Authorities in Denmark — the world’s largest producer of mink furs — said five cases of the new virus strain had been recorded on mink farms and 12 cases in humans.
- The mutation showed a decreased sensitivity against antibodies, meaning it could potentially cause a C19 vaccine to be less effective, experts said.
- “The worst-case scenario is that we would start off a new pandemic in Denmark,” Prof. Kare Molbak, a vaccine expert and director of infectious diseases at Denmark’s State Serum Institute told The Guardian.
- “There’s a risk that this mutated virus is so different from the others that we’d have to put new things in a vaccine and therefore [the mutation] would slam us all in the whole world back to the start.”
- The Scandinavian nation announced on Wednesday that it would cull its mink population of up to 17 million over the new virus strain.
- Minks are seen at Hans Henrik Jeppesen’s farm near Soroe after the government’s decision to cull his entire herd due to a new C19 outbreak in Denmark.
- “We have a great responsibility towards our own population, but with the mutation that has now been found, we have an even greater responsibility for the rest of the world as well,” Prime Minister Mette Frederiksen said at a news conference.
- Outbreaks at mink farms have persisted in the country despite repeated efforts to exterminate infected animals since June.
- Denmark’s police, army and home guard will be deployed to speed up the killing process, Frederiksen said.
2. Autoantibodies Causing C19 Blood Clots That Wreak Havoc on Patients
- Blood clots continue to wreak havoc for patients with severe C19 infection, and a new study explains what may spark them in up to half of patients.
- The culprit: an autoimmune antibody that’s circulating in the blood, attacking the cells and triggering clots in arteries, veins, and microscopic vessels. Blood clots can cause life-threatening events like strokes. And, in C19, microscopic clots may restrict blood flow in the lungs, impairing oxygen exchange.
- Outside of novel coronavirus infection, these clot-causing antibodies are typically seen in patients who have the autoimmune disease antiphospholipid syndrome. The connection between autoantibodies and C19 was unexpected, says co-corresponding author Yogen Kanthi, M.D., an assistant professor at the Michigan Medicine Frankel Cardiovascular Center and a Lasker Investigator at the National Institutes of Health’s National Heart, Lung, and Blood Institute.
- “In patients with C19, we continue to see a relentless, self-amplifying cycle of inflammation and clotting in the body,” Kanthi says. “Now we’re learning that autoantibodies could be a culprit in this loop of clotting and inflammation that makes people who were already struggling even sicker.”
‘Some of the worst clotting we’ve ever seen’
- Co-corresponding author Jason Knight, M.D., Ph.D., a rheumatologist at Michigan Medicine, has been studying antiphospholipid syndrome antibodies in the general population for years.
- “Half of the patients hospitalized with C19 were positive for at least one of the autoantibodies, which was quite a surprise,” says Knight, also an associate professor of internal medicine and a leading expert on diseases caused by autoantibodies.
- In the new Science Translational Medicine publication, they found about half of the patients who were very sick with C19 were exhibiting a combination of high levels of both the dangerous antibodies and super-activated neutrophils, which are destructive, exploding white blood cells. In April, the team was the first to report that patients hospitalized for severe C19 had higher levels of neutrophil extracellular traps in their blood.
- To learn more, they studied the explosive neutrophils and the C19 antibodies together in mouse models to see if this could be the dangerous combination behind the clots.
- “Antibodies from patients with active C19 infection created a striking amount of clotting in animals – some of the worst clotting we’ve ever seen,” Kanthi says. “We’ve discovered a new mechanism by which patients with C19 may develop blood clots.”
Attacking C19 blood clots from all angles
- The researchers say these findings aren’t yet ready for clinical practice, but they add a new perspective to the robust thrombosis and inflammation research in patients with C19.
- Kanthi, Knight, first author Yu (Ray) Zuo, M.D., and colleagues now want to know whether severely ill patients with high levels of these antibodies would have better outcomes if the antibodies are blocked or removed.
- If so, that might warrant an aggressive treatment like plasmapheresis, which is commonly used in severe autoimmune diseases, Zuo explains. It involves draining blood through an IV, filtering it and replacing it with fresh plasma that doesn’t contain those antibodies associated with blood clots.
- “We know people with the highest levels of autoantibodies did worse in terms of respiratory function, and the antibodies caused inflammation even in healthy cells,” says Zuo, an assistant professor of internal medicine and a rheumatologist at Michigan Medicine.
- “We don’t yet know what is triggering the body to produce these antibodies, so the next step would be additional research to identify the triggers and the targets of the antibodies,” Knight adds.
- In addition, these findings bring up new questions surrounding the use of convalescent plasma as a possible C19 treatment, but the team says more research is needed to examine this concern.
- “We’re now investigating how long these antibodies remain in circulation after recovery from the novel coronavirus,” Knight says.
- The researchers are also currently running a randomized clinical trial called DICER, which is testing a well-known anti-clotting agent, dipyridamole, in patients with C19 to determine whether it’s more effective than a placebo in reducing excessive blood clots.
- “Dipyridamole is an old drug that is safe, inexpensive, and scalable,” Kanthi says. “The FDA approved it 20 years ago to prevent clotting, but we only recently discovered its potential to block this specific type of inflammation that occurs in COVID.”
3. Investigations of Deceased C19 Patients Reveal Lung Damage Caused by Persistence of “Abnormal Cells”
- The study, published today (November 3, 2020) in The Lancet’s eBioMedicine, by King’s College London in collaboration with University of Trieste and the International Centre for Genetic Engineering and Biology in Italy, shows the unique characteristics to the coronavirus (SARS-CoV-2) and may explain why patients suffer from ‘long COVID’.
- Patients with C19 can experience symptoms such as blood clotting and loss of smell and taste. Some who survive the infection can experience the effects of the disease for months — known as ‘long COVID’ — with a feeling of fatigue and lack of breath. There have been a limited number of studies that have analyzed the organs of C19 patients which means the characteristics of the disease are still largely unknown.
- Researchers analyzed the organs of 41 patients who died of C19 at the University Hospital of Trieste, Italy, from February to April 2020, at the start of the pandemic. The team took lung, heart, liver, and kidney samples to examine the behavior of the virus.
- Findings show extensive lung damage in most cases, with patients experiencing profound disruption of the normal lung structure and the transformation of respiratory tissue into fibrotic material.
- Almost 90% of patients showed two additional characteristics that were quite unique to C19 compared to other forms of pneumonia. First, patients showed extensive blood clotting of the lung arteries and veins (thrombosis). Second, several lung cells were abnormally large and had many nuclei, resulting from the fusion of different cells into single large cells. This formation of fused cells (syncytia) is due to the viral spike protein, which the virus uses to enter the cell. When the protein is present on the surface of cells infected by the C19 virus, it stimulates their fusion with other normal lung cells, which can be a cause for inflammation and thrombosis.
- Additionally, research showed the long-term persistence of the viral genome in respiratory cells and in cells lining the blood vessels, along with the infected cell syncytia. The presence of these infected cells can cause the major structural changes observed in lungs, which can persist for several weeks or months and could eventually explain ‘long COVID’.
- The study found no overt signs of viral infection or prolonged inflammation detected in other organs.
- Professor Mauro Giacca, at the British Heart Foundation Centre at King’s College London, said: “These findings are very exciting. The findings indicate that C19 is not simply a disease caused by the death of virus-infected cells but is likely the consequence of these abnormal cells persisting for long periods inside the lungs.”
- The team is now actively testing the effect of these abnormal cells on blood clotting and inflammation and are searching for new drugs that can block the viral spike protein which causes cells to fuse.
4. Coronavirus puts a plug in cellular defenses
- One of the novel coronavirus’ most insidious tricks is that it can block the ability of cells to produce protective proteins without hindering its own ability to replicate.
- Now, a multidisciplinary team of Yale researchers has discovered how the coronavirus (SARS-CoV-2) accomplishes this trick by blocking production of cellular proteins, including immune molecules, and contributes to severe illness in its host.
- “The virus essentially reprograms host cells, and by understanding this mechanism we can hopefully design new therapeutics,” said Yong Xiong, professor of molecular biophysics and biochemistry and co-corresponding author of the research published in the journal Molecular Cell.
- Previous studies had implicated a viral protein, nonstructural protein 1 or Nsp1, in the C19 virus’ ability to block cells’ ability to produce new proteins. But exactly how NsP1 works in a cell was not known.
- Using advanced genetic screening and cryogenic electron microscopy (cryo-EM), the Yale team was able to show that Nsp1 is one of SARS-CoV-2’s most pathogenic viral proteins. In human lung cells, it can drastically alter host cell gene expression and essentially form a plug that prevents the ribosome, the cell’s protein-making machinery, from receiving genetic instructions for new proteins encoded in messenger RNA.
- “This is the entry channel for genetic material, and when it is blocked no protein can be made,” Xiong explained. “We didn’t understand this mechanism before, but now we know.”
- This process affects protein production in many parts of the body, and high levels of Nsp1 may help explain why some people fare poorly after infection by the virus, he said.
- However, it remains unknown how the virus is still able to produce its own proteins, using the same ribosome, to replicate in the cell after it disables the cell’s ability to make normal proteins, Xiong said.
5. Risk for severe disease up for pregnant women with C19
- Pregnant women with the coronavirus (SARS-CoV-2) have increased risks for severe C19-associated illness, according to research published in the Nov. 2 early-release issue of the U.S. Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report.
- The CDC received reports for 1,300,938 women aged 15 to 44 years with laboratory results indicative of acute infection with SARS-CoV-2. The researchers found that for 35.5 percent of women with laboratory-confirmed infection, data on pregnancy status were available, and 88.7 percent were symptomatic. Among symptomatic women, 5.7 percent were reported to be pregnant. Pregnant women were significantly more likely to be admitted to an intensive care unit, receive invasive ventilation, receive extracorporeal membrane oxygenation, and die compared with nonpregnant women after adjustment for age, race, and underlying medical conditions (adjusted risk ratios, 3.0, 2.9, 2.4, and 1.7, respectively). Disparities in risk by subgroup were highlighted on stratification by age and race/ethnicity.
- “Understanding the risk posed by SARS-CoV-2 infection in pregnant women can inform clinical practice, risk communication, and medical countermeasure allocation,” the authors write. “Pregnant women should be informed of their risk for severe C19-associated illness and the warning signs of severe C19.”
6. Asymptomatic C19 Carrier Shed Virus For 70 Days
- A team of researchers and doctors has now reported the case of one woman with leukemia who had no symptoms of C19 but 70 days after her first positive test, she was still shedding infectious SARS-CoV-2 particles.
- This result is much longer than previous reports of hospitalised adults found shedding infectious SARS-CoV-2 virus up to 20 days after their C19 diagnosis, plus other accounts of people shedding genetic material from the virus up to 63 days after their symptoms first appeared.
- The new report should alert doctors and public health experts alike to the fact that people without symptoms and with weakened immune systems, such as cancer patients, can seemingly shed the SARS-CoV-2 virus for a really long time. In this case, even months.
- “Although it is difficult to extrapolate from a single patient, our data suggest that long-term shedding of infectious virus may be a concern in certain immunocompromised patients,” the research team wrote in their paper describing the case.
- An estimated 3 million people in the US have some kind of condition that compromises or weakens their immune system, making them vulnerable to infections. Cancer patients on chemotherapy and transplant recipients who take immunosuppressant drugs are some examples.
- “As this virus continues to spread, more people with a range of immunosuppressing disorders will become infected, and it’s important to understand how SARS-CoV-2 behaves in these populations,” said virologist and co-author Vincent Munster from the US National Institute of Allergy and Infectious Diseases.
- Virologists like Munster would have been on the lookout in this pandemic for prolonged viral shedding of SARS-CoV-2. It has been well established that immunocompromised people can shed common seasonal coronaviruses for weeks after infection.
- Studies of Middle East respiratory syndrome (MERS) have likewise shown immunocompromised people shedding the virus that causes this illness for up to one month after infection.
- But the proportion of asymptomatic C19 cases still remains unclear. The danger is that these carriers of the virus could easily go about their days unaware of their capability of spreading the virus.
- In this case, doctors detected, isolated and tracked one woman’s SARS-CoV-2 infection using diagnostic PCR tests and throat swabs. A decade ago, the 71-year-old woman was diagnosed with chronic lymphocytic leukemia (CCL), a cancer of white blood cells that most commonly affects older adults and progresses slowly.
- She first tested positive for SARS-CoV-2 on 2 March 2020 after she was admitted to hospital for severe anaemia related to her cancer. She then tested positive for C19 another 13 times and yet showed no symptoms of the disease.
- Twice she received plasma from people who had recovered from C19, and eventually cleared the virus from her system sometime in mid-June.
- Doctors don’t know exactly when she acquired the coronavirus, but most likely it was at a rehabilitation facility which had a large C19 outbreak in February, where the woman had stayed days earlier.
- From the throat swabs collected over the course of her 15-week infection, the researchers showed that the woman was shedding infectious SARS-CoV-2 particles for 70 days. Some of its genetic material was also detected up to 105 days after she first tested positive.
- We have to be careful here to distinguish between infectious viral particles and the results of a diagnostic test, which just detects shreds of viral RNA. Importantly, in this study the researchers actually isolated SARS-CoV-2 from a few swab samples – day 70 included – to test whether the virus collected was able to replicate in lab-grown cells, which it was.
- “This indicates that, most likely, the infectious virus shed by the patient would still be able to establish a productive infection in contacts upon transmission,” the researchers wrote.
- Additionally, once the doctors were alerted to the woman’s case, they also quickly recognised it as an opportunity to study how SARS-CoV-2 might evolve over the course of such a long infection.
- The researchers sequenced the virus’ genetic material from various samples to see how this particular SARS-CoV-2 virus changed while circulating through the woman’s body. Different viral variants became more dominant at certain times, but the turnover was high and none stuck.
- Further experiments with the isolated virus in lab-grown cells also showed that these genetic changes didn’t affect how fast the virus replicated.
- While these are some valuable insights, more research still needs to be done.
- “Understanding the mechanism of virus persistence and eventual clearance will be essential to providing appropriate treatment and preventing transmission of SARS-CoV-2, as persistent infection and prolonged shedding of infectious SARS-CoV-2 occur more frequently,” the study authors wrote in their paper.
- And yes, this is a single case study, so we can’t make any generalisations about persistent viral shedding in people with other immunocompromising conditions, or how effective convalescent plasma is as a treatment for C19, the study authors warn.
- It is, however, “the longest case of anyone being actively infected with SARS-CoV-2 while remaining asymptomatic,” according to the medical research team. They think the woman remained infectious for so long because her compromised immune system never allowed her to mount a response.
- “We’ve seen similar cases with influenza and with Middle East respiratory syndrome, which is also caused by a coronavirus,” Munster said. “We expect to see more reports like ours coming out in the future.”
- With each one, we’ll surely learn more about this virus, how long it persists, and what we need to do to take care of the most vulnerable people in our communities.
- The study was published in the journal Cell.
G. Masks & Testing
1. Stanford Engineers Develop Genetic Microlab That Can Detect C19 in Minutes
- Throughout the pandemic, infectious disease experts and frontline medical workers have asked for a faster, cheaper and more reliable C19 test. Now, leveraging the so-called “lab on a chip” technology and the cutting-edge genetic editing technique known as CRISPR, researchers at Stanford have created a highly automated device that can identify the presence of the novel coronavirus in just a half-hour.
- “The microlab is a microfluidic chip just half the size of a credit card containing a complex network of channels smaller than the width of a human hair,” said the study’s senior author, Juan G. Santiago, the Charles Lee Powell Foundation Professor of mechanical engineering at Stanford and an expert in microfluidics, a field devoted to controlling fluids and molecules at the microscale using chips.
- The new C19 test is detailed in a study published on Nov. 4 in the journal Proceedings of the National Academy of Sciences. “Our test can identify an active infection relatively quickly and cheaply. It’s also not reliant on antibodies like many tests, which only indicates if someone has had the disease, and not whether they are currently infected and therefore contagious,” explained Ashwin Ramachandran, a Stanford graduate student and the study’s first author.
- The microlab test takes advantage of the fact that the coronavirus (SARS-COV-2) leaves behind tiny genetic fingerprints wherever they go in the form of strands of RNA, the genetic precursor of DNA. If the coronavirus’s RNA is present in a swab sample, the person from whom the sample was taken is infected.
- To initiate a test, liquid from a nasal swab sample is dropped into the microlab, which uses electric fields to extract and purify any nucleic acids like RNA that it might contain. The purified RNA is then converted into DNA and then replicated many times over using a technique known as isothermal amplification.
- Next, the team used an enzyme called CRISPR-Cas12 – a sibling of the CRISPR-Cas9 enzyme associated with this year’s Nobel Prize in Chemistry – to determine if any of the amplified DNA came from the coronavirus.
- If so, the activated enzyme triggers fluorescent probes that cause the sample to glow. Here also, electric fields play a crucial role by helping concentrate all of the important ingredients – the target DNA, the CRISPR enzyme and the fluorescent probes – together into a tiny space smaller than the width of a human hair, dramatically increasing the chances they will interact.
- “Our chip is unique in that it uses electric fields to both purify nucleic acids from the sample and to speed up chemical reactions that let us know they are present,” Santiago said.
- The team created its device on a shoestring budget of about $5,000. For now, the DNA amplification step must be performed outside of the chip, but Santiago expects that within months his lab will integrate all the steps into a single chip.
- Several human-scale diagnostic tests use similar gene amplification and enzyme techniques, but they are slower and more expensive than the new test, which provides results in just 30 minutes. Other tests can require more manual steps and can take several hours.
- The researchers say their approach is not specific to C19 and could be adapted to detect the presence of other harmful microbes, such as E. coli in food or water samples, or tuberculosis and other diseases in the blood.
- “If we want to look for a different disease, we simply design the appropriate nucleic acid sequence on a computer and send it over email to a commercial maker of synthetic RNA. They mail back a vial with the molecule that completely reconfigures our assay for a new disease,” Ramachandran said.
- The researchers are working with the Ford Motor Company to further integrate the steps and develop their prototype into a marketable product.
2. Confronting the notion that face masks reduce C19 ‘dose’
- When two physicians at the University of California at San Francisco published a commentary in the New England Journal of Medicine (NEJM) on Sep 8 proposing to resurrect the 18th century practice of variolation using face coverings to prevent severe C19 and confer immunity, the Internet lit up with headlines such as “Coronavirus: Another reason for that mask: You’ll get less sick.”
- The paper, written by Monica Gandhi, MD, MPH, and George Rutherford, MD, suggested that face coverings, in the absence of a vaccine, could reduce the inhaled dose of coronavirus by filtering some virus-containing droplets, leading to asymptomatic or mild disease and stimulating T- and B-cell immunity.
- Concerned that the piece, its positioning in a top medical journal, and the resulting media coverage would embolden people to abandon physical distancing and other public health measures in favor of only wearing face coverings, scientists warned against the practice in two letters to the editor in the same journal on Oct 23.
Reviving an ancient practice
- The inspiration behind Gandhi and Rutherford’s piece was variolation, the practice of inoculating healthy people with variola, the virus that causes smallpox, to give them a lower dose than would be inhaled, producing mild disease and stimulating immunity. While variolation worked in some people, others died of their infections, and it was abandoned after a vaccine became available in 1796. Gandhi and other colleagues also published a paper on the topic in July in the Journal of General Internal Medicine.
- However, Angela Rasmussen, PhD, associate research scientist at the Center for Infection and Immunity at Columbia University and coauthor of the first letter, along with Kevin Escandon MD, of Universidad del Valle in Colombia, and Saskia Popescu, PhD, of George Mason University, said the proposal is based on faulty assumptions about an emerging coronavirus about which much is yet unknown.
- “We don’t know the role that T cells play in determining disease severity,” Rasmussen said, let alone whether asymptomatic or mild disease generates the long-lasting, robust antibody responses required for durable immunity.
A hypothesis, not evidence
- Publishing a hypothesis—without describing the experiments that would need to prove or disprove it—in a prominent journal like NEJM sends the message that the concept has been borne out by evidence, Rasmussen said, adding that the paper would have been acceptable had it been framed as only a hypothesis.
- “I think that could encourage irresponsible behavior,” she said. “Of course, people should be wearing masks, but they should also be social distancing; masks are not the only nonpharmaceutical intervention.”
- Chad Roy, PhD, MSPH, of Tulane University School of Medicine, coauthor of the second letter, along with Lisa Brosseau ScD, CIH, and Michael Osterholm, PhD, MPH, both of the Center for Infectious Disease Research and Policy, publisher of CIDRAP News, called the proposal of variolation “borderline heresy” in terms of modern vaccine design and all of its complexities.
- “Variolation was used historically as an incredibly crude way of vaccinating individuals, but it was a completely uncontrolled mechanism by which to achieve vaccination,” Roy said. “Variolation should be considered an antiquity and not anything that anyone would try to use in modern medicine.”
- Also problematic is that no one knows what constitutes an infectious dose of the coronavirus, which likely varies from person to person and doesn’t appear to follow a classic dose-response relationship, Rasmussen said. And although it seems counterintuitive, high doses of coronavirus can be less virulent than low ones, Rasmussen said.
- That’s because viruses mutate, some to the point that they can no longer cause infection, and may thereby alter a host’s immune response to the virus. “They think the more virus you have the more sick you’re going to get, but that’s not necessarily true,” she said, adding that it probably depends more on the proportion of noninfectious-to-infectious virus. “There’s not always a linear relationship between dose and disease severity and outcome.”
- Roy pointed out the complexity of trying to define infectious dose in a virus that doesn’t necessarily cause symptoms, even in people with high viral loads. “Most particles are probably empty and just made up of mucous and water with no virions, or else everyone would be infected,” he said.
- Another problem with the perspective piece is that it doesn’t define what the authors consider a face covering, which range from single-layer homemade cloth masks to dependable N95 respirators, according to Rasmussen. “Certainly, masks could probably block larger droplets, and that kind of gets into the area of the whole droplet-versus-aerosols debate,” she said. “We just don’t have much evidence that masks protect the person wearing them, unless they are N95s certified by [the National Institute for Occupational Safety and Health].”
- In Gandhi and Rutherford’s response to the letters to the editor, in which they defend their assertions, they cite a non-peer-reviewed May 29 study claiming a dose response in six ferrets inoculated with the coronavirus, with a low dose resulting in only one showing signs of viral RNA replication. But Roy said that ferrets aren’t a good model because they don’t become very ill with C19, as opposed to the disease in humans and nonhuman primates.
- “Nonhuman primates are a near clinical model of human disease,” he said. “When you have that beachhead established in a higher-order model, it’s very difficult for a lower-order model to trump that observation.”
- Rasmussen agrees, saying that most of the ferrets in the study likely didn’t show signs of infection because the dose was too low. “It suggests that maybe five out of the six ferrets weren’t infected at all,” she said.
- In their response to the letters, Gandhi and Rutherford also cite a Jun 14 paper as evidence that viral load is equivalent to infectious dose, but it doesn’t describe the infectious dose that participants received, Brosseau said. “Having a high viral load doesn’t tell you anything about the dose that you received,” she said. “There is no relationship.”
- Nor did the study authors describe participant age, sex, or presence of underlying illnesses, which likely explain the results better than dose response, because they did not perform an exposure evaluation or even test all the participants for C19. “It’s just sort of chance that some got symptoms and some didn’t, depending on host characteristics and the size of the space,” Brosseau said.
- A problem with another cited study is that the researchers didn’t sample all the soldiers involved in their study—which involved physical distancing in Swiss soldiers and disease course—or describe what constituted lockdown conditions, Brosseau said. The authors of that paper also remarked that none of the group of 154 soldiers developed coronavirus symptoms after implementation of physical distancing, despite having antibodies. “They say not one of the soldiers developed severe disease, well of course not; they were all young and healthy,” she said.
- And another cited study was done with no understanding of filter science, Brosseau said. In that study, US researchers didn’t measure the flow rate of the aerosols they generated in the study, used high-speed videos rather than precision tools to measure droplet transmission, and employed much larger particle sizes than those generated in the real world.
Putting people at risk
- Gandhi and Rutherford’s paper is “really, really dangerous,” said Brosseau, adding that she has been moved to write only about three letters to the editor in her life. “They are putting people at risk by suggesting that that ‘it’ll be fine, you’ll wear your face covering, and you’ll get a low dose,'” she said. “It just goes to show what really bad science is going on out there.”
- Osterholm agrees. “What we’re worried about is people getting exposed and getting infected while thinking they were actually doing something to protect themselves,” he said.
- Rasmussen said that some scientists may be in a rush to be the first ones to present the next big idea about a virus that has been studied for only a matter of months—whether or not the science is sound. “I do wish some of these journals like the New England Journal of Medicine would be mindful of the platform they have and the credibility they can lend something when it’s published,” she said.
H. Projections & Our (Possible) Future
1. Will C19 Become Endemic?
- Reinfection, in which an individual is subject to multiple, distinct infections from the same virus species throughout their lifetime, is a salient feature of many respiratory viruses. Indeed, the persistence and ubiquity in human society of common respiratory viruses—including influenza viruses, respiratory syncytial virus (RSV), rhinovirus, and the endemic coronaviruses—are largely due to their ability to produce repeat infection. Since the emergence of the coronavirus (SARS-CoV-2), a critical concern has been whether humans will experience reinfections with this pathogen, which might enable it to become endemic.
- Typically, following an initial infection, the human adaptive immune system develops a suite of defenses, including memory B lymphocytes capable of producing neutralizing antibodies targeted to bind to that particular pathogen, and memory T lymphocytes that help regulate immune responses and induce death of infected cells. These adaptive immune components, particularly B cells, can produce sterilizing immunity in which the pathogen, if reintroduced to the host, is prevented from replicating within the body.
- However, for many viruses, a number of processes, particularly insufficient adaptive immune response, waning immunity, and immune escape, can undermine or circumvent the sterilizing character of immunity and allow subsequent reinfection. In the first instance, an initial infection with a particular agent may not engender an adaptive immune response sufficient to confer sterilizing immunity. Serological studies indicate that most SARS-CoV-2 infections, regardless of severity, induce development of some specific antibodies (1); however, despite encouraging results from the experimental vaccination of primates, it remains unclear whether those antibodies are sufficient to provide long-term effective protection or if other adaptive immune components are present and functional.
- Furthermore, immune response to SARS-CoV-2 infection is heterogeneous, with individuals who experience asymptomatic infections manifesting a weaker immune response than those experiencing more severe disease (1). It is possible that some individuals never develop sterilizing immunity following infection with SARS-CoV-2, or that multiple exposures will be needed for affinity maturation and development of long-lasting protection.
- Waning immunity, in which the initial adaptive immune response is robust and protective but dissipates over time, leaving the host vulnerable to reinfection, may also undermine sterilizing immunity. Immune escape is a third process that can facilitate reinfection, in particular by viruses. Here, a virus, during its continued serial passage through a host population, accumulates point mutations. This accumulation, termed antigenic drift, may lead to conformational changes of viral surface proteins that disrupt the binding of antibodies previously generated against an earlier variant. Immune escape is a consequence of this antigenic drift that enables reinfection through the evasion of adaptive protection.
- The time scales of waning immunity and immune escape differ by pathogen and have yet to be defined for SARS-CoV-2. Thus far, the mutation rate of the SARS-CoV-2 genome appears to be slower than that of influenza viruses. This lower rate may be a consequence of proof-reading during replication, which is exclusive to coronaviruses among RNA viruses. Conversely, human coronavirus (HCoV) OC43 is highly variable, particularly in genes encoding surface proteins such as the spike protein, indicating that considerable diversification can occur.
- To date, some evidence of SARS-CoV-2-specific antibody waning has been captured in a longitudinal study (2), and a few verified repeat SARS-CoV-2 infections have been documented (3). Although reinfections can occur, the number of reinfection cases is not currently sufficient to generalize the duration of immunity at population scales or the severity of repeat infection. Whether reinfections will be commonplace, how often they will occur, how contagious reinfected individuals will be, and whether the risk of severe clinical outcomes changes with subsequent infection remain to be understood.
- Insight from other respiratory viruses points to the possibility of reinfection with SARS-CoV-2. Naturally acquired infections with the four endemic HCoVs (OC43, HKU1, 229E, and NL63) indicate that reinfections with the same HCoV type are common within 1 year (4); sequential infections with the same influenza virus strain can occur in less than 2 years (5); and reinfections of adults with RSV within 1 year have also been documented (6). By contrast, more pathogenic viruses that induce systemic effects on the host may elicit a longer-lasting adaptive immune response. For example, longitudinal immune profiles from SARS survivors showed a stronger immune response with neutralizing antibodies persisting for 2 to 5 years (7). However, it could not be confirmed if and for how long this response conferred immunity because the SARS outbreak lasted less than 1 year.
- In addition to duration of protective immunity, the long-term effects of SARS-CoV-2 on humans will depend on the severity of reinfection. Sequential infections with influenza virus have been associated with less severe symptoms (8), whereas no association between reinfection and symptom severity was found in recurring endemic HCoV infections (4). In addition, for other viruses (e.g., RSV and dengue), suboptimal binding of naturally induced or vaccine-induced antibodies can enhance infection severity upon subsequent exposure, a phenomenon called antibody-dependent enhancement (ADE) (9). To date, responses among the few patients with verified SARS-CoV-2 reinfection have been heterogeneous with one apparent repeat infection requiring hospitalization. Thus, thorough serological and prospective studies are needed to determine whether ADE manifests among SARS-CoV-2 infections, either because of prior homologous infection or cross-reactive antibodies from other HCoVs. This will have particular relevance for vaccines and convalescent plasma therapy.
- Should reinfection prove commonplace, and barring a highly effective vaccine delivered to most of the world’s population, SARS-CoV-2 will likely become endemic (10). The typical time scale at which individuals experience reinfection and seasonal differences in transmissibility will determine the pattern of endemicity. Outside the tropics, the incidence of many common respiratory virus infections increases during particular times of the year. This phase-locked behavior is due to accumulated susceptibility to reinfection, which increases over time because of immune escape and waning immunity, and seasonal modulation of virus transmissibility derived from environmental conditions, changing behavior (e.g., mixing indoors in cold weather), or altered immune function. For example, influenza incidence is greatest during winter in temperate regions. Once expelled from an infectious host, the influenza virus appears to be more stable in low-humidity conditions (11), which are prevalent both indoors and outdoors during winter. Further, during colder months, people spend more time indoors and school is in session, which may facilitate transmission, and shorter days and less sunlight exposure may suppress immune function.
- The endemic HCoVs (OC43, HKU1, NL63, and 229E) all exhibit a seasonality in temperate regions, similar to influenza viruses (12). Consequently, numerous studies have sought to determine whether conditions such as temperature, sunlight, humidity, ozone, and pollution affect SARS-CoV-2 viability and transmissibility. The results are not currently conclusive, although it appears that environmental conditions, such as sunlight and humidity, may modulate SARS-CoV-2 transmissibility—not enough to preclude transmission during the first waves of the pandemic when immunity is generally low—but perhaps sufficient to favor seasonal, phase-locked transmission during winter in temperate regions, similar to influenza virus, once immunity increases.
- Like the 2009 influenza pandemic, the continued circulation by SARS-CoV-2 following this initial pandemic period will manifest as a function of reinfection rates, vaccine availability and efficacy, and social, immune, and innate factors that modulate virus transmissibility (see the figure). In addition, the cyclic persistence of SARS-CoV-2 in human populations may be affected by ongoing opportunities for interaction with other respiratory pathogens.
- Co-circulating respiratory viruses may interfere with one another while competing for the same resources, and their interactions have been studied at population and individual levels, in reconstructed human tissues and in animal models. The outcomes in individuals experiencing serial exposure to different viruses vary and in general appear to depend on the order and timing of exposures. Many studies have documented evidence of negative interference between viruses caused by short-lived (days) protection elicited from the first infection.
- Host antiviral interferon responses are often regarded as the main mechanism by which interference manifests; that is, as a result of a recent infection, the host cells up-regulate the synthesis of interferons, potentially inhibiting a secondary infection. Even though it is short-lived, this effect can be strong at population scales and temporarily reduce the prevalence of a virus or shift the timing of its circulation. For example, it is hypothesized that a large summer 2009 rhinovirus outbreak delayed pandemic influenza virus emergence in Europe (13).
- The clinical and population-scale interactions of SARS-CoV-2 with other respiratory viruses, particularly influenza viruses and other HCoVs, need to be monitored in the coming years. To date, some SARS-CoV-2 coinfections have been documented (14), including coinfections with influenza and RSV; however, testing for multiple pathogens has not been routinely carried out, and the scarce data that do exist, mostly for older adults with high rates of preexisting medical conditions, do not support a definitive evaluation of coinfection likelihood or severity. Studies prior to the pandemic indicate that simultaneous infections with multiple respiratory viruses are not uncommon but are not associated with increased disease severity.
- At the population scale, a possible overlap between influenza and SARS-CoV-2 outbreaks poses a serious threat to public health systems. Seasonal influenza produces millions of severe infections worldwide every year, and this additional burden could be catastrophic on systems already challenged by the C19 pandemic.
- Conversely, given similar modes of transmission among different respiratory viruses, the nonpharmaceutical interventions adopted to mitigate SARS-CoV-2 transmission (personal protective equipment, social distancing, increased hygiene, limited indoor gatherings) may reduce the magnitude of seasonal influenza outbreaks. Such increased use of nonpharmaceutical measures, and possible virus interference, could be responsible for the reduced incidence of influenza during the recent winter of the Southern Hemisphere (15).
- The phases and magnitudes of different outbreaks in a multipathogen system are dictated by the interaction dynamics between those pathogens: from large overlapping phases when pathogens enhance one another’s transmission, to complete inhibition of a strain by the neutralizing cross-reactivity of a more transmissible one (9). Several postpandemic scenarios for SARS-CoV-2 have been modeled (10), postulated on duration of immunity and cross-immunity between SARS-CoV-2 and the other betacoronaviruses (OC43 and HKU1).
- A duration of immunity similar to that of the other betacoronaviruses (∼40 weeks) could lead to yearly outbreaks of SARS-CoV-2, whereas a longer immunity profile, coupled with a small degree of protective cross-immunity from other betacoronaviruses, could lead to the apparent elimination of the virus followed by resurgence after a few years. Other scenarios are, of course, possible, because there are many processes at play and much that remains unresolved.
2. Four major predictors of C19 spread emerge in Texas A&M study
- In March 2020, New York City, an icon of America, was unfortunately named an early epicenter of the novel coronavirus. Now seven months later, America faces a new surge in coronavirus cases and researchers at Texas A&M University hope to provide information and context to help with the battle ahead.
- Rich Whittle, a doctoral student at Texas A&M, cites in a recent study that by April 2020, New York City accounted for more than a third of the nation’s confirmed cases, with a transmission rate five times higher than the rest of the country.
- Whittle wanted to look at these early stages of the pandemic spread in New York neighborhoods to discover if there were any socioeconomic factors that could be associated with the high positivity rate of C19.
- “The world is waking up to the first global pandemic in a while, but it’s not going to be the last, so understanding the contact patterns and socioeconomic factors that lead to high-detected case numbers is important for public health,” said Whittle.
- The study, published in BMC Medicine, identified four significant predictors of C19 cases in New York City: neighborhoods with higher population densities led to an increase in the positivity rate; neighborhoods with younger populations (under 18 years old) also led to an increase; households with a higher income led to a decrease; and race showed a significant association with detected C19 cases – both a lower percentage of white population and higher percentage of Black population led to increased positivity rates.
- “From what is available in the early stages, this is what we’re seeing from the data, and we know those early stages are really important to keep this and future pandemics under control,” said Dr. Ana Diaz Artiles, assistant professor in the Department of Aerospace Engineering at Texas A&M and co-author of the study.
- The study used spatial modeling techniques to look at data from roughly 60,000 cases during the first month of the pandemic in New York City.
- “I’m really interested in spatial statistics. When I was in the military, I worked in geospatial intelligence so I have a background interest in that,” said Whittle. “And I was taking Dr. Diaz Artiles’ stats class at the time, so I thought I could combine those two interests and have a look at an ecological study related to C19.”
- Whittle initiated the study as his final class project for Diaz Artiles’ spring Design of Experiments and Statistical Methods course (AERO 689).
- “This class gives the opportunity to solve problems that the students are interested in,” said Diaz Artiles. “These classes are really useful for students not only in terms of learning statistical tools, but to apply them in practical applications that could even lead to impactful results and publications.”
- In addition to academic interest, Whittle was motivated to pursue the study because of the value the results could provide, both now and in the future.
- “There’s a need to understand the beginning stage of the pandemic,” said Whittle. “And I think in America, certainly now, there’s a lot of discontent. There’s a definite public interest in understanding the response in the initial stages of the pandemic.”
- Whittle and Diaz Artiles emphasize that understanding the early factors and influences of past pandemics, such as the H1N1 pandemic of 2009 and the one we face today, is important in helping to inform future management.
- “Hopefully our study will provide a better understanding of the main factors that impact the spread of the disease, thus improving future decision making in the early stages of a pandemic,” said Diaz Artiles.
1. The 2006 Origins of the Lockdown Idea
- Now begins the grand effort, on display in thousands of articles and news broadcasts daily, somehow to normalize the lockdown and all its destruction of the last two months. We didn’t lock down almost the entire country in 1968/69, 1957, or 1949-1952, or even during 1918. But in a terrifying few days in March 2020, it happened to all of us, causing an avalanche of social, cultural, and economic destruction that will ring through the ages.
- There was nothing normal about it all. We’ll be trying to figure out what happened to us for decades hence.
- How did a temporary plan to preserve hospital capacity turn into two-to-three months of near-universal house arrest that ended up causing worker furloughs at 256 hospitals, a stoppage of international travel, a 40% job loss among people earning less than $40K per year, devastation of every economic sector, mass confusion and demoralization, a complete ignoring of all fundamental rights and liberties, not to mention the mass confiscation of private property with forced closures of millions of businesses?
- Whatever the answer, it’s got to be a bizarre tale. What’s truly surprising is just how recent the theory behind lockdown and forced distancing actually is. So far as anyone can tell, the intellectual machinery that made this mess was invented 14 years ago, and not by epidemiologists but by computer-simulation modelers. It was adopted not by experienced doctors – they warned ferociously against it – but by politicians.
- Let’s start with the phrase social distancing, which has mutated into forced human separation. The first I had heard it was in the 2011 movie Contagion. The first time it appeared in the New York Times was February 12, 2006:
- If the avian flu goes pandemic while Tamiflu and vaccines are still in short supply, experts say, the only protection most Americans will have is “social distancing,” which is the new politically correct way of saying “quarantine.”
- But distancing also encompasses less drastic measures, like wearing face masks, staying out of elevators — and the [elbow] bump. Such stratagems, those experts say, will rewrite the ways we interact, at least during the weeks when the waves of influenza are washing over us.
- Maybe you don’t remember that the avian flu of 2006 didn’t amount to much. It’s true, despite all the extreme warnings about its lethality, H5N1 didn’t turn into much at all. What it did do, however, was send the existing president, George W. Bush, to the library to read about the 1918 flu and its catastrophic results. He asked for some experts to submit some plans to him about what to do when the real thing comes along.
- The New York Times (April 22, 2020) tells the story from there:
- Fourteen years ago, two federal government doctors, Richard Hatchett and Carter Mecher, met with a colleague at a burger joint in suburban Washington for a final review of a proposal they knew would be treated like a piñata: telling Americans to stay home from work and school the next time the country was hit by a deadly pandemic.
- When they presented their plan not long after, it was met with skepticism and a degree of ridicule by senior officials, who like others in the United States had grown accustomed to relying on the pharmaceutical industry, with its ever-growing array of new treatments, to confront evolving health challenges.
- Drs. Hatchett and Mecher were proposing instead that Americans in some places might have to turn back to an approach, self-isolation, first widely employed in the Middle Ages.
- How that idea — born out of a request by President George W. Bush to ensure the nation was better prepared for the next contagious disease outbreak — became the heart of the national playbook for responding to a pandemic is one of the untold stories of the coronavirus crisis.
- It required the key proponents — Dr. Mecher, a Department of Veterans Affairs physician, and Dr. Hatchett, an oncologist turned White House adviser — to overcome intense initial opposition.
- It brought their work together with that of a Defense Department team assigned to a similar task.
- And it had some unexpected detours, including a deep dive into the history of the 1918 Spanish flu and an important discovery kicked off by a high school research project pursued by the daughter of a scientist at the Sandia National Laboratories.
- The concept of social distancing is now intimately familiar to almost everyone. But as it first made its way through the federal bureaucracy in 2006 and 2007, it was viewed as impractical, unnecessary and politically infeasible.
- Notice that in the course of this planning, neither legal nor economic experts were brought in to consult and advise. Instead it fell to Mecher (formerly of Chicago and an intensive care doctor with no previous expertise in pandemics) and the oncologist Hatchett.
- But what is this mention of the high-school daughter of 14? Her name is Laura M. Glass, and she recently declined to be interviewed when the Albuquerque Journal did a deep dive of this history:
- “Laura, with some guidance from her dad, devised a computer simulation that showed how people – family members, co-workers, students in schools, people in social situations – interact. What she discovered was that school kids come in contact with about 140 people a day, more than any other group. Based on that finding, her program showed that in a hypothetical town of 10,000 people, 5,000 would be infected during a pandemic if no measures were taken, but only 500 would be infected if the schools were closed.”
- Laura’s name appears on the foundational paper arguing for lockdowns and forced human separation. That paper is Targeted Social Distancing Designs for Pandemic Influenza (2006). It set out a model for forced separation and applied it with good results backwards in time to 1957. They conclude with a chilling call for what amounts to a totalitarian lockdown, all stated very matter-of-factly:
- “Implementation of social distancing strategies is challenging. They likely must be imposed for the duration of the local epidemic and possibly until a strain-specific vaccine is developed and distributed. If compliance with the strategy is high over this period, an epidemic within a community can be averted. However, if neighboring communities do not also use these interventions, infected neighbors will continue to introduce influenza and prolong the local epidemic, albeit at a depressed level more easily accommodated by healthcare systems.”
- In other words, it was a high-school science experiment that eventually became law of the land, and through a circuitous route propelled not by science but politics.
- The primary author of this paper was Robert J. Glass, a complex-systems analyst with Sandia National Laboratories. He had no medical training, much less an expertise in immunology or epidemiology.
- That explains why Dr. D.A. Henderson, “who had been the leader of the international effort to eradicate smallpox,” completely rejected the whole scheme.
- Says the NYT:
- Dr. Henderson was convinced that it made no sense to force schools to close or public gatherings to stop. Teenagers would escape their homes to hang out at the mall. School lunch programs would close, and impoverished children would not have enough to eat. Hospital staffs would have a hard time going to work if their children were at home.
- The measures embraced by Drs. Mecher and Hatchett would “result in significant disruption of the social functioning of communities and result in possibly serious economic problems,” Dr. Henderson wrote in his own academic paper responding to their ideas.
- The answer, he insisted, was to tough it out: Let the pandemic spread, treat people who get sick and work quickly to develop a vaccine to prevent it from coming back.
- AIER’s Phil Magness got to work to find the literature responding to the 2006 paper by Robert and Laura M. Glass and discovered the following manifesto: Disease Mitigation Measures in the Control of Pandemic Influenza. The authors included D.A. Henderson, along with three professors from Johns Hopkins: infectious disease specialist Thomas V.Inglesby, epidemiologist Jennifer B. Nuzzo, and physician Tara O’Toole.
- Their paper is a remarkably readable refutation of the entire lockdown model:
- There are no historical observations or scientific studies that support the confinement by quarantine of groups of possibly infected people for extended periods in order to slow the spread of influenza. … It is difficult to identify circumstances in the past half-century when large-scale quarantine has been effectively used in the control of any disease. The negative consequences of large-scale quarantine are so extreme (forced confinement of sick people with the well; complete restriction of movement of large populations; difficulty in getting critical supplies, medicines, and food to people inside the quarantine zone) that this mitigation measure should be eliminated from serious consideration…
- Home quarantine also raises ethical questions. Implementation of home quarantine could result in healthy, uninfected people being placed at risk of infection from sick household members. Practices to reduce the chance of transmission (hand-washing, maintaining a distance of 3 feet from infected people, etc.) could be recommended, but a policy imposing home quarantine would preclude, for example, sending healthy children to stay with relatives when a family member becomes ill. Such a policy would also be particularly hard on and dangerous to people living in close quarters, where the risk of infection would be heightened….
- Travel restrictions, such as closing airports and screening travelers at borders, have historically been ineffective. The World Health Organization Writing Group concluded that “screening and quarantining entering travelers at international borders did not substantially delay virus introduction in past pandemics . . . and will likely be even less effective in the modern era.”… It is reasonable to assume that the economic costs of shutting down air or train travel would be very high, and the societal costs involved in interrupting all air or train travel would be extreme. …
- During seasonal influenza epidemics, public events with an expected large attendance have sometimes been cancelled or postponed, the rationale being to decrease the number of contacts with those who might be contagious. There are, however, no certain indications that these actions have had any definitive effect on the severity or duration of an epidemic. Were consideration to be given to doing this on a more extensive scale and for an extended period, questions immediately arise as to how many such events would be affected. There are many social gatherings that involve close contacts among people, and this prohibition might include church services, athletic events, perhaps all meetings of more than 100 people. It might mean closing theaters, restaurants, malls, large stores, and bars. Implementing such measures would have seriously disruptive consequences…
- Schools are often closed for 1–2 weeks early in the development of seasonal community outbreaks of influenza primarily because of high absentee rates, especially in elementary schools, and because of illness among teachers. This would seem reasonable on practical grounds. However, to close schools for longer periods is not only impracticable but carries the possibility of a serious adverse outcome….
- Thus, cancelling or postponing large meetings would not be likely to have any significant effect on the development of the epidemic. While local concerns may result in the closure of particular events for logical reasons, a policy directing communitywide closure of public events seems inadvisable. Quarantine. As experience shows, there is no basis for recommending quarantine either of groups or individuals. The problems in implementing such measures are formidable, and secondary effects of absenteeism and community disruption as well as possible adverse consequences, such as loss of public trust in government and stigmatization of quarantined people and groups, are likely to be considerable….
- Finally, the remarkable conclusion:
- Experience has shown that communities faced with epidemics or other adverse events respond best and with the least anxiety when the normal social functioning of the community is least disrupted. Strong political and public health leadership to provide reassurance and to ensure that needed medical care services are provided are critical elements. If either is seen to be less than optimal, a manageable epidemic could move toward catastrophe.
- Confronting a manageable epidemic and turning it into a catastrophe: that seems like a good description of everything that has happened in the C19 crisis of 2020.
- Thus did some of the most highly trained and experienced experts on epidemics warn with biting rhetoric against everything that the advocates of lockdown proposed. It was not even a real-world idea in the first place and showed no actual knowledge of viruses and disease mitigation. Again, the idea was born of a high-school science experiment using agent-based modelling techniques having nothing at all to do with real life, real science, or real medicine.
- So the question becomes: how did the extreme view prevail?
- The New York Times has the answer:
- The [Bush] administration ultimately sided with the proponents of social distancing and shutdowns — though their victory was little noticed outside of public health circles. Their policy would become the basis for government planning and would be used extensively in simulations used to prepare for pandemics, and in a limited way in 2009 during an outbreak of the influenza called H1N1. Then the coronavirus came, and the plan was put to work across the country for the first time.
- [Post-publication note: You can read the 2007 CDC paper here. It is arguable that this paper did not favor full lockdown. I’ve spoken to Rajeev Venkayya, MD, who regards the 2007 plan as more liberal, and assures me that they never envisioned this level of lockdown: “lockdowns and shelter-in-place were not part of the recommendations.” To my mind, fleshing out the full relationship between this 2007 document and current policy requires a separate article.]
- The Times called one of the pro-lockdown researchers, Dr. Howard Markel, and asked what he thought of the lockdowns. His answer: he is glad that his work was used to “save lives” but added, “It is also horrifying.” “We always knew this would be applied in worst-case scenarios,” he said. “Even when you are working on dystopian concepts, you always hope it will never be used.”
- Ideas have consequences, as they say. Dream up an idea for a virus-controlling totalitarian society, one without an endgame and eschewing any experienced-based evidence that it would achieve the goal, and you might see it implemented someday. Lockdown might be the new orthodoxy but that doesn’t make it medically sound or morally correct. At least now we know that many great doctors and scholars in 2006 did their best to stop this nightmare from unfolding. Their mighty paper should serve as a blueprint for dealing with the next pandemic.
J. Practical Tips & Other Useful Information
1. Indoor concerts are safe from C19 — with a catch, study says
- Entertainers have pulled out all the stops to revive the decimated concert industry, from VIP-like boxes to individual bubbles for every attendee.
- But breakthrough scientific research might be music to live-show lovers’ ears.
- Concerts are not the riskiest endeavors in the age of C19, according to a new study out of Germany which tested attendees at an indoor venue.
- The researchers ran simulations based on the behavior of masked participants over a 10-hour span. All the participants tested negative for the virus before joining the experiment. Using computerized models, the researchers tested different scenarios — such as entering and exiting and taking breaks — and looked at everything from airflow to exposure to aerosolized droplets.
- In their simulation, the researchers were able to see how even normal ventilation could minimize the amount of potentially infected particles wafting through the venue. Adding more entrances also helped reduce the risk.
- They also found that regular social distancing did a whole lot of good in lowering the risk of contamination — the real-life effect of not doing that was seen over the summer at the Sturgis Motorcycle Rally, which scientists have since labeled a “superspreader event.” Densely packed crowds may have contributed to a spike in cases in South Dakota.
- But the few extra precautions studied by the German researchers could go a long way in preventing this kind of impact. In all, as long as the ventilation was good, people wore masks and stayed about 6 feet apart, less than 10 people out of the 1,200 people in the venue were exposed to potentially contaminated particles.
- The study, which is not yet peer reviewed, stressed that wearing masks — particularly N95 masks — and social distancing were still extremely important.
- “The expected additional effect of indoor [mass-gathering events] on burden of infections is low if hygiene concepts are applied and adequate ventilation exists,” they wrote in the study.
- But researchers not associated with the event pointed out that the factors still need to be studied more before we can definitively join a sweaty mosh pit once again.
K. Johns Hopkins COVID-19 Update
November 4, 2020
1. Cases & Trends
- The WHO C19 Dashboard reports 47.36 million cases and 1.21 million deaths as of 10:00am EST on November 4.
- The US CDC reported 9.27 million total cases and 230,893 deaths, including 86,190 new cases reported yesterday, the fourth highest daily total to date. The daily C19 incidence continues to increase and set new records. With an average of 84,029 new cases per day, the US is now exceeding the previous peak in late July by more than 20%, and it is more than 2.5 times the first peak in mid-April.
- The daily incidence has more than doubled since the low on September 12, and it is rapidly approaching India’s record of 93,199 new cases per day, set in mid-September. Since October 18, the US C19 mortality has increased from approximately 700 deaths per day to 829, an 18% increase and the highest average since September 16.
- More than half of all US states have reported more than 100,000 cumulative cases, including 14 with more than 200,000 cases:
>500,000: New York
- In order to better account for the level of transmission in many states across the Midwest and Mountain regions, the COVID Exit Strategy website added a new category. The new classification, greater than 500 cases per million population (purple), covers 11 states. Notably, North and South Dakota are reporting 1,510 and 1,312 daily cases per million population. To put those figures in context, that corresponds to more than 1 out of every 1,000 people in those states testing positive for SARS-CoV-2 every day.
- In addition to C19 incidence, the US is reporting increasing impact on hospitals and increasing C19 mortality. Nationally, emergency department (ED) visits for C19 have increased steadily over the past several weeks. The percentage of ED visits for C19 coronavirus-like illness increased from approximately 2% in early September to nearly 3.5% in early November, a 65% increase.
- This trend is even more pronounced in some states, including Alaska (up from 2.5% to more than 6%), Connecticut (1% to nearly 4%), Idaho (2.5% to more than 7%), Illinois (2.5% to 6.5%), Montana (2% to 8%), Nebraska (1.5% to more than 6%), New Mexico (1.5% to 5%), North Dakota (3% to 11%), Utah (2.5% to 8%), and Wisconsin (1.5% to more than 5%). On a regional basis, Region 5 (Illinois, Indiana, Michigan, Ohio, Wisconsin) increased from 1.7% to 5% and Region 8 (Colorado, Montana, North and South Dakota, Utah, Wyoming) increased from 2% to more than 6%.*
- Over the past week, 9 states have reported per capita C19 mortality greater than 0.5 deaths per 100,000 population, including 3 states with 1 or greater. Indiana, Missouri, Mississippi, and Tennessee all reported 0.5 deaths per 100,000, and Arkansas and Wisconsin both reported 0.7. South Dakota reported 1 C19 death per 100,000; Montana reported 1.1; and North Dakota reported 1.5. With the exception of Mississippi, all of these states are reporting increasing C19 mortality over the past several weeks. In some cases, like Arkansas and Tennessee, the trend has persisted for months, whereas most began approximately 3-4 weeks after the most recent surge in incidence. For example North and South Dakota’s incidence began to surge in mid-to-late August, followed by mortality in mid-September. Montana’s most pronounced surge in mortality started in mid-October, following a surge in incidence that began in mid-to-late September.
- The Johns Hopkins CSSE dashboard reported 9.39 million US cases and 232,742 deaths as of 11:30am EST on November 4.
2. US ELECTION
- After many months of US presidential campaigns defined, in large part, by the C19 pandemic, the US general election was held yesterday. Even in a typical election year, many polling sites can face long lines and wait times of several hours or longer, and 2020 was no exception.
- While a record number of Americans cast their votes before election day, either by mail or in person, many millions voted in person yesterday. In addition to record-setting voter turnout in this year’s presidential election, social distancing and enhanced hygiene procedures at polling sites posed additional challenges and, to some degree, slowed the voting process. Tallying of the votes is still underway. At this time, no victor has been declared in the presidential election, and some states anticipate counting votes over the next several days.
- In addition to the direct impact on the voting process, the outcome of the presidential election promises to have major implications for the US C19 response. As the campaigns came to a close, C19 remained a major talking point for both US President Donald Trump and former Vice President Joe Biden. President Trump continually argued that the US epidemic had turned a corner, despite record daily incidence, and focused on the economic damage associated with social distancing policies recommended by experts. Former Vice President Biden emphasized the absence of a national C19 response strategy and repeatedly stated that he would follow the guidance of the nation’s scientific experts. Regardless of the final official result, it may be unlikely that a C19 stimulus package is finalized during the Congressional “lame duck” session between now and Inauguration Day in January.
3. C19 IN CHILDREN
- According to data published by the American Academy of Pediatrics (AAP), more than 61,000 pediatric cases of C19 were reported in the US in the last week of October, the highest weekly total to date. Through October 29, more than 850,000 pediatric cases have been reported nationally since the onset of the pandemic, representing 11% of all US cases. The data continue to indicate that severe illness is relatively rare among children; however, a number of states—including Missouri and North Dakota—recently reported deaths in teenagers, their youngest C19 deaths to date.
- Beyond severe acute disease and mortality, the AAP calls for expanded efforts to evaluate the risk of longer-term health effects due to SARS-CoV-2 infection, including physical and mental health issues. This is particularly important for Black and Hispanic children, who are disproportionately affected by C19. The AAP also notes that the pediatric data likely underestimates the true C19 incidence in children. While many pediatric infections result in mild illness or asymptomatic infection, they can still lead to longer-term health effects or allow transmission of the infection to higher-risk individuals.
4. IMMIGRATION DETENTION FACILITIES
- A study published in JAMA analyzed SARS-CoV-2 testing and C19 incidence among detainees at US Immigration and Customs Enforcement (ICE) facilities from April-August, based on data published on the ICE C19 website. Compared to the pre-pandemic totals in February, ICE’s average daily detained population decreased by 45% through August, likely due to efforts to reduce the detained population during the pandemic. By the end of August, ICE had reported 5,379 cumulative cases of C19 among ICE detainees, including 6 deaths. Notably, 20 of the 135 facilities accounted for more than 70% of the C19 cases, indicating major outbreaks in these facilities.
- ICE’s test positivity decreased from 47% in April to 11% in July, as testing capacity increased (from 3,224 tests per 100,000 detainees to 46,874); however, test positivity subsequently increased in August to 18%. In August, per capita testing volume decreased 23% compared to July, but incidence increased by 26%. The per capita incidence in ICE facilities was more than 13 times that of the broader US population, despite the per capita testing in ICE facilities only being 4.6 times the US public. At the peak in June, ICE facilities were reporting C19 incidence nearly 22 times the per capita incidence in the US while performing fewer than 7 times the number of tests per capita. Consistent with previous studies, these data indicate that C19 is spreading more rapidly among ICE detention facilities.
- The researchers cite potential difficulties implementing ICE’s C19 response plan—which includes guidelines for social distancing, enhanced hygiene and disinfection, testing protocols, and expedited detainee release—as a potential barrier to combating C19 within ICE facilities, and they call for an independent assessment of the C19 measures implemented in ICE facilities. They also advocate for expanded testing, including for asymptomatic individuals, in order to mitigate transmission risk.
5. ANTI-ASIAN RACISM
- Racism against Asian Americans continues to be an issue across the US. A report to the UN Office of the High Commissioner for Human Rights (UN Human Rights) noted that “racially motivated violence and other incidents against Asian-Americans have reached an alarming level across the United States since the outbreak of C19,” affecting Chinese Americans as well as individuals descending from other Asian nations. The documented incidents spanned a wide range, from verbal harassment to vandalism, to physical violence. Additionally, Asian Americans have been denied service at restaurants and retail stores, residences, and public transportation or ride-sharing services.
- Notably, the incidents disproportionately affected women of Asian descent. These incidents and trends are not exclusive to the US. study by researchers at Australian National University found that 84.5% of Asian Australians reported at least one instance of discrimination between January and October 2020. The study also found that Asian Australians were more likely to hold jobs that have been affected by the pandemic and social distancing policies, and Asian Australians reported feeling “more anxious about the pandemic” than those of other races or ethnicities.
6. TESTING OVERSIGHT
- Early in the US C19 epidemic, the country struggled to rapidly scale up testing capacity. One component of the effort to increase the volume of available tests was permitting laboratories—including at health departments, hospitals, universities, and private sector companies—to develop their own diagnostic tests. Laboratory developed tests (LDTs) were initially overseen by the US FDA, under Emergency Use Authorizations (EUAs), but the FDA stopped requiring EUAs for LDTs in August, at the direction of senior leadership at the US Department of Health and Human Services.
- This decision enabled increased access to the tests, due to reduced regulatory requirements; however, it reduced oversight of test quality and reliability. An investigation by STAT News discovered that HHS leadership and its general counsel were aware of “major concerns” about the quality and accuracy for “many of the LDTs” in August, when the department directed the FDA to stop requiring the EUAs. Notably, tests that were issued EUAs prior to the policy change are required to report problems with the tests to the FDA, including false positive/negative test results, but the STAT News report indicates that the “vast majority of false C19 results…are simply never reported.”
7. ESSENTIAL WORKERS
- Researchers from Harvard and Boston Universities (Massachusetts, US) analyzed exposure and infection risks among 104 employees at a Boston-area grocery store. The study, published in BMJ, also evaluated the employees’ mental health, specifically evaluating for signs of anxiety and depression. As part of a testing program mandated by the local government, all employees underwent PCR-based diagnostic testing, and 21 tested positive for SARS-CoV-2. Notably, 76% of the positive employees were not symptomatic at the time of testing. Employees whose jobs involved direct interaction with customers were 5 times more likely to test positive for SARS-CoV-2 than those without direct customer contact.
- Among 99 participants who completed the mental health assessments, 24 reported “at least mild anxiety” and 8 “screened positive for at least mild depression.” Individuals who were able to practice effective social distancing at work were less likely to experience both anxiety and depression. Additionally, those who were able to commute to work without using public transportation (e.g., walk, bicycle, private vehicle) exhibited a 90% reduction in the risk depression.
- A study published in JAMA: Network Open developed a stochastic model to analyze exposure risk among construction site workers in Austin, Texas (US). Using local demographic data and reported C19 hospitalization rates, the researchers modeled 15 scenarios representing various worksite area sizes and degrees of transmission between workers, corresponding to the implementation of various C19 control measures.
- Notably, at the time of the study, the researchers estimated that the per capita C19 hospitalization rate among construction workers was 4.5 times the rate among the entire Austin population. The model illustrated that close contact in high-risk worksites with large construction crews not only corresponded to elevated workplace transmission and construction worker hospitalizations, but also increased community transmission. Based on the results of the study led local authorities in Austin to impose more restrictive worksite safety requirements, including increased cleaning of shared equipment, daily symptom monitoring, and enhanced documentation to support contact tracing.
8. INFECTION RISK FACTORS
- A study published in Clinical Infectious Diseases examined the risk factors associated with SARS-CoV-2 infection in the US Veterans Affairs (VA) healthcare system. The study population included more than 88,000 VA patients across the country who underwent PCR-based diagnostic testing for SARS-CoV-2 between March and May. Among these individuals, 11.5% tested positive for SARS-CoV-2 infection. The researchers found that male sex, older age, and non-White race/ethnicity were associated with increased odds of testing positive for SARS-CoV-2.
- It is well documented that individuals with underlying medical conditions, including overweight/obesity and diabetes, are at elevated risk of severe C19 disease and death, but this study also found that having overweight/obesity or diabetes were also associated with increased risk of testing positive for SARS-CoV-2. Individuals who smoked were also more likely to test positive. While these findings are not unique to this study, the study setting of the VA national health system provides a more streamlined comparison between regions due to similar protocols and patient populations. Understanding infection risk can “help public health and health system initiatives to target testing, education, and preventive efforts.”
9. AGE-SPECIFIC MORTALITY
- A study published in Nature evaluated age-specific C19 mortality and seroprevalence based on data from 45 countries, representing a combined population of approximately 3.4 billion people, and 22 serological studies. The researchers developed a model that merges seroprevalence study data with time-series mortality data to estimate the corresponding infection fatality ratio (IFR) for the 45 countries. The study found that C19 mortality trends for individuals under the age of 65 were relatively consistent across countries and that mortality for individuals aged 65 and older was more heterogeneous.
- Consistent with the current understanding of C19 risk, children generally exhibited lower IFR than adults. The estimated IFR ranged from 0.002% among children aged 5-9 years to 8.29% among individuals aged 80 years and older. Starting at age 10, the IFR increased approximately 0.6% with an increase of 5 years in age. Considering challenges and limitations in testing and reporting, particularly for mild cases and asymptomatic infections, C19 mortality can be among the most reliable data available. With that in mind, the researchers identified considerable variation in mortality data for individuals aged 65 and older.
- Notably, “many countries in South America had significantly fewer reported deaths in individuals ≥65 years than expected,” corresponding to as many as several thousand “missing deaths” in some countries. Conversely, European countries tended to report elevated mortality among older individuals than would be expected based on the model. The mortality model was highly sensitive to mortality estimates among nursing home populations, and the researchers note that the discrepancies in IFR among older individuals highlight the challenge of comparing mortality data between countries, particularly those that experienced “very different levels of transmission [among] hyper-vulnerable communities.”
- Despite tens of millions of cases worldwide and nearly a year’s worth of data on C19, many questions remain regarding the body’s lasting antibody response to SARS-CoV-2 infection. A study of more than 30,000 infected individuals in New York City, published in Science, analyzed the neutralizing antibody response. From March to October, Mount Sinai Health System screened more than 72,000 individuals using an in-house serological assay.
- The researchers found that the “vast majority” of patients who were seropositive, indicating prior infection with SARS-CoV-2, had moderate-to-high titers for antibodies against the SARS-CoV-2 spike protein. The researchers acknowledge that the screening effort could have failed to identify individuals who were previously infected but did not produce lasting antibodies; however, prior research indicates that this is likely to be a small fraction of infected individuals.
- Additional analysis using 120 specimens, including specimens ranging from seronegative to high antibody titers, determined that the neutralization capacity of the specimens correlated strongly with the spike protein antibody titer. The researchers also analyzed the duration of neutralizing antibody activity using additional specimens collected from 121 patients—representing “a variety of titer levels”—at approximately 82 and 148 days after symptom onset. Generally, the specimens exhibited a steady decline in antibody titer over time, but the specimens exhibited similar trends in neutralizing capacity as the initial specimens (ie, higher titers corresponds to increased neutralization), indicating that the antibodies against the spike protein could provide some measure of durable protection against subsequent infection.
- The researchers also observed an initial increase in titer among some individuals with initially low antibody levels, but several individuals with very low titers in the initial specimen had undetectable antibody levels in the subsequent specimens. This illustrates that some individuals with milder immune response can take time to build up antibody levels following infection; however, those with very low immune response can be at risk for losing antibody protection over a relatively soon after infection. The researchers intend to continue following this patient cohort over time to gather additional data.