September 26, 2020
Without reliable information, we rely on fear or luck.
1. Cases & Tests
3. Top 5 States in Cases, Deaths, Hospitalizations & Positivity
4. Nationwide C19 Metrics Since April 1, 2020
4. Why children may be protected from the virus
6. Convalescent plasma falls flat in first randomized trial (!) (Link Only)
9. Could Zinc Help Fight C19? (Link Only)
2. Beware young spreaders
6. Pandemic hair loss
2. How South Korea Successfully Managed Coronavirus (Link Only)
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A. The Pandemic As Seen Through Headlines
(In no particular order)
- CDC Data Shows High Virus Survival Rate: 99%-Plus for Ages 69 and Younger, 94.6% for Older
- Florida Gov. DeSantis lifts all coronavirus restrictions
- Dr. Fauci: NJ Can Now Reopen ‘Competently’ Amid Coronavirus
- Coronavirus cases in the United States surpassed 7 million less than a month after reaching 6 million
- Scientist warns true global COVID death toll could be twice recorded total
- WHO says ‘Not Impossible’ 2 million could die of COVID-19 before vaccine
- Johnson & Johnson COVID-19 vaccine shows promising results in mid-stage trials
- Novavax Enters Final Stage of Coronavirus Vaccine Trials
- Novavax stock soars after start of late-stage COVID-19 vaccine trial
- With AstraZeneca’s vaccine trial still on pause in US, questions abound about study participants’ mysterious illnesses
- China vaccine test subjects have antibodies 6 months later
- China can produce 1 billion vaccines a year
- CDC says nearly 50% of coronavirus patients did not report their close contacts
- Deborah Birx denies reports she’s leaving COVID-19 task force over ‘diminished’ role
- Researchers found 0.23% of students had confirmed or suspected cases of the virus, while the rate among educators was 0.51%
- Less than 10% of Americans have coronavirus antibodies, a new study finds
- In the U.S., the virus is spreading fastest in the heartland
- ‘I feel sorry for Americans’: The world watches the U.S. response to the virus
- Pharmacies are bracing for a surge in demand for flu shots amid the Covid-19 pandemic
- NYC threatens to shut non-essential businesses in COVID hot spots
- Trump rips Gov. Cuomo over plan to slow-walk a COVID-19 vaccine in New York
- 18 to 22-year-olds banned from gathering in Boulder, Colorado, after coronavirus surge
- United to offer Hawaii-bound passengers coronavirus tests, a possible blueprint for flights abroad
- Argentina’s death rate soars as the virus spreads in provinces far from the capital
- Netherlands posts new case record
- London added to list of COVID hotspots
- Madrid imposes local lockdown on more than 1 million people
- Poland prepares new restrictions
- Madrid braces for possible lockdown
- UK’s Tesco imposes new limits on items like wipes and toilet paper
- Russia, Iran team up for vaccine production
- North Dakota, Wisconsin report records, near-records
- Germany records most new infections since late April
- Orthodox doctor warns High Holy Days ceremonies could fuel COVID-19 outbreak
- As cases surge in Israel, the government imposed new limits on citizens traveling abroad.
- Two former leaders of a Massachusetts veterans’ home were indicted on charges of criminal neglect in connection to the coronavirus deaths of at least 76 residents at their facility.
- For the first time in a century, Brazil’s world-famous carnival parade will be postponed amid concerns about the coronavirus outbreak
- The mayor of Moscow asked older people to stay at home and businesses to move to remote work as cases rise in the city
- London will be made an “area of concern” and could soon be subject to a local lockdown
- The death rate in Argentina is soaring as the virus spreads in provinces far from the capital
- More cases have been announced in Oklahoma over the past week than in any other 7 day stretch of the pandemic (7 day average of 1,133 new cases)
- Tens of thousands of Australians have been stranded abroad after the government limited the number of people allowed on flights into the country
- College students in Scotland were banned from going to bars and restaurants and socializing with other households
- The number of U.S. workers who filed unemployment claims last week rose to 825,000, as layoffs remained high during the pandemic
- NY Gov. Andrew Cuomo said NY will conduct its own review of vaccines, citing concerns that the federal approval process has become politicized
- Women Are Struggling Around the World
- College enrollment in the U.S. dropped by 2.5% from last fall
- NYC Mayor de Blasio makes outdoor dining permanent and ‘year-round’
- De Blasio still has no coronavirus recovery plan for NYC
- A government minister in India became the country’s first high-ranking official to die from the coronavirus.
- Officials in Montana reported 347 new cases, a single-day record for the state
- North Dakota, which reported 9 deaths, has announced more deaths over the past week than in any other seven-day stretch of the pandemic
- Wisconsin parents knowingly sending COVID-infected kids to school
- Maryland man sentenced to prison for throwing parties against COVID-19 orders
- Chancellor Sebastian Kurz of Austria said that while ski resorts would be allowed to open, after-ski gatherings would not be allowed
- Federal Trade Commission said that Americans have lost more than $145 million to fraud related to the coronavirus
- Keeping track of U.S. cases is an enormous task made harder by glitches, delays and outdated equipment
- Three churchgoers arrested for failing to wear masks at Idaho protest
- Immigrants in the U.S. continue to send money home, often more than usual, despite the hardships of the pandemic
- Pharmacies are bracing for a surge in demand for flu shots amid the Covid-19 pandemic
- North Korean troops shot and killed a South Korean official near the border and then burned his body in an apparent attempt to contain the virus
- Choir practice in Spain infects 30 of 41 members with coronavirus
- Saturday is the next chance to take the SAT, but many students can’t get a spot
- The French Open is scaled back as France’s caseload surges
- Google Maps adds COVID-19 tracker to expose hot spots
- Singapore testing out automated COVID-19 ‘SwabBot’
- Indonesia gives free Bali staycations to test tourism readiness
- Florida Gov. wants to protect partying students from punishment amid COVID-19
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
- Total Cases = 32,753,099
- New Cases = 318,804
- New Cases (7 day average) = 284,719 (-549) (-0.2%)
- 2nd highest number of new cases
- 7 day average is approx. 5,000 cases less than peak on 9/19, a decline of approx. 1.5%
- 1,000,000+ cases every 4 days (based on 7 day average)
US Cases & Testing:
- Total Cases = 7,244,184
- New Cases = 53,629
- Percentage of New Global Cases = 16.8%
- New Cases (7 day average) = 41,499 (+295) (+0.7%)
- Total Number of Tests = 102,547,355
- Percentage of positive tests (7 day average) = 5.3%
- 7 day average of new cases has been relatively flat since 7/19 (+/- 0.8%)
- 7 day average is approx. 28,200 cases less than 2nd peak on 7/25, a decline of approx. 40.5%
- Total Deaths = 992,078
- New Deaths = 4,918
- New Deaths (7 day average) = 5,317 (+91) (+1.7%)
- 7 day average of new cases has been relatively flat since 9/19 (+/- 2.5%)
- 7 day average is 604 new cases lower than 2nd peak on 8/13, a decrease of 10.2%
- Total Deaths = 208440,
- New Deaths = 895
- Percentage of Global New Deaths = 18.2%
- New Deaths (7 day average) = 751 (-8) (-1.1%)
- 7 day average of new deaths has been mostly declining since 2nd peak on 8/4, although the average has been relatively flat since 9/22 (+/- 2.8%)
- 7 day average is 527 new deaths less than 2nd peak, a decrease of 36.2%
3. Top 5 States in Cases, Deaths, Hospitalizations & Positivity (9/25)
- New cases of the coronavirus across the U.S. have “plateaued or actually increased a bit over the past two weeks,” said Adm. Brett Giroir, an assistant secretary for health at the Department of Health and Human Services who is in charge of the government’s testing efforts.
- Cases remain down about 35% from the peak earlier this summer, he added, and hospitalizations, the number of patients in intensive care units and Covid-19 deaths all “continue to decrease.”
- Giroir said that about 4.32% of all tests across the country are coming back positive, and that figure continues to decline. That figure’s important, epidemiologists say, because it gives an indication of whether the country’s testing enough and if the virus’ spread is truly slowing.
- Giroir added that the federal government is prioritizing “shielding the elderly” by marshaling testing resources to nursing homes, along with communities experiencing outbreaks.
4. Nationwide C19 Metrics Since April 1, 2020 (9/25)
C. New Scientific Findings & Research
1. Scientists trace severe C19 to faulty genes and an autoimmune condition
- More than 10% of young and healthy people who develop severe C19 have misguided antibodies that attack not the virus, but the immune system itself, new research shows. Another 3.5%, at least, carry a specific kind of genetic mutation.
- In both groups, the upshot is basically the same: The patients lack type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. Whether the proteins have been neutralized by so-called auto-antibodies, or were not produced in sufficient amounts in the first place due to a faulty gene, their missing-in-action appears to be a common theme among a subgroup of C19 sufferers whose disease has thus far been a mystery.
- Published in two papers in Science, the findings help explain why some people develop a disease much more severe than others in their age group–including, for example, individuals who required admission to the ICU despite being in their 20s and free of underlying conditions. They may also provide the first molecular explanation for why more men than women die from the disease.
- “These findings provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening C19,” says Jean-Laurent Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University and a Howard Hughes Medical Institute investigator. “And at least in theory, such interferon problems could be treated with existing medications and interventions.”
Genetics of C19 outliers
- The way coronavirus affects people differently has been puzzling. The virus can cause a symptom-free infection and go away quietly, or it can kill in a few days. Casanova’s research over the past two decades has shown that unusual susceptibility to certain infectious diseases can be traced to single-gene mutations that affect an individual’s immune response.
- Since February, his team and their collaborators have been enrolling thousands of C19 patients to find out whether something in their genetic make-up drives the disparate clinical outcomes the disease produces.
- In one study, the researchers genetically analyzed blood samples from more than 650 patients who had been hospitalized for life-threatening pneumonia due to SARS-CoV-2, 14% of whom had died. They also included samples from another group of over 530 people with asymptomatic or benign infection. They initially searched for differences between the two groups across 13 genes known to be critical for the body’s defense against the influenza virus. These genes govern type I interferons.
- It soon became obvious that a significant number of people with severe disease carried rare variants in these 13 genes, and more than 3% of them were in fact missing a functioning gene. Further experiments showed that immune cells from these patients did not produce any detectable type I interferons in response to the coronavirus.
- Interferons are part of the intrinsic and innate immunity, kicking in before the adaptive immune system mounts an antibody response. They are known to play an important role in immediately heightening the cells’ defenses in response to several viruses. Follow up experiments led by Rockefeller’s Charles M. Rice showed that this is also the case for coronavirus: Human fibroblast cells with mutations affecting the interferon type I pathway were more vulnerable to the virus, and died in higher numbers–and faster–than cells without those mutations.
A mysterious autoimmune condition
- Three other infectious diseases caused by mutations affecting an immune signaling protein can also be caused by auto-antibodies against that protein. So next, the team checked for the possibility of a similar scenario.
- Examining 987 patients with life-threatening C19 pneumonia, they found that more than 10% had auto-antibodies against interferons at the onset of their infection. The majority of them, 95%, were men.
- Biochemical experiments confirmed these auto-antibodies can effectively curb the activity of interferon type I. In some cases, they could be detected in blood samples taken before patients became infected; in others, they were found in the early stages of the infection, before the immune system had the time to mount a response.
- These auto-antibodies seem to be rare in the general population. Out of 1,227 randomly selected healthy people, only four were found to have them.
- “All of these findings strongly indicate that these auto-antibodies are actually the underlying reason some people get very sick, and not the consequence of the infection,” Casanova says.
- The findings point to certain medical interventions to consider for further investigation, Casanova says. For example, there are already two types of interferons available as drugs and approved for use to treat certain conditions such as chronic viral hepatitis.
- The team continues to look for genetic variations that may affect other types of interferons or additional aspects of the immune response in C19 outliers.
2. Falling C19 viral loads may explain lower rates of ICU use, deaths
- The findings of two studies presented at this week’s virtual European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Conference on Coronavirus Disease suggest that patients’ loads of SARS-CoV-2, the virus that causes C19, declined as the pandemic progressed, which may help explain falling rates of coronavirus-related intensive care unit (ICU) use and deaths.
- Both unpublished studies were observational, however, so they cannot determine cause and effect, only highlight the association.
Measuring the progress of the pandemic
- The first study, conducted by Wayne State University researchers in Detroit, involved a retrospective analysis of 708 initial nose-throat swabs from hospitalized coronavirus patients tested from Apr 4 to Jun 5 using reverse transcription polymerase chain reaction (RT-PCR). The goal was to better describe the effects of changing viral loads—which is a measure of virus density—at a population level.
- In the first week of the study, 48.7% of viral loads were characterized as intermediate, versus 25.5% in both the low and high viral load categories. Thereafter, the percentage of high and intermediate loads progressively fell at the same time as the proportion of low viral loads rose.
- Five weeks into the study, 70% of the samples showed a low initial viral load, corresponding to a decrease in the death rate; 45% of patients with high viral loads died, in contrast with 32% in those with intermediate loads and 14% in those with low loads.
- At week 5 the rate of patients with an intermediate load was around 18%, and about 12% had high viral loads. By week 6, no patients had high viral loads.
- The authors concluded that the downward trend in viral load may indicate that the pandemic is becoming less severe, implementation of physical distancing and lockdowns may have decreased overall exposure to the coronavirus, and analyzing viral loads over time may be a good way to assess pandemic progress.
- “Though confounding variables have not been evaluated, this suggests an association between initial viral load and mortality,” they said in an ESCMID press release.
Severity of signs, symptoms
- The second unpublished study, conducted by researchers in Italy, suggests that as pandemic lockdowns in that country began, resulting in lower case numbers, C19 patient viral loads on nose-throat swabs tested by RT-PCR also fell from March to May. The authors said that their findings may account for lower percentages of patients needing intensive care and dying of their infections over time.
- Researchers analyzed data from 373 C19 patients in an emergency department in the northern city of Negrar to assess a possible association between the severity of coronavirus signs and symptoms with viral load as the pandemic transitioned from high to low transmission.
- As patient viral loads declined over the course of the pandemic, the percentage of patients admitted to the ICU declined substantially from March (6.7%) to April (1.1%), and May (0.0%).
- “As the epidemiological context changed from high to low transmission setting, people were presumably exposed to a lower viral load, which has been previously associated with less severe clinical manifestations,” the authors wrote.
3. Temperature and humidity critical to C19 transmission as weather changes
- As C19 cases continue to rise worldwide, it is increasingly urgent to understand how climate impacts the continued spread of the coronavirus, particularly as winter virus infections are more common and countries in the northern hemisphere will soon see cooler temperatures.
- In a paper in Physics of Fluids, by AIP Publishing, researchers studied the effects of relative humidity, environmental temperature, and wind speed on the respiratory cloud and virus viability. They found that a critical factor for the transmission of the infectious particles, which are immersed in respiratory clouds of saliva droplets, is evaporation.
- “Suppose we have a better understanding of the evaporation and its relation to climate effects. In that case, we can more accurately predict the virus concentration and better determine its viability or the potential for virus survival,” said Dimitris Drikakis, one of the authors.
- Despite the importance of airborne droplet transmission, research regarding heat and mass transfer around and within respiratory droplets containing the virus has been scarce.
- To address the challenge, the researchers developed theoretical correlations for the unsteady evaporation of coronavirus-contaminated saliva droplets. They implemented the theory in an advanced computational fluid dynamics platform and studied the effects of weather conditions on airborne virus transmission.
- “We found high temperature and low relative humidity lead to high evaporation rates of saliva-contaminated droplets, thus significantly reducing the virus viability,” said co-author Talib Dbouk.
- Additionally, the researchers observed the travel distance and concentration of the droplet cloud continued to be significant, even at high temperatures if the relative humidity is high. The wind speed is another crucial factor that might alter all the rules for the social distancing guidelines.
- These findings help explain why the pandemic increased during July in different crowded cities around the world, such as Delhi, which experienced both high temperatures and high relative humidity. It also provides a crucial alert for the possibility of a second wave of the pandemic in the coming autumn and winter seasons, where low temperatures and high wind speeds will increase airborne virus survival and transmission.
- This study adds to the growing body of research that reinforces the importance of social distancing and the use of face masks to prevent full virus spread. The results reveal the importance of weather conditions in the virus’s viability, which can help guide the design of measures in both indoor and outdoor environments, to reduce airborne virus transmission in private and public spaces.
4. Why children may be protected from the virus
- Why does the coronavirus terrorize some adults but leave children relatively untouched?
- The vast majority of children do not get sick at all; if they do contract the virus, almost all recover fully. A new study — the first to compare the immune response in children and adults — suggests that in children, a branch of the immune system that evolved to protect people from unfamiliar pathogens quickly destroys the virus before it can damage their bodies.
- When our bodies encounter new germs, they respond with a flurry of immune activity. Children’s bodies typically respond with an innate response that is quick and overwhelming because most pathogens they encounter are new.
- Adult bodies, on the other hand, react in a more specialized and sophisticated way, since it’s rare that they encounter new germs.
- Children and adults have both systems, but the innate response is much stronger in children.
- Our colleague, Apoorva Mandavilli, put it this way: If the strong innate immune response resembles emergency responders first on the scene, the adaptive response represents the skilled specialists at the hospital. In the time it takes for an adult body to get the specialized adaptive system up and running, the virus has had more time to do harm.
Source: New York Times Coronavirus Briefing
5. Early immune response may be why young people get less sick from C19
- One of the lingering questions of the pandemic is why C19 symptoms tend to be milder in children and young adults than in older people. A new study suggests that the immune systems of people younger than 24 deal the coronavirus a strong first punch. Those early immune defenses, which set off alarm bells for the body to go on the attack no matter what the invader, may be weaker in older adults.
- Having more muted frontline defenses could allow an infection with SARS-CoV-2, the virus that causes C19, get a foothold, resulting in worse symptoms for older people, researchers report September 21 in Science Translational Medicine.
- The results add to evidence that boosting early immune responses to the virus with a vaccine or drugs like interferons — which are based on proteins the body produces to stimulate immune cells — could help protect people.
- Researchers have had some ideas why younger people generally get less sick. It’s possible that compared with adults and older kids, younger children have lower amounts of the ACE2 protein in their upper respiratory tracts. That’s a protein that the virus uses to break into cells (SN: 8/4/20). Another explanation could have been that young people have less virus in their bodies, which could mean milder symptoms, although studies have shown that viral load is similar across people no matter their age. Or differences in the immune system, which tends to become less robust with age, could play a role.
- In the new study, pediatric infectious diseases physician and virologist Betsy Herold and colleagues divided 125 C19 patients hospitalized at Montefiore Medical Center in New York City into five categories. People younger than 24 were split into three groups: those with symptoms who did not need a ventilator, those that did need ventilation and a third group that included kids who developed a coronavirus-related inflammatory syndrome that mainly affects children younger than 5 (SN:6/3/20). Adult patients older than 24 fell into two groups: people who needed a ventilator or died and those who recovered.
- When the team compared the immune responses among groups, it found that younger people, including those with the inflammatory syndrome, had higher amounts of an immune signaling molecule called IL-17A than older adults. That protein is typically associated with T cells — immune cells that recognize fragments of specific viruses and can kill infected cells or help activate other parts of the immune system. T cells normally are part of a second wave of defense launched by the immune system.
- But IL-17A is also produced by immune cells from the body’s first line of defense. Both older and younger people had similar numbers of T cells linked to the signaling molecule. That means the abundance of IL-17A seen in young people likely came from immune cells tied to the body’s early defenses against the virus, the researchers suggest.
- Compared with adults who had severe C19, younger patients who did not need a ventilator also had lower levels of other immune signaling proteins involved in inflammation, like one called IL-6 that has been linked to an overactive immune response. That overreaction is responsible for severe symptoms in many of the sickest C19 patients.
- One potential issue with the study is that the results weren’t adjusted for underlying conditions, says Mark Slifka, a viral immunologist at Oregon Health & Science University in Portland. Adults in the study were more likely to have high-risk conditions like diabetes and high blood pressure, which could help explain the differences in disease compared with younger people (SN: 3/20/20).
- Older adults did ultimately mount a stronger virus-specific immune response later in infection, compared with younger people. How helpful that response actually is remains unknown. Older adults, especially those on a ventilator or who had died, had a stronger response of T cells that recognized a protein on the virus’ surface, called the spike, compared with younger people. People older than 24 also made more antibodies that prevent the virus from infecting new cells, called neutralizing antibodies.
- “It’s not that [adults] can’t make a neutralizing antibody response,” says Herold, of the Albert Einstein College of Medicine and the Children’s Hospital at Montefiore in New York City. “It’s not that they can’t make a good T cell response. Maybe they make too much of [a late immune response] or a dysregulated one.”
- The fact that severely ill adults had more T cells than younger people is interesting, Slifka says, in part because the role those immune cells have in C19 is still unclear (SN: 5/15/20). In the study, a high T cell response wasn’t associated with mild disease, hinting that those responses weren’t necessarily protective, Slifka says. But studies need to be done with more patients to know for sure. “We’re still trying to figure out if T cells play a role in protection,” he says.
D. Vaccines & Testing
1. In the race for a C19 vaccine, slow starters could still win out
- The race is not always to the swift, as the cocky hare learned in Aesop’s classic fable, “The Hare and the Tortoise.” Those handicapping the so-called competition to develop C19 vaccines would do well to keep an eye on the slower runners in this pursuit.
- Corporate giants Sanofi and Merck, which got a relatively late start in developing C19 vaccines, may seem far behind the frontrunners. But experts say they also have such deep experience developing and testing vaccine candidates, and producing vaccine at commercial scale, that both could well close the gap considerably in the months ahead.
- Each is developing two vaccines, in partnership with others.
- Saad Omer, a vaccinologist and director of the Yale Institute for Global Health, noted that some companies closer to the front of the pack lack Sanofi’s competitive advantages.
- Cambridge, Mass.-based Moderna, for instance, has not yet brought a vaccine through the approval process and is now attempting to produce doses of a C19 vaccine at a massive scale. It estimates it should be able to make between 500 million and 1 billion doses a year — an output target that would be daunting to even a seasoned manufacturer.
- “Would you rather have … a company that has done scaled-up manufacturing under strict regulations and has substantial muscle memory of doing that?” Omer wondered, speaking about the appeal of a vaccine veteran. “That gives you some reassurance.”
- Robin Robinson, the former head of the Biomedical Advanced Research and Development Authority, similarly noted that Merck, with its large global footprint, has experience conducting clinical trials around the world and significant manufacturing know-how.
- “They can move fast,” he said.
- A vaccine being produced by Pfizer in partnership with BioNTech appears poised to be the first to produce data that will show if it protects against C19 infection. Moderna appears to be a close second, followed by a vaccine being developed by University of Oxford and AstraZeneca — the study of which is still on hold in the United States because of an adverse event in Britain — and Johnson & Johnson, which started its Phase 3 trial this week. Novavax, which also has yet to bring a vaccine to market, is currently running Phase 2 trials.
- Sanofi and Merck are behind this group of five. But the race for a vaccine is not a winner-take-all situation. The world is expected to need vaccines from any number of manufacturers to curb the C19 pandemic, and it’s likely that some that aren’t among the first to cross the finish line will have advantages the earliest vaccines do not.
- “The best outcome for us is to have several across the finish line because the global need is tremendous,” said Luciana Borio, a former acting chief scientist at the Food and Drug Administration who is now vice president at In-Q-Tel, a not-for-profit investment group.
- “Speed is just one parameter. And actually in the global scheme, it’s not the most important one,” said Borio, who stressed the need for safe and effective C19 vaccines.
- Sanofi and Merck are both known to prefer underpromising and overdelivering.
- “We’re not a flashy, you know, press-release-everyday kind of company,” said Nicholas Kartsonis, who leads infectious disease clinical research for Merck Research Laboratories.
- “We tend to be more conservative for our positions because we know the complexities and the challenges, especially for making vaccines,” said John Shiver, head of vaccine R&D for Sanofi.
- Shiver initially estimated that it would take “several years” to develop and license a C19 vaccine during a meeting with President Trump and other vaccine manufacturers at the White House in March. Trump appeared more taken with Moderna CEO Stéphane Bancel’s projection that his company could generate clinical efficacy data for a vaccine in mere months.
- Moderna, along with Pfizer and BioNTech, are making messenger-RNA vaccines, which are far quicker to develop in the early stages than some of the more established vaccine constructs. While there is hope that with that great speed, mRNA vaccines will be the answer to newly emerging diseases in future, some experts question whether the technology is ready for a prime-time debut now. Much rides on how well the vaccines stimulate the immune system and how durable that effect is.
- “In terms of making billions of doses, we’re probably a little premature for that to be as cheap and available at some of the other approaches,” philanthropist Bill Gates, whose Bill and Melinda Gates Foundation funded the science behind the RNA vaccine platform, told STAT in a recent interview.
- “Five to 10 years from now, if things go well for that platform, it would be the primary and perhaps even the only response that we make here. So that timing’s a bit unfortunate,” Gates said.
- One of Sanofi’s C19 candidates is an mRNA vaccine, which it is developing with Translate Bio, a Lexington, Mass.-based biotech that has been developing therapeutics using mRNA. The company has a decade’s worth of experience learning how to manufacture mRNA to substantial scale, Shiver said, adding the partners believe they can make between 90 million and 360 million doses of this two-dose vaccine in 2021.
- “The mRNA, for example, is a very interesting technology. That’s one of the reasons why we’re also pursuing that with a partner. But there are no licensed products with mRNA. No one’s ever made hundreds of millions of doses either before,” he noted, adding the Phase 1/2 trial for this vaccine is expected to start by the end of November.
- Shiver said the earliest the vaccine might be approved — if it’s proven safe and effective — would be the second half of 2021.
- Sanofi’s other vaccine is being developed using the same platform the company uses to make its Flublok vaccine. That’s a plus: There’s always a greater degree of comfort and confidence on the part of regulatory agencies when a vaccine is made using a platform that they are familiar with and that has an established safety record.
- (Likewise, by the time Sanofi has data on its mRNA vaccine, it may be able to benefit from the regulatory agencies’ evaluations of Moderna’s and Pfizer’s vaccines, Omer noted.)
- This Sanofi vaccine, called a recombinant protein vaccine, will be used with an adjuvant — a compound that boosts the immune system’s response — made by GSK.
- A Phase 1/2 clinical trial — involving 440 subjects, large for an early trial — is already underway. Shiver said the company expects to have safety and immunogenicity data by the end of December. It also expects to have 100 million doses of the vaccine made by then — should the Food and Drug Administration start to issue emergency use authorizations for C19 vaccines.
- Shiver said Sanofi expects to be able to produce 1 billion doses of this vaccine in 2021. The vaccine is likely to require two doses — though the company is also testing a single dose.
- Another advantage: This vaccine does not need to be shipped and stored at the ultra-cold temperatures of the mRNA vaccines, which makes distribution and administration easier.
- One of the Merck vaccines is also being made using a platform that regulatory agencies already know. The vaccine is made by fusing genetic material from the SARS-CoV-2 virus, which causes C19, onto a livestock virus that can infect people but does not sicken them. The vesicular stomatitis virus, or VSV, backbone triggers a rapid and robust immune response — and all research on the backbone to date shows it does it with a single dose.
- It’s the same platform that was used to develop Merck’s Ebola vaccine, which has shown strong results. It has “not good and not very good, but outstanding efficacy” said Robinson, the former head of BARDA.
- Merck is developing this vaccine in conjunction with IAVI — the International AIDS Vaccine Initiative — which is run by former Merck chief scientist Mark Feinberg.
- Kartsonis noted Merck’s Ebola vaccine worked as well in the elderly as it did in young, healthy adults. That’s not a common feature of vaccines, and if the same is true for a VSV-vectored Covid vaccine, that would be a big selling point — given the elderly are at the highest risk from SARS-2. “There may be scenarios where this is a great vaccine for the elderly or a great vaccine for certain patient populations,” Kartsonis said.
- Another potential plus: IAVI is working to see if the vaccine could be given orally. A vaccine that doesn’t need to be injected “would be the crown jewel of having a vaccine for this,” Kartsonis said.
- This vaccine is not yet in clinical trials, though Merck expects to start them before the end of the year. The company said it is too soon to say when Phase 3 studies — the large studies that show if a vaccine works — could take place.
- The second vaccine that Merck is making — in collaboration with its newly acquired subsidiary, Austrian-based Themis BioScience — is already in clinical trials. It uses an attenuated (weakened) measles virus as a vector with which to introduce genetic material from SARS-2 to the immune system. There are no licensed vaccines using this backbone, but clinical trials of a chikungunya virus vaccine using this approach show promise.
- “Timing is important. Don’t get me wrong. It’s very important. But at the end of the day where we all want is a vaccine that highly effective, highly well tolerated and safe and is as durable as it can be,” Kartsonis said.
- He and Shiver both expressed the hope that multiple vaccines will work and that others are approved before their companies’ products are ready for use. But both expressed a fair amount of confidence that as the C19 market establishes itself, there will be some vaccines that perform better than others.
- “The race has started. But I mean, how many marathon runners do you know in mile 1 win a race?” Kartsonis asked.
- With other diseases, being fourth or fifth (or sixth or seventh) to market might make pursuit of a vaccine, even if promising, financially infeasible. But the global need for C19 vaccine has introduced a whole new type of calculus to these considerations, said Omer.
- “It’s not necessarily that the first vaccine is the one that establishes the market share,” he said. “Because the pie is so big.”
E. Improved & Potential Treatments
1. The spike protein on C19 interferes with pain perception and could lead to new pain treatments
- Imagine being infected with a deadly virus that makes you impervious to pain. By the time you realize you are infected, it’s already too late. You have spread it far and wide. Recent findings in my lab suggest that this scenario may be one reason that people infected with the coronavirus may be spreading the disease without knowing it.
- Most accounts to date have focused on how the virus invades cells via the ACE2 protein on the surface of many cells. But recent studies, which have not yet been peer-reviewed, suggest there is another route to infecting the cell that enables it to infect the nervous system. This led my research group to uncover a link between a particular cellular protein and pain – an interaction that is disrupted by the coronavirus. Our research has now been peer-reviewed and will be published in the journal PAIN.
- I am a scientist who studies how proteins on cells trigger pain signals that are transmitted through the body to the brain. When these proteins are active, the nerve cells are talking to each other. This conversation occurs at deafening levels in chronic pain. So by studying what causes the excitability of nerve cells to change, we can begin to unravel how chronic pain becomes established. This also allows us to design ways to mute this conversation to blunt or stop chronic pain.
- My laboratory has a longstanding interest in designing nonopioid-based alternatives for pain management.
Linking coronavirus and pain
- You might be wondering how my lab began to probe the connection between the coronavirus and pain. We were inspired by two preliminary reports that appeared on the preprint server BioRxiv that showed that the infamous spike proteins on the surface of the coronavirus bound to a protein called neuropilin-1. This means that the virus can also use this protein to invade nerve cells as well as through the ACE2 protein.
- For the past year, some six months before the pandemic took hold, my colleagues and I had been studying the role of neuropilin-1 in the context of pain perception. Because neuropilin-1, like the ACE2 receptor, allowed spike to enter the cells, we wondered if this alternate gateway could also be related to pain.
- Under normal circumstances, the neuropilin-1 protein controls the growth of blood vessels, and as well as the growth and survival of neurons.
- However, when neuropilin-1 binds to a naturally occurring protein called called Vascular endothelial growth factor A (VEGF-A), this triggers pain signals. This signal is transmitted via the spinal cord into higher brain centers to cause the sensation we all know as pain.
- Staring at this jigsaw puzzle – neuropilin-1 and VEGF-A and neuropilin and spike – we wondered if there was a link between spike and pain.
- Previous research has shown a link between VEGF-A and pain. For people with osteoarthritis, for instance, studies have shown that increased activity of the VEGF gene in fluids lubricating joints, like the knee, is associated with higher pain scores.
- Although activity of the neuropilin-1 gene is higher in biological samples from C19 patients compared to healthy controls and activity of the neuropilin-1 gene is increased in pain-sensing neurons in an animal model of chronic pain, the role of neuropilin-1 in pain has never been explored until now.
- In in vitro studies done in my lab using nerve cells, we showed that when spike binds to neuropilin-1 it decreases pain signaling, which suggests that in a living animal it would also have a pain-dulling effect.
- When the spike protein binds to the neuropilin-1 protein, it blocks the VEGF-A protein from binding and thus hijack’s a cell’s pain circuitry. This binding suppresses the excitability of pain neurons, leading to lower sensitivity to pain.
- Crystal structure of neuropilin-1 b1 domain (white surface with binding site in red) showing binding of VEGF-A (left), spike protein (middle), and the neuropilin-1 inhibitor EG00229 (right).
From the C19 fog a new pain target emerges
- If our finding that the new coronavirus is attacking cells through a protein associated with pain and disabling the protein can be confirmed in humans, it may provide a new pathway for drug development to treat C19.
- A small molecule, called EG00229, targeting neuropilin-1 had been reported in a 2018 study. This molecule binds to the same region of the neuropilin-1 protein as the viral spike protein and VEGF-A. So I and my colleagues asked if this molecule was able to block pain. It did, during pain simulations in rats. Our data reaffirmed the notion of neuropilin-1 as a new player in pain signaling.
- There is precedence for targeting the neuropilin-1 protein for cancer treatment: for example, a Phase 1a clinical trial of an antibody called MNRP1685A (known under the product name Vesencumab) that recognizes and binds to neuropilin-1 and blocks VEGF-binding. This was mostly well tolerated in cancer patients, but it caused pain rather than blocking it.
- Our studies identify a different approach because we targeted blocking the pain-triggering VEGF-A protein, which then resulted in pain relief. So our preclinical work described here provides a rationale for targeting the VEGF-A/NRP-1 pro-pain signaling system in future clinical trials.
- Analysis of the structure of the neuropilin-1 receptor protein may allow design of drugs targeting this critical site which also controls axon growth, cell survival – in addition to pain relief.
- For instance, these neuropilin-1 receptor targeted drugs could potentially block viral infection. The testing of several candidate compounds, some of them on the FDA’s generally regarded as safe list, is currently underway by my group.
- Sneaky virus, fooling people into believing that they do not have C19. But, ironically, it may be gifting us with the knowledge of a new protein, critical for pain. Two roads emerge in the forest ahead: (1) block neuropilin-1 to limit coronavirus entry, and (2) block neuropilin-1 to block pain.
F. Concerns & Unknowns
1. C19 mutation may be evolving to bypass mask-wearing, hand-washing
- Scientists in Houston on Wednesday released a study of more than 5,000 genetic sequences of the coronavirus that reveals the virus’s continual accumulation of mutations, one of which may have made it more contagious.
- The new report, however, did not find that these mutations have made the virus deadlier or changed clinical outcomes. All viruses accumulate genetic mutations, and most are insignificant, scientists say.
- Coronaviruses such as SARS-CoV-2 are relatively stable as viruses go, because they have a proofreading mechanism as they replicate. But every mutation is a roll of the dice, and with transmission so widespread in the United States — which continues to see tens of thousands of new, confirmed infections daily — the virus has had abundant opportunities to change, potentially with troublesome consequences, said study author James Musser of Houston Methodist Hospital.
- “We have given this virus a lot of chances,” Musser told The Washington Post. “There is a huge population size out there right now.”
- The new study, which has not been peer-reviewed, was posted Wednesday on the preprint server MedRxiv. It appears to be the largest single aggregation of genetic sequences of the virus in the United States thus far. A larger batch of sequences was published earlier this month by scientists in the United Kingdom, and, like the Houston study, concluded that a mutation that changes the structure of the “spike protein” on the surface of the virus may be driving the outsized spread of that particular strain.
- David Morens, a virologist at the National Institute of Allergy and Infectious Diseases, reviewed the new study and said the findings point to the strong possibility that the virus, as it has moved through the population, has become more transmissible, and that this “may have implications for our ability to control it.”
- Morens noted that this is a single study, and “you don’t want to over-interpret what this means.” But the virus, he said, could potentially be responding — through random mutations — to such interventions as mask-wearing and social distancing, Morens said Wednesday.
- “Wearing masks, washing our hands, all those things are barriers to transmissibility, or contagion, but as the virus becomes more contagious it statistically is better at getting around those barriers,” said Morens, senior adviser to Anthony S. Fauci, the director of the NIAID.
- This has implications for the formulation of vaccines, Morens said. As people gain immunity, either through infections or a vaccine, the virus could be under selective pressure to evade the human immune response.
- “Although we don’t know yet, it is well within the realm of possibility that this coronavirus, when our population-level immunity gets high enough, this coronavirus will find a way to get around our immunity,” Morens said. “If that happened, we’d be in the same situation as with flu. We’ll have to chase the virus and, as it mutates, we’ll have to tinker with our vaccine.”
- Peter Thielen, a molecular biologist at the Johns Hopkins University Applied Physics Laboratory, said scientists will need to continue studying the virus to see whether the new mutations identified by the Houston researchers change the “fitness” of the virus, “and if SARS-CoV-2 transmissibility is truly increased as a result of these mutations.”
- Another scientist who has studied the coronavirus, Jeremy Luban, a virologist at the University of Massachusetts Medical School, said in an email Wednesday that “the Houston paper highlights the fact that, with respect to SARS-CoV-2, we need to remain vigilant, and increase our capacity to monitor the virus for mutations.”
- At Houston Methodist, whose main hospital is part of the Texas Medical Center in central Houston but also includes hospitals around the city, scientists have been sequencing the 30,000-character genome of the coronavirus since early March, when the virus first appears to have arrived in the metropolitan area of 7 million. The paper documents 5,085 sequences.
- The research shows that the virus disseminated across Houston neighborhoods in two waves, first striking wealthier and older individuals but then spreading, in the second wave, to younger people and lower-income neighborhoods — affecting many Latino city residents.
- At the same time, as the virus spread Zip code by Zip code, it also compiled a catalogue of mutations, many affecting the spike protein. That structure on the surface of the virus, which resembles a tree decked with curled ribbons, enables the virus to enter cells.
- The genetic data shows the virus arrived in Houston many separate times, presumably at first by air travel. Notably, 71 percent of the viruses that arrived initially were characterized by a now famous mutation, which appears to have first originated in China, that scientists increasingly suspect may give the virus a biological advantage in how it spreads. It is called D614G, referring to the substitution of an amino acid called aspartic acid (D) for one called glycine (G) in a region of the genome that encodes the spike protein.
- By the second wave of the outbreak in Houston, the study found that this variant had leaped to 99.9 percent prevalence — completing its domination of the outbreak. The researchers found that people infected with the strain had higher loads of virus in their upper respiratory tracts, a potential factor in making the strain spread more effectively.
- Kristian Andersen, an immunologist at the Scripps Research Institute in California, who was not involved in the new research, downplayed the significance of the new study. He said it “just confirms what has already been described — G increased in frequency over time.” As for the numerous other mutations the study finds, “they just catalogue them, but we don’t know if any of them have any functional relevance.”
- Musser said his interpretation is that D614G has been increasingly dominant in Houston and other areas because it is better adapted to spreading among humans. He acknowledged that the scientific case is not closed on this matter.
- “This isn’t a murder trial,” Musser said. “We’re not looking for beyond a reasonable doubt. This is a civil trial, and clearly, it’s the preponderance of the evidence that I think forces all of us into the same conclusion, which is there’s something biologically different about that strain, that family of strains.”
- Recently, the even larger study of the spread of the coronavirus in the United Kingdom, based on some 25,000 genomes, also found evidence that this variant of the virus outdistances its competitors “in a manner consistent with a selective advantage.”
- In general, scientists would expect natural selection to favor mutations that help the virus spread more effectively — since that allows it to make more copies of itself — but not necessarily ones that make it more virulent. Killing or incapacitating the host would generally not help the virus spread to more people.
- The study found 285 separate mutation sites that change a physical building block of the spike protein, which is the most important part of the coronavirus in the sense that it is what allows it to infect and harm humans. Forty-nine of the changes at these sites had not been seen before in other genomes sequenced around the world.
- The study characterizes some of the spike protein mutations as “disconcerting.” While the paper does not present strong proof that any additional evolution of the spike protein is occurring, it suggests that these repeated substitutions provide a hint that, as the virus interacts with our bodies and our immune systems, it may be learning new tricks that help it respond to its host.
- “I think there’s pretty good evidence that’s consistent with immunologic selection acting on certain regions of the spike protein,” Musser said.
- The actual mutations in the virus occur randomly as it makes mistakes trying to copy its genome within our cells. But every new case gives a chance for more mutations to occur, which in turn increases the chance that one of these mutations will be useful to the virus, just as D614G apparently already has been.
- Given the changes that are already occurring to the genetic code of the virus, one key conclusion of Musser’s is that we are not sequencing it nearly enough if we want to be able to anticipate what the virus will do next.
- While some large metropolitan areas in the United States, such as Seattle and Boston, are also doing a great deal of sequencing, the country as a whole is missing many areas — and many potential virus variants, as a result. Even in Houston, the study estimates that only about 10% of known coronavirus cases have been sequenced.
- “I think we need to be doing this pretty aggressively in multiple locations on a real-time basis,” Musser said. “I think it’s shameful that we’re not doing that.”
2. Beware young spreaders
- Young adults make up a growing percentage of coronavirus cases in the United States and Europe, and early indications are that they tend to fare better with the disease, suffering fewer deaths and hospitalizations. But the story doesn’t end there.
- New research from the CDC found that young adults who catch the virus may seed waves of infection that travel up the generations, infecting middle-aged and then older people. The new data suggests that outbreaks linked to bars, restaurants and college dorms aren’t just dangerous for the 20-somethings — but for their friends, families and neighbors as well.
- After analyzing case data and hospital visits this summer, C.D.C. researchers concluded that spikes in cases among young people were often quickly followed by a jump in infections in older people. In Southern states like Alabama, Florida and Georgia, a spike in cases among those ages 20 to 39 led to a jump in cases 9 days later among those ages 40 to 59, followed by a jump in cases 15 days later among those 60 and older.
- College campuses are a particular threat. In a recent study, researchers found that spikes in cases occurred about two weeks after colleges reopened, with a higher increase for those adopting in-person models than those teaching online.
- A similar pattern also seems to be emerging in Europe, where infections “are moving up the age bands, from younger people to older people,” according to Chris Whitty, the U.K.’s chief medical officer.
Source: New York Times Coronavirus Briefing
3. Coronavirus is spreading among young Americans at an alarming rate
- A fresh analysis of age-based statistics offers solid evidence that C19 is becoming more widespread among young Americans.
- According to data released by the U.S. Centers for Disease Control and Prevention on Sept. 23, children and adults under 30 accounted for more than a third of all C19 cases reported in the U.S. in July and August. That’s up from around 16% in January through April.
- The trend is particularly stark among people in their 20s, who made up more than 20% of reported cases in recent months, a higher number than any other age group. Though younger people are less likely to develop severe coronavirus symptoms, this is yet another signal that those of all age groups need to follow guidelines like social distancing and wearing face coverings if we want to tamp down the pandemic.
- In addition, the data show that the growth rate of new cases among younger people recently accelerated: the monthly case count more than doubled for kids, teens and 20-somethings over the summer. For instance, there were 189,000 cases among 20-year-olds in August—a nearly 100,000 increase from May. In contrast, the month-by-month case numbers didn’t increase dramatically among elderly groups, and actually decreased among those older than 80.
- The CDC’s report affirms that the age demographics of C19, on a national level, continue to skew younger as the pandemic progresses. In August, the most recent month presented in the report, the median age of C19 cases stood at 38. Earlier in the pandemic, the median age was 48, according to previously published data from the agency.
- The reason for the shifting case loads is likely due to a variety of factors. Outbreaks at colleges and universities may be one. But testing among younger people has expanded as well, particularly as schools and workplaces are requiring C19 tests to contain the virus on their premises. More testing of this group is exposing cases, both symptomatic and asymptomatic, that would otherwise not get tallied.
- Despite their growing share of cases, younger people still appear less likely to get severely ill from C19, and the vast majority of deaths related to C19 have consistently been adults 65 and older.
- But to contain a viral pandemic, even those unlikely to get critical symptoms need to follow public health measures to prevent the virus from spreading—especially to those who are at higher risk, in this case parents, grandparents and other older adults in young people’s lives.
4. Battle Rages Inside Hospitals Over How COVID Strikes and Kills
- Front-line health care workers are locked in a heated dispute with many infection control specialists and hospital administrators over how the novel coronavirus is spread ― and therefore, what level of protective gear is appropriate.
- At issue is the degree to which the virus is airborne ― capable of spreading through tiny aerosol particles lingering in the air ― or primarily transmitted through large, faster-falling droplets from, say, a sneeze or cough. This wonky, seemingly semantic debate has a real-world impact on what sort of protective measures health care companies need to take to protect their patients and workers.
- The CDC injected confusion into the debate Friday with guidance putting new emphasis on airborne transmission and saying the tiny aerosol particles, as well as larger droplets, are the “main way the virus spreads.” By Monday that language was gone from its website, and the agency explained that it had posted a “draft version of proposed changes” in error and that experts were still working on updating “recommendations regarding airborne transmission.”
- Dr. Anthony Fauci, the top U.S. infectious disease expert, addressed the debate head-on in a Sept. 10 webcast for the Harvard Medical School, pointing to scientists specializing in aerosols who argued the CDC had “really gotten it wrong over many, many years.”
- “Bottom line is, there’s much more aerosol [transmission] than we thought,” Fauci said.
- The topic has been deeply divisive within hospitals, largely because the question of whether an illness spreads by droplets or aerosols drives two different sets of protective practices, touching on everything from airflow within hospital wards to patient isolation to choices of protective gear. Enhanced protections would be expensive and disruptive to a number of industries, but particularly to hospitals, which have fought to keep lower-level “droplet” protections in place.
- The hospital administrators and epidemiologists who argue that the virus is mostly droplet-spread cite studies that show it spreads to a small number of people, like a cold or flu. Therefore, N95 respirators and strict patient isolation practices aren’t necessary for routine care of C19 patients, those officials say.
- On the other side are many occupational safety experts, aerosol scientists, front-line health care workers and their unions, who are quick to note that the novel coronavirus is far deadlier than the flu ― and argue that the science suggests that high-quality, and costlier, N95 respirators should be required for routine C19 patient care.
- The highly protective respirators have been in short supply nationwide and have soared in price, from about $1 to $7 each. Meanwhile, research has shown high rates of asymptomatic virus transmission, putting N95s in high demand among front-line health care workers in virtually every setting.
- The debate has come to a head at hospitals from coast to coast, as studies have emerged showing that live virus hangs in C19 patients’ hospital rooms even in the absence of “aerosol-generating” procedures (such as intubations or breathing treatments) and has contributed to outbreaks at a nursing home, shuttle bus and choir practice.
- KHN and The Guardian U.S. are examining more than 1,200 health care worker deaths from C19, including many in which their family or colleagues reported they worked with inadequate personal protective gear.
- Yet some front-line workers and managers disagree about exactly how and why health care workers are getting sick.
- The hospital infection-control and epidemiology leaders cite studies suggesting that many health care workers are contracting the virus outside of work and at rates that mirror what’s happening in their communities.
- A group of Penn Medicine epidemiologists in late July characterized research on aerosol transmission as unconvincing and cited “extensive published evidence from across the globe” showing the “overwhelming majority” of coronavirus spread is “via large respiratory droplets.”
- Unions, occupational health researchers and aerosol scientists, though, reference another pile of studies showing health care workers have been hit far harder than average people ― and a study that showed active viral particles can drift in the air up to 15 feet from a patient in a hospital room. Such particles can hang in the air for up to three hours.
- Backing their concerns, a July 6 letter signed by 239 scientists urged the medical community and World Health Organization to recognize “the potential for airborne spread of C19.”
- The letter pointed to studies that say talking, exhaling and coughing emit tiny particles that remain suspended in the air far longer than droplets and “pose a risk of exposure.”
- In one ward of a Dutch nursing home with recirculated air, researchers found that 81% of the residents were diagnosed with C19. Half of the workers on the ward ― who all wore surgical masks during patient care but not during breaks ― also tested positive for the virus.
- Although researchers couldn’t exclude transmission by another method, the “near-simultaneous detection” of the virus among nearly all the residents pointed to aerosol spread.
- The idea that the virus is spread by either droplets or aerosols is an oversimplification, said Dr. Shruti Gohil, associate medical director of epidemiology and infection prevention at the University of California-Irvine School of Medicine.
- Gohil said it’s more of a spectrum, with the virus being transmitted by some droplets and some large aerosol particles as well.
- One metric people in the hospital infection-control field focus on, though, is how many people one sick person infects. For C19, research has shown that the number is about two ― similar to a cold or the flu. For an unequivocally airborne disease like measles, the number is closer to 12 to 18.
- Measles is “what airborne [transmission] looks like,” Gohil said. “If this was truly a primary aerosol-transmissible disease, we’d be in a world of hurt.”
- Hospital epidemiologists are also focused on the rate of household spread of the novel coronavirus. With the measles, the risk of an unvaccinated member of a household getting sick is 85%, said Dr. Rachael Lee, a hospital epidemiologist and assistant professor at the University of Alabama-Birmingham. For C19, she said, the risk is closer to 10%.
- Though the virus is believed to be spread more by droplets than aerosol particles, Lee said, staffers at UAB University Hospital wear an N95 respirator for an extra layer of protection and because the patients require so many breathing treatments or procedures considered “aerosol-generating.”
- Such practices are not universal. At the University of Iowa’s hospital, health care workers use N95s and face shields for aerosol-generating procedures but otherwise use surgical masks and face shields for routine care of COVID patients, said Dr. Daniel Diekema, director of the division of infectious diseases at the university.
- He said such “enhanced droplet precautions” are working. Places where workers are correctly using regular medical masks and face shields are finding no significant spread of the disease among staffers, although one such report focused on the spread from a single patient.
- Elsewhere, patients have also been safe on floors where C19 patients and those without the virus have been placed in adjacent rooms ― a practice those concerned about aerosol spread do not endorse.
- “It’s not an airborne disease the way measles or tuberculosis is,” said Dr. Shira Doron, an epidemiologist at Tufts Medical Center in Boston and an assistant professor at Tufts medical school. “We know because we don’t see outbreaks that affect multiple patients on a floor.”
Origin of the Debate
- The CDC helped set the stage for the current debate. In March, the agency issued revised guidance essentially saying it was “acceptable” for health care workers to use surgical masks ― instead of N95s ― for routine care. The guidance said respiratory droplets were the most likely source of transmission and recommended N95s only for aerosol-generating procedures.
- “The contribution of small respirable particles, sometimes called aerosols or droplet nuclei, to close proximity transmission is currently uncertain. However, airborne transmission from person-to-person over long distances is unlikely,” according to the guidance.
- The California Hospital Association sent a letter to the state’s congressional delegation urging the revised guidance be made permanent.
- “We need the CDC to clearly, not conditionally, move from airborne to droplet precautions for patients and health care workers,” the letter said. Doing so would enable hospitals to preserve PPE supplies and limit the use of special isolation rooms for COVID patients.
- An association spokesperson told KHN that the group wasn’t weighing in on the science, merely pressing for clarity of the rules.
- Christopher Friese, professor of nursing, health management and policy at the University of Michigan, is among the experts who think those rules have endangered health care workers.
- “We lost a tremendous amount of time and, candidly, lives because the early guidance was to wear N95s only for those specific procedures,” Friese said.
- Family members and union leaders from Missouri to Michigan to California have raised concerns about nurses dying of C19 after caring for virus patients without N95 respirators. In such cases, hospitals have said they followed CDC guidance.
- Friese echoed some occupational safety experts who suggested stronger guidance from the CDC early on calling the disease airborne might have had an impact ― perhaps pressuring President Donald Trump to invoke the Defense Production Act to boost supplies of N95s so “we might have the supply we need everywhere we need,” Friese said.
- Surveys across the country show there’s still a shortage of personal protective equipment at many health care facilities.
- The CDC guidance posted Friday would have put pressure on some hospitals to bolster their protective measures, something they have reportedly resisted. It said the virus can spread when a person sings, talks or breathes.
- “These particles can be inhaled into the nose, mouth, airways, and lungs and cause infection,” the site said. “This is thought to be the main way the virus spreads.”
- By Monday morning, the website was back to saying the virus mainly spreads through droplets, noting that draft language had been posted in error.
- The University of Nebraska Medical Center has been taking so-called airborne precautions from the start. There, Dr. James Lawler, a physician and director of the Global Center for Health Security at the university, said his colleagues documented that the virus can drift in the air and live on surfaces at an extensive distance from patients.
- He said the hospital tests all admitted patients for the virus and keeps C19 patients apart from the general population. He said they pay close attention to cleaning shared spaces and monitoring airflow within the restricted-access unit. Workers also had N95 respirators or PAPRS, which are fitted hoods with filtered air pumped in.
- All of it has added up to a “very low” rate of health care worker infections.
- Amid uncertainty about the virus, and as an unprecedented number of health care workers are dying, adopting the “highest possible” forms of protection seems the best course, said Betsy Marville, nurse organizer for the 1199SEIU United Healthcare Workers East union in Florida.
- That would mean a departure from CDC guidelines that now say health care workers need an N95 respirator only for “aerosol-generating” procedures, like intubations or other breathing treatments. She said the rule has left the nurses she represents in Florida scrambling for protective gear ― or unprotected ― when patients need such treatments urgently.
- “You don’t leave your patient in distress and go looking for a mask,” she said. “That’s crazy.”
5. Hidden immune weakness found in 14% of gravely ill COVID-19 patients
“At least 10% of critical C19 is an autoimmune attack.” — Jean-Laurent Casanova, Rockefeller University
- From the first months of the C19 pandemic, scientists baffled by the disease’s ferocity have wondered whether the body’s vanguard virus fighter, a molecular messenger called type I interferon, is missing in action in some severe cases. Two papers published online in Science this week confirm that suspicion. They reveal that in a significant minority of patients with serious C19, the interferon response has been crippled by genetic flaws or by rogue antibodies that attack interferon itself.
- “Together these two papers explain nearly 14% of severe C19 cases. That is quite amazing,” says Qiang Pan- Hammarström, an immunologist at the Karolinska Institute.
- Tadatsugu Taniguchi, a pioneering interferon scientist and emeritus professor at the University of Tokyo, calls the discoveries “remarkable.” He says they highlight the “critical” role of type I interferons in SARS-CoV-2 infection and the development of potentially lethal C19.
- Co-author Isabelle Meyts, a pediatric immunologist at the University Hospitals Leuven, was struck by one paper’s finding that rogue antibodies underlie C19 in 10% of gravely ill patients: “There has never been any infectious disease explained at this level by a factor in the human body. And it’s not an isolated cohort of Europeans. Patients are from all over the world, all ethnicities.” Another finding, that 94% of the patients with interferon-attacking antibodies were male, also helps explain why men face higher risk of severe disease.
- The paired studies have immediate practical implications. Synthetic interferons, long used to treat other diseases, might help some at-risk patients, as might other therapies aimed at removing the damaging antibodies. A common kind of antibody test could be readily developed and return answers in hours. Those found to be at high risk of developing severe C19 could take precautions to avoid exposure or be prioritized for vaccination, says Elina Zuniga, an immunologist who studies interferons at the University of California, San Diego.
- The findings also raise a red flag for plasma donations from recovered patients. Because it may be rich in antibodies to the virus, “convalescent plasma” is already given to some patients to fight the infection. But some donations could harbor the interferon-neutralizing antibodies. “You should eliminate these patients from the pool of donors,” Zuniga says. “You definitely don’t want to be transferring these autoantibodies into another person.”
- Type I interferons are made by every cell in the body and are vital leaders of the antiviral battle early in infection. They launch an immediate, intense local response when a virus invades a cell, triggering infected cells to produce proteins that attack the virus. They also summon immune cells to the site and alert uninfected neighboring cells to prepare their own defenses.
- In one study, Jean-Laurent Casanova, an infectious disease geneticist at Rockefeller University, and his team examined blood samples from 987 gravely ill patients from around the world. In 10.2% of the patients, the researchers identified antibodies that attacked and neutralized the patients’ own type I interferon. A subgroup of affected patients had extremely low or undetectable blood levels of this interferon. Lab studies confirmed the antibodies knocked the interferon out of action and cells exposed to the patients’ plasma failed to fend off invasion by the new coronavirus.
- None of the 663 people in a control group with mild or asymptomatic SARS-CoV-2 infection had those damaging antibodies. The antibodies were also scarce in the general population, showing up in only 0.33% of more than 1200 healthy people tested. “What this means is that at least 10% of critical C19 is an autoimmune attack against the immune system itself,” Casanova says.
- The preponderance of male patients was a surprise, because women have higher rates of autoimmune disease. “Our favorite hypothesis is that it is an X-linked recessive trait,” Casanova says. “Women with two X chromosomes are protected and men, with one, are not.” Supporting that suspicion, one woman with a rare condition that silences one X chromosome was among the severely ill patients with autoantibodies.
- If these striking results hold up, they might also help explain the increased vulnerability of older people to severe C19: Half the gravely ill patients with autoantibodies were older than 65.
- The second paper found genetic flaws in patients that led to the same end result: a grossly inadequate interferon response to SARS-CoV-2 infection. The team sequenced DNA from 659 critically ill C19 patients and from 534 controls with mild or asymptomatic disease. They examined 13 genes, chosen because flaws in them impair the body’s production or use of type I interferon; mutations in the genes underlie life-threatening influenza or other viral illnesses. The researchers found that 3.5% of the critically ill patients harbored rare mutations in eight of those genes. In patients for whom blood samples were available, interferon levels were vanishingly small. No members of the control group carried any of the mutations. “This is the first paper to pin down indisputably disease-causing mutations underlying severe C19,” Pan-Hammarström says.
- But it’s “probably the tip of the iceberg,” says Paul Hertzog, an interferon expert at the Hudson Institute of Medical Research. Many other damaging mutations, interferon related and not, may influence the development of severe C19, he says.
- Zuniga notes that none of the patients who made antibodies against interferon or had the mutations had a history of life-threatening viral illnesses requiring hospitalization. “This suggests that we are more reliant on type I interferons to protect ourselves against SARS-CoV-2 versus other viral infections,” she says. “That makes it important to try therapies aimed at boosting type I interferon responses.”
- Dozens of randomized clinical trials are now deploying interferons against SARS-CoV-2. One, led by Tom Wilkinson at the University of Southampton, reported promising findings in a small group of hospitalized C19 patients. But synthetic interferons won’t help patients who harbor mutations that prevent interferons from working, or those with antibodies that attack them.
- Some researchers caution that the interferon-neutralizing antibodies could be a consequence, rather than a cause, of severe C19. “It’s possible that they develop during the disease,” says Miriam Merad, an immunologist at the Icahn School of Medicine at Mount Sinai. That would explain why the patients hadn’t faced life-threatening viral infections before, she says.
- But Casanova, who has made a career of discovering mutations that confer susceptibility to infectious diseases, says there is a strong case for causality. He points out that preexisting blood samples from a handful of patients showed they had the antibodies in their blood before contracting SARS-CoV-2. He argues that, in response to infection, it’s unlikely that the body could quickly generate the high levels of anti-interferon antibodies his team saw.
- Yanick Crow, a clinical geneticist at the University of Edinburgh who studies interferon signaling, calls the antibody paper “shocking,” in part because men were so much more likely than women to carry the rogue antibodies. Tests screening for the antibodies can and should be rapidly developed, he says, and will quickly reveal whether the new findings hold up. Given tens of millions of cases worldwide, he says, “10% is such a high figure and the implications are very important.”
6. Pandemic hair loss
- Doctors have identified another disturbing side effect of the coronavirus pandemic: infected patients shedding large quantities of hair.
- The phenomenon, doctors believe, may not stem from the virus itself, but from the psychological stress of fighting it off.
- It’s normal for some people who have gone through a traumatic experience to suffer hair loss, and many of the people losing hair during the pandemic have never been infected. Instead, they may be shedding hair because of emotional stress from job loss, deaths in the family or other trying experiences.
- Experts say the pandemic is actually leading to two types of hair loss. One is called telogen effluvium, in which a stressful experience trips up the cycle of shedding and growing, leading to hair loss that usually lasts around six months.
- The other condition is alopecia areata, in which the immune system attacks hair follicles, and usually starts with a patch of hair on the scalp or beard. Experts think that the storm of immune system inflammation set off in some C19 patients might elevate molecules linked to conditions like alopecia.
- Doctors say the conditions should be temporary, although they can last months. If a patient continues to experience stress, the condition may become chronic.
Source: New York Times Coronavirus Briefing
G. The Road Back?
1. How 4 Different European Countries Are Trying to Stop A Second Wave
- A resurgence in C19 cases has gripped countries across Europe, leaving politicians grappling with how to curb the spread of the virus. Governments are now strengthening regulations around mask-wearing, limiting the number of people that can gather in public spaces, and honing in on areas with particularly high numbers of cases.
- This week, Europe experienced a record high number of new coronavirus cases reaching 71,365 on Sept. 21, according to the European Centre for Disease Prevention and Control. “More than half of European countries have reported a greater than 10% increase in the past two weeks,” Hans Kluge, the World Health Organization’s regional director for Europe said at a briefing.
- Even countries that had largely avoided the first coronavirus wave—such as Czech Republic—are now seeing surges. Stricter regulations to try and curb the spread of the virus could remain in place for the entire winter. In the United Kingdom, for example, where case rates are doubling by the week, Prime Minister Boris Johnson announced new restrictions yesterday that could last six months, warning that the country is at “a perilous turning point.”
- Many of the new restrictions, however, look different to those imposed at the beginning of the pandemic. Rather than implementing uniform, nationwide regulations, many countries are now opting for more localized approaches.
- Countries are wary of nationwide lockdowns that would have crippling impacts on their economies. Local restrictions allow governments to curb the spread of the virus while keeping parts of the country—and the economy—open.
- But restrictions are also different this time because the nature of the pandemic itself has changed. New infection clusters appear to be linked to younger people, who are less likely to die of the virus. The result is that this latest surge of cases has so far been less deadly than the first back in March and less burdensome to healthcare services.
- “Even if the number of cases are high, the impact in terms of hospitalization and deaths is very different [compared to March]”, says Dr Jacobo Mendioroz, the director and coordinator of the committee responding to coronavirus in Catalonia. Rather than calling for stay-at-home orders, many new restrictions target bars, restaurants or other public venues that young people may be more likely to frequent.
- But the new restrictions could change if older people begin falling ill in greater numbers. Already, there has been a significant increase in the number of older people testing positive for the virus in France and Spain over the past two weeks, leading to upticks in hospital admissions. Rising case numbers threaten to overrun hospitals and health care services if not managed carefully. “We are not in the situation we were in March yet,” says Dominique Costalgliola, a member of the French Academy of Science and the vice-dean of research for the faculty of medicine at the Sorbonne University.
- Here is how 4 European countries are responding to the recent surge of coronavirus cases:
- Spain has been facing a resurgence of C19 cases since July and has the highest infection rate in Europe. Over the past two weeks, 122,000 new C19 cases have been reported, with close to a third of cases occurring in Madrid, the country’s capital. The total number of confirmed cases now stands at more than 640,000 and hospitals are reaching their maximum capacity.
- On Sept. 18, Isabel Díaz Ayuso, the president of the Madrid region, announced a partial lockdown of the 37 most affected parts of the region, which came into effect on Monday. The measures—which affect close to 850,000 people, many of whom live in the poorest parts of the city—require individuals to provide justification for trips out of their neighborhoods and has limited the number of people allowed in restaurants or retail establishments.
- The news of the lockdown sparked protests in Madrid, where hundreds gathered on Sept. 20. The groups that organized the protests said in a statement that the government has done little to protect vulnerable people in the city and have “instead opted for stigmatization, exclusion and territorial discrimination.”
- On Sept. 19, 13,498 new cases were reported, the highest number since the pandemic began in March. Since then, daily cases have risen to more than 13,000. The cumulative number of C19 cases is now at 453,763 and continues to rise. It has the second highest number of total cases in Europe, after Spain.
- The government has delegated the task of implementing new regulations to regional authorities. Prime Minister Jean Castex said that a nationwide lockdown would have unnecessary economic repercussions.
- In Paris, Marseille and Bordeaux, all major hotspots for the virus, authorities have implemented local measures to curb the spread. In Bordeaux and Marseille dancing has been banned at bars and weddings and local companies have been asked to make their employees work from home if possible. In Marseille and Paris, the sale and consumption of alcohol on the streets after 8p.m. has been banned. Wearing a face mask in public is now mandatory across Paris and many of its surrounding areas. Riot police units have been deployed to enforce these measures.
- However, despite the new restrictions, the government announced on Sept. 20 that quarantine rules in elementary schools would be relaxed, amid evidence that children pose a small risk for the transmission of C19. Schools will now only shut if a minimum of three students test positive for the virus.
- Ireland is facing a rise in C19 cases, particularly in Dublin, the country’s capital. On Sept. 22, 188 new daily cases were reported by the National Public Health Emergency Team, 76 of which are in Dublin. Ireland has logged 33,121 C19 cases, in a country of 4.6 million.
- The government introduced a new plan for ‘Living With Covid’ with five different levels. Dublin has been placed under level 3 restrictions, while the rest of the country is at level 2. Under level 2, schools, restaurants and pubs remain open but there are limitations on the number of people that can gather in private and public spaces. In Dublin, indoor social gatherings have been limited to visitors from only one other household and cannot exceed six people. All museums and other cultural attractions have been closed. Restaurants, cafes and pubs can only stay open for take-away services or for outdoor dining. Everyone has been asked to work from home if possible.
- At a C19 briefing on Sept. 21, Liz Canavan, the assistant secretary general at the Department of Taoiseach (the Irish’s Prime Minister’s office), said there was now “worrying trends in most areas,” making it possible that restrictions in Dublin could be extended to other parts of the country.
- Germany has one of the most effective test, track and tracing systems in the world for C19. And while the country is faring better than others in Europe, Germany is nevertheless seeing a rise in cases, with 1,345 new cases reported on September 20. German Health Minister Jens Spahn has said that surges in infection rates in neighboring countries have affected—and would inevitably continue to affect—Germany, given travel between countries in the European Union.
- In the southern state of Bavaria, the most affected part of the country, the government implemented new measures on Sept. 22, including a five-person (or two-household) limit on social gatherings, a ban on alcohol consumption in public places, and a curfew on restaurants.
- These are the toughest restrictions Germany has seen since it began relaxing measures back in May.
H. Back to School!?
1. College reopenings could be to blame for 3,000 new coronavirus cases per day in the US
- Once again, the hopeful trend in the US’s coronavirus outbreak didn’t last. Although the country’s weekly average of coronavirus cases began dropping in July, new daily cases have risen by nearly 15% over the past week, according to data from Pantheon Macroeconomics.
- The uptick isn’t surprising, experts say. Many US colleges welcomed students back in late August. Even before classes officially started, outbreaks were recorded among student athletes, linked to fraternity parties, and traced to crowded local bars near campuses.
- New research attempts to quantify the link between college reopenings and the recent uptick in the country’s C19 cases. According to that math, resuming in-person classes at colleges has added more than 3,000 new coronavirus cases per day to the US tally since July.
- The study, which was released as a preprint and isn’t yet peer reviewed, traced cell-phone activity across nearly 780 counties with college campuses from July 15 to September 13. The researchers then compared that data to confirmed C19 cases during that time period.
- “Colleges are bringing people together from all over the country and that’s creating this mixing environment,” Martin Andersen, a coauthor of the new study, told Business Insider. “Whenever you have mixing or this increase in flow, you would expect to see a potential for increased disease transmission.”
Classrooms probably aren’t the main culprit
- Public-health experts say it often takes about two weeks for a coronavirus case to become part of the official total, since infections take five days to manifest in symptoms, on average. Then people usually wait a bit time before getting tested, and the results usually take at least three business days to come back.
- That explains why college outbreaks are being reflected in the data we see now, but didn’t immediately lead to a bump in the first days after classes resumed.
- “It takes a little while for these effects to show up,” Andersen said. “It’s not like a campus reopens and immediately there’s a spike in C19 cases.”
- Andersen’s research found that in the two weeks after college classes started, the average number of cell phones on a given campus rose by 47% compared to the two weeks prior. The increase in the number of cell phones was higher on campuses that resumed in-person classes: around 56%. Campuses that continued primarily with online learning only saw a 33% jump in the number of cell phones — probably because some students still returned to the dorms or local apartments, and teaching staff may have returned to campus as well.
- But the researchers don’t think classrooms are the epicenter of transmission on college campuses. Instead, they think colleges that resumed in-person classes are probably also less likely to require masks, and perhaps more likely to allow fraternity parties or fans at sporting events.
- “Sitting in a classroom with a mask and instructor in a mask — we don’t think that’s a big opportunity for C19 to be spread,” Andersen said. “So it’s probably these other things that are happening, you know, the college parties, the dorms, et cetera.”
- He noted, however, that his current data doesn’t prove that yet.
- Other data supports the theory that colleges are driving recent coronavirus transmission in the US.
- More than 81,000 coronavirus cases were recorded at colleges from late July to mid-September, according to data from The New York Times. A new report from the Centers for Disease Control and Prevention also found that people in their 20s accounted for 20% of all C19 cases from June to August — the highest of any age group. That’s a jump from May, when people in their 20s accounted for only 15% of cases.
- Andersen said his study doesn’t mean that reopening a college inevitably leads to an outbreak, though.
- “Where you draw students from matters a lot,” he said. “Counties with schools that draw students from higher-risk places or places where the incidence of C19 is going up have disproportionately larger increases in case counts.”
- That means colleges should be able to reasonably assess the risks they take when bringing students back.
- “They know where their students are coming from,” Andersen said. “They can do the math better than we can about the profile of their incoming class and how risky that is.”
- If students are getting sick on campus, public-health experts say, colleges should not ask them to return home, since that could lead them to infect others.
- “They should be able to accommodate the students in a facility, maybe a separate dorm or a separate floor, so they don’t spread among the student body,” Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, said at a Senate hearing on Wednesday. “But do not send them home to their community.”
2. The College C19 Scare. Cases spike on campus but with very few hospitalizations
- After a late summer lull, virus cases are increasing again as colleges and schools reopen, and the media are declaring a “third wave.” While another surge is possible, most new cases are among younger people and seem to be relatively mild.
- The lockdown-loving media luxuriate in studies based on virus models that report bad news. They got another dopamine rush Tuesday when researchers from the University of North Carolina, University of Washington, Indiana University and Davidson College published a study linking the reopening of college campuses to 3,200 more cases a day in the U.S. [NOTE: Read the article above]
- They found an increase of 2.4 cases daily per 100,000 people in counties with college campuses that reopened for in-person classes versus those with colleges that stuck with primarily online instruction. To put these numbers in context, 3,200 equates to about 7% to 10% of the 35,000 to 42,000 daily reported average U.S. cases this month. The U.S. is recording 11 to 13 cases per 100,000 population each day, and states currently with “surges” like Wisconsin more than 30 per 100,000.
- Young people account for a large share of new cases in many states. Cases in Wisconsin among 18- to 24-year-olds spiked 220% between the week of Aug. 23 and Sept. 6 while ticking up 30% among those age 65 and older. The University of Wisconsin has reported 1,945 cases since students returned to campus last month.
- Yet colleges are also doing regular testing to detect asymptomatic and mild cases to stop outbreaks. Most colleges test students weekly, and some daily. Students who test positive are isolated, and their close contacts are typically tested too. This may keep the virus from spreading to more vulnerable folks who are more likely to get severely ill.
- Twenty-nine large universities including Notre Dame, the University of North Carolina, and Illinois State had reported some 26,000 cases by Sept. 9 yet no hospitalizations. Nationwide, hospitalizations are down 16% or so from Sept. 1 and half since their peak on July 23, according to the Covid Tracking Project.
- Arizona’s rolling seven-day average has more than doubled in the last two weeks, mostly in the Tucson area around the University of Arizona. Yet hospitalizations statewide have been flat and are about the same as in early April. Only 122 intensive-care beds in the state are occupied by Covid patients, compared to 970 at the peak two months ago.
- During the summer, many young people living at home went out to party (and protest) and then brought the virus home where they may have unknowingly infected vulnerable family members. Reopening college campuses for in-person classes may keep older generations safer and perhaps limit a third wave.
- Notably, CDC data show per capita hospitalizations declined 70% among those 65 and older in the week ending Sept. 12 (the latest data) from the week ending July 25. Among 18- to 29-year-olds, per capita hospitalizations have fallen 77%. Trends could change, but there’s no reason so far to panic over Covid on campus.
3. C19’s Emotional Toll on the World’s Youngsters
- As C19 drags into a new school year, and second waves threaten many countries lucky enough to have escaped their first, the more intangible consequences of illness, lockdown and quarantine are becoming gradually apparent.
- According to a disturbing new report from Save the Children, the pandemic’s impact on the youngest generation has been deep and detrimental — and is getting worse. The 37-country survey taken from May through July 2020 of 17,565 parents and caregivers, and 8,069 children aged between 11 and 17, revealed:
- More than 8 in 10 children felt they were learning little or nothing at all
- 37% of children said they had no one to help them with their schoolwork
- Only 68% of children had access to textbooks; 42% to reading books; 7% to an educational cellphone or tablet app; and 2% for an educational computer program
- Less than 1% of children from poor households had internet access for remote learning, compared with 19% of non-poor children
- 63% of girls reported doing more household chores during C19, and 52% spent more time caring for siblings; the rates for boys were 43% and 42%, respectively
- Reports of household violence doubled from 8% to 17% during school closure; 32% of households reported physical or emotional violence in their home during the pandemic
- Of the study’s many unsettling findings, one may bode especially ill for the future wellbeing of a global cohort of impressionable minds: how the pandemic’s psychological impact has intensified over time.
- As the chart below illustrates, while 63% of children experienced an increase in “negative feelings” during the initial weeks of school closure, this rate rose steeply as the lockdown continued. Indeed, by month five of closure, 95% of children reported greater negative feelings — the same rate as their adult parents or caregivers. If this emotional burden persists, it could well become a formative psychological scar for “Generation Covid.”
I. Herd Immunity
1. Japanese study suggests 50% of population may have had C19
- Mortality from C19 has been low in Japan as compared to the United States and European countries. The reasons for the low number of deaths are unknown and may relate to either low prevalence of coronavirus infections in the general population or diminished fatality rates among those infected.
- Distinguishing which of these factors come into play requires data on the total prevalence of coronavirus, particularly among the asymptomatic general population. To estimate the incidence of C19, serology tests were obtained in asymptomatic individuals throughout the summer of the year 2020, incorporating the time before, during, and after the well-documented “second wave” of C19 infection in Japan.
- For each participant, serology tests were offered twice, separated by approximately a month, to provide self-references of test results, to identify cases of both seroconversion and seroreversion, and to estimate the seroprevalence of the general population in Tokyo over time.
- Six hundred fifteen healthy volunteers from 1877 employees of a large Japanese company were enrolled from 11 disparate locations across Tokyo.
- As is the general practice in Japan, participants commuted daily to their workplace: remote working was not practiced. Tests were performed weekly from May 26 to August 25 (except for 6/2, and 8/11; those designated to 8/11 were rescheduled to 8/18). Participants having fever, cough, or shortness of breath at the time of testing were excluded. Fingertip blood was applied onto the cassette of the COVID19 IgM/IgG rapid test kit (Aurora Biomed, Vancouver Canada) to detect antibodies.
- A second subsequent test was offered 3-5 weeks after the first. For each week, less than 150 participants received the tests across the study cohort. Data were combined every two weeks, and Seropositivity Rates (SPR) were calculated.
- Seropositivity was defined as having either IgM or IgG positive results. The SPR 95 % confident interval (95% C.I.) was calculated by binomial distribution [±1.96×√(p(1-p)/n)].
- An outside ethical committee reviewed and approved the protocol. Results The demographic characteristics of participants were composited every two weeks and summarized in Table 1.
- Seroprevalence increased from 5.8 % to 46.8 % throughout the summer (Figure). The most dramatic increase in SPR occurred in late June and early July, paralleling the rise in daily confirmed cases within Tokyo1, which peaked on August 4.
- Out of the 615 participants, 350 individuals completed both offered tests. The interval between tests was 30.5 + 5.6 days (Mean + S.D.). From the subset of individuals who initially tested seronegative, 21.4 % (54/252) seroconverted to a seropositive result (Table 2).
- For the individuals who initially tested IgM positive, 81.1% (73/90) became IgM negative. Seroreversion was found in 12.2 % (12/98) of initially seropositive participants. There were no instances where serological tests revealed a physiologically unexpected result – for example, a case where IgM negativity and IgG positivity became IgM positive at the subsequent test. Out of all possible states, IgM+/IgG- was the least common, 0.4% (3/700 total tests), suggesting that the window when IgM is positive before the onset of IgG positivity is short in duration.
- None of the seroconverted individuals were hospitalized or had died.
- In this cohort, the SPR increased to an unexpectedly high 46.8 % by the end of the summer after the peak of the second-wave. This rate exceeds the estimated seroprevalence of C19 in a known epicenter like New York City (20.2 %)2.
- Although our cohort was not selected from a broader, random sampling of Tokyo, this data may still be generalizable to the greater metropolitan area for a number of reasons: participants were sampled from multiple disparate locations across Tokyo; they had limited physical interactions with each other given the organizational structure of the company – limiting the role of clustering; participants were well-distributed across age and gender; and the initial SPR for this cohort started low at 5.9 % mirroring the pattern seen in Tokyo. Moreover, the exclusion of individuals with clinical symptoms may have led to an underestimation of total SPR.
- A high seropositivity rate in Tokyo may not be fully unexpected given its remarkably high population density, tight spacing, the widespread use of public transportation, and no implementation of a “lockdown”.
- This study is unique in its utilization of sequential serological testing in a moderately sized cohort of asymptomatic individuals.
- The paired testing allows for an understanding of the temporal dynamics of the immunoglobulin response:
- First, the rapid tests did not yield any unreasonable answers: there were no illogical transitions (e.g., IgM-/IgG+ to IgM+/IgG-), and the overall SPR pattern remained stable over the course of testing (Figure).
- Second, IgM positivity is short-lived, typically turning negative over one month.
- Third, seroreversion was not infrequent, seen in 12% of participants over the one-month span between tests.
- This suggests that serological testing may significantly underestimate past C19 infections, particularly when applied to an asymptomatic population.
- These findings should also take into context the epidemiological dynamics seen during this C19 wave. Japan took the atypical step of not instituting a mandatory lockdown. During this time, businesses, restaurants, and transportation were kept open, and public life continued relatively unabated. Nevertheless, the second wave peaked and subsided on its own.
- With the rise in SPR nearing 50% within our cohort, matching the time when C19 cases waned, the possibility of herd immunity should be considered, particularly in the highly-dense urban scenario like Tokyo.
- If this were true, then the remarkably low mortality related to C19 should also be examined. Much like our cohort which had no reported hospitalizations, clinical severity in Tokyo was low.
- During the second surge, only 31 fatal cases (observed between June 22 and August 25) were reported in Tokyo, while the first surge (March 20 to May 20) claimed 244 lives.
- Assuming an infection rate of 40% within the Tokyo urban population (14 million), the infection fatality rate (IFR) during this period could potentially be as low as 0.0006%, which is as low as the lowest IFR observed among teens in Switzerland.
- Future studies may consider evaluating whether lifestyle/habits, viral strain, the widespread use of masks, and/or host factors such as immunological memory are responsible for the observed low fatality.
- This study has several limitations. First, the cohort was a sampling of a single large company in Tokyo and not of the population, in general. Second, detailed medical histories and behavioral patterns of each employee were not obtained. Such information would have been helpful in understanding the role of cross-exposure and the factors associated with reduced fatality. Third, paired testing was separated by a month. Closer intervals may have yielded more granular insights into the immunological responses to coronavirus infection.
- Despite these limitations, this study is one of the first, to our knowledge, to obtain sequential C19 serological testing in an asymptomatic population and also provides an explanation for why rates of C19 had declined in Tokyo despite the absence of a public lock-down.
J. New Technology & Equipment
1. As hospitals look to prevent infections, a chorus of researchers make a case for copper surfaces
- Keeping patients from getting sick during an inpatient stay has long been a problem for hospitals — and it’s an issue that has grown all the more pressing during a pandemic.
- Even before the rise of C19, hospitals have increasingly struggled to get health-care associated infections in check. There are 2 million such infections — and 90,000 related deaths — in U.S. hospitals every year.
- As hospitals across the country hunt for ways to reduce the spread of pathogens to patients, a growing chorus of researchers is arguing that a simple swap might help: replace stainless steel surfaces with copper.
- “Copper is the fastest thing that can kill anything,” said Michael Schmidt, a professor of microbiology and immunology at the Medical University of South Carolina and a leading researcher on antimicrobial copper.
- Copper’s ability to neutralize microbes is well-known. Researchers studying SARS-CoV-2, the disease that causes C19, noted back in March that the virus lasts for several days on stainless steel — which most hospitals use for the majority of surfaces — but dies within hours of landing on copper.
- Despite the evidence on copper’s ability to bust up bacteria, many hospital leaders remain unconvinced. They argue it’s still not clear whether reducing the amount of a pathogen in a particular area of a hospital actually translates to a lower risk of infection.
- “In infection prevention, we’re a pretty pragmatic bunch. We want to know that something is effective,” said Graham Snyder, medical director of infection prevention at UPMC in Pittsburgh. “There’s no doubt about it: Organisms are less likely to survive on an antimicrobial surface. Is that less likely to reduce infections? That’s very hard to prove.”
- Schmidt and other researchers studying copper are hopeful that a growing body of research will help make the case for copper. In 2007, he began a study inside eight intensive care unit rooms at three U.S. hospitals where copper was installed on different objects: bedrails, overbed tray tables, intravenous poles, and armrests of visitors’ chairs, as well as on surfaces like nurses’ call buttons. Over six years, Schmidt found that infections in these rooms dropped 58% compared to eight unmodified ICU rooms. He also found significantly lower rates of VRE and MRSA bacteria, notorious for causing inpatient infections, in the copper rooms.
- More recent research on copper shows similar promise. A 2016 clinical trial at Sentara Leigh Hospital in Virginia found that copper oxide surfaces led to a 78% reduction in drug-resistant microbes. Another clinical trial carried out that same year in Iowa demonstrated the same.
- And last fall, Schmidt published his latest research, a nearly two-year study that showed that copper beds inside the ICU of a hospital in Indiana harbored an average of 95% fewer bacteria. (That study was supported by an “unrestricted research grant” from Bed Techs, which retrofits hospital beds with copper. Schmidt’s work has largely been funded by the Department of Defense, but he has also received support from a copper industry group to study the metal in non-patient-care settings.)
- Researchers who study copper say its power lies in how it attacks a pathogen. In the presence of bacteria like E. coli, copper releases reactive ions that punch holes in the cell membrane, invade, and then shred the DNA and proteins within. Sometimes copper metal is even more, well, metal. Unlike gold or silver, copper contains a free electron in its outer orbital shell, which interacts with oxygen in the air — resulting in an energized form of oxygen, a molecular grenade of sorts that blasts through viral envelopes and blows up the germ-replicating instructions on the inside.
- Hospitals have a clear incentive to curb the spread of pathogens. The average single-bed hospital room in the U.S. sees between four or five infections annually, and the cost, in terms of money wasted and lives lost, is high. For every one person who contracts an infection while in the hospital, their stays are estimated to be as much as 19 days longer, as well as about $43,000 more expensive.
- While there is a correlation between installing copper and reducing the burden of bacteria, there is no proven causation between the presence of copper and the decrease in the number of patient infections a hospital sees — an outcome that some hospital leaders said they would like to see before making the switch.
- There’s also the equally pragmatic matter of the overall cost of installing copper, which is far more expensive than plastic or stainless steel. For hospitals, which generally run on small operating margins, it’s more worthwhile to put extra money into patient care, including existing resources intended to keep people safe.
- “It’s a zero-sum game. We don’t have the resources to do everything,” said David Weber, who, as medical director of epidemiology at UNC Health Care in North Carolina, works to help prevent health care-associated infections.
- And as it currently stands, many hospitals already have easy-to-clean surfaces.
- “I don’t need an antimicrobial surface to make sure bedrails aren’t a route of transmission,” Snyder said. “I might decide a better investment is making sure my environmental services team does a good job at cleaning.”
- Some hospital leaders also said they’re not convinced that copper’s effectiveness will readily translate to the general hospital environment, given that most studies have been in the ICU.
- “The health care community wants to know if this will work in all hospital rooms, and, candidly, we don’t know,” Schmidt said. “That’s one of the principal reasons hospitals are saying they’re reluctant to adopt.”
- Still, Schmidt said the results gathered from studies in the ICU suggest that a hospital, on the whole, is likely to see a decrease in health care-associated infections with copper surfaces.
- “The mission was to ask a simple question: Could I reduce the incidents of health care-associated infections? My answer was yes,” he said. “And I thought the market would take that observation and run with it.”
2. Japanese firm develops first UV lamp that safely kills coronavirus
- A Japanese company that teamed up with Columbia University has developed a first-of-its-kind ultraviolet lamp that can kill the coronavirus without harming people’s health, according to a report.
- Light equipment maker Ushio’s Care 222 UV lamp is expected to be used to disinfect heavily trafficked spaces where people run the risk of contracting the deadly bug, including buses, trains, elevators and offices, Japan Today reported.
- UV lamps have been widely used for sterilization, notably in the medical and food-processing industries, and JetBlue recently announced plans to use the technology aboard its planes.
- However, conventional UV rays cannot be used when people are present because they cause skin cancer and eye problems.
- But Ushio’s new UV lamp emits rays with a wavelength of 222 nanometers, as opposed to the conventional 254-nanometer wavelength, making them deadly to germs but harmless to humans, the news outlet reported.
- At 222 nanometers, the UV rays cannot penetrate the skin and eyes to cause cancer-causing genetic defects and other damage, according to Ushio.
- When emitted from a ceiling, the UV from the new machine snuffs out 99 percent of viruses and bacteria in the air and up to a 32-square-foot surface of objects about eight feet away from the lamp, in six to seven minutes, Japan Today reported.
- The 2.6-pound Care 222 device, which is about the size of a hardcover book, costs about $2,800.
- Ushio said it only accepts orders from medical institutions for now, but that it will serve other customers once production catches up with demand.
K. Johns Hopkins C19 Update
September 25, 2020
1. Cases & Trends
- The WHO C19 Dashboard reports 32.03 million cases and 979,212 deaths as of 6:34am EDT on September 25. At 35-40,000 deaths per week, the global mortality could surpass 1 million deaths in the next week.
- As the US surpasses 200,000 cumulative deaths and the global total approaches 1 million, we want to take a closer look at cumulative deaths at the national level. In terms of total cumulative deaths, the US maintains a sizable lead over all other countries. Brazil is #2 with nearly 140,000 deaths. India appears to be on a trajectory that could eventually surpass the US; however, it is currently reporting fewer than half of the US total, so the situation could change.
- On a per capita basis, the top 20 countries are largely divided between 2 groups: European countries affected severely early in the pandemic and Central and South American countries that peaked more recently. These groups are fairly easy to distinguish by the shapes of their curves in the figure, with European countries increasing sharply in April before leveling off and Central/South American countries increasing more slowly starting in May and June and just now beginning to taper off. The US is a notable exception, with peaks in the spring and summer. With more than 1,200 cumulative deaths per million population, San Marino is #1 globally; however, that corresponds to fewer than 50 total deaths nationwide. Peru is reporting more than 950 deaths per million population and steadily increasing, and it is on a trajectory to overtake San Marino in the coming weeks. With the exception of San Marino and Andorra, most of the countries in the top 20 have reasonably large populations. There is considerable overlap between the total and per capita top 20 lists, owing to the very large mortality totals in these countries, particularly in Europe and Central and South America.
- The US CDC reported 6.92 million total cases and 201,411 deaths as of 12 PM ET on September 24. The US is averaging 43,245 new cases and 732 deaths per day. The cumulative US C19 mortality surpassed 200,000 deaths, representing more than 20% of the global total. After reaching a minimum of 34,371 new cases per day on September 12, following the Labor Day holiday weekend, the US has reported increasing incidence for nearly 2 weeks, surpassing its previous plateau and up to its highest average daily incidence since August 22. In total, 22 states (no change) are reporting more than 100,000 cases, including California and Texas with more than 700,000 cases; Florida with more than 600,000; New York with more than 400,000; Georgia with more than 300,000; and Arizona, Illinois, and New Jersey with more than 200,000.
- The Johns Hopkins CSSE dashboard reported 6.98 million US cases and 202,827 deaths as of 9:45am EDT on September 23.
2. UNITED KINGDOM
- While the UK’s C19 epidemic has not yet returned to the height of its first peak, it is nearly there and still accelerating rapidly. UK health officials forecast that the country could potentially reach 50,000 new cases per day by mid-October, nearly 10 times the current current daily incidence. The average number of daily deaths has also increased in the UK; however, the daily mortality is still considerably lower than it was at the height of the “first wave”—fewer than 40 deaths per day, compared to more than 800. C19 hospitalizations are beginning to increase as well. Based on the current C19 trends, the Chief Medical Officers for England, Scotland, Wales, and Northern Ireland all recommended moving their respective countries to C19 Alert Level 4.
- UK Prime Minister Boris Johnson announced a number of policies to strengthen existing social distancing restrictions. The measures expand mandatory mask use, including for retail and hospitality businesses; prohibit in-person food and alcohol service after 10pm; and limit the size of gatherings, generally a maximum of 6 people with some exceptions. Businesses will also be required to display a QR code to support contact tracing efforts via a smartphone application, and businesses that repeatedly violate the restrictions will face fines of up to £10,000 (~US$12,700). Additionally, Prime Minister Johnson continued to encourage individuals to work from home to the extent possible. He also indicated that the restrictions could be in place for 6 months, which would potentially last through the majority of the 2020-21 influenza season. The new restrictions also resulted in a suspension of plans to allow spectators to begin returning to sporting events.
3. BRAZIL SEROPREVALENCE
- A team of researchers published a pre-print examining the seroprevalence of C19 in two Brazilian cities. From February to August, researchers conducted a cross-sectional monthly estimate of seroprevalence among blood donors samples from Manaus and Sao Paulo, Brazil. After adjusting for the sensitivity and specificity of their diagnostic tests and weighting their values to account for differences in sex and age, the researchers saw a peak in their Manaus collection with 51.8% of samples containing SARS-CoV-2 antibodies this past June. The researchers did note that Manaus’ community immunity waned in the following months falling to 40% and 30.1% in July and August respectively. While significantly lower than the Manaus sample, researchers saw a similar trend in the samples from Sao Paulo. The authors note that they are unsure what contributed to such high rates of seroprevalence among blood donors in Manaus, and share that other studies from the region present differing results despite covering a similar time period. They describe a number of possibilities for this difference, including test sensitivity and sampling methods. The authors present an argument for the possibility of community immunity in regions with high C19 transmission, like Manaus, and cite challenges of potential waning immunity.
4. CHINA TRAVEL RESTRICTIONS
- China’s early response to the C19 pandemic included domestic travel restrictions. As the pandemic spread to other parts of the world, China also limited foreign travel into the country. China continues to keep a relatively low daily incidence rate of C19 cases, and recently announced a roll-back of several external travel policies. Now foreign individuals with Chinese visas or residence permits can return to the country for economic or personal matters. They also have announced a reopening of their visa office.
5. VACCINES ALLOCATION & DISTRIBUTION
- Earlier this week the WHO announced that 64 higher-income, “self-financing” countries are now part of the COVAX Facility to provide funding support for lower-income countries to purchase a future SARS-CoV-2 vaccine, and an additional 38 economies are expected to join soon. Of these, 29 are from Europe, participating as part of an agreement with the European Commission. A total of 156 countries are participating in the COVAX Facility, representing approximately 64% of the global population. Notably, the US and China are not participating. The allocation plan for the program expected to provide enough vaccine to cover approximately 20% of the population in receiving countries.
6. REFUGEES & DISPLACED POPULATIONS
- The Norwegian Refugee Council published a report this week discussing the impact of C19 on refugees and displaced populations. The report describes results of a survey of 1,400 people across 8 countries who have been impacted by conflict within their countries and/or have been displaced from their homes as well as more targeted surveys and needs assessments across a total of 14 countries. The survey found that 77% of respondents have lost their jobs or income since March, and 62% who normally receive financial support from family abroad are receiving less money now than they were before the pandemic. Financial insecurity is also impacting families’ ability to send children to school and pay for medical expenses, and the risk of eviction or other housing insecurity increased as well. Food insecurity has increased as well, with 70% reporting that their household has reduced the number of meals since the start of the pandemic. The report recommends that G20 countries scale up bilateral financial assistance and implement plans for debt relief for countries experiencing large numbers of internally displaced or refugee populations. Additionally, the report calls for national governments to explicitly include refugee and displaced populations in economic stimulus efforts and expand the reach of social support programs.
- The Internal Displacement Monitoring Centre published a report outlining the displacement among vulnerable populations amid the C19 pandemic. The organization’s mid-year update reported more than 14 million new internal displacements across 127 countries in the first 6 months of 2020 alone. Of these, 4.8 million displacements were caused by violence, and 9.8 million were caused by disasters. Notably, the numbers displaced by violence was a sharp increase for several countries compared to previous years. Notably, the totals for the first half of 2020 were higher than the full-year 2019 total in Cameroon, Mozambique, Niger, and Somalia. Populations were displaced by disasters in countries representing all income categories, and many affected populations face prolonged displacement, particularly if their homes were destroyed.
- The pandemic is driving a myriad of downstream effects on displaced population. The report indicates that populations living in camps may not have access to appropriate testing or clinical care for C19. Like the NRC report, financial, housing, and food insecurity have been exacerbated by C19. The report also indicates that stress stemming from the pandemic and its downstream effects could be driving an increase in violence among displaced populations, particularly toward women and children. Finally, the pandemic is also impacting humanitarian aid operations, including aid workers being evicted by local communities over fear that they will bring C19.
7. PEDIATRIC VACCINE
- The world awaits a SARS-CoV-2 vaccine, but regardless of the timeline, it is clear that it will not be available for everyone initially. Beyond the initial limited supply, there are other barriers for some populations. Even if sufficient supply is available, a vaccine may not necessarily be authorized for use in children, due in part to their exclusion from ongoing clinical trials. The decision to omit children is supported by various leading experts, and it is a function of multiple factors both specifically in the context of C19 and based on historical practice. One of the primary concerns is that children are not a high-risk group for severe C19 disease, which places them as a lower priority from that perspective. Additionally, clinical trials in children traditionally only begin once safety and efficacy are established in healthy adults in order to reduce the possibility of harm in children. Some argue, however, that Phase 2 trials in children should begin soon, because children can still suffer from severe C19 disease and because time is needed to assess possible long-term effects of vaccine candidates in children. As the age distribution of C19 cases shifts toward younger individuals, it is clear that children and adolescents can transmit the infection, including to older or other high-risk individuals. Furthermore, ensuring that a safe and efficacious vaccine for children is available by the start of the 2021 school year could be an important tool for resuming normal social and economic activities, particularly for parents and guardians who are currently unable to return to work while their children are not in school.
8. VACCINE CHALLENGE TRIAL
- The UK government is reportedly considering challenge trials for candidate SARS-CoV-2 vaccines. In contrast to traditional, placebo-controlled clinical trials, participants in challenge trials all receive the vaccine and are then deliberately exposed to the virus in order to determine the efficacy of the vaccine. According to the reports, the trial could begin in January 2021, and the effort is supported by 1Day Sooner, an organization that “advocates on behalf of C19 challenge trial volunteers.” While challenges trials could potentially provide more rapid assessment of vaccine efficacy, it poses a number of ethical challenges, particularly in the absence of a more effective treatment or a well-characterized understanding of the required exposure dose. Some experts, including at the US National Institutes of Health argue that the additional protective measures and monitoring for challenge trials could actually prevent them from providing results more quickly than traditional clinical trials.
9. PHUKET C19 RESPONSE
- A new paper in EClinicalMedicine, details the potential impact of non-pharmaceutical interventions in limiting the spread of C19. The paper examines the C19 response in Thailand’s Phuket Island, one of Thailand’s most popular tourist destinations. The region maintained a relatively low number of C19 cases despite a surge in activity earlier this spring. The paper provides a detailed outlook of state-run contact tracing efforts, and their process for quarantine. The findings suggest that 80% of new C19 cases occurred in individuals they had identified as “high-risk” contacts. The authors suggest that this finding emphasizes the importance of contact tracing in an effort to identify such individuals and for proper quarantine as a necessary tool in stopping the chain of transmission.
10. COVID-SNIFFING DOGS
- SARS-CoV-2 testing would likely be less scary or uncomfortable if it was conducted by puppies. Perhaps that is part of the motivation behind Finland’s new plan to deploy “coronavirus-sniffing dogs” at the Helsinki Airport. The airport is conducting a pilot project that uses specially-trained dogs to detect SARS-CoV-2 infection in passengers based on their scent. Dogs have been used in a similar manner to detect other infections or diseases that cause a distinct odor in patients, including cancer and Clostridium difficile, sometimes before the onset of symptoms. Samples are taken by swabbing passengers’ necks and then delivered to the dogs in a separate room. One researcher from the University of Helsinki indicated that the dogs can approach 100% sensitivity and can detect infection up to 5 days before the onset of symptoms. A similar program was also recently implemented in the Dubai International Airport. The use of dogs to detect SARS-CoV-2 has not been sufficiently assessed in scientific studies, so passengers identified by the dogs will be administered a more traditional test to confirm infection. Further research is needed to demonstrate the accuracy of this surveillance method, but it could provide rapid assessment capability, particularly for high-traffic areas like airports.
11. US FDA VACCINE REVIEW & AUTHORIZATION
- As we covered earlier this week, the US FDA signaled its intent to publish additional details regarding the process and standards for evaluating candidate SARS-CoV-2 vaccines undergoing Phase 3 clinical trials. According to multiple media reports, the proposed standards are currently under review at the White House, and some experts argue that the influence of officials outside of the FDA adds to concerns about the extent to which vaccine authorization decisions will be driven by political demands. US President Donald Trump suggested that the FDA announcement was politically motivated and that the forthcoming standards would need to be approved by White House officials. President Trump’s comments exacerbate a contentious debate regarding the independence and objectivity of US regulatory authorities and public health agencies and the role of appointed officials in reporting data and developing guidance.