August 9, 2020
Without reliable information, we rely on fear or luck.
A. Numbers & Trends
1. Cases & Tests
3. Top 5 States in Cases, Deaths, Hospitalizations, and Positivity
4. International Resurgence
B. New Scientific Findings & Research
C. Improved & Potential Treatments
D. Vaccines & Testing
E. Concerns & Unknowns
F. The Road Back?
G. Back To School!?
H. Projections & Our (Possible) Future
I. Practical Tips & Other Useful Information
J. Johns Hopkins COVID-19 Update (8/7)
K. Links to Other Stories
- How a Zoom forum is changing ICU treatment of C19 patients In recent months, dozens of critical-care doctors from around the world have gathered virtually on Zoom on Friday afternoons to discuss their dilemmas with a life-support technology known as ECMO — or extracorporeal membrane oxygenation. It’s essentially an artificial lung that helps the sickest Covid-19 patients breathe when their lungs fail. Physicians are seeing an uptick of serious complications in patients on the machines, and the meetings have helped them find others with similar cases. In the absence of concrete answers on what may be happening, these Zoom meetings are now serving as an opportunity to figure out immediate solutions for those in need.
- Many health departments losing race to warn contacts of COVID victims With the pandemic claiming hundreds of American lives daily, many city and county health departments say they lack the money and staff to warn people who have been exposed, a Reuters survey finds. At least one jurisdiction has given up, asking people with the coronavirus to tell contacts themselves.
- Life Is Now a Game of Risk. Here’s How Your Brain Is Processing It Americans are faced with more risk than ever. Understanding how the brain navigates this new reality can build confidence and empathy in everyday decision-making.
- Nine Important Things We’ve Learned about the Coronavirus Pandemic So Far Some early public health messages about C19 have been overturned
- Could My Symptoms Be C19? These days, every cough, sneeze or headache makes you wonder: Could it be C19? Medical experts are viewing C19 as a multi-organ disease that can affect the body from head to toe and everywhere in between. Here’s a guide to help you understand the symptoms. Click on the article link above to see an interactive guide to symptoms.
- Orchestras are totally safe. Just stay away from the flute player How scientists armed with saline solution and slow-mo cameras proved that it was safe for the show to go on.
- C19 Is Raging. How Safe Is Your Backyard Party? Awash in coronavirus data, misinformation and tremendous uncertainty, we need to put our risk analysis skills to the ultimate test.
A. Numbers & Trends
Note: Unless otherwise noted, (i) all cases/deaths are confirmed cases/deaths that have been reported, and (ii) all numbers reported in this update are as of the end of the most recent reporting period. Green highlights indicate a decrease or no change and yellow highlights indicate an increase.
1. Cases & Tests (8/8)
- Total Cases = 19,795,061 (+2.8%)
- New Cases = 262,524 (-20,485) (-7.6%)
- New Cases (7 day average) = 254,566 (+536) (+0.2%)
- 7 day average of new cases has been generally trending lower since 7/30
- 1,000,000+ new cases every 4 days (based on 7 day average)
US Cases & Testing:
- Total Cases = 5,149,723 (+2.3%)
- New Cases = 54,199 (-9,047) (-7.7%)
- Percentage of New Global Cases = 20.6%
- New Cases (7 day average) = 54,870 (-620) (-1.1%)
- Total Number of Tests = 64,610,547
- Percentage of positive tests (7 day average) = 7.4%
- 7 day average of new cases has been declining since 7/25
- Since 7/25, 7 day average of new cases has declined from 69,190 to 54,870, a decrease of 14,320, or 20.7%
- The percentage of positive tests has declined significantly during the last week, dropping from 8.0% to 7.4%
- Total Deaths = 728,795 (1.7%)
- New Deaths = 5,611 (-837) (-13.0%)
- New Deaths (7 day average) = 5,787 (-7) (+0.2%)
- 7 day average of new deaths has declined slightly for 2 days
- Total Deaths = 165,070 (+1.4%)
- New Deaths = 976 (-314)
- Percentage of Global New Deaths = 17.4%
- New Deaths (7 day average) = 1,025 (-22) (-2.1%)
- 7 day average of new deaths has been declining since 8/4, indicating that the increase in new deaths since 7/5 has peaked and is beginning to decline
3. Top 5 States in Cases, Deaths, Hospitalizations, and Positivity (8/8)
4. International Resurgence
- Numerous countries around the world that previously had success against C19 are experiencing an increase in incidence. Countries in East and Southeast Asia as well as the Western Pacific were among the first to experience the C19 pandemic, and several—including Japan and South Korea—were able to gain relative control of their epidemics through strict “lockdowns,” expansive testing and contact tracing programs, and public cooperation with various social distancing and other risk mitigation measures, including mask use.
- Several countries in the region are now taking renewed action against C19 due to recent increases in transmission. In central Japan, the Aichi prefecture is implementing a local state of emergency, including advisories against travel and a nighttime curfew. Businesses are also being asked to limit their hours or close altogether. In Danang, Viet Nam, the Tien Son Sports Palace, a 10,000 square meter arena, has been converted into a field hospital to provide 1,000 additional beds to supplement local hospitals. Viet Nam previously went 3 months without reporting community transmission, but Danang has reported more than 200 cases since July 25. Following the initial outbreak report, thousands of tourists were evacuated from Danang in an effort to limit local transmission. Government officials in Viet Nam’s capital of Hanoi are retesting 72,000 people who recently returned from Danang using more sensitive nasopharyngeal swab tests rather than the blood-based rapid tests that Viet Nam uses for screening purposes.
- In Melbourne, Australia, the government has imposed more restrictive“lockdown” measures to combat its surging outbreak, including a curfew between 8pm and 5am. The state of Victoria, where Melbourne is located, reported 725 new cases on Wednesday, compared to only 14 new cases for the rest of Australia. Approximately 250,000 people are out of work due to new prohibitions on non-essential activities. Melbourne was placed under lockdown earlier in the pandemic, but it was forced to re-institute similar restrictions 4 weeks ago. Now, the restrictions have been enhanced to Stage 4, and the new lockdown is scheduled to last for another 6 weeks.
Source: Johns Hopkins COVID-19 Update (8/7)
B. New Scientific Findings & Research
1. Even Asymptomatic People Carry the Coronavirus in High Amounts
- Of all the coronavirus’s qualities, perhaps the most surprising has been that seemingly healthy people can spread it to others. This trait has made the virus difficult to contain, and continues to challenge efforts to identify and isolate infected people.
- Most of the evidence for asymptomatic spread has been based on observation (a person without symptoms nevertheless sickened others) or elimination (people became ill but could not be connected to anyone with symptoms).
- A new study in South Korea, published Thursday in JAMA Internal Medicine, offers more definitive proof that people without symptoms carry just as much virus in their nose, throat and lungs as those with symptoms, and for almost as long. [Read the study here]
- “It’s important data, that’s for sure,” said Benjamin Cowling, an epidemiologist at the University of Hong Kong who was not involved in the work. “And it does confirm what we’ve suspected for a long time — that asymptomatic cases can transmit infection.”
- Discussions about asymptomatic spread have been dogged by confusion about people who are “pre-symptomatic” — meaning they eventually become visibly ill — versus the truly asymptomatic, who appear healthy throughout the course of their infection.
- The new study is among the first to clearly distinguish between these two groups.
- “There’s been this big question pretty much since January, since data started coming out of China, about people that were asymptomatic or pre-symptomatic,” said Jason Kindrachuk, a virologist at the University of Manitoba who was not involved in the work. “What we haven’t really had any clue of yet is what role people who are asymptomatic play in transmission of disease.”
- The new study measured the virus’s genetic material in the patients; the researchers did not follow the chain of transmission or grow live virus, which might have more directly confirmed active infections.
- Still, experts said the results strongly suggest that asymptomatic people are unwitting broadcasters of the virus.
- “They don’t look any different from the symptomatic population” in terms of how much virus they carry, said Marta Gaglia, a virologist at Tufts University in Massachusetts who was not involved in the work. “There’s no actual reason to believe a priori that they would transmit any differently.”
- Dr. Cowling was more circumspect. Because asymptomatic people do not cough or sneeze, he said, it is possible that they are less efficient at expelling the virus than those who are clearly unwell.
- On the other hand, Dr. Gaglia offered, people who feel ill tend to take to the bed or couch, whereas the infected but unaware may carry on with their business, sickening others along the way.
- The South Korean team analyzed samples taken between March 6 and March 26 from 193 symptomatic and 110 asymptomatic people isolated at a community treatment center in Cheonan. Of the initially asymptomatic patients, 89 — roughly 30 percent of the total — appeared healthy throughout, while 21 developed symptoms.
- The participants were mostly young, with a median age of just 25. (A study last week found that children, who are mostly mildly infected, also harbor at least as much virus as adults do.)
- “The real strength of the study is they have a very large number of patients and they have very good follow-up,” Dr. Gaglia said. “When they talk about asymptomatic patients, they really, really know that these were true asymptomatics.”
- The study’s estimate that 30 percent of infected people never develop symptoms is in line with findings from other studies. In a television interview on Wednesday, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, tendered 40 percent as the figure.
- “The good news about C19 is that about 40 percent of the population have no symptoms when they get infected,” Dr. Fauci said. But “even though you are likely not going to get symptoms, you are propagating the outbreak, which means that you’re going to infect someone, who will infect someone, who then will have a serious consequence.”
- The participants in the new study were all isolated when they tested positive for the virus and did not have the opportunity to infect others. Doctors and nurses tracked their temperatures and other symptoms, and tested their sputum — which indicates virus present in the lungs — as well as their noses and throats.
- “Both groups had similar amounts of virus pretty much throughout the entire course of infection,” Dr. Kindrachuk said. Asymptomatic people became virus-free a little sooner: around Day 17, compared with Day 19 or 20 for those with symptoms.
- Both estimates are much longer than the period of isolation required in most countries, Dr. Gaglia noted. The Centers for Disease Control and Prevention recently decreased the recommended isolation for infected people without symptoms to 10 days from 14.
- Several studies have suggested that infected people shed — or pass into the environment — live coronavirus for only about a week, even though the tests may pick up viral fragments in their bodies for much longer.
- Dr. Cowling also noted that the study was retrospective, meaning the researchers looked at samples collected from people who had tested positive earlier, instead of following a group of people over time, identifying everyone who became infected as well as their contacts, and assessing their symptoms and virus levels.
- “It would still be valuable to design a study like that,” he said. Still, he conceded that comparing people with symptoms and without was challenging because infected people are found in varying ways.
- Most testing plans focus on people who need medical care, and rarely whole groups regardless of symptoms — especially in places like the United States, where tests are often scarce to begin with.
- A lack of testing can also influence how much asymptomatic people contribute to the size of an outbreak.
- With enough testing, everyone found to be infected could be separated from others. But if the testing is barely enough to catch the visibly ill, then asymptomatic people — particularly the young and social — may fan out into society and keep the virus circulating at high levels.
- Many other viruses can be spread by people without symptoms, usually at negligible levels, Dr. Kindrachuk said.
- It’s still unclear whether the new coronavirus is unusual in this respect, able to spread widely from asymptomatic people, he added, or whether it just seems so prolific because of the scale of the pandemic. Studies addressing those questions are underway.
- “There are all these small nuances about this virus that are coming to light each day,” Dr. Kindrachuk said.
2. Common Colds May Have ‘Primed’ People’s Immune Systems For C19
- A cold you got years ago may prove helpful if your body has to fight the new coronavirus.
- According to a study published Tuesday, some people who’ve never been exposed to the new coronavirus may nonetheless have T cells that react to it. Scientists think that’s because those cells previously learned how to identify and fight coronaviruses that cause common colds.
- A type of white blood cell, T cells are a crucial part of the body’s defence against a virus: They identify and destroy infected cells while also informing B cells about how to craft new antibodies. When you’re infected, your immune system generates both antibodies and these white blood cells.
- Antibody levels can drop in the months following an infection, but memory T cells stick around for years and can help mount another attack should the same virus ever return.
- Recent research suggests that T cells that remember how to fight other coronaviruses may give people an immunological head start against the new coronavirus.
- “This could help explain why some people show milder symptoms of disease while others get severely sick,” Alessandro Sette, a coauthor of the new study, said in a press release. He cautioned, though, that it’s too soon to tell whether that preexisting immunological memory affects C19 patients’ outcomes.
Some T cells recognise the new coronavirus without having seen it before
- Sette’s team analysed blood samples collected between 2015 and 2018 from 25 people who, of course, had never had C19. They found that those unexposed individuals had memory T cells that could recognise both the new coronavirus and the four types of common cold coronaviruses.
- Those findings were based on research Sette published in May, in which he described 10 people who had never been exposed to the new coronavirus yet had helper T cells capable of identifying and responding to it.
- He also did a larger analysis looking at data from cohorts in the US, Netherlands, Germany, Singapore, and the UK, and concluded that white blood cells from 20 percent to 50 percent of unexposed people significantly react to the new coronavirus.
- “Pre Existing immune reactivity exists to some degree in the general population,” Sette wrote in the analysis.
Two other recent studies offer even more evidence for this conclusion
- The first, published last month, found that among 68 healthy Germans who’d never had C19, more than one-third had T cells that reacted to the virus. The second, published in the journal Nature, found that more than half of a group of 37 healthy people who had never gotten C19 had memory T cells that could recognise the new coronavirus.
- The Nature study also examined 23 people who’d survived SARS – which is a coronavirus, too – and found that they still had SARS-specific memory T cells 17 years after getting sick. Those same T cells could recognise the new coronavirus as well.
People with cross-reactive T cells might mount a faster immune response
- The likeliest explanation for these observations is a phenomenon called cross-reactivity: when T cells developed in response to one virus react to a similar, but previously unknown, pathogen.
- That can give the immune system a leg up.
- “You’re starting with a little bit of an advantage – a head start in the arms race between the virus that wants to reproduce and the immune system wanting to eliminate it,” Sette previously told Business Insider.
- In the absence of cross-reactive T cells, your body has to mount its defence from scratch – which could impact how expediently your immune system can respond to the invading virus. Varying levels of cross-reactivity might therefore “translate to different degrees of protection,” Sette said.
- “Having a strong T cell response, or a better T cell response may give you the opportunity to mount a much quicker and stronger response,” he added.
C. Improved & Potential Treatments
1. Two Existing Medications May Be An Effective Treatment Against C19
- A team of chemists from HSE University and the Zelinsky Institute of Organic Chemistry used molecular modeling to find out that two medications that have been known for a long time can be used to fight the coronavirus.
- These are disulfiram, which is used to treat alcoholism, and neratinib, an experimental drug being used to treat breast cancer. Both drugs are potential covalent inhibitors of the coronavirus virus main protease Mpro – a key enzyme responsible for coronavirus replication (copying its genetic material and building the new virus particles).
What Is This About?
- A coronavirus was first detected in a patient with acute respiratory infection long ago, in 1965, but it was only about two decades ago that humanity faced really dangerous representatives of this family. Unfortunately, since the first SARS-CoV epidemic didn’t leave Asia (mostly, China) in 2002-2004 and the MERS outbreak in 2012-2015 seriously affected only Saudi Arabia and Korea, the global pharmaceutical industry has made virtually no effort to develop effective treatments for coronaviruses. Tests and medications have been actively developed almost exclusively for the needs of veterinary medicine.
- Broad-spectrum medicines were used during previous epidemics, but the experience of medics in Chinese Wuhan demonstrated that this was not enough. Clinicians around the world have risked trying various experimental protocols, with the use of medicines used to treat HIV (lopinavir and ritonavir), malaria (chloroquine and hydroxychloroquine), and other diseases. But they were looking for the drugs being effectively blindfolded.
- The global pharmaceutical industry was caught unaware, and there was no time to create brand new medicines. Even if potentially effective substances are detected, their preclinical and clinical trials would take from four to seven years.
- That’s why the most reasonable solution has been to search among known drugs that have proven to be safe for human health. This path – repurposing medicine – has been effectively used for a long time. The only problem is: how do we learn whether they are able to fight the coronavirus?
- Computer modeling can help. This approach is called in silico — similarly to in vivo (in a living body) and in vitro (in a test tube). It allows numerical models to be used to test hundreds of various medications and determine their potential effectiveness and the mechanism of action. Chemists at HSE University and the RAS Zelinsky Institute of Organic Chemistry have been carrying out such research for many years. In 2014, they modeled a leukemia treatment, and in 2017, a treatment for rheumatoid arthritis. With such a background, the researchers jumped into the search for a SARS-CoV-2 treatment in 2020.
How Was it Studied?
- The coronavirus, like many other viruses, mutates quite quickly. Its genome contains about 30,000 nucleotides – specific ‘building blocks’ of the genetic code. On average, one mutation, or more precisely, one SNP (single nucleotide polymorphism) happens in a virus RNA once every two weeks.
- This means that new strains of the coronavirus appear regularly. In Russia alone, there are nine unique coronavirus lineages that are not present in other countries.
- This is why the structural elements of the virus that are less subject to mutation during its evolution should be chosen as a target for the potential treatment. Otherwise, a medication effective against one strain would no longer be effective against another.
- The best candidates for this are conservative proteins, such as the coronavirus main protease Mpro. In addition to being resistant to mutations, Mpro plays a major role in coronavirus replication, which means that its inhibition (blocking its function) is able to slow down or even completely stop its reproduction inside the body.
- Usually, the process of docking, as with a port dock and a ship entering it, is used for molecular modeling in simple cases. Two molecules participate in docking. One is called a ‘ligand’ (here, it is a medicine), and the other one is ‘receptor’ (or active site) of the target protein, such as Mpro, which can be used to ‘dock’. An effective drug docks with the active site, by covalent links, which makes the enzyme dysfunctional or destroys it.
A visualization of docking of a small ligand molecule (blue) with protein receptor (red).
- To simulate the docking, researchers need to know the precise spatial structure of the drug molecule (they are available in special databases) and the precise configuration of the target protein’s active site. Here, researchers may face the first challenges: there might be dozens or even hundreds of such sites, and they are not fixed in space. That’s why classical docking does not work in the coronavirus.
- To overcome this problem, chemists from HSE University and the Zelinsky Institute decided to use ‘on-top docking’, which they came up with shortly before the pandemic. They decided not to focus on the previously described active site, but to investigate the whole surface of Mproprotein with many medications, hoping that the big calculation powers would return useful ‘dockings’.
- The potential drugs were taken from the database of medications approved by the United States FDA. The research team’s own algorithms were used for modeling.
What Were the Results?
- The modeling data demonstrated that sulfur-containing drugs show unusually high ligand efficiency at the active center of the coronavirus main protease Mpro, but only disulfiram 4 retains stable interactions.
Structure formula of disulfiram.
- Today, disulfiram is most commonly used for treating alcoholism, since disulfiram inhibits the acetaldehyde dehydrogenase enzyme. As a result, the conversion of ethanol in the liver stops on the stage of acetaldehyde. Its concentration in the body grows, leading to acute intoxication, accompanied by sickness, vomiting and extreme pain. As a result, alcohol addicts acquire a conditioned reflex of disgust to the smell and taste of alcohol-containing drinks. This means that if the effectiveness of disulfiram against the novel coronavirus will be confirmed, this would help to solve two problems in Russia at once, at the same time decreasing alcohol addiction in the population.
- Disulfiram fights the coronavirus in two ways. First, as previously demonstrated in vitro with SARS and MERS coronaviruses, it is a covalent inhibitor. In addition, it fights C19 symptoms such as the significant decrease in reduced glutathione, which is an important antioxidant. This deficiency may lead to severe manifestations of the disease.
- In addition to disulfiram, the Russian chemists were the first to predict the potential efficiency of neratinib, an irreversible tyrosine kinase inhibitor, against the coronavirus. Just recently, in 2017, FDA approved neratinib as an adjuvant treatment of breast cancer.
How Can This Be Used?
- Modeling has shown that both potential inhibitors of the main coronavirus protease (Mpro) are, presumably, covalent. For example, disulfiram can probably block the Mpro enzymatic activity by thiol–disulfide exchange reaction, while neratinib binding suggests the possibility of covalent interaction similarly to covalent peptide inhibitors.
- It’s important to clarify that any modeling can only predict such interactions, but not prove their presence. The research cycle consists of at least three stages: modeling, synthesis of potentially active structures, and biological (pharmaceutical) testing of the necessary activity – real, rather than calculated effectiveness of the drug. Modeling alone, just like any other theoretical research, means nothing without following experimental confirmations. That’s why now is time for extensive practical work on validating the results received as part of ‘on-top docking’.
- The tests that were performed on July 27, 2020, at Reaction Biology Corp., a certified laboratory in the U.S., demonstrated that disulfiram really inhibits Mpro in 100 nm concentration, which confirmed the results of the modeling. Unfortunately, the second substance – neratinib – demonstrated activity on Mpro, but it was insufficient for clinical use. On September 1, 2020, clinicians will start drug trials in vitro and in experimental treatments of patients with the coronavirus.
- Chinese biochemists carried out a massive experimental search for active structures simultaneously and independently of the Russian researchers. They have also detected potential activity of disulfiram to the coronavirus main protease Mpro. Unfortunately, they did it two weeks earlier than the Russian chemists, so the publication in Nature is theirs (the paper will be issued in August). This serves as additional evidence of the importance of having powerful computational resources for modelling and capabilities for biological experiments.
- Meanwhile, the main achievement is the demonstration that the ‘on-top docking’ approach is working and returns quite realistic and controllable results. The team’s plans for late 2020 and 2021 include molecular modeling of treatments for diseases that have demonstrated their harmfulness but have not yet spread over the world.
- It’s important to mention that any molecular modeling requires significant computational resources, and before cooperating with HSE University, the chemists had been able to use their method only on very limited terms. Today, they have access to HSE University’s powerful supercomputer, which can help them search among existing drugs and perform targeted synthesis of new pharmaceutical products.
- This is a brilliant example of fruitful cooperation between a university and a Russian Academy of Sciences institute. An obvious next step in such academic cooperation is organizing a Laboratory of Molecular Modelling at HSE University. This laboratory would not only create drugs, but it would model various chemical processes both by means of docking or other simple methods and by more universal and complicated quantum chemistry methods.
- Meanwhile, the global chemistry community is facing the next challenge – modeling the structure of an inhibitor for the protein of the G4 EA H1N1 virus – a novel swine flu that was recently been detected in China. Researchers believe that this infection is much more dangerous and transfers more quickly from a human to human than C19. To deal with it, researchers will need support, both in terms of resources and tools, and they will also need support organizing productive academic work and priority setting.
D. Vaccines & Testing
1. A simpler, faster C19 test
- In some parts of the U.S. right now, it can take weeks to get results for a simple C19 test, a delay that renders the results largely useless.
- So a handful of city governments and schools are turning to an entirely different type of C19 test that they say is simpler, easier, and most importantly faster — and therefore more meaningful.
- The tests are like a streamlined version of the far more common PCR tests used to diagnose C19. The test’s simpler process requires fewer materials and less equipment; the results can be read by eye within an hour. But the technique — known as LAMP — can also, in some situations, be less sensitive and less accurate than PCR tests. And it can be hard to run many of the tests at once outside of a central laboratory; people can only work so quickly.
- Enter Color Genomics, a California-based, direct-to-consumer DNA test company that says it has solved many of the problems associated with the technique. Its C19 tests are just as accurate as PCR tests, according to the documents it filed to the F for an emergency authorization. And it’s automated the process enough to run thousands of tests each day. Already, Color is processing about half of all the daily tests run in San Francisco and returning results in one to three days.
- But Color’s improvements come with tradeoffs. Experts told STAT that an additional step in the company’s process means it costs more and takes more time than others. Color’s automation setup might not be cheap to replicate around the country. And since Color uses the same swabs and some of the same chemicals that so many PCR tests rely on, it could also face some of the same supply chain issues that have plagued other testing efforts.
- “It opens up the flexibility of the supply chain to this PCR alternative, which is nice. But it doesn’t overcome some of the common barriers to testing,” said Matthew Lalli, a researcher studying genomics technologies at Washington University in St. Louis.
- The technology behind the tests is known as LAMP, or loop-mediated isothermal amplification. It’s been around since the 1990s, when a Japanese scientist developed it as a less-intensive alternative to PCR, or polymerase chain reaction-based tests.
- Both PCR-based and LAMP-based tests look for genetic strands of a given virus in a sample collected from a patient. But PCR requires that a sample be repeatedly heated up and cooled down in precise intervals using an expensive machine known as a thermocycler.
- LAMP does not require a thermocycler. The reaction can be run at a constant temperature — about 65 or 70 degrees Celsius, or 150 degrees Fahrenheit. That makes it far simpler to run, and far less equipment-intensive. The reaction also creates a change in the acidity level of a sample; often, a compound that changes color from pink to yellow in different pH conditions is added to the tube, which means anyone can read the results.
- Before this year, LAMP-based tests have been used for screening animal food for Salmonella as well as diagnosing C. difficile infections in humans and chlamydia in koalas.
- And several groups around the world are developing new C19 testing programs around LAMP. Many are relatively basic: In Racine, Wis., for example, researchers are running LAMP tests in an unused corner of city hall with minimal equipment and supplies, as Wired reported last month. Another Wisconsin group is running tests in elementary school parking lots. And a hospital in Germany is experimenting with a LAMP-based surveillance protocol developed at the Broad Institute.
- But many of those point-of-care LAMP tests have an admitted shortcoming: Though they are simple, cheap, and fast, they are also less sensitive than PCR tests. Because of that, it’s often used for screening groups to try to catch most of the people who might have a disease — not to formally diagnose someone.
- There’s a type of PCR, for example, that “has a nearly perfect sensitivity. You cannot beat that,” said Jonathan Schmid-Burgk, a professor at University Hospital Bonn who has also developed a test that relies on LAMP technology and who is not affiliated with Color Genomics.
- Color Genomics’ LAMP-based tests solve that problem by adding a little complexity. Before Color actually runs the LAMP protocol on a swab, it extracts and purifies the RNA. This step, which is done on a particular machine that uses magnetic beads, concentrates the RNA.
- “This [step] directly translates to sensitivity,” said Schmid-Burgk — that is, it can make it more likely that a test will give accurate negative results.
- The company’s EUA paperwork indicates that for more than 500 samples, its test gave the same results as the C19 diagnostic test developed by the Centers for Disease Control and Prevention.
- Color’s been using the technology for C19 tests since April; the company got the first-ever FDA emergency authorization for the test in May.
- The 7-year-old company is far better known for selling genetic tests — work that investors and governments alike have been willing to fund. It raised $215 million from venture capitalists and received grants worth millions through the NIH’s All of Us program, which intended to sequence q million Americans’ genomes.
- When the pandemic came to the U.S., Color expected that it would be helping labs figure out how to automate certain processes to take some of the human effort out of running C19 tests.
- “The deciding factor for us was the realization that no one we were talking to was taking an integrated approach similar to what had made us successful in genetics,” said Color spokesperson Benjamin Kobren. “Lab people were trying to build a lab. Logistics people were trying to set up drive-through sites, and so on.”
- But in the early days of the pandemic, supplies to run PCR tests were in very short supply. Color’s team worried that competing with other labs for limited supplies might exacerbate the testing problem. So they looked at alternate protocols, like LAMP, that wouldn’t add stress to some of the PCR supply chains.
- “The thing that made it good for point-of-care testing was actually the thing that we thought would make it really good for super high-throughput labs — which is that it’s a relatively simple process,” said Color’s CEO, Othman Laraki. “We’re able to run almost the entire process on a single robot.”
- San Francisco’s city government began working with Color in early April, according to a spokesperson. Color is one of a handful of labs behind the CityTestSF program, which offers testing by appointment for San Francisco residents and essential workers. The company charges about $100 per test, a San Francisco city representative told STAT; that figure is about the same as Medicare’s current reimbursement rate for C19 PCR tests.
- Kobren, the company’s spokesman, noted that the price of a test can vary, depending on how many tests are included in a particular contract and what kind of group that contract covers.
- Since the program began, Color says it has been able to deliver results far more quickly than many other laboratories. Results from Color are usually available within one to three days, the company’s website states.
- That kind of turnaround time has been critical, said Sarah Owens, the deputy press director for San Francisco’s mayor.
- “Effective contact tracing depends on C19 results being received in a timely manner,” Owens said. Getting results back quickly “allows us to contact people who test positive and begin the process of reaching out to their close contacts more quickly, thereby slowing the spread of C19 in the community.”
- Color’s LAMP tests are also the foundation of the University of Southern California’s testing program; the company said in a press release that it expects to run at least 500 tests per day on samples collected at three different sites.
- Experts caution Color’s test isn’t suddenly going to replace PCR tests around the country.
- For one, its product is proprietary; only Color’s lab can process the tests, necessarily limiting how many can be run in a day. Color’s worked hard to increase the number — its automated process can now handle 10,000 tests per day.
- “Purifying RNA is really tedious,” said Schmid-Burgk. Adding purification may increase a test’s sensitivity. However, it also increases the time a test needs to process and can ultimately cuts down on the number of tests a lab can process each day.
- “You kind of lose the speed advantage by adding an RNA extraction step,” said Lalli, the Washington University in St. Louis researcher.
- Color’s automated setup is also expensive. Replicating Color’s automation would require about $500,000 worth of equipment, according to Chris Mason, a computational genomics specialist at Weill Cornell Medicine.
- Even existing clinical laboratories with deep pockets might hesitate before ordering equipment and supplies to set up an entirely new protocol when PCR machines are already sitting in their facilities.
- “Most labs have PCR equipment, but many do not have LAMP, so it logistically makes it more difficult to bring up in the scale needed for widespread testing,” a Quest spokesperson noted.
- Another potential challenge: While some parts of Color’s LAMP reaction uses machines and chemicals that are completely distinct from those needed for PCR tests, Color’s process still requires some of the same supplies — like swabs, RNA extraction kits and pipette tips.
- The New York Times reported that those supplies may become scarce again soon — which means that even Color itself could ultimately be unable to use its lab’s full capacity or unable to process tests as quickly as it is now.
- But Color’s team is optimistic that it’s prepared for that possibility. The company is hiring more people, adding additional equipment, and partnering with other labs that can run PCR tests in order to handle potential increases in demand. And Kobren, the company spokesman, told STAT that the company believes its automation “enables us to reduce per-test consumption of scarce resources such as pipette tips and tubes.”
- “We continue to invest resources and R&D to make our processes as efficient as possible.”
E. Concerns & Unknowns
1. Implications of Coronavirus Mutations
- On July 2, researchers from Los Alamos Laboratory released a new study in Cell (available here) that examines whether a particular mutation of the coronavirus increases the virus’ transmission rate. Of primary concern to the study’s authors is the G614 mutation on the spike protein of the coronavirus, the protein responsible for invading host cells. The authors contend that this mutation began circulating throughout Europe in early February and began displacing the D614 form of the virus that originated in Wuhan, China. According to the study, this G614 variant possesses a higher transmission rate, results in a higher viral load, and consistently becomes the dominant form of the virus wherever it spreads.
- Understanding how a virus is mutating is important for several reasons. Do mutations make the virus more dangerous, as described above? If there are different strains, will they respond to treatments differently, or target different segments of the population? And what does it all mean for having an effective vaccine?
- While some researchers immediately embraced this study as a clear indicator that this particular mutation is increasing the virus’ transmissibility rate, others are less convinced. Dr. Raul Andino-Pavlovsky, a professor of microbiology and immunology at the University of California at San Francisco, called the spike protein mutation findings “intriguing,” but told The Dispatch “it may be a little too early to say that [these mutations] are being selected.” Dr. William Schaffner, an infectious disease specialist at the Vanderbilt University Medical Center, told us “it is too early to draw those conclusions.”
- Other scientists suggest that gene sequencing studies focus too much on singular mutations when there’s so much about the virus we still don’t know. “People who are writing papers about sequence variation want to highlight the variation that they find because that’s how they’re going to publish the paper,” said Dr. Colin Parrish, a professor of virology at Cornell University. Excessive gene sequencing for the coronavirus has already become the norm, meaning that moving forward, researchers will continue talking about mutations “as if they’re more important than they may well be.”
- According to Parrish, “There are a hundred people doing sequencing for every one person that’s doing biology or actually going back and testing mutations for their real effect on the virus’ replication.” But even if particular mutations are unlikely to change viral behavior, tracing a virus’ lineage—or phylogeographic variation—can be helpful from a public health point of view. “There are sufficient mutations so that virologists can track the lineage of the virus,” Schaffner said, meaning “they can distinguish the viruses that probably came to the U.S. from Europe from those that came to us from Asia.”
- What makes this mutation worth highlighting? According to Bette Korber, the study’s leading author, the coronavirus is shifting toward the “G clade” form (which refers to the particular descendant of the coronavirus that contains the G614 mutation on the virus’ spike protein). This mutation, she claims, is not due to random chance, but rather a fitness advantage.
- She explains that random things, like superspreader events or human hosts moving into new regions, “are by definition just that, random.” So, if the two forms were equally likely to propagate,” she said, “you wouldn’t expect such a shift to almost always go in one direction, towards higher frequency G clade.” The repetition of this particular pattern in nearly all of the locations they studied—with few exceptions—is what Korber and her colleagues “found to be compelling evidence of positive selection,” meaning a mutation that improves the overall fitness of the virus.
- Before jumping to conclusions, it’s worth mentioning that viral mutations are a normal part of the evolutionary process. Every time a virus infects a new host, it takes over the host’s replication machinery to reproduce billions of genetic copies of itself so that the virus can spread to other cells. When viruses reproduce, they will inevitably make mistakes—mutations—that become incorporated into the viral genome. Whereas DNA viruses—such as smallpox and HPV—have a low mutation rate, RNA viruses regularly mutate. According to Parrish, most of these RNA mutations “decrease the fitness of the virus and so they generally get purged from the virus over time.”
- But some phylogenetic patterns accumulate over time, creating new lineages within the virus’ evolutionary tree. In a process called genetic drift, some mutations cause the frequency of an existing gene variant within a particular population to change over time by chance alone. Of course, not all of these fixed mutations from genetic drift confer evolutionary benefits to the virus.
- If, however, mutations do provide an advantage to the virus, then they will be selected for, meaning they will be more likely to replicate and transmit over time. These adaptive mutations—which are essentially happy accidents from a virus’ point of view—often take the form of improving transmissibility and resistance to antiviral drugs like remdesivir. Selective mutations can also change a virus’ antigenic properties, allowing it to cause disease in formerly resistant hosts, or its “pathogenicity,” meaning its ability to infect and harm its host in the first place.
- But how do we know when a new mutation constitutes a new viral strain? “In our original preprint we used the word ‘strain’ to refer to viruses that carried the G614D,” Korber told The Dispatch. She said this term was rejected by many other scientists who said the word “strain” should be used more judiciously. For example: Only if the genetic variant is associated with unique phenotypic characteristics that are different from the compared reference virus.”
- “If you call it a new strain then there’s zillions of new strains out there because almost every virus will have some mutation that may or may not be of any importance,” said Dr. Diane Griffin, a professor in the department of molecular microbiology and immunology at the
- Johns Hopkins Bloomberg School of Public Health. Typically, a strain refers to a mutation that is similar enough to be part of the same species of virus but deserves some degree of differentiation because it behaves differently. One way to determine whether a mutation constitutes a strain is to see if it confers functional differences in terms of its virulence, resistance, or transmissibility. Scientists can also look at phenotypic variation between mutations, including its reproductive capabilities, increased titers, or survival rate.
- “We don’t have any evidence for greater or lesser virulence,” said Dr. Paul Offit—director of the Vaccine Education Center at Children’s Hospital of Philadelphia—regarding G614 mutation, “but I think there is reasonable evidence for increased transmissibility.” Still, this functional difference does not necessarily constitute a new strain. “It’s tricky because essentially you’re always making strains,” he added.
- Looking beyond the specific mutation the study’s authors cite, it’s important to consider how often a virus mutates. Whereas some viruses—like polio, HIV and influenza—are constantly mutating, other viruses remain stable over long stretches of time. Influenza is a single stranded RNA virus that serves as a perfect example of what scientists call a very “plastic” virus. The flu mutates so much from one year to the next that natural infection or immunization from the previous year does not typically protect individuals from the functional mutation of the new virus, hence the need for a new vaccine each year. Sometimes there is a carry-over effect, although this is quite rare.
- But other viruses, like measles, hardly mutate at all. “The essential measles virus is the same virus that was around in 1934, just to pick a number out of the hat,” said Schaffner. “It’s pretty darn stable, and that’s why we have one measles vaccine. It works around the world, it’s worked for 50 years, and it’s going to keep working because this is a very stable virus.”
- The coronavirus is somewhere in the middle. According to Diana Griffin, coronaviruses “have some editing function, but they still have an error prone polymerase.” This means that unlike most other RNA viruses, coronaviruses have some capacity to identify errors while copying nucleic material, thus reducing the mutation rate. Because of its low mutation rate, the coronavirus has remained generally stable, which is a good sign for vaccine research.
- “This is very important.” Schaffner said, “particularly as regards the now notorious spike protein on its surface, because that means all this vaccine work that’s going on around the world is more likely to result in successful vaccines, because the virus, unlike flu, is not mutating in its essence.” Whereas many vaccines undergoing trial tests are targeting the coronavirus’ spike protein in particular, scientists are also developing RNA vaccines, DNA vaccines, viral vector vaccines, and recombinant vaccines, among others, which target other parts of the virus.
- It is possible that after a long period of time—say, 10 to 20 years—the virus may vary sufficiently such that it can start to evade the vaccines that we make now. But there is some good news about the mutation that is the subject of the Cell study. As much as it might be increasing transmission rate, “the G614 form is actually more sensitive to neutralizing antibodies,” said Korber. This means that even if the G614 mutation continues to spread, a vaccine targeting it will likely be extremely effective.
Study: Full study is available at https://www.cell.com/cell/fulltext/S0092-8674(20)30820-5#%20
2. America’s Obesity Epidemic Threatens Effectiveness of Any COVID Vaccine
- For a world crippled by the coronavirus, salvation hinges on a vaccine.
- But in the United States, the promise of that vaccine is hampered by a vexing epidemic that long preceded C19: obesity.
- Scientists know that vaccines engineered to protect the public from influenza, hepatitis B, tetanus and rabies can be less effective in obese adults than in the general population, leaving them more vulnerable to infection and illness. There is little reason to believe, obesity researchers say, that C19 vaccines will be any different.
- “Will we have a COVID vaccine next year tailored to the obese? No way,” said Raz Shaikh, an associate professor of nutrition at the University of North Carolina-Chapel Hill.
- “Will it still work in the obese? Our prediction is no.”
- More than 107 million American adults are obese, and their ability to return safely to work, care for their families and resume daily life could be curtailed if the coronavirus vaccine delivers weak immunity for them.
- In March, still early in the global pandemic, a little-noticed study from China found that heavier Chinese patients afflicted with C19 were more likely to die than leaner ones, suggesting a perilous future awaited the U.S., whose population is among the heaviest in the world.
- And then that future arrived.
- As intensive care units in New York, New Jersey and elsewhere filled with patients, the federal Centers for Disease Control and Prevention warned that obese people with a body mass index of 40 or more — known as morbid obesity or about 100 pounds overweight — were among the groups at highest risk of becoming severely ill with C19. About 9% of American adults are in that category.
- As weeks passed and a clearer picture of who was being hospitalized came into focus, federal health officials expanded their warning to include people with a body mass index of 30 or more. That vastly expanded the ranks of those considered vulnerable to the most severe cases of infection, to 42.4% of American adults.
- Obesity has long been known to be a significant risk factor for death from cardiovascular disease and cancer. But scientists in the emerging field of immunometabolism are finding obesity also interferes with the body’s immune response, putting obese people at greater risk of infection from pathogens such as influenza and the novel coronavirus. In the case of influenza, obesity has emerged as a factor making it more difficult to vaccinate adults against infection. The question is whether that will hold true for C19.
- A healthy immune system turns inflammation on and off as needed, calling on white blood cells and sending out proteins to fight infection. Vaccines harness that inflammatory response. But blood tests show that obese people and people with related metabolic risk factors such as high blood pressure and elevated blood sugar levels experience a state of chronic mild inflammation; the inflammation turns on and stays on.
- Adipose tissue — or fat — in the belly, the liver and other organs is not inert; it contains specialized cells that send out molecules, like the hormone leptin, that scientists suspect induces this chronic state of inflammation. While the exact biological mechanisms are still being investigated, chronic inflammation seems to interfere with the immune response to vaccines, possibly subjecting obese people to preventable illnesses even after vaccination.
- An effective vaccine fuels a controlled burn inside the body, searing into cellular memory a mock invasion that never truly happened.
- Evidence that obese people have a blunted response to common vaccines was first observed in 1985 when obese hospital employees who received the hepatitis B vaccine showed a significant decline in protection 11 months later that was not observed in non-obese employees. The finding was replicated in a follow-up study that used longer needles to ensure the vaccine was injected into muscle and not fat.
- Researchers found similar problems with the hepatitis A vaccine, and other studies have found significant declines in the antibody protection induced by tetanus and rabies vaccines in obese people.
- “Obesity is a serious global problem, and the suboptimal vaccine-induced immune responses observed in the obese population cannot be ignored,” pleaded researchers from the Mayo Clinic’s Vaccine Research Group in a 2015 study published in the journal Vaccine.
- Vaccines also are known to be less effective in older adults, which is why those 65 and older receive a supercharged annual influenza vaccine that contains far more flu virus antigens to help juice up their immune response.
- By contrast, the diminished protection of the obese population — both adults and children — has been largely ignored.
- “I’m not entirely sure why vaccine efficacy in this population hasn’t been more well reported,” said Catherine Andersen, an assistant professor of biology at Fairfield University who studies obesity and metabolic diseases. “It’s a missed opportunity for greater public health intervention.”
- In 2017, scientists at UNC-Chapel Hill provided a critical clue about the limitations of the influenza vaccine. In a paper published in the International Journal of Obesity, they showed for the first time that vaccinated obese adults were twice as likely as adults of a healthy weight to develop influenza or flu-like illness.
- Curiously, they found that adults with obesity did produce a protective level of antibodies to the influenza vaccine, but they still responded poorly.
- “That was the mystery,” said Chad Petit, an influenza virologist at the University of Alabama.
- One hypothesis, Petit said, is that obesity may trigger a metabolic dysregulation of T cells, white blood cells critical to the immune response. “It’s not insurmountable,” said Petit, who is researching C19 in obese patients. “We can design better vaccines that might overcome this discrepancy.”
- Historically, people with high BMIs often have been excluded from drug trials because they frequently have related chronic conditions that might mask the results. The clinical trials underway to test the safety and efficacy of a coronavirus vaccine do not have a BMI exclusion and will include people with obesity, said Dr. Larry Corey, of the Fred Hutchinson Cancer Research Center, who is overseeing the phase 3 trials sponsored by the National Institutes of Health.
- Although trial coordinators are not specifically focused on obesity as a potential complication, Corey said, participants’ BMI will be documented and results evaluated.
- Dr. Timothy Garvey, an endocrinologist and director of diabetes research at the University of Alabama, was among those who stressed that, despite the lingering questions, it is still safer for obese people to get vaccinated than not.
- “The influenza vaccine still works in patients with obesity, but just not as well,” Garvey said. “We still want them to get vaccinated.”
F. The Road Back?
1. 40% of people with coronavirus have no symptoms. Might they be the key to ending the pandemic?
- When researcher Monica Gandhi began digging deeper into outbreaks of the novel coronavirus, she was struck by the extraordinarily high number of infected people who had no symptoms.
- A Boston homeless shelter had 147 infected residents, but 88% had no symptoms even though they shared their living space. A Tyson Foods poultry plant in Springdale, Ark., had 481 infections, and 95% were asymptomatic. Prisons in Arkansas, North Carolina, Ohio and Virginia counted 3,277 infected people, but 96% were asymptomatic.
- During its seven-month global rampage, the coronavirus has claimed more than 700,000 lives. But Gandhi began to think the bigger mystery might be why it has left so many more practically unscathed.
- What was it about these asymptomatic people, who lived or worked so closely to others who fell severely ill, she wondered, that protected them? Did the “dose” of their viral exposure make a difference? Was it genetics? Or might some people already have partial resistance to the virus, contrary to our initial understanding?
- Efforts to understand the diversity in the illness are finally beginning to yield results, raising hope that the knowledge will help accelerate development of vaccines and therapies – or possibly even create new pathways toward herd immunity in which enough of the population develops a mild version of the virus that they block further spread and the pandemic ends.
- “A high rate of asymptomatic infection is a good thing,” said Gandhi, an infectious-disease specialist at the University of California at San Francisco. “It’s a good thing for the individual and a good thing for society.”
- The coronavirus has left numerous clues – the uneven transmission in different parts of the world, the mostly mild impact on children. Perhaps most tantalizing is the unusually large proportion of infected people with mild symptoms or none at all. The CDC last month estimated that rate at about 40%.
- Those clues have sent scientists off in different directions: Some are looking into the role of the receptor cells, which the virus uses to infiltrate the body, to better understand the role that age and genetics might play. Others are delving into masks and whether they may filter just enough of the virus so those wearing them had mild cases or no symptoms at all.
- The theory that has generated the most excitement in recent weeks is that some people walking among us might already have partial immunity.
- When the coronavirus was first identified on Dec. 31, 2019, public health officials deemed it a “novel” virus because it was the first time it had been seen in humans who presumably had no immunity from it whatsoever. There’s now some very early, tentative evidence suggesting that assumption might have been wrong.
- One mind-blowing hypothesis – bolstered by a flurry of recent studies – is that a segment of the world’s population may have partial protection thanks to “memory” T cells, the part of our immune system trained to recognize specific invaders. This could originate from cross-protection derived from standard childhood vaccinations. Or, as a paper published Tuesday in Science suggested, it could trace back to previous encounters with other coronaviruses, such as those that cause the common cold.
- “This might potentially explain why some people seem to fend off the virus and may be less susceptible to becoming severely ill,” National Institutes of Health Director Francis Collins remarked in a blog post this past week.
- On a population level, such findings, if validated, could be far-reaching.
- Hans-Gustaf Ljunggren, a researcher at Sweden’s Karolinska Institute, and others have suggested that public immunity to the coronavirus could be significantly higher than what has been suggested by studies. In communities in Barcelona, Boston, Wuhan and other major cities, the proportion of people estimated to have antibodies and therefore presumably be immune has mostly been in the single digits. But if others had partial protection from T cells, that would raise a community’s immunity level much higher.
- This, Ljunggren said, would be “very good news from a public health perspective.”
- Some experts have gone so far as to speculate about whether some surprising recent trends in the epidemiology of the coronavirus – the drop in infection rates in Sweden where there have been no widespread lockdowns or mask requirements, or the high rates of infection in Mumbai’s poor areas but little serious disease – might be due to preexisting immunity.
- Others say it’s far too early to draw such conclusions. Anthony Fauci, the United States’ top infectious-disease expert, said in an interview that while these ideas are being intensely studied, such theories are premature. He said at least some partial preexisting immunity in some individuals seems a possibility.
- And he said the amount of virus someone is exposed to – called the inoculum – “is almost certainly an important and likely factor” based on what we know about other viruses.
- But Fauci cautioned that there are multiple likely reasons – including youth and general health – that determine whether a particular individual shrugs off the disease or dies of it. That reinforces the need, in his view, for continued vigilance in social distancing, masking and other precautions.
- “There are so many other unknown factors that maybe determine why someone gets an asymptomatic infection,” Fauci said. “It’s a very difficult problem to pinpoint one thing.”
- News headlines have touted the idea based on blood tests that 20% of some New York communities might be immune, 7.3% in Stockholm, 7.1% in Barcelona. Those numbers come from looking at antibodies in people’s blood that typically develop after they are exposed to a virus. But scientists believe another part of our immune system – T cells, a type of white blood cell that orchestrates the entire immune system – could be even more important in fighting against the coronavirus.
- Recent studies have suggested that antibodies from the coronavirus seem to stick around for two to three months in some people. While work on T cells and the coronavirus is only getting started – testing T cells is much more laborious than antibody testing – previous research has shown that, in general, T cells tend to last years longer.
- One of the first peer-reviewed studies on the coronavirus and T cells was published in mid-May in the journal Cell by Alessandro Sette, Shane Crotty and others at the La Jolla Institute for Immunology near San Diego.
- The group was researching blood from people who were recovering from coronavirus infections and wanted to compare that to samples from uninfected controls who were donors to a blood bank from 2015 to 2018. The researchers were floored to find that in 40% to 60% of the old samples, the T cells seemed to recognize the coronavirus.
- “The virus didn’t even exist back then, so to have this immune response was remarkable,” Sette said.
- Research teams from five other locations reported similar findings. In a study from the Netherlands, T cells reacted to the virus in 20% of the samples. In Germany, 34%. In Singapore, 50%.
- The different teams hypothesized this could be due to previous exposure to similar pathogens. Perhaps fortuitously, the coronavirus is part of a large family of viruses. Two of them – SARS and MERS – are deadly and led to relatively brief and contained outbreaks. Four other coronavirus variants, which cause the common cold, circulate widely each year but typically result in only mild symptoms. Sette calls them the “less-evil cousins of the coronavirus.”
- This week, Sette and others from the team reported new research in Science providing evidence the T cell responses may derive in part from memory of “common cold” coronaviruses.
- “The immune system is basically a memory machine,” he said. “It remembers and fights back stronger.”
- The researchers noted in their paper that the strongest reaction they saw was against the spike proteins that the virus uses to gain access to cells – suggesting that fewer viral copies get past these defenses.
- “The current model assumes you are either protected or you are not – that it’s a yes or no thing,” Sette added. “But if some people have some level of preexisting immunity, that may suggest it’s not a switch but more continuous.”
- More than 2,300 miles away, at the Mayo Clinic in Cleveland, Andrew Badley was zeroing in the possible protective effects of vaccines.
- Teaming up with data experts from Nference, a company that manages their clinical data, he and other scientists looked at records from 137,037 patients treated at the health system to look for relationships between vaccinations and coronavirus infection.
- They knew that the vaccine for smallpox, for example, had been shown to protect against measles and whooping cough. Today, a number of existing vaccines are being studied to see whether any might offer cross-protection against the coronavirus.
- The results were intriguing: Seven types of vaccines given one, two or five years in the past were associated with having a lower rate of infection with the new coronavirus. Two vaccines in particular seemed to show stronger links: People who got a pneumonia vaccine in the recent past appeared to have a 28% reduction in coronavirus risk. Those who got polio vaccines had a 43% reduction in risk.
- Venky Soundararajan, chief scientific officer of Nference, remembers when he first saw how large the reduction appeared to be, he immediately picked up his phone and called Badley: “I said, ‘Is this even possible?'”
- The team looked at dozens of other possible explanations for the difference. It adjusted for geographic incidence of the coronavirus, demographics, comorbidities, even whether people had had mammograms or colonoscopies, under the assumption that people who got preventive care might be more apt to social distance. But the risk reduction still remained large.
- “This surprised us completely,” Soundararajan recalled. “Going in we didn’t expect anything or maybe one or two vaccines showing modest levels of protection.”
- The study is only observational and cannot show a causal link by design, but Mayo researchers are looking at a way to quantify the activity of these vaccines on the coronavirus to serve as a benchmark to the new vaccines being created by companies such as Moderna. If existing vaccines appear as protective as new ones under development, he said, they could change the world’s whole vaccine strategy.
- Meanwhile, at NIH headquarters in Bethesda, Md., Alkis Togias has been laser-focused on one group of the mildly affected: children. He wondered whether it might have something to do with the receptor known as ACE2, through which the virus hitchhikes into the body.
- In healthy people, the ACE2 receptors perform the important function of keeping blood pressure stable. The novel coronavirus latches itself to ACE2, where it replicates. Pharmaceutical companies are trying to figure out how to minimize the receptors or to trick the virus into attaching itself to a drug so it does not replicate and travel throughout the body.
- Was it possible, Togias asked, that children naturally expressed the receptor in a way that makes them less vulnerable to infection?
- He said recent papers have produced counterintuitive findings about one subgroup of children – those with a lot of allergies and asthma. The ACE2 receptors in those children were diminished, and when they were exposed to an allergen such as cat hair, the receptors were further reduced. Those findings, combined with data from hospitals showing that asthma did not seem to be a risk factor for the respiratory virus, as expected, have intrigued researchers.
- “We are thinking allergic reactions may protect you by down-regulating the receptor,” he said. “It’s only a theory of course.”
- Togias, who is in charge of airway biology for the National Institute of Allergy and Infectious Diseases, is looking at how those receptors seem to be expressed differently as people age, as part of a study of 2,000 U.S. families. By comparing those differences and immune responses within families, they hope to be able to better understand the receptors’ role.
- Separately, a number of genetic studies show variations in genes associated with ACE2 with people from certain geographic areas, such as Italy and parts of Asia, having distinct mutations. No one knows what significance, if any, these differences have on infection, but it’s an active area of discussion in the scientific community.
- Before the pandemic, Gandhi, the University of California researcher, specialized in HIV. But like other infectious-disease experts these days, she has spent many of her waking hours thinking about the coronavirus. And in scrutinizing the data on outbreaks one day, she noticed what might be a pattern: People were wearing masks in the settings with the highest percentage of asymptomatic cases.
- The numbers on two cruise ships were especially striking. In the Diamond Princess, where masks weren’t used and the virus was likely to have roamed free, 47% of those tested were asymptomatic. But in the Antarctic-bound Argentine cruise ship, where an outbreak hit in mid-March and surgical masks were given to all passengers and N95 masks to the crew, 81% were asymptomatic.
- Similarly high rates of asymptomatic infection were documented at a pediatric dialysis unit in Indiana, a seafood plant in Oregon and a hair salon in Missouri, all of which used masks. Gandhi was also intrigued by countries such as Singapore, Vietnam and the Czech Republic that had population-level masking.
- “They got cases,” she noted, “but fewer deaths.”
- The scientific literature on viral dose goes back to around 1938 when scientists began to find evidence that being exposed to one copy of a virus is more easily overcome than being exposed to a billion copies. Researchers refer to the infectious dose as ID50 – or the dose at which 50% of the population would become infected.
- While scientists do not know what that level might be for the coronavirus (it would be unethical to expose humans in this way), previous work on other nonlethal viruses showed that people tend to get less sick with lower doses and more sick with higher doses. A study published in late May involving hamsters, masks and SARS-CoV-2 found that those given coverings had milder cases than those who did not get them.
- In an article published this month in the Journal of General Internal Medicine, Gandhi noted that in some outbreaks early in the pandemic in which most people did not wear masks, 15% of the infected were asymptomatic. But later on, when people began wearing masks, the rate of asymptomatic people was 40% to 45%.
- She said the evidence points to masks not just protecting others – as U.S. health officials emphasize – but protecting the wearer as well. Gandhi makes the controversial argument that while people mostly have talked about asymptomatic infections as terrifying due to how people can spread the virus unwittingly, it could end up being a good thing.
- “It is an intriguing hypothesis that asymptomatic infection triggering immunity may lead us to get more population-level immunity,” Gandhi said. “That itself will limit spread.”
G. Back to School!?
1. Why It’s (Mostly) Safe to Reopen the Schools
- Every American has a stake in the ongoing debate over how, when and if to reopen schools this fall. Last spring’s pandemic-driven closures affected 62 million pre-primary, primary and secondary school students, not to mention their parents.
- With the arrival of the school year, the temperature of the debate has risen. The second-largest teachers union, the American Federation of Teachers, is preparing for its members to go on strike if schools reopen without their assent. President Trump has expressed a desire to “cut off funding” for schools that don’t reopen. It doesn’t help that the debate is taking place during the 2020 presidential campaign and a late-summer rise in coronavirus-related cases, hospitalizations and deaths.
- The good news is that amid the heated rhetoric—and the genuine fear—the accumulating scientific evidence and real-world experience is reasonably consistent. We do have a path to reopening schools this fall, especially for our youngest children. For older children, the story is also encouraging but less definitive.
- We must start with the fact that school closures cause significant damage to children—damage that videoconferences cannot repair. In Boston, the city reported last spring that more than one in five public school children who participated in virtual learning dropped out. Low-income children, in particular, are less likely to have high-speed internet access at home and often lack the extracurricular educational opportunities that wealthier parents can provide. School closures also increase food insecurity, because 30 million children receive free or reduced-price meals through the National School Lunch Program.
- Children may be increasingly physically insecure as well. In a paper published this May in the online social-science journal SSRN, researchers found that C19 school closures have led to a 27% decline in reports of child abuse. Because school personnel are often the first people to notice maltreatment, a decline in reported cases is possibly a sign that more child abuse is going undetected.
- The American Academy of Pediatrics has succinctly and forcefully summarized the case for reopening: “The importance of in-person learning is well-documented, and there is already evidence of the negative impacts on children because of school closures in the spring of 2020. Lengthy time away from school and associated interruption of supportive services often results in social isolation, making it difficult for schools to identify and address important learning deficits as well as child and adolescent physical or sexual abuse, substance use, depression and suicidal ideation. This, in turn, places children and adolescents at considerable risk of morbidity and, in some cases, mortality.”
- Nor are children the only ones adversely affected by school closures. According to the Pew Research Center, in June, the unemployment rate for women was 20% higher than for men, in part because of their much higher level of participation in the education sector. And many mothers have been forced out of the workforce due to their inability to find child care.
- Fortunately, while the harm caused by school closures is obvious, the risk to children of severe C19 illness or death is very low. While there are 45 million children in prekindergarten, kindergarten, elementary or middle school, as of July 29, only 28 Americans ages 1–15 have died of the coronavirus, according to the Centers for Disease Control and Prevention. Though 28 is not zero, it is a number worth putting in context. For example, in 2016, 190 children ages 1–14 died of influenza or pneumonia, 625 died of homicide, 1,257 died of cancer and 2,895 died of unintentional injuries like car accidents, according to the National Center for Health Statistics.
- The most important question for school reopenings, then, is not the risk to children from C19 but rather the risk to adults—parents, teachers and school staff. Every parent and teacher has had the experience of catching whatever bug was circulating among their children in school. Could the same be true of the novel coronavirus?
- Here we can learn a great deal from the experience of other industrialized countries. Iceland, the Netherlands, Belgium, Denmark, Norway, Austria, Germany, Finland, France and Sweden reopened schools in April and May, and their experience has been largely positive. Every European country that reopened schools in the spring plans to start the fall school year on time.
- These countries have taken several different approaches to reopening. Denmark, the first country to reopen schools, announced its plan on April 6, just as C19 cases were peaking there and elsewhere in Europe. Kindergartens and elementary schools reopened the following week in order to help working parents; children over 12 followed a month later. The Netherlands announced its plan in mid-April and also took a staggered approach when it began opening in May. Germany had similar timing but started with older students, on the premise that adolescents would be more likely to adhere to distancing and hand-washing guidelines. Sweden has kept its schools open throughout the pandemic for those under 16 and reopened high schools and colleges in mid-June.
- The results, thus far, have been pretty consistent across these countries. Denmark trod carefully, requiring children to stay 2 meters apart wherever possible. Children were grouped into “bubbles” of 12 and were required to wash their hands every two hours but not to wear masks. It worked. Denmark’s case and mortality counts continued to decline after reopening schools, according to data from the European CDC, leading Peter Andersen of the Danish Serum Institute to conclude that “you cannot see any negative effects from the reopening of schools.”
- The Netherlands imposed neither distancing nor masking requirements when it reopened schools in May, and C19 cases and deaths continued to decline there as well. In a study of 54 families with C19 by the Dutch National Institute for Public Health and the Environment, no child under 12 was found to be the “index” patient—that is, the first patient in the family. These results, the institute concluded, “confirm the impression that children do not play a significant role in the transmission of the virus.”
- A similar study by Icelandic researchers across the entire country’s population was published in June in the New England Journal of Medicine, with similar results. Kári Stefánsson, one of the leaders of the research group, said, “We have not found a single instance of a child infecting parents.”
- After Germany’s C19 caseload peaked on March 28, Angela Merkel’s government carefully reopened schools in May, with class sizes cut in half, one-way hallways, staggered breaks, masks for teachers and free twice-weekly C19 tests for students and teachers. Some schools required masks in hallways and bathrooms but not when seated at desks. A study of 2,045 students and teachers in the German state of Saxony, by researchers at the Technical University of Dresden, found only 12 positive cases of C19. “The dynamics of virus spreading have been overestimated….[and] schools did not become hot spots after reopening,” the university wrote. Reinhard Berner, chief of the department of pediatrics at the university’s hospital, said, “We are going into the summer vacation of 2020 with an immunity status that is no different from that in March 2020,” adding that “children may even act as a brake on infection.”
- The totality of the evidence makes clear the compelling case for reopening schools for younger children.
- France announced its reopening plans on April 21, three weeks after its new cases peaked, and opened schools gradually over the course of May and June, with mask requirements for high-school students but not younger children. Attendance was voluntary. A study by researchers at Institut Pasteur of students ages 6–11 found that “there was no evidence of onwards transmission from children in the school setting.” Notably, the study was conducted in Crépy-en-Valois, a town north of Paris that had seen an outbreak originating with two high-school teachers that spread to adolescent students. France’s success with reopening led the government to reduce its distancing mandate from four square meters between students to one linear meter and to make attendance mandatory for primary and middle schools.
- Sweden, famously, has taken a unique approach to the pandemic, barring large gatherings but keeping its businesses and schools open, without strict distancing and mask requirements. Finland took a more conventional approach to lockdowns. Yet a study by Swedish and Finnish health authorities found nearly identical infection rates of 5 per 10,000 in children ages 1–19. Surveying the broad experience in their countries, the health authorities concluded that “Finland has not shown children to be contributing much in terms of transmission” to adults, and in Sweden there was “no increased risk for teachers.”
- Skeptics argue that the European experience isn’t useful for the U.S. because America’s performance during the pandemic has been so much worse. They point to the fact that the U.S. reports higher case counts per capita than many other countries. But comparing case counts across countries is problematic, due to variations in testing volume, reporting methodologies and the age mix of those infected. Take France and Germany. The shapes of the C19 case curves in each are remarkably similar, with comparable peaks at the end of March and start of April, troughs of under 10 cases per million in early July and an uptick in recent weeks. But as of August 3, France’s mortality rate from C19 was 464 per million residents, more than four times higher than Germany’s, at 109 deaths per million.
- A study of 5,706 South Korean index patients published in the journal Emerging Infectious Diseases suggested that children ages 10–19 may transmit C19 at rates comparable to those of adults. In 231 relatives of 124 such index children, 43 of the relatives tested positive: a rate of 19%. By contrast, only 5% of the relatives of children under 10 tested positive. These figures compared with positive rates of 12% to 18% in the relatives of adult index patients.
- The totality of the evidence makes clear the compelling case for reopening schools for younger children. “It is extremely difficult to find any instance anywhere in the world…of a child [under 15] transmitting to a teacher in school,” observes Mark Woolhouse, an epidemiologist at the University of Edinburgh. The experience of school reopenings has been positive in countries that started with the youngest children, like the Netherlands, and those that started with the oldest children, like Germany. It has been positive in countries that mandated strict physical distancing in schools, like Denmark, and also in countries that did not, like Sweden. And it has been positive in countries where the pandemic has been as deadly as in the U.S. and also in countries where it has not.
- The case for reopening high schools, however, is less definitive and requires more caution. The Israeli experience, along with a recent outbreak at a Georgia summer camp, suggest that while high-schoolers themselves are at little risk of severe illness or death from C19, they are capable of serving as reservoirs of the virus and of transmission to adults, particularly when infection rates are high.
- And in all age groups, we must still take seriously the risk that teachers and school staff will transmit the coronavirus to each other, as we would in any other workplace or gathering space. This is especially true where transmission is substantial and uncontrolled, as defined by the CDC. In places like New York City, where many schools are located in cramped and antiquated buildings with poor ventilation, safety may remain a concern. Older teachers and those with underlying health conditions that make them more susceptible to C19 should remain home and receive paid medical leave.
- It is inevitable that we will see cases of C19 in schools, especially among adolescents and adults, for the same reasons we see them in the broader community. Remember that school-aged children represent nearly one-fifth of the U.S. population. It will be essential for schools that do reopen to set realistic expectations and plan for problems. Infected individuals and their close contacts need to stay home. Schools that cluster groups of students in identical class schedules should fare better. Leaders should keep an eye out for schools where adherence to public health guidelines is poor and step in to help where needed.
- One way to keep schools safe is temperature sensors. Many public health experts have cast doubt on the effectiveness of temperature sensors, because people can spread C19 without an elevated body temperature. But in most places, conventional lab tests are unavailable for asymptomatic individuals. Even where lab tests are widely available, results can take up to a week to deliver. Contactless temperature sensors, by contrast, are reusable, easy to buy and able to deliver results in less than one second. Schools should require parents to check and log their kids’ temperatures before sending them to school and to keep them at home if they are showing any Covid-like symptoms. Temperature checks should also become part of daily attendance routines at schools, serving as an early warning system for potential outbreaks.
- High schools should consider beginning with a staggered model, as New York City is attempting, in which subgroups of students attend school at different times, supplemented with virtual learning. This is far from ideal, especially for lower-income students, but there is enough evidence regarding transmission from adolescents to adults to warrant a careful autumn.
- Policy makers could help solve this problem by enabling low-income students and their parents to form microschools, or “pods,” which serve as a kind of middle ground between home schooling and traditional school. Parents with means are banding together in small groups and hosting for-hire teachers in their living rooms and are finding that this 18th-century technique is far superior to learning on a computer screen.
- Microschools need not be reserved for the wealthy and healthy. Both Congress and state legislatures can fund Education Savings Accounts, and realign school funding formulas, so that low-income parents can band together just as high-earners are doing. Microschools require no overhead and very little infrastructure, enabling parents to pay good teachers well. Their diversity and variety can help us discover new ways for children to learn. And they just might give us a way to build something beneficial and lasting out of this exceptionally trying year.
2. Ventilation should be part of the conversation on school reopening
- Like every other parent with a school-age child, I want schools to reopen in the fall — including the one I’m attending.
- On the best of days, my son can be described as “spirited.” After four months of being cared for by his grandparents, he is practically feral. He needs the physical and social outlet that school provides, and I need the anatomy lab to reopen because human dissection is an irreplaceable part of my medical education.
- But I am also an epidemiologist, and after reading the CDC’s guidelines for school reopening and the various accompanying news coverage and think-pieces, I can’t convince myself that following its rules will keep my family — or yours — safe.
- Why? Because the primary way C19 is transmitted is through respiratory droplets that careen through the air, and yet the capricious nature of air circulation and the lack of filtration systems in our already underfunded public school systems is absent from the conversation.
- Since New York state started reopening, I have received emails from my medical school’s working group about the plan to bring us back to campus. Its plan is to follow the basic script seen in school reopening strategies all over the country: frequently sanitized high-touch surfaces, 6-foot distances, unidirectional hallways, reduced capacity elevators and classrooms, health questionnaires, and contact-free temperature checks upon entry (more on that in a minute).
- My school is not negligent, but like many other educational institutions, its efforts are dangerously misdirected. We are collectively engaging in what Derek Thompson describes in the Atlantic as “hygiene theater,” in which organizations looking to reopen focus intensively on arduous decontamination strategies to mitigate surface transmission — even though that is not the primary route for C19 transmission, and some scientists argue that there is no direct evidence the virus spreads this way at all. I’d also like to add temperature checks to the hygiene theater playbill, as they too fail to successfully screen potential C19 carriers, but have somehow made their way onto every screening list I’ve seen.
- Why is this happening? The CDC is supposed to determine the national priorities for American health.
- Of the eight bullet points in its “staff safety” section, four address surface transmission. The three bullet points dedicated to respiratory droplets warn people to stay 6 feet away from each other, cough into their elbows, and wear a mask.
- The current CDC guidance about ventilation is as follows, “Ensure ventilation systems operate properly and increase circulation of outdoor air as much as possible, for example by opening windows and doors.” But if opening windows or doors increases the risk of asthma, or falling out the window, the guidelines go on to advise that they should be closed. That is all the guidance has to say. It does not mention air filtration, or the fact that we have pretty good data to suggest that without addressing air filtration and circulation, the 6-feet rule does not prevent transmission indoors.
- Here are the things that caught my attention as an epidemiologist as schools played Tetris with classroom furniture and agonized over hybrid schedules.
- On May 6, Erin Bromage, a microbiologist at the University of Massachusetts at Dartmouth, published a widely read article detailing the role of air circulation at three major indoor transmission events: a call center in South Korea, a restaurant in Guangzhou, China, and the infamous choir practice in Washington state. Each of these events taught us that transmission happens when you spend significant time indoors. Being 50 feet apart with “a low dose of the virus in the air, over a sustained period, was enough to cause infection and in some cases, death.” This happens because infectious particles from individuals are pushed by the ventilation system to the other side of the room. Bromage’s post appeared 127 days before the first day of school in New York City.
- HEPA filters are able to effectively capture particles the size of SARS-CoV-2. The CDC currently recommends their use for this purpose in hospitals, but their capacity to prevent the spread of C19 in other public buildings remains under-explored. Though the CDC has stayed silent on the use of HEPA filters outside hospitals, on May 25 a group of ENT doctors made the case for installing them in doctors’ offices where “aerosol generating procedures” are being performed, because of evidence they can help prevent the spread other infections such as SARS-CoV-1, measles, and influenza. That was published 108 days before the first day of school in New York City.
- On May 27, a group of 36 scientists from around the world in a variety of fields penned an article in the journal Environment International titled, “How can airborne transmission of C19 indoors be minimised?” As they wrote, “Here, in the face of such uncertainty, we argue that the benefits of an effective ventilation system, possibly enhanced by particle filtration and air disinfection, for contributing to an overall reduction in the indoor airborne infection risk, are obvious.” It’s obvious to me as well, and deserves to be our primary concern in reopening schools, far more urgently than distance or Lysol. That was 106 days before the first day of school in New York City.
- McKinsey & Company reviewed research regarding airborne spread of SARS-CoV-2 and on July 9 posted an article suggesting possible upgrades to existing heating, ventilation, and air conditioning (HVAC) systems. A key recommended change was to increase the number of times HVAC systems exchange air per hour, which would push the infectious particles outside and prevent them from being blown across the room. This article appeared 63 days before the first day of school in New York City.
- When I mentioned these possibilities to a friend who teaches in the New York City schools, she replied, “Don’t worry about our HVAC systems. They’re all broken.”
- Instead of using limited time and funding to engage in hygiene theater, we should be investigating how to address ventilation. Or at the very least, be honest with the public about some institutions’ inability to make interior spaces safe.
- As a result of months of misapplied focus on surface disinfection, the importance of air circulation and the potential use of filtration is missing from the national debate on school reopening. My son’s school and mine are both concerned with delivering our education safely. My son’s preschool director was worried sick about not being able to adequately decontaminate on a daily basis because she loves both the kids and her school.
- It shouldn’t be her responsibility to research ventilation theory and filtration techniques and air flow patterns. It’s not my job as a medical student to Google these things trying to get enough information to decide what to do about my son’s school, and mine, starting imminently. And it’s not up to the administrators at my school, who I know have been working around the clock these last few months, to figure this out.
- This is supposed to be done by the CDC. Here we are, about a month before public schools are supposed to begin, and the CDC is still failing to signal the crucial importance of addressing ventilation.
- We need to include air circulation patterns and filtration options in the conversation. If we’re not willing or able to fund necessary upgrades to school ventilation systems, let’s admit that. Until we have that public discussion, I am not comfortable exposing my family to schools. Because if I can’t trust that the people making these decisions are reading the literature, how can I trust them with my family’s health?
H. Projections & Our (Possible) Future
1. How the pandemic might play out in 2021 and beyond
- June 2021. The world has been in pandemic mode for a year and a half. The virus continues to spread at a slow burn; intermittent lockdowns are the new normal. An approved vaccine offers six months of protection, but international deal-making has slowed its distribution. An estimated 250 million people have been infected worldwide, and 1.75 million are dead.
- Scenarios such as this one imagine how the C19 pandemic might play out. Around the world, epidemiologists are constructing short- and long-term projections as a way to prepare for, and potentially mitigate, the spread and impact of the coronavirus, the virus that causes C19. Although their forecasts and timelines vary, modellers agree on two things: C19 is here to stay, and the future depends on a lot of unknowns, including whether people develop lasting immunity to the virus, whether seasonality affects its spread, and — perhaps most importantly — the choices made by governments and individuals. “A lot of places are unlocking, and a lot of places aren’t. We don’t really yet know what’s going to happen,” says Rosalind Eggo, an infectious-disease modeller at the London School of Hygiene & Tropical Medicine (LSHTM).
- “The future will very much depend on how much social mixing resumes, and what kind of prevention we do,” says Joseph Wu, a disease modeller at the University of Hong Kong. Recent models and evidence from successful lockdowns suggest that behavioural changes can reduce the spread of C19 if most, but not necessarily all, people comply.
- Last week, the number of confirmed C19 infections passed 15 million globally, with around 650,000 deaths. Lockdowns are easing in many countries, leading some people to assume that the pandemic is ending, says Yonatan Grad, an epidemiologist at the Harvard T. H. Chan School of Public Health in Boston, Massachusetts. “But that’s not the case. We’re in for a long haul.”
- If immunity to the virus lasts less than a year, for example, similar to other human coronaviruses in circulation, there could be annual surges in C19 infections through to 2025 and beyond. Here, Nature explores what the science says about the months and years to come.
What happens in the near future?
- The pandemic is not playing out in the same way from place to place. Countries such as China, New Zealand and Rwanda have reached a low level of cases — after lockdowns of varying lengths — and are easing restrictions while watching for flare-ups. Elsewhere, such as in the United States and Brazil, cases are rising fast after governments lifted lockdowns quickly or never activated them nationwide.
- The latter group has modellers very worried. In South Africa, which now ranks fifth in the world for total C19 cases, a consortium of modellers estimates that the country can expect a peak in August or September, with around one million active cases, and cumulatively as many as 13 million symptomatic cases by early November. In terms of hospital resources, “we’re already breaching capacity in some areas, so I think our best-case scenario is not a good one”, says Juliet Pulliam, director of the South African Centre for Epidemiological Modelling and Analysis at Stellenbosch University.
- But there is hopeful news as lockdowns ease. Early evidence suggests that personal behavioural changes, such as hand-washing and wearing masks, are persisting beyond strict lockdown, helping to stem the tide of infections. In a June report, a team at the MRC Centre for Global Infectious Disease Analysis at Imperial College London found that among 53 countries beginning to open up, there hasn’t been as large a surge in infections as predicted on the basis of earlier data. “It’s undervalued how much people’s behaviour has changed in terms of masks, hand washing and social distancing. It’s nothing like it used to be,” says Samir Bhatt, an infectious-disease epidemiologist at Imperial College London and a co-author of the study.
- Researchers in virus hotspots have been studying just how helpful these behaviours are. At Anhembi Morumbi University in São Paulo, Brazil, computational biologist Osmar Pinto Neto and colleagues ran more than 250,000 mathematical models of social-distancing strategies described as constant, intermittent or ‘stepping-down’ — with restrictions reduced in stages — alongside behavioural interventions such as mask-wearing and hand washing.
- The team concluded that if 50–65% of people are cautious in public, then stepping down social-distancing measures every 80 days could help to prevent further infection peaks over the next two years. “We’re going to need to change the culture of how we interact with other people,” says Neto. Overall, it’s good news that even without testing or a vaccine, behaviours can make a significant difference in disease transmission, he adds.
- Infectious-disease modeller Jorge Velasco-Hernández at the National Autonomous University of Mexico in Juriquilla and colleagues also examined the trade-off between lockdowns and personal protection. They found that if 70% of Mexico’s population committed to personal measures such as hand washing and mask-wearing following voluntary lockdowns that began in late March, then the country’s outbreak would decline after peaking in late May or early June. However, the government lifted lockdown measures on 1 June and, rather than falling, the high number of weekly C19 deaths plateaued. Velasco-Hernández’s team thinks that two public holidays acted as superspreading events, causing high infection rates right before the government lifted restrictions6.
- In regions where C19 seems to be on the decline, researchers say that the best approach is careful surveillance by testing and isolating new cases and tracing their contacts. This is the situation in Hong Kong, for instance. “We are experimenting, making observations and adjusting slowly,” says Wu. He expects that the strategy will prevent a huge resurgence of infections — unless increased air traffic brings a substantial number of imported cases.
- But exactly how much contact tracing and isolation is required to contain an outbreak effectively? An analysis by the Centre for the Mathematical Modelling of Infectious Diseases C19 Working Group at the LSHTM simulated fresh outbreaks of varying contagiousness, starting from 5, 20 or 40 introduced cases. The team concluded that contact tracing must be rapid and extensive — tracing 80% of contacts within a few days — to control an outbreak. The group is now assessing the effectiveness of digital contact tracing and how long it’s feasible to keep exposed individuals in quarantine, says co-author Eggo. “Finding the balance between what actually is a strategy that people will tolerate, and what strategy will contain an outbreak, is really important.”
- Tracing 80% of contacts could be near-impossible to achieve in regions still grappling with thousands of new infections a week — and worse, even the highest case counts are likely to be an underestimate. A June preprint from a Massachusetts Institute of Technology (MIT) team in Cambridge analysing C19 testing data from 84 countries suggests that global infections were 12 times higher and deaths 50% higher than officially reported (see ‘Predicting cases and deaths’). “There are many more cases out there than the data indicate. As a consequence, there’s higher risk of infection than people may believe there to be,” says John Sterman, co-author of the study and director of the MIT System Dynamics Group.
- For now, mitigation efforts, such as social distancing, need to continue for as long as possible to avert a second major outbreak, says Bhatt. “That is, until the winter months, where things get a bit more dangerous again.”
What will happen when it gets cold?
- It is clear now that summer does not uniformly stop the virus, but warm weather might make it easier to contain in temperate regions. In areas that will get colder in the second half of 2020, experts think there is likely to be an increase in transmission.
- Many human respiratory viruses — influenza, other human coronaviruses and respiratory syncytial virus (RSV) — follow seasonal oscillations that lead to winter outbreaks, so it is likely that the coronavirus will follow suit. “I expect the coronavirus infection rate, and also potentially disease outcome, to be worse in the winter,” says Akiko Iwasaki, an immunobiologist at the Yale School of Medicine in New Haven, Connecticut. Evidence suggests that dry winter air improves the stability and transmission of respiratory viruses, and respiratory-tract immune defence might be impaired by inhaling dry air, she adds.
- In addition, in colder weather people are more likely to stay indoors, where virus transmission through droplets is a bigger risk, says Richard Neher, a computational biologist at the University of Basel in Switzerland. Simulations by Neher’s group show that seasonal variation is likely to affect the virus’s spread and might make containment in the Northern Hemisphere this winter more difficult.
- In future, coronavirus outbreaks could arrive in waves every winter. The risk to adults who have already had C19 could be reduced, as with flu, but it would depend on how rapidly immunity to this coronavirus wears off, says Neher. What’s more, the combination of C19, flu and RSV in autumn and winter could be challenging, says Velasco-Hernández, who is setting up a model of how such viruses might interact.
- It remains unknown whether infection with other human coronaviruses can offer any protection against the coronavirus. In a cell-culture experiment involving the coronavirus and the closely related the coronavirus, antibodies from one coronavirus could bind to the other coronavirus, but did not disable or neutralize it.
- To end the pandemic, the virus must either be eliminated worldwide — which most scientists agree is near-impossible because of how widespread it has become — or people must build up sufficient immunity through infections or a vaccine. It is estimated that 55–80% of a population must be immune for this to happen, depending on the country11.
- Unfortunately, early surveys suggest there is a long way to go. Estimates from antibody testing — which reveals whether someone has been exposed to the virus and made antibodies against it — indicate that only a small proportion of people have been infected, and disease modelling backs this up. A study of 11 European countries calculated an infection rate of 3–4% up to 4, inferred from data on the ratio of infections to deaths, and how many deaths there had been. In the United States, where there have been more than 150,000 C19 deaths, a survey of thousands of serum samples, coordinated by the US Centers for Disease Control and Prevention, found that antibody prevalence ranged from 1% to 6.9%, depending on the location.
What happens in 2021 and beyond?
- The pandemic’s course next year will depend greatly on the arrival of a vaccine, and on how long the immune system stays protective after vaccination or recovery from infection. Many vaccines provide protection for decades — such as those against measles or polio — whereas others, including whooping cough and influenza, wear off over time. Likewise, some viral infections prompt lasting immunity, others a more transient response. “The total incidence of the coronavirus through 2025 will depend crucially on this duration of immunity,” wrote Grad, Harvard epidemiologist Marc Lipsitch and colleagues in a May paper exploring possible scenarios (see ‘What happens next?’).
- Researchers know little so far about how long the coronavirus immunity lasts. One study of recovering patients found that neutralizing antibodies persisted for up to 40 days after the start of infection; several other studies suggest that antibody levels dwindle after weeks or months. If C19 follows a similar pattern to SARS, antibodies could persist at a high level for 5 months, with a slow decline over 2–3 years. Still, antibody production is not the only form of immune protection; memory B and T cells also defend against future encounters with the virus, and little is known so far about their role in the coronavirus infection. For a clear answer on immunity, researchers will need to follow a large number of people over a long time, says Michael Osterholm, director of the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, Minneapolis. “We’re just going to have to wait.”
- If infections continue to rise rapidly without a vaccine or lasting immunity, “we will see regular, extensive circulation of the virus”, says Grad. In that case, the virus would become endemic, says Pulliam. “That would be really painful.” And it is not unimaginable: malaria, a preventable and treatable disease, kills more than 400,000 people each year. “These worst-case scenarios are happening in many countries with preventable diseases, causing huge losses of life already,” says Bhatt.
- If the virus induces short-term immunity — similar to two other human coronaviruses, OC43 and HKU1, for which immunity lasts about 40 weeks — then people can become reinfected and there could be annual outbreaks, the Harvard team suggests. A complementary CIDRAP report, based on trends from eight global influenza pandemics, points to significant C19 activity for at least the next 18–24 months, either in a series of gradually diminishing peaks and valleys, or as a “slow burn” of continuing transmission without a clear wave pattern. Yet these scenarios remain only guesses, because this pandemic has so far not followed the pattern of pandemic flu, says Osterholm. “We’re in a coronavirus pandemic for which we have no precedents.”
- Another possibility is that immunity to the coronavirus is permanent. In that case, even without a vaccine, it is possible that after a world-sweeping outbreak, the virus could burn itself out and disappear by 2021. However, if immunity is moderate, lasting about two years, then it might seem as if the virus has disappeared, but it could surge back as late as 2024, the Harvard team found.
- That forecast, however, does not take the development of effective vaccines into account. It’s unlikely that there will never be a vaccine, given the sheer amount of effort and money pouring into the field and the fact that some candidates are already being tested in humans, says Velasco-Hernández. The World Health Organization lists 26 C19 vaccines currently in human trials, with 12 of them in phase II trials and six in phase III. Even a vaccine providing incomplete protection would help by reducing the severity of the disease and preventing hospitalization, says Wu. Still, it will take months to make and distribute a successful vaccine.
- The world will not be affected equally by C19. Regions with older populations could see disproportionally more cases in later stages of the epidemic, says Eggo; a mathematical model from her team, published in June and based on data from six countries, suggests that the susceptibility to infection in children and people under 20 years old is approximately half that of older adults.
- There is one thing that every country, city and community touched by the pandemic has in common. “There is so much we still don’t know about this virus,” says Pulliam. “Until we have better data, we’re just going to have a lot of uncertainty.”
I. Practical Tips & Other Useful Information
1. Indoor air is riskier than outdoor air. So what do you do if it’s really hot out?
- Despite its critical role in our daily lives, air is not something most of us spend a great deal of time thinking about. It’s that easy to take for granted. Unlike water, we don’t need to fill up a cup to consume it. If some escapes from the room, more will find its way back in, whether we open the door or not.
- “If you are comfortable, you ignore it,” said Wade H. Conlan, a mechanical engineer who evaluates ventilation systems on behalf of Hanson Professional Services.
- But like so many little luxuries we once took for granted, our days of blissfully ignoring air may be numbered. Because a growing number of scientists are convinced that a significant amount of coronavirus transmission occurs through the air in indoor spaces, and that poor ventilation magnifies the risk.
- Not everyone has the ability or resources to make the changes to a home or workplace to improve air circulation. But scientists and engineers say that it’s worth trying to understand the basics of how airflow works — in case there is a relatively easy tweak that could keep you a bit safer.
- When in doubt, open the windows. And remember that outdoor air is good.
- The precise way that viral particles flow through a room when an infected person talks, sings, exhales or eats is something that scientists are continuing to investigate. Previous case studies have shown that it’s complicated. If there is one easy-to-understand principle that aerosol scientists and engineers have come to agree on, though, it’s this: The more outdoor air coming into a room, the better for dispersing that cloud of viral particles that might be lingering. And one of the most reliable and cost-effective ways to get outdoor air into a room is to open a window.
- “If you don’t know if the place is well ventilated, but you have the ability to open a window I would do it,” said Shelly Miller, a professor of mechanical engineering at the University of Colorado Boulder. That, she said, or get out quickly if you’re swinging by an indoor location with other people in it.
- The outdoor air that comes in will eventually replace the indoor air, according to Jose-Luis Jimenez, an aerosol scientist at the University of Colorado Boulder.
- “The more outside air you have, the more you dilute the virus,” said Dr. Jimenez, who was among the scientists and engineers who sent a letter that pushed the World Health Organization to acknowledge that airborne transmission of the novel coronavirus is a threat in indoor spaces.
- If you want to speed up the flow of outdoor air into a room, you could also take a box fan, place it in a window and blast it outward, Dr. Jimenez said. When any amount of air leaves, that same amount of air returns — it’s a fixed volume. Therefore, the fan should help pull in the same amount of outdoor air.
Your type of air-conditioner matters
- Some pull in outdoor air. Others simply recirculate indoor air.
- If you have air-conditioning in your home, no one is saying that you need to give up on it entirely. When it’s sweltering out, air-conditioning can be essential not only to help you function but also to avoid heatstroke.
- But if you are going to spend time in a cooled space with other people, it may be worth understanding a bit more about the cool air you are breathing. Basically, all air-conditioning falls into one of three categories.
- The unit cools both indoor and outdoor air.
- The unit cools and recirculates only indoor air.
- The unit relies entirely on pulling in outdoor air. (These are uncommon outside hospitals and labs.)
- Centralized-air systems, such as those common in office buildings, dorms and some large apartment buildings, often fall in category one. Dr. Jimenez and other building scientists involved in coronavirus prevention are currently advising owners of businesses and buildings with category one systems to adjust the ratio to pull in more outdoor air, an enterprise that can be costly. Take a casino in Las Vegas, which is kept cool enough to keep people gambling inside while it’s 120 degrees Fahrenheit outside. Cooling that hot outdoor air will be more expensive than recirculating the already cool inside air. But given that keeping customers healthy is also a priority, more are willing to revisit their approach, Dr. Jimenez said.
- Few of us have the ability to adjust our air-conditioning in this way. Most window units sitting with their rears facing the outdoors, for example, fall into category two. Instead of pulling in outdoor air, they are dumping heat from the room outdoors, said William Bahnfleth, a professor of architectural engineering at Penn State’s Institutes of Energy and the Environment.
- If you live alone, or with people you’re sure aren’t infectious, those units are fine. But if you give in to throwing that birthday dinner for your parents, or if your teenager has been less than strict about staying home, it’s worth remembering that “any virus that’s present will be mixed in” to the recirculating indoor air, Dr. Jimenez said.
- And so, if you have to have people over, it may be preferable to revert to rule one: When in doubt, open the windows. Or better yet, go outside.
Not all filters are equal
- But a good filter can be just as effective as pulling in outside air.
- So what do you do if you’re stuck with a unit that primarily recirculates indoor air and it’s unrealistic to open the window? This is where filters come in. The right filter is just as effective as pulling in outside air, said Dr. Edward A. Nardell, a professor at Harvard Medical School who has written about the role that air-conditioning plays in spreading airborne diseases.
- Along with removing dust, pollen, cooking odors, tobacco smoke and chemicals, filters can take viral particles from the air. Some filters go directly in air-conditioning units and central air systems. Others are designed to stand alone. MERV and HEPA are two widely trusted, certified types.
- MERV filters are rated on how efficiently they remove particles in a specific size range from the air. ASHRAE, a professional society of air-conditioning, heating and refrigerating engineers, recommends MERV 13 and above for filtering out the coronavirus, said Dr. Bahnfleth, who leads the group’s epidemic task force. It is what Dr. Bahnfleth has in his own house. Any HEPA filter is even more efficient than the highest-rated MERV filter, he added, so either should effectively capture coronavirus particles.
- Many central-air systems are designed to incorporate specialized filters. But not all can handle the most advanced filters. Lower-rated filters still could be helpful, Dr. Conlan said — it’s not that they won’t ever catch smaller particles; they just won’t do it as frequently. Window units are typically designed for comfort, not health, and have even more filter limitations.
- For those who can afford them — or push their employers or landlords to buy them — a stand-alone HEPA filter is a good option Dr. Bahnfleth said. Some are designed for bigger spaces than others. The key, Dr. Jimenez added, is picking one that will filter all the air in the room at least twice an hour.
- Be aware that if an air-filtration system sounds too good to be true, your instincts may be right. Some of them appear to rely on questionable marketing and science, Dr. Jimenez said.
There’s no ‘good spot’ in a room
- Instead, keep your distance, wear a mask, get out quickly if you can.
- Now that you’re an air expert, it may be tempting to think that you know how to pick the safest position in a restaurant or other indoor space you might find you have a reason to be in.
- But even experts cannot easily eyeball the lowest risk location, said Andrew Persily, who oversaw the development of an online tool to estimate exposure to infectious aerosols in rooms and buildings as chief of the Energy & Environment Division at the National Institute of Standards and Technology.
- “Depending on the airflow pattern and where the aerosols are released, there may be regions in the room that result in higher exposure than others,” he said. “It’s tough to predict.”
- It’s also hard to gauge how many is too many people in a given space. After all it only takes one infected person to get other people sick. If you have a carbon dioxide detector, you could try a technique previously used to manage the spread of tuberculosis, and use that to tip you off, Dr. Miller suggests. If CO₂ levels are above 1,000 parts per one million, you’d be wise to decrease the number of people in the indoor space, increase the amount of outdoor air or both, she says.
- An alternate approach is to look around. Do you see other people? If so, leave.
J. Johns Hopkins COVID-19 Update
August 7, 2020
1. Numbers & Trends
- The WHO C19 Situation Report for August 6 reports 18.61 million cases (259,344 new) and 702,642 deaths (6,488 new). The WHO data indicates that the global daily incidence could potentially be approaching a peak or plateau. This afternoon’s update will be the 200th daily C19 Situation Report published by the WHO, dating back to January 21.
- The continent of Africa is expected to surpass 1 million cases in this afternoon’s Situation Report. Notably, Africa includes countries from both the WHO African Region and Eastern Mediteranean Region. The African Region has reported 848,053 cases, but when adding the incidence for Djibouti, Egypt, Libya, Morocco, Somalia, Sudan, and Tunisia, the total across the continent totals 997,841 cases. South Africa represents more than half of all cases reported in Africa. While South Africa’s incidence is beginning to taper off, however, the continental total continues to increase steadily, indicating that the incidence reported in other countries continues to increase.
South & Central America
- Brazil reported 53,139 new cases, and it appears as though it is on pace to report decreased incidence compared to the previous 2 weeks. Brazil remains #3 globally in terms of daily incidence. Colombia reported 11,996 new cases, its highest daily incidence to date. Columbia’s average daily incidence has doubled since July 15, and it remains #4 globally in terms of daily incidence. Mexico’s average daily incidence has decreased slightly over the past several days, and it may be approaching a peak or plateau. Mexico fell to #7 globally in terms of daily incidence. Including Brazil, Colombia, and Mexico, the Central and South American region represents 5 of the top 10 countries globally in terms of daily incidence, along with Peru (#7) and Argentina (#8), and multiple other countries in the region are reporting more than 1,000 new cases per day. Additionally, the region includes 5 of the top 10 countries in terms of per capita daily incidence—Panama (#2), Peru (#3), Brazil (#4), Colombia (#5), and Bolivia (#9)—and several other countries are reporting more than 100 new daily cases per million population.
- Following several days of decreasing daily incidence, India reported 2 consecutive sharp increases, up to a new high of 62,538. India technically remains #2 globally in terms of daily incidence, but it is reporting essentially the same incidence as the US and still increasing. We expect India to surpass the US as #1 globally in terms of daily incidence in its next update. The Philippines continues to average more than 4,000 new cases per day, but it may be starting to level off.
- The Philippines remains #10 in terms of daily incidence.
- South Africa reported 8,307 new cases and remains among the top countries globally in terms of both per capita (#10) and total daily incidence (#5).
- Bahrain (#6) is the only country in the Eastern Mediterranean region remaining in the global top 10 in terms of per capita daily incidence, and Kuwait is the only other country in the region reporting more than 100 new daily cases per million population. Nearby Israel (#8), in the WHO’s European region, remains among the top countries globally as well.
- The Maldives is the only country reporting more than 250 new daily cases per million population, and it remains #1 globally in terms of per capita daily incidence.
- The US CDC reported 4.80 million total cases (53,685 new) and 157,631 deaths (1,320 new). This is the second consecutive day that the CDC reported more than 1,000 deaths. The US will likely reach 5 million cases by the end of this weekend or Monday. In total, 13 states are reporting more than 100,000 cases, including California with more than 500,000; Florida with nearly 500,000; and Texas with more than 450,000. The US remains #7 in terms of per capita daily incidence, and it is still #1 in terms of total daily incidence, but India is reporting essentially the same daily average. We expect the US to fall to #2 in the next update.
- The US may be approaching a peak in terms of daily mortality, and reporting over the next several days will provide insight on the longer-term trend. The peak daily incidence was on July 25, so the timing is appropriate to begin observing an associated peak in mortality.
- The Johns Hopkins CSSE dashboard reported 4.90 million US cases and 160,255 deaths as of 1:30pm on August 7.
2. Vaccine Trials & Evaluation
- As we look ahead to future SARS-CoV-2 vaccines, it is critical to establish public trust and support in order to ensure the vaccine is widely accepted. Growing vaccine hesitancy and the rapid development and evaluation of SARS-CoV-2 vaccine candidates, along with widespread misinformation efforts and mistrust of government officials and agencies, is giving rise to concerns about the public’s willingness to receive a SARS-CoV-2 vaccination if or when one becomes available. With this challenge in mind, a coalition of more than 400 medical and public health experts issued an open letter to US FDA Commissioner Dr. Stephen Hahn calling for increased transparency around the US government’s evaluation of SARS-CoV-2 candidate vaccines. In the letter, the authors emphasize the importance of providing insight into the evaluation and associated deliberations regarding potential vaccines, including on expected benefits and risks, in order to establish trust in the public regarding the evaluation process. Concerns regarding the authorization and recommendations regarding hydroxychloroquine have raised concerns that the vaccine evaluation process could be impacted by political considerations, which could erode public confidence and adversely affect willingness to be vaccinated. Even if a vaccine is efficacious against the virus, it will not be an effective tool unless the public is willing to receive it.
3. Pandemic Insurance
- Businesses around the world pay insurance premiums for business interruption policies, which are designed to offset financial losses if businesses cannot operate as the result of an emergency. Many of these businesses, however, are finding that their policies may not cover pandemics, driving some to file lawsuits against their insurance companies. Following the emergence of the original SARS virus in 2003—which caused major economic disruptions, particularly in Asia—insurance companies realized that they could simply not afford to make insurance payouts as a result of disease-related emergencies. In contrast to many other types of emergencies—such as natural disasters, fires, and floods—disease events can have a much larger geographic spread and can affect many aspects of social and economic activity without having to cause any physical damage. Some of these businesses are arguing that the inability to open constitutes a “loss” of their building, which could be viewed as a form of physical damage, but these lawsuits will likely take months or years to resolve. From a financial perspective, the principles on which insurance is built—essentially, pooling risk across many individuals or businesses so that those not affected by an event can pay for those that are—break down for a pandemic scenario, in which all businesses or individuals are affected.
4. Estimating C19 Mortality
- The WHO published a Scientific Brief to outline challenges and recommendations for estimating C19 mortality in real time. Challenges in testing, diagnosis, and reporting introduce numerous barriers into calculations of case fatality ratio (CFR) and infection fatality ratio (IFR; which accounts for asymptomatic infections). Reported incidence typically underestimates the true scale of an epidemic, in particular for mild cases and populations that have poorer access to testing and healthcare services. Additionally, cases take time to progress through disease to death, so estimating mortality at any given point in time does not account for the current cases that will eventually die, leading to an underestimate of mortality. The guidance provides information for estimating both CFR and IFR and discusses challenges and limitations of these calculations in the context of an ongoing epidemic.
- In addition to the traditional CFR and IFR calculations, the document provides an alternative calculation that aims to mitigate the effect of current cases that will ultimately die. Rather than including all known cases/infections in the CFR/IFR calculation, estimates can be generated based on only those with known outcomes (ie, the sum of deaths and recoveries) as the denominator. This requires access to patient-level data to identify recovered patients, but it could reduce the degree to which the standard approach underestimates CFR and IFR. The guidance also recommends estimating CFR and IFR for different risk groups (eg, age, sex, underlying health conditions) in order to better characterize variations in mortality across populations. Finally, the document highlights common biases in CFR/IFR estimates, including the effects stemming from delays in reporting cases and deaths, focusing on severe cases early in an epidemic, and challenges determining the correct cause of death.
5. US Schools Reopening
- Schools in numerous US states have started reopening for in-person classes. As classes resume, health officials and other experts are monitoring them closely for signs of increased transmission within schools and in the community. Tennessee has reported at least 14 C19 cases in 2 school districts that are connected to schools that recently reopened, driving both to close or alter their schedules. Mississippi, Indiana, and North Carolina have also reported cases among students following schools reopening. Families that are uncomfortable sending their children back for in-person classes have faced tough choices, with some schools allegedly threatening suspension or expulsion for students who do not return. Teachers have faced similar threats, with some reportedly being told to resign if they had concerns of being infected at schools.
- Despite guidance from the US CDC and other experts regarding appropriate risk mitigation strategies for C19, there is evidence that some schools are not implementing some of these recommended measures. In Georgia, for example, photos of a high school show students packed closely together in a hallway, with few wearing masks and nobody maintaining appropriate physical distancing. The school district superintendent commented that the schools are learning from their experiences and updating policies to promote a safe learning environment, although mask use will not be mandated. The specific risk mitigation protocols used will inevitably vary between schools and communities, but experts generally agree that physical and social distancing practices, including mask use and proper ventilation, and enhanced hygiene and sanitization standards can mitigate transmission risk to some degree. The current CDC guidance notes that the level of community transmission should be a principal consideration when making decisions regarding when and how to reopen schools.
6. Remdesivir Production & Pricing
- On August 4, a bipartisan group of 31 state Attorneys General (AGs) issued an open letter to senior US health agencies urging the federal government to permit other companies to manufacture remdesivir in order to increase availability, arguing that the drug’s developer and manufacturer, Gilead Sciences, has not yet provided sufficient supply. Remdesivir is the only drug that has demonstrated efficacy as a C19 treatment in randomized clinical trials. The letter was sent to HHS, NIH, and the FDA urging them to remove Gilead’s exclusive rights over the product, in light of the company’s inability to produce the drug at reasonable prices and volume. The AGs also argue that Gilead’s projection of 2 million treatment courses by the end of the year is too low to manage the US epidemic, and they highlight that Gilead received substantial funding from the US government to facilitate development, testing, and production of the drug.
- Gilead responded with a statement arguing that the AGs misrepresented the situation. Gilead stated that it is largely meeting existing demand and that it is investing in production capacity and should exceed global demand by October. Gilead has also worked with manufacturers in India and Pakistan to improve access to remdesivir in other countries. It should be noted that remdesivir produced by Gilead costs approximately US$340 per vial, while the generic product manufactured in India costs only US$60 per vial. The AGs argued that allowing other manufacturers to produce generic forms of remdesivir in the US will alleviate domestic supply and pricing barriers.
7. Hand Sanitizer Poisoning
- The US CDC published findings from an investigation of multiple instances of individuals ingesting hand sanitizer. The study, published in the CDC’s Morbidity and Mortality Weekly Report (MMWR), addresses a series of 15 individuals from Arizona and New Mexico who were hospitalized for methanol poisoning in May and June after ingesting hand sanitizer. Among these patients, 7 were discharged from the hospital, 4 remained hospitalized at the time the report was written, and 4 died. Of those who were discharged, 3 reported new visual impairment. Methanol poisoning can cause headache, blurred vision, and nausea or vomiting, and severe or untreated cases can lead to seizures, blindness, or death.
- Hand sanitizer should contain at least 60% ethanol or 70% isopropyl alcohol to be effective, but it should not contain methanol, which can be toxic to humans. The US FDA is closely monitoring hand sanitizers, and it has generated a list of unsafe products and issued numerous orders to stop production and recall unsafe products. The current list includes 115 products, added between July 2 and August 3, including more than 100 that contain methanol or were produced at facilities that made other products contaminated with methanol. Methanol can be absorbed through the skin, but methanol poisoning via this route of exposure is relatively rare.
- It is not clear exactly why these individuals ingested the hand sanitizer products, but there are reports of some individuals ingesting them as a substitute for traditional alcoholic beverages and children swallowing them unintentionally. The CDC and FDA recommend checking hand sanitizer products and disposing of any that contain methanol—in hazardous waste containers and not flushed or poured down a drain. As more hand sanitizer products have become available during the pandemic, particularly from companies that do not have a well-established history of manufacturing them, it is important to ensure that you are using safe and authorized products and doing so in an appropriate manner.
8. US Travel Advisories
- The US Department of State updated its travel advisories yesterday to remove the global Level 4 (Do Not Travel) advisory. Rather, the State Department replaced the global advisory with individual countries, based on country-specific risk assessments. The list now includes more than a full page of entries for Level 4 advisories, nearly 3 pages of Level 3, four Level 2 advisories, and two Level 1 advisories (Macau and Taiwan). Notably, not all of the advisories updated yesterday pertain directly to C19 (eg, Level 2 advisory for Antarctica for weather-related hazards). The global Level 4 advisory had been in place since March 19. Despite these changes, travel restrictions still exist in many countries for travelers arriving from the US.
- The US CDC also updated its travel alerts to transition from a global alert to individual countries. The vast majority of countries remain at Level 3 (C19 Risk is High; Avoid Nonessential Travel), and the CDC notes that non-US citizens/residents who have been in Brazil, China, Iran, Ireland, the UK, and most of Europe in the past 14 days are prohibited from entering the US. The CDC also published a new C19 travel guidance webpage, which provides a number of recommendations, considerations, and other information for before, during, and after travel.
9. US C19 Stimulus Bill
- Efforts to finalize a Phase 5 C19 stimulus package continue between the US Senate, House of Representatives, and White House. After more than a week of negotiations, it appears that there are still major barriers to reaching an agreement, and it is unclear what timeline might be necessary to reach a compromise on the outstanding issues. Notably, at least a handful of Republican Senators have indicated that they are opposed to any stimulus package, which could make it even more difficult to pass a bill through the Congress. Like last week, when expanded unemployment payments and eviction protections expired, several provisions of the CARES Act will end this week if a new agreement is not reached today, including the Paycheck Protection Program, which helps small businesses continue to pay employees. US President Donald Trump indicated that his staff is preparing executive orders to continue certain portions of the emergency C19 funding and that he could sign them as early as this weekend, if Congressional leaders are not able to reach an agreement.
10. US C19 Mortality
- Following comments made by President Trump in a recent interview with Axios, there has been considerable attention on C19 mortality in the US, particularly with respect to how it compares to other countries. There are many ways to evaluate disease mortality, and regardless of the method used, analysis is limited by the quality of available data. With that in mind, the data and metrics used can have a major effect on how we understand disease mortality. In light of this recent attention, here is a look at how the US is faring in terms of C19 mortality, including some challenges associated with various mortality metrics.
- Perhaps the most obvious number to start with is cumulative deaths. From this perspective the US is #1 globally with 157,631 total C19 deaths since the onset of the pandemic. While this allows us to compare the full magnitude and severity of national C19 epidemics, it poses challenges in comparing countries with different size populations. To account for population size, we can look at per capita mortality. This is often displayed in terms of “per 100,000 population” or “per million population,” but as long as you are using the same scale for both countries, the comparison is the same. In terms of per capita deaths, the US has reported approximately 484 C19 deaths per million population, which places it #10 globally. Notably, the top 10 also includes San Marino and Andorra, both of which have very few total deaths (42 and 52, respectively) but very small populations.
- It is also important to evaluate the number of deaths compared to the number of cases, which can provide insight into how countries’ health systems are able to handle the epidemic. For this, we look at case fatality—the number of deaths divided by the number of cases, or infection fatality—based on the number of total infections, including asymptomatic infections. As discussed above, challenges and delays associated with detecting and reporting cases and deaths make case fatality and infection fatality notoriously difficult to determine in real time. In terms of case fatality, the US is somewhere in the middle of the pack compared to other countries. At an estimated 3.28%, the US is faring better than approximately one-third of countries, but many countries are doing better. The US case fatality has decreased over the past several weeks, due in part to increased testing and surging transmission; however, it appears to be leveling off.
- We can also use daily mortality to evaluate current trends, as opposed to the cumulative totals. Daily reports can vary widely, particularly over weekends and holidays, so using weekly averages helps to smooth out these variations. Looking at the total daily mortality, the US recently surpassed Brazil as #1 globally, reporting approximately 1,148 new deaths per day. On a per capita basis, the US is reporting approximately 3.47 new deaths per day per million population, putting it at #10 globally. Additionally, reported C19 mortality depends heavily on the quality of C19 surveillance and testing systems. Alternative methods, such as excess mortality, can help estimate the disease burden that may not be captured by C19 specific reporting systems. These analyses can involve various reporting databases, however, which can make them difficult to compile and compare across many countries, and they can include deaths not directly due to C19.
- While there are many other metrics, and variations on those metrics (eg, different windows over which to average daily reports), these are among the most common ways to evaluate disease mortality. Whether you look at total deaths or mortality with respect to population or reported cases, the US remains either relatively high or near the top of all of the metrics described here. This illustrates that the US continues to struggle with its C19 epidemic. National daily incidence may be continuing to decline, but we have not yet observed a similar decrease in deaths. Mortality trends typically lag several weeks behind incidence, so we could potentially expect daily mortality in the US to reach a peak in the near future.