Virus World

Highlights

Summary

The study involving more than 2,300 people also found that women were 33% less likely to fully recover than men.  Not even 1 in 4 people have completely recovered from the coronavirus a full year after being hospitalized with the disease, a U.K. study indicated Sunday, warning that long COVID-19 could become a common condition. The study involving more than 2,300 people also found that women were 33% less likely to fully recover than men. It also found that obese people were half as likely to fully recover, while those who needed mechanical ventilation were 58% less likely. The study looked at the health of people who were discharged from 39 British hospitals with COVID-19 between March 2020 and April 2021, then assessed the recovery of 807 of them five months and one year later. Just 26% reported a full recovery after five months, and that number rose only slightly to 28.9% after a year, according to the study published in the Lancet Respiratory Medicine journal.

“The limited recovery from five months to one year after hospitalization in our study across symptoms, mental health, exercise capacity, organ impairment and quality-of-life is striking,” said study co-leader Rachel Evans of the National Institute for Health and Care Research. The most common long-COVID-19 symptoms were fatigue, muscle pain, poor sleep, slowing down physically and breathlessness. “Without effective treatments, long-COVID could become a highly prevalent new long-term condition,” said study co-lead Christopher Brightling of the University of Leicester. The study, which will be presented at the European Congress of Clinical Microbiology and Infectious Diseases, is ongoing and will continue to monitor the patients’ health.

Published in The Lancet Respiratory Medicine (April 23, 2022):

https://doi.org/10.1016/S2213-2600(22)00127-8 

The BA.2 COVID variant now spreading worldwide disarms a crucial monoclonal-antibody therapy in laboratory tests.  The rapidly spreading BA.2 variant of SARS-CoV-2 could once again make doctors rethink antibody treatments for COVID-19. Manufactured immune molecules called monoclonal antibodies are essential for keeping people with COVID-19 out of hospital. Now, early laboratory data1,2 hint that the key antibody sotrovimab could lose effectiveness against the rapidly spreading BA.2 variant. Sotrovimab is one of the few therapies for COVID-19 caused by the Omicron variant, which overpowers several antibody treatments that were effective against previous strains. Just in time, US regulators have given emergency approval to another monoclonal antibody, bebtelovimab, that inhibits both the original Omicron strain3 and BA.21 in laboratory assays.  But for many researchers, the sotrovimab findings are a testament to the uphill battle of keeping up with SARS-CoV-2 as it evolves to evade immune systems, antibody treatments and vaccines. “With monoclonal antibodies, we’re trying to hit a moving target,” says David Ho, a virologist at Columbia University in New York City and a co-author of one of the studies. “It’s a really difficult endeavour to chase after a virus.” Most antibody treatments target and attach to SARS-CoV-2’s spike protein, which the virus uses to enter cells. But the protein is also a hotbed for mutations as the coronavirus evolves to evade the immune system. Omicron, for example, has dozens of new mutations in its spike protein. These might explain why two monoclonal-antibody cocktails used to treat the highly virulent Delta variant proved powerless against Omicron4. That left sotrovimab as the only FDA-approved monoclonal-antibody treatment option for infected people at high risk of developing severe COVID-19. The first known variant of Omicron, named BA.1, remains the most prevalent variety of the virus in many countries, including the United States and the United Kingdom. But cases of BA.2, which is related to BA.15, are rising in countries including Denmark, India and China.

Antibody escape

To see how common antibody treatments stood up to the newer varieties of SARS-CoV-2, Ho and his colleagues tested the treatments against a purpose-built virus that included the BA.2 spike. The results1, which have not been peer reviewed, revealed a steep drop in sotrovimab’s ability to neutralize BA.2. Those findings were reinforced by another preprint2, in which a team at the New York University Grossman School of Medicine reported a similar reduction in sotrovimab’s neutralization strength against BA.2. But researchers caution that it is too early to say what these numbers mean for the front-line treatment of COVID-19. “We cannot extrapolate laboratory findings to human treatment outcomes,” says Ho. “We’re just drawing attention to the fact that BA.2 is quite resistant to sotrovimab in the lab, and that raises questions about whether you can adequately cover BA.2 in patients.” Ho notes that sotrovimab also showed reduced efficacy against BA.2 in a preprint6 posted 18 February by scientists at Vir Biotechnology, the company based in San Francisco, California, that produces the antibody. The study has not yet been peer reviewed. In a statement, Vir says the research suggests that sotrovimab “retains neutralizing activity” against BA.2.

A new antibody to the rescue?

Regardless of sotrovimab’s abilities, bebtelovimab could become a go-to antibody to prescribe for people infected with BA.2. Ho and his colleagues found that it is active against both BA.1 and BA.2. The possibility of sotrovimab losing its edge against a new variant isn’t unexpected, says Miles Davenport, an immunologist at the University of New South Wales in Sydney, Australia. Like vaccines, he says, antibody treatments can become less effective when the virus evolves. But he adds that even if sotrovimab doesn’t provide the same level of protection that it did against previous variants, it could still give some relief to people infected with BA.2. “Just because monoclonal antibodies bind less well to the variants, does not mean they will be useless,” he says.

Keeping ahead of the virus

Rajesh Gandhi, an infectious-disease physician at Massachusetts General Hospital in Boston, says that sotrovimab will probably continue to be used while BA.1 remains prevalent. In the meantime, he and other experts say that the questions about sotrovimab underline the need to develop and deploy treatments for COVID-19 that remain effective even when the virus mutates. “If COVID has taught us anything, it’s that we need to prepare,” says Gandhi. “If BA.2 doesn’t become the most dominant variant, good. But if it does, it’s good to have some thoughts around it, so we can optimize treatments for our patients.”

Published in Nature (Feb. 23, 2022): 

https://doi.org/10.1038/d41586-022-00419-6 

Four seasonal coronaviruses—2 of which are betacoronaviruses, like SARS-CoV-2—cause about 30% of common colds. Instead of helping to fight off COVID-19, antibodies to these pathogens may interfere with the SARS-CoV-2 immune response, a recent study of health care workers suggests. Although these preexisting antibodies are ubiquitous, individuals’ varying levels of them might factor into the broad spectrum of responses to the novel coronavirus, which range from immunity against infection all the way to severe respiratory distress and death.

The CDC shortened the recommended times that people should isolate when they've tested positive for Covid-19 from 10 days to five days if they don't have symptoms -- and if they wear a mask around others for at least five more days.  The CDC also shortened the recommended time for people to quarantine if they are exposed to the virus to a similar five days if they are vaccinated. People who are fully vaccinated and boosted may not need to quarantine at all, the CDC said. "Given what we currently know about COVID-19 and the Omicron variant, CDC is shortening the recommended time for isolation from 10 days for people with COVID-19 to five days, if asymptomatic, followed by five days of wearing a mask when around others," the CDC said in a statement. People whose symptoms are getting better may also leave their homes after five days so long as their symptoms are improving, the CDC said. People who have a fever should stay home until the fever clears up, the CDC added.  "The change is motivated by science demonstrating that the majority of SARS-CoV-2 transmission occurs early in the course of illness, generally in the 1-2 days prior to onset of symptoms and the 2-3 days after. Therefore, people who test positive should isolate for five days and, if asymptomatic at that time, they may leave isolation if they can continue to mask for five days to minimize the risk of infecting others." Quarantine refers to the time people stay away from others if they are exposed to a disease but not yet testing positive or showing symptoms. CDC changed those recommendations, too. "For people who are unvaccinated or are more than six months out from their second mRNA dose (or more than two months after the J&J vaccine) and not yet boosted, CDC now recommends quarantine for five days followed by strict mask use for an additional five days," it said.

North Carolina and Colorado sites were temporarily shut down after several people suffered reactions.  The race to vaccinate hit more roadblocks on Thursday, as several patients at a mass vaccination site in North Carolina suffered immediate reactions to the Johnson & Johnson shot. A day earlier, 11 people had adverse reactions in Denver, ranging from dizziness to nausea.  Both sites temporarily shut down. 

"At this point we have no reason to believe there's anything wrong with the vaccine itself," said Dr. Shauna Gulley, a Centura Health chief clinical officer. "This is a temporary pause of one brand of vaccine so that we can investigate further."  The news comes as distribution of the Johnson & Johnson vaccine is expected to fall 85% next week due in part to a factory mix-up.  Meanwhile, the Midwest is on the verge of a relapse. In the last week, COVID-19 hospitalizations increased 11% on average among adults under 50 compared to the prior week. But in the Midwest, those hospitalizations jumped 42%. The hardest hit state is Michigan, where one doctor tweeted a desperate plea on Thursday. "We need some help," Dr. Justin Dimick wrote.  Variants continue to complicate the country's recovery. Of all new coronavirus cases last week, children accounted for roughly one in five. Children are especially susceptible to the variant first found in the U.K., which was discovered at a recent outbreak at a Wisconsin childcare center.  "Prior to this time, young kids, particularly those in eighth grade or younger, rarely got infected or seriously ill with the virus and importantly did not transmit the virus in the community. Today that has been turned on its head," said Dr. Michael Osterholm, the director of the Center for Infectious Disease Research and Policy.  It's hitting college students, too. The University of Chicago said 50 students have tested positive. Some cases were linked to fraternity parties. 

In small-town Villa Grove, Illinois, a bar's indoor opening event was linked to 46 cases in February, spanning eight households. That led to the hospitalization of an elderly resident and forced a school to temporarily close, impacting 650 students. "Mask use was inconsistent and that six feet of distance was not maintained," said Centers for Disease Control and Prevention Director Rochelle Walensky. "These findings underscore the vast impact of a single event." 

New studies underscore how coronaviruses frequently mix their genetic components — which could contribute to the rise of dangerous variants.  In recent weeks, scientists have sounded the alarm about new variants of the coronavirus that carry a handful of tiny mutations, some of which seem to make vaccines less effective. But it is not just these small genetic changes that are raising concerns. The novel coronavirus has a propensity to mix large chunks of its genome when it makes copies of itself. Unlike small mutations, which are like typos in the sequence, a phenomenon called recombination resembles a major copy-and-paste error in which the second half of a sentence is completely overwritten with a slightly different version. A flurry of new studies suggests that recombination may allow the virus to shapeshift in dangerous ways. But in the long term, this biological machinery may offer a silver lining, helping researchers find drugs to stop the virus in its tracks. “There’s no question that recombination is happening,” said Nels Elde, an evolutionary geneticist at the University of Utah. “And in fact, it’s probably a bit underappreciated and could be at play even in the emergence of some of the new variants of concern.”  The coronavirus mutations that most people have heard about, such as those in the B.1.351 variant first detected in South Africa, are changes in a single “letter” of the virus’s long genetic sequence, or RNA. Because the virus has a robust system for proofreading its RNA code, these small mutations are relatively rare.

Greatest risk of passing the virus on is in the first few days of having symptoms, analysis suggests. The research indicates patients had the highest levels of virus early on in their illness and "live" virus, capable of replicating, was found up to nine days after symptoms began. UK scientists say their study emphasises early isolation is critical to stopping spread. 

Peak Infectivity

How infectious individuals are depends on many factors, including how much viable virus (essentially, virus that is able to replicate) they are carrying and the amount of virus they have in their bodies. Some reports have shown people are most infectious just before they have symptoms and in the first week of having the virus. Scientists examined 79 global studies on Covid-19, involving symptomatic people in hospitals who had already tested positive for the virus. Researchers were able to identify and replicate viable virus from throat samples taken up to nine days after infections started. And they found the amount of viral RNA particles (fragments of genetic material from the virus) in people's throat samples peaked at the time symptoms began or within five days.  Meanwhile, inactive viral RNA fragments were still found in nose and throat samples on average up to 17 days after symptoms started.

The biotech, among the furthest along in coronavirus vaccine development, is the first developer to share the so-called study protocol of its large Phase 3 trial. Moderna on Thursday took the unusual step of making public the detailed study plan for the company's large coronavirus vaccine trial, becoming the first developer in late-stage testing to do so amid calls for greater transparency by researchers and public health experts. The so-called study protocol, a lengthy document that's typically closely kept while testing is ongoing, gives outside observers a better sense of how the trial is being run. Most importantly, the plans help clarify how — and when — an independent committee in charge of reviewing data from the study would determine whether the vaccine is safe and effective. "We want to ensure that what we know is shared with the public, with the media, with clinicians who aren't part of the company so we can develop confidence," said Stéphane Bancel, Moderna's CEO, in an interview. "Submitting the protocol online is another step," he added. "We want the world to know they can trust us."

Trust has been in short supply, however. As Moderna and fellow coronavirus frontrunnners Pfizer and AstraZeneca have raced through early-stage testing, scrutiny of the companies and their clinical programs has ratcheted up. All three are now studying their experimental shots in late-stage trials involving tens of thousands of volunteers each. Their rapid progress has brought concerns that they, or regulators, may rush to declare a vaccine ready for use before having sufficient data in hand to prove their shots are safe and effective. In the U.S., the question is intensely political, as President Donald Trump has said a vaccine could be available before election day on Nov. 3. Government officials, including the head of the Trump administration's vaccine initiative, have indicated that's unlikely, although Pfizer anticipates the first results from its Phase 3 trial could come by the end of October. Moderna expects an initial readout from its late-stage study a little later, likely in the latter half of November, Bancel said. The company recently slowed enrollment to ensure it recruits a more diverse group of trial volunteers. 

But that timeline could still slip, should infection rates in the U.S. decline further. Moderna's trial, as with the others, measures vaccine effectiveness by comparing the number of COVID-19 cases in vaccinated participants to those who received placebo, meaning the study's outcome is dependent on infections occurring. Moderna had previously said that an independent data monitoring committee would compare the vaccine to placebo at two interim time points, when 53 and 106 cases were confirmed. The principal comparison will take place after 151 cases. The trial protocol shared by the biotech Thursday fills in some missing details on how the committee will conduct those analyses. Summary statistical plans included in the protocol, for instance, indicate the vaccine would need to be more than 70% effective for the trial to be considered positive at the first interim data check. The trial would not be stopped early in the event of a positive interim analysis, according to the protocol. The protocol also reveals statistical assumptions Moderna made to design its study, such as what percentage of participants will develop COVID-19, as well as how the data monitoring committee will convene and report its recommendations to a study oversight group. That group consists of representatives from the company and two government agencies that have helped fund and test its vaccine...

Study Protocol available at:

https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf

Pregnant women with severe and critical COVID-19 had rapid improvement in their heart and lung function along with decreased inflammation when given inhaled nitric oxide gas, a new Massachusetts General Hospital study shows.  “We noted rapid relief from breathlessness in these patients, with lower respiratory rate and better oxygenation after mask administration of high concentration nitric oxide, with no adverse side effects,” said Dr. Lorenzo Berra, investigator in the department of anesthesia, critical care and pain medicine at MGH. Nitric oxide, known for saving the lives of oxygen-starved newborns, was given to six pregnant coronavirus patients at MGH at a high dosage for 30-60 minutes, twice a day, for a total of 39 treatments.  The patients were severe — all six needed supplemental oxygen, four were treated in the ICU and two were intubated, according to the study in Obstetrics & Gynecology.

Sanofi and GlaxoSmithKline’s next generation Covid-19 vaccine could be used as a booster, after new data suggested that it elicited a strong immune response against the Omicron variant. The French healthcare company said the “next-generation” booster jab delivered a “strong immune response” against variants of Covid, including Omicron, after two trials. It was safe and well tolerated in the study of 247 people. The vaccine makers said their jab increased antibodies to tackle the BA.1 Omicron strain by 40-fold in participants who had received two messengerRNA shots, the technology used in popular vaccines from Moderna and BioNTech/Pfizer. They reported that the vaccine outperformed a third dose of the current BioNTech/Pfizer jab, eliciting double the number of neutralising antibodies to BA.1 and BA.2. Thomas Triomphe, executive vice-president of Sanofi Vaccines, said Covid kept evolving and waning immunity was likely to lead to the need for additional booster shots, at least in some populations....

BACKGROUND:  The SARS-CoV-2 Omicron (B.1.1.529) variant has two main sub-lineages, BA.1 and BA.2 with significant genetic distance between them. This study investigated protection of infection with one sub-lineage against reinfection with the other sub-lineage in Qatar during a large BA.1 and BA.2 Omicron wave, from December 19, 2021 to February 21, 2022. METHODS: Two national matched, retrospective cohort studies were conducted to estimate effectiveness of BA.1 infection against reinfection with BA.2 (N=20,197; BA.1-against-BA.2 study), and effectiveness of BA.2 infection against reinfection with BA.1 (N=100,925; BA.2-against-BA.1 study). Associations were estimated using Cox proportional-hazards regression models.

RESULTS: In the BA.1-against-BA.2 study, cumulative incidence of infection was estimated at 0.03% (95% CI: 0.01-0.07%) for the BA.1-infected cohort and at 0.62% (95% CI: 0.51-0.75%) for the uninfected-control cohort, 15 days after the start of follow-up. Effectiveness of BA.1 infection against reinfection with BA.2 was estimated at 94.9% (95% CI: 88.4-97.8%). In the BA.2-against-BA.1 study, cumulative incidence of infection was estimated at 0.03% (95% CI: 0.02-0.04%) for the BA.2-infected cohort and at 0.17% (95% CI: 0.15-0.21%) for the uninfected-control cohort, 15 days after the start of follow-up. Effectiveness of BA.2 infection against reinfection with BA.1 was estimated at 85.6% (95% CI: 77.4-90.9%).

CONCLUSIONS: Infection with an Omicron sub-lineage appears to induce strong, but not full protection against reinfection with the other sub-lineage, for at least several weeks after the initial infection.

Preprint in medRxiv (Feb. 25, 2022):

https://doi.org/10.1101/2022.02.24.22271440 

The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human cells is an essential step for virus transmission and development of COVID 19. Although the lung epithelial cells are its initial target, SARS-CoV-2 also can infect endothelial cells. Endothelial cells are the major constituents of the vascular system and cardiovascular complication is a hallmark of severe COVID-19. Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for SARS-CoV-2. However, the possible involvement of other cellular components in the viral entry is not fully understood.  A team of researchers from the Boston University School of Medicine (BUSM) has identified extracellular vimentin as an attachment factor that facilitates SARS-CoV-2 entry into human cells. Vimentin is a structural protein that is widely expressed in the cells of mesenchymal origin such as endothelial cells and a potential novel target against SARS-CoV-2, which could block the infection of the SARS-CoV-2. "Severe endothelial injury, vascular thrombosis, and obstruction of alveolar capillaries (tiny air sacs scattered throughout the lungs) are common features of severe COVID-19.

Identification of vimentin as a host attachment factor for SARS-CoV-2 can provide new insight into the mechanism of SARS-CoV-2 infection of the vascular system and can lead to the development of novel treatment strategies," said corresponding author Nader Rahimi, Ph.D., associate professor of pathology & laboratory medicine at BUSM. The researchers used liquid chromatography–tandem mass spectrometry (LC-MS/MS) and identified vimentin as a protein that binds to the SARS-CoV-2 spike (S) protein and facilitates SARS-CoV-2 infection. They also found that depletion of vimentin significantly reduces SARS-CoV-2 infection of human endothelial cells. In contrast, over-expression of vimentin with ACE2 significantly increased the infection rate. "More importantly, we saw that the CR3022 antibody inhibited the binding of vimentin with CoV-2-S-protein, and neutralized SARS-CoV-2 entry into human cells," explained Rahimi. 

Findings Published in P.N.A.S. (Jan. 25, 2022):

https://doi.org/10.1073/pnas.2113874119 

Compared with earlier variants, Omicron may cause less damage to the lungs, new animal research suggests.  A spate of new studies on lab animals and human tissues are providing the first hints of why the Omicron variant causes milder disease than previous versions of the coronavirus. In studies on mice and hamsters, Omicron produced less damaging infections, often limited largely to the upper airway: the nose, throat and windpipe. The variant did much less harm to the lungs, where previous variants would often cause scarring and serious breathing difficulty. “It’s fair to say that the idea of a disease that manifests itself primarily in the upper respiratory system is emerging,” said Roland Eils, a computational biologist at the Berlin Institute of Health, who has studiedhow coronaviruses infect the airway. In November, when the first report on the Omicron variant came out of South Africa, scientists could only guess at how it might behave differently from earlier forms of the virus. All they knew was that it had a distinctive and alarming combination of more than 50 genetic mutations. Previous research had shown that some of these mutations enabled coronaviruses to grab onto cells more tightly. Others allowed the virus to evade antibodies, which serve as an early line of defense against infection. But how the new variant might behave inside of the body was a mystery. “You can’t predict the behavior of virus from just the mutations,” said Ravindra Gupta, a virologist at the University of Cambridge. Over the past month, more than a dozen research groups, including Dr. Gupta’s, have been observing the new pathogen in the lab, infecting cells in Petri dishes with Omicron and spraying the virus into the noses of animals. As they worked, Omicron surged across the planet, readily infecting even people who were vaccinated or had recovered from infections. But as cases skyrocketed, hospitalizations increased only modestly. Early studies of patients suggested that Omicron was less likely to cause severe illness than other variants, especially in vaccinated people. Still, those findings came with a lot of caveats. For one thing, the bulk of early Omicron infections were in young people, who are less likely to get seriously ill with all versions of the virus. And many of those early cases were happening in people with some immunity from previous infections or vaccines. It was unclear whether Omicron would also prove less severe in an unvaccinated older person, for example.

Several Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) neutralising monoclonal antibodies (mAbs) have received emergency use authorisation by regulatory agencies for treatment and prevention of Coronavirus Disease 2019 (COVID-19), including in patients at risk for progression to severe disease. Here we report the persistence of viable SARS-CoV-2 in patients treated with sotrovimab and the rapid development of spike gene mutations that have been shown to confer high level resistance to sotrovimab in vitro. We highlight the need for SARS-CoV-2 genomic surveillance in at risk individuals to inform stewardship of mAbs use and prevent potential treatment failures.

Preprint available in medRxiv (Dec. 21, 2021):

https://doi.org/10.1101/2021.12.18.21267628 

Two studies confirm that a new coronavirus mutant in California is more contagious, although the scale of its threat is unclear.  A variant first discovered in California in December is more contagious than earlier forms of the coronavirus, two new studies have shown, fueling concerns that emerging mutants like this one could hamper the sharp decline in cases over all in the state and perhaps elsewhere. In one of the new studies, researchers found that the variant has spread rapidly in a San Francisco neighborhood in the past couple of months. The other report confirmed that the variant has surged across the state, and revealed that it produces twice as many viral particles inside a person’s body as other variants do. That study also hinted that the variant may be better than others at evading the immune system — and vaccines. “I wish I had better news to give you — that this variant is not significant at all,” said Dr. Charles Chiu, a virologist at the University of California, San Francisco. “But unfortunately, we just follow the science.” Neither study has yet been published in a scientific journal. And experts don’t know how much of a public health threat this variant poses compared with others that are also spreading in California. A variant called B.1.1.7 arrived in the United States from Britain, where it swiftly became the dominant form of the virus and overloaded hospitals there. Studies of British medical records suggest that B.1.1.7 is not only more transmissible, but more lethal than earlier variants.

European countries impose travel bans as scientists probe whether new strain spreads faster or causes more severe COVID-19.  On 8 December, during a regular Tuesday meeting about the spread of the pandemic coronavirus in the United Kingdom, scientists and public health experts saw a diagram that made them sit up straight. Kent, in the southeast of England, was experiencing a surge in cases, and a phylogenetic tree showing viral sequences from the county looked very strange, says Nick Loman, a microbial genomicist at the University of Birmingham. Not only were half the cases caused by one specific variant of SARS-CoV-2, but that variant was sitting on a branch of the tree that literally stuck out from the rest of the data. “I've not seen a part of the tree that looks like this before,” Loman says. Less than 2 weeks later, that variant is causing mayhem in the United Kingdom and elsewhere in Europe. Yesterday, U.K. Prime Minister Boris Johnson announced stricter lockdown measures, saying the strain, which goes by the name B.1.1.7, appears to be better at spreading between people. The news led many Londoners to leave the city today, before the new rules take effect, causing overcrowded railway stations. The Netherlands, Belgium, and Italy announced they were temporarily halting passenger flights from the United Kingdom. The Eurostar train between Brussels and London will stop running tonight at midnight, for at least 24 hours. Scientists, meanwhile, are hard at work trying to figure out whether B.1.1.7 is really more adept at human-to-human transmission—not everyone is convinced yet—and if so, why. They’re also wondering how it evolved so fast. B.1.1.7 has acquired 17 mutations all at once, a feat never seen before. “There's now a frantic push to try and characterize some of these mutations in the lab,” says Andrew Rambaut, a molecular evolutionary biologist at the University of Edinburgh.

Too many unknowns

Researchers have watched SARS-CoV-2 evolve in real time more closely than any other virus in history. So far, it has accumulated mutations at a rate of about one to two changes per month. That means many of the genomes sequenced today differ at about 20 points from the earliest genomes sequenced in China in January, but many variants with fewer changes are also circulating. “Because we have very dense surveillance of genomes, you can almost see every step,” Loman says. But scientists have never seen the virus acquire more than a dozen mutations seemingly at once. They think it happened during a long infection of a single patient that allowed SARS-CoV-2 to go through an extended period of fast evolution, with multiple variants competing for advantage.  One reason to be concerned, Rambaut says, is that among the 17  utations are eight in the gene that encodes the spike protein on the viral surface, two of which are particularly worrisome. One, called N501Y, has previously been shown to increase how tightly the protein binds to the angiotensin-converting enzyme 2 receptor, its entry point into human cells. The other, named 69-70del, leads to the loss of two amino acids in the spike protein and has been found in viruses that eluded the immune response in some immunocompromised patients.  A fortunate coincidence helped show that B.1.1.7 (also called VUI-202012/01, for the first “variant under investigation” in December 2020), appears to be spreading faster than other variants in the United Kingdom. One of the polymerase chain reaction (PCR) tests used widely in the country, called TaqPath, normally detects pieces of three genes. But viruses with 69-70del lead to a negative signal for the gene encoding the spike gene; instead only two genes show up. That means PCR tests, which the United Kingdom conducts by the hundreds of thousands daily and which are far quicker and cheaper than sequencing the entire virus, can help keep track of B.1.1.7.

In a press conference on Saturday, chief science adviser Patrick Vallance said that B.1.1.7, which first appeared in a virus isolated on 20 September, accounted for about 26% of cases in mid-November. “By the week commencing the ninth of December, these figures were much higher,” he said. “So, in London, over 60% of all the cases were the new variant.” Johnson added that the slew of mutations may have increased the virus’s transmissibility by 70%.  Christian Drosten, a virologist at Charité University Hospital in Berlin, says that was premature. “There are too many unknowns to say something like that,” he says. For one thing, the rapid spread of B.1.1.7 might be down to chance. Scientists previously worried that a variant that spread rapidly from Spain to the rest of Europe—confusingly called B.1.177—might be more transmissible, but today they think it is not; it just happened to be carried all over Europe by travelers who spent their holidays in Spain. Something similar might be happening with B.1.1.7, says Angela Rasmussen, a virologist at Georgetown University. Drosten notes that the new mutant also carries a deletion in another viral gene, ORF8, that previous studies suggest might reduce the virus’ ability to spread. But further reason for concern comes from South Africa, where scientists have sequenced genomes in three provinces where cases are soaring: Eastern Cape, Western Cape, and KwaZulu Natal. They identified a lineage separate from the U.K. variant that also has a N501Y mutation in the spike gene. “We found that this lineage seems to be spreading much faster,” says Tulio de Oliveira, a virologist at the University of KwaZulu-Natal whose work first alerted U.K. scientists to the importance of N501Y. (A preprint of their results on the strain, which they are calling 501Y.V2, will be released on Monday, de Oliveira says.) Another worry is B.1.1.7 could cause more severe disease. There is anecdotal evidence that the South African variant may be doing that in young people and those who are otherwise healthy, says John Nkengasong, director of the Africa Centres for Disease Control and Prevention. “It’s concerning, but we really need more data to be sure.” The African Task Force for Coronavirus will convene an emergency meeting to discuss the issue on Monday, Nkengasong says....

Preliminary characterization of the new variant available in Virological (Dec. 18, 2020): https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563

See also ICOG Report (Dec.19, 2020): https://www.cogconsortium.uk/wp-content/uploads/2020/12/Report-1_COG-UK_19-December-2020_SARS-CoV-2-Mutations.pdf

CDC Comments on UK's variant (Dec. 22, 2020):

https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-emerging-variant.html

Moderna, a biotech advancing one of the leading COVID-19 vaccine candidates, has faced questions for several months over its patents and intellectual property. Responding to investor questions, the company now says it won't enforce its vaccine patents against other companies during the pandemic. In a Wall Street Journal interview, company President Stephen Hoge said Moderna is “quite studiously not asserting infringement.” Without naming names, the biotech says other COVID-19 vaccines in development might be using Moderna-patented technology. “We’re not interested in using that IP to decrease the number of vaccines available in a pandemic,” Hoge told the WSJ. Further, the company is open to licensing its technology after the pandemic. Moderna made the pledge in response to investor questions around its patents, Hoge told the newspaper. Moderna says it has spent billions of dollars on mRNA research over the years, but its patents have come under scrutiny on several occasions during the pandemic. Over the summer, the company lost an attempt to invalidate a patent held by Arbutus Biopharma, prompting analysts to wonder how the decision might affect Moderna's COVID-19 work. At the time, a patent lawyer told Reuters the decision increased the pressure on Moderna to seek a sublicense on technology covered by the patent.  

Still, it isn’t completely clear whether Moderna’s potential launch would be affected by Arbutus’ patent. Moderna has a “broad [intellectual property] portfolio covering our development and commercialization of mRNA vaccine and therapeutic programs,” the company said in its latest quarterly filing with the Securities and Exchange Commission. But there are risks. Messenger RNA is a new field, and various patent applications are being processed around the world. There’s “uncertainty about which patents will issue, and, if they do, as to when, to whom, and with what claims,” the company noted in the filing. It’s “possible that one or more organizations will hold patent rights to which we may need a license, or hold patent rights which could be asserted against us," Moderna added. Pfizer and BioNTech are advancing the other lead mRNA vaccine candidate, but a Pfizer spokeswoman told the WSJ that BioNTech holds the patents for that project.

For its part, Public Citizen has argued the U.S. government has partial rights to Moderna coronavirus vaccine patents. The company’s latest move “presumably is designed to help the corporation avoid costly patent litigation,” Peter Maybarduk, the group’s access to medicines director, said in a statement.   Public Citizen’s research has found that U.S. taxpayers will end up having to pay twice for the vaccine—first through initial research and then through the procurement of doses. Further, the U.S. government may have some rights to key patents, Public Citizen concluded in an analysis of documents obtained by Axios. 

The world's largest randomised trial of potential medicines for COVID-19 is to add Regeneron's experimental antiviral antibody cocktail REGN-COV2 to the drugs it is testing in patients hospitalised with the disease. The UK RECOVERY trial, which has been testing a range of potential COVID-19 treatments since it began in April, will compare the effects of adding REGN-COV2 - a lab-manufactured monoclonal antibody - to standard care. “This is the first drug actually designed for this disease,” said Martin Landray, a professor of medicine & epidemiology at Oxford University who is co-leading the trial. “There are lots of good reasons for thinking this might be really quite a powerful treatment,” he told Reuters in an interview. The addition of Regeneron’s drug to the RECOVERY trial comes amid growing hopes that monoclonal antibodies may emerge as effective ways to treat COVID-19.  Until now, the RECOVERY trial had mostly been studying whether existing drugs could be re-purposed to tackle the new disease, and it has already found answers on a number of them.

In June and September, trial results showed that widely used steroids such as dexamethasone and hydrocortisone were able to reduce death rates among severely-ill COVID-19 patients.  Also in June, RECOVERY trial results showed that the anti-malarial drug hydroxychloroquine, once touted by U.S. President Donald Trump as a potential “game changer” in the pandemic, was of no benefit in treating COVID-19 patients.  Regeneron’s REGN-COV2 cocktail, which the company is already testing in late-stage clinical trials in people, combines one Regeneron-made antibody and a second antibody isolated from people who have recovered after being infected with COVID-19.  The combination is designed to bind to the spike protein used by the new coronavirus to gain access to human cells, limiting the virus’s ability to escape.  Regeneron developed the biological drug before linking up with Roche ROG.S to expand its manufacturing capacity in hopes of meeting global demand, should the medicine prove effective. Regeneron would handle U.S. sales, with Roche selling the medicine around the world.

Landray said his team had secured enough supply of the drug so that up to “several thousand” patients could be given it in the trial and compared with several thousand controls. “Given that the second phase (of COVID-19 infections in the UK) seems to be coming now, it is a really good time to be starting this,” he said. The United States already has a $450 million deal for the cocktail in place, under the terms of which Regeneron will sell it around 70,000 to 300,000 potential treatment doses or 420,000 to 1.3 million prevention doses of REGN-COV2. Data is due later this month, Regeneron has said.  Alongside Regeneron, Eli Lilly LLY.N, working with biotech firm AbCellera, is seen as a leading contender in the antibody race. In August it started testing whether its antibody can prevent COVID-19 infections in nursing homes. A separate trial testing the compound on recently diagnosed COVID patients may yield initial data in September or shortly after. GlaxoSmithKline GSK.L and partner Vir Biotechnology VIR.O also began testing an experimental antibody on newly diagnosed COVID-19 patients late last month. AstraZeneca AZN.L is for now testing its antibody-based cocktail on healthy volunteers for tolerability.

A slew of detailed studies has now quantified the increased risk the virus poses to older people, men, and other groups. For every 1,000 people infected with the coronavirus who are under the age of 50, almost none will die. For people in their fifties and early sixties, about five will die — more men than women. The risk then climbs steeply as the years accrue. For every 1,000 people in their mid-seventies or older who are infected, around 116 will die. These are the stark statistics obtained by some of the first detailed studies into the mortality risk for COVID-19. Trends in coronavirus deaths by age have been clear since early in the pandemic. Research teams looking at the presence of antibodies against SARS-CoV-2 in people in the general population — in Spain, England, Italy and Geneva in Switzerland — have now quantified that risk, says Marm Kilpatrick, an infectious-disease researcher at the University of California, Santa Cruz. “It gives us a much sharper tool when asking what the impact might be on a certain population that has a certain demographic,” says Kilpatrick. The studies reveal that age is by far the strongest predictor of an infected person’s risk of dying — a metric known as the infection fatality ratio (IFR), which is the proportion of people infected with the virus, including those who didn’t get tested or show symptoms, who will die as a result. “COVID-19 is not just hazardous for elderly people, it is extremely dangerous for people in their mid-fifties, sixties and seventies,” says Andrew Levin, an economist at Dartmouth College in Hanover, New Hampshire, who has estimated that getting COVID-19 is more than 50 times more likely to be fatal for a 60-year-old than is driving a car.

But “age cannot explain everything”, says Henrik Salje, an infectious-disease epidemiologist at the University of Cambridge, UK. Gender is also a strong risk factor, with men almost twice more likely to die from the coronavirus than women. And differences between countries in the fatality estimates for older age groups suggest that the risk of dying from coronavirus is also linked to underlying health conditions, the capacity of health-care systems, and whether the virus has spread among people living in elderly-care facilities.

To estimate the mortality risk by age, researchers used data from antibody-prevalence studies. In June and July, thousands of people across England received a pinprick antibody test in the post. Of the 109,000 randomly selected teenagers and adults who took the test, some 6% harboured antibodies against SARS-CoV-2. This result was used to calculate an overall IFR for England of 0.9% — or 9 deaths in every 1,000 cases. The IFR was close to zero for people between the ages of 15 and 44, increasing to 3.1% for 65–74-year-olds and to 11.6% for anyone older. The results of the study have been posted to the medRxiv preprint server.

Another study from Spain that started in April, and tested for antibodies in more than 61,000 residents in randomly selected households, observed a similar trend. The overall IFR for the population was about 0.8%, but it remained close to zero for people under 50, before rising swiftly to 11.6% for men 80 years old and over; it was 4.6% for women in that age group. The results also revealed that men are more likely to die of the infection than are women — the gap increasing with age. “Men face twice the risk of women,” says Beatriz Pérez-Gómez, an epidemiologist at the Carlos III Institute of Health in Madrid, who was involved in the Spanish study. The results have also been posted to the medRxiv server.Differences in the male and female immune-system response could explain the divergent risks, says Jessica Metcalf, a demographer at Princeton University, New Jersey. “The female immune system might have an edge by detecting pathogens just a bit earlier,” she says...