4 most urgent questions about long COVID

 When Claire Hastie fell ill in March of last year, she reacted the way she usually would to a minor ailment: she tried to ignore it. “It started off incredibly mild,” she says. “I would normally have paid no attention to it whatsoever.”

But within a week she was flattened. “I had just never felt ill in this way before. I felt like I had an elephant sitting on my chest.” At times, she became convinced she was going to die.

A single mother of three, Hastie “said what I thought might be my final words to the one child who happened to be walking past my bedroom door”. Although her condition is not quite as overwhelming one year on, she says, “I’ve never had a symptom-free day since.”

Hastie has what is now called long COVID: a long-lasting disorder that arises following infection with SARS-CoV-2, the virus that causes COVID-19.

Surveys of thousands of people have revealed an extensive list of symptoms, such as fatigue, dry cough, shortness of breath, headaches and muscle aches. A team led by Athena Akrami, a neuroscientist at University College London who has long COVID, found 205 symptoms in a study of more than 3,500 people1. By month 6, the most common were “fatigue, post-exertional malaise, and cognitive dysfunction”. These symptoms fluctuate, and people often go through phases of feeling better before relapsing2.

In the first months of the pandemic, the idea that the virus might cause a chronic condition was overlooked in the desperate struggle to deal with acute cases. But Hastie soon realized that she was not alone in having a lingering form of the disease. In May 2020, she started a Facebook group for people with long COVID. Today, it has more than 40,000 members and works with research groups studying the condition — with Hastie sometimes appearing as a co-author of papers.

Meanwhile, long COVID has moved from a curiosity, dismissed by many, to a recognized public-health problem. In January, the World Health Organization revised its guidelines for COVID-19 treatment to include a recommendation that all patients should have access to follow-up care in case of long COVID.

Funding agencies are also paying attention. On 23 February, the US National Institutes of Health (NIH) announced that it would spend US$1.15 billion over four years into research on long COVID, which it refers to as “post-acute sequelae of COVID-19 (PASC)”. In the United Kingdom, the National Institute for Health Research (NIHR) announced in February that it was investing £18.5 million (US$25.8 million) to fund four studies of long COVID — and the following month, it launched another round of funding worth £20 million. The UK BioBank plans to send self-testing kits to all its 500,000 participants, so that those with SARS-CoV-2 antibodies can be identified and invited for further studies.

As the number of confirmed COVID cases tops 170 million across the globe, millions of people might be experiencing persistent symptoms and searching for answers about their future health. Here, Nature looks at four of the biggest questions that scientists are investigating about the mysterious condition known as long COVID.

How many people get long COVID and who is most at risk?

There is increasing clarity on the overall prevalence of long COVID, thanks to a series of surveys — but it is less certain who is most at risk, and why it affects only some.

Most of the early prevalence studies looked only at people who had been hospitalized with acute COVID-19. Ani Nalbandian, a cardiologist at Columbia University Irving Medical Center in New York, and her colleagues collated nine such studies for a review published on 22 March3. They found that between 32.6% and 87.4% of patients reported at least one symptom persisting after several months.

But most people with COVID-19 are never ill enough to be hospitalized. The best way to assess the prevalence of long COVID is to follow a representative group of people who have tested positive for the virus. The UK Office of National Statistics (ONS) has done just that, by following more than 20,000 people who have tested positive since April 2020 (see ‘Uncertain endpoint’). In its most recent analyses, published on 1 April, the ONS found that 13.7% still reported symptoms after at least 12 weeks (there is no widely agreed definition of long COVID, but the ONS considers it to be COVID-19 symptoms that last more than 4 weeks).

Source: UK Office for National Statistics

“I think that’s the best estimate so far,” says Akrami, who now splits her research time between her original focus, neuroscience, and work on long COVID.

In other words, more than one in 10 people who became infected with SARS-CoV-2 have gone on to get long COVID. If the UK prevalence is applicable elsewhere, that’s more than 16 million people worldwide.

The condition seems to be more common in women than in men. In another ONS analysis, 23% of women and 19% of men still had symptoms 5 weeks after infection. That is “striking”, says Rachael Evans, a clinician scientist at the University of Leicester, UK, and a member of the Post-Hospitalisation COVID-19 study (PHOSP-COVID). “If you’re male and get COVID, you’re more likely to go to hospital and you’re more likely to die. Yet if you survive, actually it’s females that are much more likely to get the ongoing symptoms.”

There is also a distinctive age distribution. According to the ONS, long COVID is most common in middle-aged people: the prevalence was 25.6% at 5 weeks for those between 35 and 49 years old. It is less common in younger people and older people — although Evans says the latter finding is probably due to ‘survivor bias’, because so many old people who have had COVID-19 have died.

And although long COVID is rarer in younger people, that does not mean it is absent. Even for children aged 2–11, the ONS estimates that 9.8% of those who test positive for the virus still have symptoms after at least 5 weeks, reinforcing the suggestion from other studies that children can get long COVID4. Yet some medical professionals play down the idea, says Sammie Mcfarland, who founded the UK-based support group Long Covid Kids. “Long COVID in children isn’t believed. The symptoms are minimized.”

Nevertheless, age and sex are surprisingly powerful for identifying people at risk. A paper published in March presented a model that successfully predicted whether a person would get long COVID using only their age, their sex and the number of symptoms reported in the first week5.

Still, many uncertainties remain. In particular, if about 10% of people infected with SARS-CoV-2 get long COVID — as the ONS data suggest — why those 10%?

What is the underlying biology of long COVID?

Although researchers have exhaustively surveyed the diverse symptoms of long COVID, no clear explanation for them exists. “We need people to be looking at the mechanisms,” says Hastie. This will not be easy: studies have shown that many people with long COVID have problems with multiple organs6, suggesting that it is a multisystem disorder.

It seems unlikely that the virus itself is still at work, says Evans. “Most of the studies have shown that after a few weeks you’ve pretty much cleared it, so I very much doubt it’s an infective consequence.”

However, there is evidence that fragments of the virus, such as protein molecules, can persist for months7, in which case they might disrupt the body in some way even if they cannot infect cells.

A further possibility is that long COVID is caused by the immune system going haywire and attacking the rest of the body. In other words, long COVID could be an autoimmune disease. “SARS-CoV-2 is like a nuclear bomb in terms of the immune system,” says Steven Deeks, a physician and infectious-disease researcher at the University of California, San Francisco. “It just blows everything up.” Some of those changes might linger — as has been seen in the aftermath of other viral infections (see ‘What is the relationship between long COVID and other post-infection syndromes?’).

Still, it is too early to say which hypothesis is correct, and it might be that each is true in different people: preliminary data suggest that long COVID could be several disorders lumped into one.

Symptoms such as fatigue and difficulty exercising are common in people with long COVID, and can persist for months after infection.Credit: Jessica Rinaldi/The Boston Globe/Getty

Some researchers are taking that next step, hoping to unpick the biology. PHOSP-COVID has recruited more than 1,000 UK patients and taken blood samples to look for evidence of inflammation, cardiovascular problems and other changes. Similarly, Deeks has helped to recruit almost 300 COVID-19 patients who have since been followed up every 4 months and have given blood and saliva samples. “We have a massive specimen bank,” says Deeks. “We’re looking at inflammatory outcomes, changes in the coagulation system, evidence that the virus persists.” The team has found altered levels of cytokines — molecules that help to regulate immune responses — in the blood of people who have had COVID-19, suggesting that the immune system is indeed out of balance, as well as protein markers suggesting neuronal dysfunction8.

A better understanding of the underlying biology will point the way to treatments and medications, says Evans. But it seems unlikely that there is a single, neat explanation for long COVID. Most researchers now suspect several mechanisms are at work, so one person’s long COVID might be profoundly different from another’s. In October, a review published by the NIHR raised the possibility that long COVID symptoms “may be due to a number of different syndromes”. “There is a story emerging,” says Deeks. “There’s not one clinical phenotype. There’s different flavours, different clusters. They all may have different mechanisms.” His group plans to use machine learning to work out how many types there are and how they differ.

Evans and her PHOSP-COVID colleagues have taken a stab at this, in a preprint posted on 25 March9. They studied 1,077 COVID-19 patients, recording symptoms including physical impairments, mental-health difficulties such as anxiety, and cognitive impairments in areas such as memory and language. The researchers also recorded basic information such as age and sex, and biochemical data such as levels of C-reactive protein — a measure of inflammation. The team then used a mathematical tool called cluster analysis to see whether there were identifiable groups of patients with similar profiles.

“We would think if you had a terrible acute lung injury and multi-organ failure, those would be the people that would have the ongoing pathology,” says Evans. But the study found little relationship between the severity of the acute phase, or levels of organ damage, and the severity of long COVID.

The reality was more complicated. The analysis identified four clusters of long COVID patients whose symptoms were distinct. Three of the groups had mental-health and physical impairments to varying degrees, but few or no cognitive difficulties. The fourth cluster showed only moderate mental-health and physical impairments, but had pronounced cognitive problems.

“Cognition was really quite separate, and we weren’t expecting that,” says Evans. She emphasizes that the study does not unpick the underlying mechanisms. “But it is definitely a first step.”

What is the link between long COVID and other post-infection syndromes?

Some scientists weren’t surprised by long COVID. Illnesses that linger after an infection have been reported in the scientific literature for 100 years, says Anthony Komaroff, an internal-medicine physician at Harvard Medical School in Boston, Massachusetts.

He noted that fact in March, during a webinar organised by MEAction, an organization based in Santa Monica, California, that works to raise awareness of myalgic encephalitis, also known as chronic fatigue syndrome (ME/CFS). People with this debilitating illness become exhausted after even mild activity, alongside experiencing other symptoms such as headaches. Long dismissed by some medical professionals because it had no clear biological underpinning, ME/CFS is often post-viral.

It isn’t uncommon for an infection to trigger long-lasting symptoms. One study of 253 people diagnosed with certain viral or bacterial infections found that after 6 months, 12% reported persistent symptoms including “disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance”10. That percentage is strikingly similar to the long COVID prevalence observed in the United Kingdom by the ONS.

Some people with long COVID will probably meet the diagnostic criteria for ME/CFS, according to Komaroff and his colleague Lucinda Bateman, founder of the Bateman Horne Center in Salt Lake City, Utah, which specializes in treating ME/CFS11. But there do seem to be differences: for instance, people with long COVID are more likely to report shortness of breath than are those with ME/CFS, Komaroff says. Furthermore, if long COVID does end up being subdivided into multiple syndromes, that will further complicate comparisons between it and ME/CFS.

“I’ve so far resisted saying long COVID is ME/CFS, because I really think it is an umbrella term and there are multiple things happening in this long COVID umbrella,” says Nisreen Alwan, a public-health researcher at the University of Southampton, UK. And Deeks speaks for many: “I think everybody needs to be a bit agnostic now, and not make too many assumptions, and not put all these different syndromes into the same bucket.” What many do agree on, however, is that the two conditions could productively be studied in tandem. “There should be a coalition,” says Alwan. Some researchers are already planning to collaborate. For instance, a major study called DecodeME aims to recruit 20,000 people to find genetic factors that contribute to ME/CFS — and Evans says PHOSP-COVID will be sharing data with it.

“I’m really hopeful that the silver lining will be, at the end of the day, we gain better insight into other post-viral problems,” says Akrami.

Hastie puts it more bluntly: “Let’s not waste a good crisis.”

What can be done to help people with long COVID?

Right now, the options are fairly limited, because the disorder is so poorly understood.

Some countries are opening clinics for people with long COVID. In Germany, a company called MEDIAN has begun accepting people with long COVID at some of its private rehabilitation clinics. In England, the National Health Service has provided £10 million for a network of 69 clinics: these have started to assess and help people with the condition.

That is a welcome first step, says Hastie, but few evidence-based treatments exist. There is a growing consensus that multidisciplinary teams are needed, because long COVID affects so many parts of the body. “Every person on average has, like, 16 or 17 symptoms,” says Akrami. Often the clinics do not have such teams.

Much of the challenge will be social and political, because people with long COVID must rest, often for months at a time, and they need support while they do so. Their conditions “need to be recognized as a disability”, says Hastie.

People with long COVID are often left with respiratory difficulties, and some clinics are offering rehabilitation.Credit: Jennifer Lorenzini/Reuters

In terms of medicines, a handful are being tested. Biotechnology company PureTech Health in Boston, Massachusetts, announced in December that it was starting a clinical trial of deupirfenidone, an anti-fibrotic and anti-inflammatory agent that it has developed. Results are expected in the second half of 2021. In the United Kingdom, intensive-care specialist Charlotte Summers at the University of Cambridge and her colleagues have launched a study called HEAL-COVID, which aims to prevent long COVID from taking hold. Participants who have been hospitalized with COVID-19 will be given one of two drugs after being discharged: apixaban, an anticoagulant that might reduce the risk of dangerous blood clots; and atorvastatin, an anti-inflammatory. In the United States, the NIH is funding a trial of existing drugs that people with mild COVID-19 can administer at home. Participants will be followed for 90 days to test the drugs’ impact on longer-term symptoms.

Finally, there is the question of what part COVID-19 vaccines might play. Although many of them prevent death and severe illness, scientists do not yet know whether they prevent long COVID.

What about the impact of vaccines in people who already have long COVID? A UK survey of more than 800 people with long COVID, which has not been peer reviewed, reported in May that 57% saw an overall improvement in their symptoms, 24% no change and 19% a deterioration after their first dose of vaccine12. In April, Akrami’s team launched a systematic survey to shed more light. “People need to get vaccinated to come out of the pandemic, but we need to first address their concern of whether the vaccine is going to help, or not harm, or [be] harmful.”

Similarly, Akiko Iwasaki, an immunobiologist at Yale University in New Haven, Connecticut, is recruiting people with long COVID who have not been vaccinated, so she and her colleagues can track how their bodies react to the vaccine. She hypothesizes that the vaccine might improve symptoms by eliminating any virus or viral remnants left in the body, or by rebalancing the immune system.

People with long COVID just want something that works. “How can we get better?” asks Hastie. “That’s what we want to know.”

Nature 594, 168-170 (2021)

doi: https://doi.org/10.1038/d41586-021-01511-z

https://www.nature.com/articles/d41586-021-01511-z

More transmissible, wilier variant makes Covid-19 vaccinations even more crucial

 It’s getting even riskier to remain unvaccinated.

The United States, as a whole, is still in good shape for the summer of reunions and revived activities. But for those who haven’t been immunized against Covid-19, there is a new concern: the emergence of yet another coronavirus variant, one with a nasty combination of features that makes it even more dangerous than the other strains that have caused global alarms.

The variant, known as Delta, was first spotted in India and helped power that country’s recent explosive outbreaks. Also called B.1.617.2, it seems to be the most transmissible version of the coronavirus seen thus far, but also carries some ability to get around the body’s immune protection generated after vaccination or an initial infection. (There’s also some evidence that it is more likely to cause severe disease, though researchers are still trying to confirm that.)

“It’s really like the worst of both worlds,” said epidemiologist Nathan Grubaugh of the Yale School of Public Health.

Globally, the variant’s march around the world could ignite major epidemics, given vaccine shortages in many nations. In unvaccinated populations, experts generally have greater fears about more transmissible variants than ones that are, say, just deadlier, because by causing more cases than would have occurred otherwise, the faster spreading strains can result in greater hospitalizations and deaths overall. Delta appears to be able to do that and more.

“Taken all together, this is something which is really, really anxiety-inducing from a global health perspective,” said epidemiologist William Hanage of Harvard’s T.H. Chan School of Public Health.

In the United States, Delta accounts for just 6% of sequenced cases, federal health officials said this week, though its prevalence is building.

On an individual level, people who have had their full vaccine regimens — a figure that this week in the U.S. crossed 50% among those 12 and older — don’t need to be particularly worried about Delta. The Covid-19 immunizations retain the large bulk of their effectiveness against the variant, though with different vaccines used in different parts of the world, scientists are still parsing how each of them fare. Experts so far have been particularly impressed with how strongly the two-dose mRNA vaccines from Moderna and Pfizer-BioNTech, which account for the bulk of shots delivered in the U.S., stand up to different versions of the virus.

But it’s not as if the SARS-CoV-2 virus has disappeared from the United States. It’s been clear that it would continue to circulate among unvaccinated people going forward. Now, any clusters that emerge and are driven by Delta will grow bigger and faster. And for those who do contract it — with some evidence from England indicating that people infected with Delta are more likely to be hospitalized —“it’s going to be worse for them,” Hanage said.

With so many people vaccinated, whatever outbreaks occur likely won’t lead to huge spikes that inundate hospitals — but they will lead to some people dying.

Nationwide, cases have plunged from where they were just months ago, though the pace of decline has slowed. Study after study has shown the vaccines aren’t just protecting people from Covid-19, but are blunting transmission.

That wall of protection will benefit people who are unvaccinated as well, as will other factors that could be contributing to lower transmission rates, including immunity levels from natural infection and seasonal factors that seem to put some brake on spread.

But some unvaccinated people remain more vulnerable than others.

The story of the pandemic — both globally and within the United States — has been one of hot spots and areas that are better protected. Now, states where immunization rates are lagging — like Idaho, Wyoming, Louisiana, Alabama, Tennessee, and Mississippi — are going to be more susceptible to ongoing outbreaks than states like those in the Northeast, where vaccine uptake has been much higher, particularly as communities slough off remaining countermeasures.

Plus, more transmissible variants like Delta require a higher level of population immunity to be slowed.

The silver lining of the appearance of different variants is that, for whatever twists evolution has thrown our way, the vaccines have largely been able to withstand them. Variants that have some capability to “escape” the immune response elicited by vaccines might cause breakthrough infections at higher rates, and their transmission might not be slowed as quickly. The shots, however, have maintained their incredibly robust ability to prevent sickness and severe outcomes from Covid-19.

But research into Delta has also underscored the importance of getting both shots of the two-dose vaccines. A study from Public Health England last month showed the Pfizer regimen was 88% effective at protecting against symptomatic illness from the variant, and the AstraZeneca vaccine was 60% effective  — just slight drops in performance compared to other forms of the virus. But after just one shot, those figures plummeted to 33% for both vaccines. (The AstraZeneca vaccine has not been authorized in the United States.)

“After the second dose, we see the amount of antibody in a person’s blood is even higher than after the first dose, and therefore more people will be above a threshold,” Wendy Barclay, a virologist at Imperial College London, said at a press briefing Wednesday. “There’s a certain level of antibody and immunity you need to be protected. We know that’s a certain level for the Alpha variant, and there will be a slightly higher level required to protect against Delta variant.”

The Alpha variant Barclay referenced is also known as B.1.1.7 and first appeared last fall in the United Kingdom. Before Delta, it was the most transmissible variant and became dominant in a number of countries, including the United States, but does not have any meaningful immune escape prowess.

Scientists have estimated that Delta is perhaps 60% even more transmissible than Alpha. And in the U.K., it’s overtaken Alpha in frequency — which some experts have speculated could happen in the United States as well. The latest U.S. data indicate Alpha accounted for nearly 70% of sequenced cases, but Delta is amassing.

The urgency, then, is to get as many people immunized as quickly as possible, so more people are protected and there are fewer infections overall, as Delta increasingly accounts for more of the country’s cases.

“If you’ve had your first dose, make sure you get that second dose, and for those who have been not vaccinated yet, please, get vaccinated,” Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, said at a White House briefing Tuesday, where he highlighted the threat of Delta.

There are several factors that appear to give Delta its transmission boost over Alpha. For one, Delta “can transmit more easily in a vaccinated population than the Alpha variant can,” epidemiologist Neil Ferguson of Imperial College London told reporters Wednesday. That advantage will become particularly noticeable in countries with higher vaccination coverage, like the United Kingdom and the United States, because Alpha will encounter greater barriers as it tries to spread. (It’s not that Delta can run rampant through vaccinated populations; it’s a matter that it can transmit comparatively more efficiently because of its immune escape capability.)

In fact, some experts anticipate that in the United States, variants like Delta, Beta, and Gamma could start to claw away at Alpha’s dominance because they have greater abilities to spread among vaccinated populations, though the likelihood of that will depend on how many people remain unvaccinated. (Beta, or B.1.351, first appeared in South Africa, while Gamma, or P.1, emerged in Brazil.)

But Delta also appears to have some other advantages. “The virus itself is fitter in human airway cells,” Barclay said about what early research indicates. That means that an infected person will likely emit more virus into the air, and that the virus is more adept at infecting cells, so people need to be exposed to less of it to contract it.

https://www.statnews.com/2021/06/10/more-transmissible-variant-covid-19-vaccinations-even-more-crucial/

Are Vindictive Variants Threatening Our COVID-19 Recovery?

 A variant by any other name – scientific classifier, place-of-origin, or the new Greek alphabet moniker   – is a potential threat to the freedom America is now enjoying thanks to a successful COVID-19 vaccine rollout. With alarm surrounding the Delta variant, or B.1.617.2, escalating, BioSpace thought it was a good time to take an in-depth look at the most notorious variants of concern (VOC) wreaking havoc across the globe.

B.1.1.7 (Alpha)

Viruses need to mutate in order to survive, and it is common for small variations to their genetic material to occur with each outbreak. The N501Y mutation, shared by the Alpha, Gamma and Beta variants appears to be responsible for their increased infection and transmission rates. 

First picked up in the southeastern England county of Kent in early December 2020, the Alpha variant quickly escaped its U.K. origins and spread across the world. Since its emergence, multiple studies have shown that Alpha is more transmissible, but the scientific community has been conflicted on whether or not it causes more severe disease than the original SARS-CoV-2 virus. Recent research and prevailing opinions have decided that it does not, and also that the rate of reinfection with B.1.1.7 is low.  

An April study conducted by the London School of Hygiene and Tropical Medicine stated that Alpha is 43 to 90% more transmissible than the original virus.

Fortunately, the currently approved BioNTech/Pfizer and Moderna vaccines appear to be standing their ground against Alpha. Both companies expressed early confidence, and recent research has proven them correct, showing that the antibodies developed from these two mRNA vaccines are only slightly less potent against Alpha, Beta and the New York variant of interest (VOI) than the initial wildtype strain.

B.1.351 (Beta)

First identified in October 2020 in the Eastern Cape province of South Africa and reported to the World Health Organization (WHO) in December, the Beta VOC is suspected in a large portion of the deaths of more than 56,000 South Africans. The Beta variant was first detected in the U.S. at the end of January 2021.

Beta’s most concerning mutations are K417N, E484K and N501Y. Variants with the E484K have demonstrated the ability to evade the antibodies generated by the immune system against the original SARS-CoV-2 virus. Put together with the increased transmissibility caused by the N501Y mutation, this quickly becomes a recipe for disaster.

P.1. (Gamma)

First discovered in Japan in January 2021, infecting four recent visitors to the Brazilian state of Amazonas, the Gamma variant was declared to be actively circulating in that country. Like Beta, Gamma made its first appearance in the U.S. at the end of January. It consists of 10 defining mutations, including N501Y and E484K. 

The Gamma variant caused widespread global panic in the early spring as it appeared to cause higher fatality rates among the previously largely spared 20 to 39-year-old demographic. The fire was particularly stoked when Brazilian researchers posted a study on the preprint server, medRxiv, in March, reporting a sudden spike in case fatality rates among this age group in Brazil’s largest southern state, Paraná. The authors found that this rate tripled in 20-29 year-olds. 

B.1.617.2 (Delta)

While the U.K. was dealing with the emergence of the Alpha variant, B.1.617.2 (Delta) was beginning to make its presence known in India. As the crisis reached a fever pitch in India, the World Health Organization (WHO) declared Delta a VOC in the second week of May. It is potentially the most homicidal agent yet.

While officially isolated in December, India began to really feel Delta’s effects in March when it is suspected that the variant became a catalyst for the wave currently devastating that country.

Delta is part of a triple mutant strain named B.1.617, which is split into three lineages. Sub-variant, B.1.617.2, is the lineage that is sparking fear across the world, while the B.1.617.1 sub-variant, named Kappa, has been downgraded to a variant-of-interest (VOI).

Delta has gone on to infect thousands across Southeast Asia and has now spread to at least 62 countries, including the U.S. and Canada. According to the CDC, the Delta variant now accounts for more than 6% of infections in the U.S. and may be responsible for 18% of cases in some Western states. 

In the U.K., Delta has now usurped Alpha as the primary cause of disease. On Monday, British Health Secretary Matt Hancock told Parliament that the British government believes the variant to be 40% more transmissible than the Alpha variant. In a letter published last week in The Lancet, scientists from the Francis Crick Institute in London revealed that neutralizing antibodies generated by the Pfizer/BioNTech were lower against the Delta variant than the original virus.

The researchers found that individuals fully vaccinated with two doses of the vaccine had antibodies that were six times lower against Delta when compared to the original strain. The antibody response was even lower after one dose, spurring redoubled calls to reach full vaccination faster. A recent study conducted by Public Health England found the Pfizer/BioNTech vaccine to be 88% effective against symptomatic disease from the Delta variant 2 weeks after the second dose.

Alarming symptoms not seen before in other variants, such as hearing impairment, severe gastric upsets, and blood clots leading to gangrene, are being reported in India.  

Variants of Interest (VOI)

Variants of Interest, which are suspected to either be more contagious than the initial strain, cause more severe disease, or escape the protection offered by vaccines, have also been given Greek alphabet monikers. Of most recent domestic intrigue are B.1.427 and B.1.429, jointly named Epsilon, and B.1.526 (Iota).

The Epsilon “twins” were first identified by researchers from the University of California, San Francisco in December. Data gathered by UCSF scientists from 44 California counties indicated that Epsilon was more transmissible and associated with more severe disease.

Iota began appearing in samples in November and picked up speed in New York City in February 2021. Studies conducted by Caltech and Columbia spurred fears that Iota could weaken the effectiveness of some of the vaccines. 

https://www.biospace.com/article/are-vindictive-variants-threatening-our-covid-19-recovery-/

Could Elemental Metals Be Key to Effective Alzheimer's Treatments?

 Researchers have grappled with Alzheimer's Disease for decades, with each discovery providing a little fresh spark of hope for treatment options and, dare we say, a cure. Researchers from the UK universities Keele and Warwick published the latest research in Science Advances this week, showing biogenic metallic elements in the brains of deceased Alzheimer's patients. 

The researchers used intense X-ray beams to find nanoparticles of the elemental form of copper and iron in "chemically reduced states". While these metals do occur naturally in the body and are necessary for brain function, they are usually stored in an oxidized form. 

This is the first confirmation of elemental metals in human brain tissue. Researchers hope it can contribute to the ongoing Herculean task of finding a cure for devastating neurodegenerative diseases like Parkinson's and Alzheimer's. 

While high levels of zinc, iron, and copper have long been linked to the hallmark buildup of amyloid and tau in the brains of AD patients, there is not yet evidence to show whether this relationship causes the disease. 

It has previously been suggested that coming into contact with these metals through cookware and food increases your risk of developing the disease. But research does not support those claims.

Neil Telling, professor of biomedical nanophysics at Keele said in a statement that there is "absolutely no reason to think that everyday exposure to these metals could cause their presence in the brain." 

Typically, the body clears metals in small amounts through the kidneys. It has been shown that if they are not removed by the kidneys, either by organ failure or exposure through extremely high doses, these metals can deposit in the brain.  

While "unexpected," Telling clarifies that with the team's discovery of copper and iron in the brain, it is "not yet clear whether such particles are indeed linked to the disease. At the very least, their presence indicates that there is much more to learn about the way in which metals are processed in the brain." 

While the find of elemental metals was "unexpected," considerably more research is needed before the discovery can impact treatments for AD. The next question would potentially focus on how these metals interact with amyloid proteins that form the plaque buildup found in Alzheimer's patients. 

"Ultimately, this line of research could lead to new treatments that target metals as well as the amyloid proteins currently under consideration." 

The research team hopes their discovery could aid in the development of new lines of therapies that would work to restore mental balance in diseased brains to slow or prevent the devastating progression of these incurable neurodegenerative diseases. 

Currently, over 6 million Americans have been diagnosed with Alzheimer's disease. It is estimated that, without more medical breakthroughs to prevent or slow the condition, that number will grow to 12.7 million, racking up an enormous financial and emotional toll.  

In the past week, Biogen's aducanumab, marketed as Aduhelm, was the first drug approved in almost 20 years for Alzheimer's. It was the first drug ever approved to treat an underlying cause of the disease.  

However, that endorsement comes with its own slew of challenges and controversy. Many argue that the drug has not proven its efficacy enough for approval. Others feel that any amount or chance of improvement is better than nothing for AD patients with no other hope.  

The drug did prove its ability to reduce amyloid beta plaques – a longtime target for AD researchers. The question comes whether clearing the plaque will result in clinical benefit. With the approval comes the stipulation of proving benefit with real-world data. 

"Aducanumab is just the first of several Alzheimer's drugs that will become available in the next five to 10 years," said Alzheimer's Drug Discovery Foundation CSO Howard Fillit, M.D. "The robust Alzheimer's research pipeline, complemented by a growing number of biomarkers and other important research tools, means that the clinical trials underway today are more rigorous and more promising than ever." 

https://www.biospace.com/article/elemental-metals-discovered-in-alzheimer-s-brains-could-be-next-key-for-treatment-options-/

Health data giants Ciox, Datavant merge in $7B deal

 

• Ciox Health and Datavant are merging in a deal valuing the combined health data companies at $7 billion, the latest in a string of mergers meant to unite siloed data in healthcare.
• The combined company, called Datavant, will facilitate data exchange across a network of thousands of hospitals and clinics, and bring in annual revenue of $700 million, according to the Wednesday announcement.
• The merger, expected to close in the third quarter, could pave the way for an initial public offering in the future, unnamed sources close to the deal told Bloomberg.

Real-world health data company Datavant and health record IT firm Ciox Health say combining forces will result in the largest health data ecosystem in the U.S., making patient-level medical information more widely accessible to doctors and researchers.

Together, San Francisco-based Datavant and Alpharetta, Ga.-based Ciox have a network of more than 2,000 U.S. hospitals and 15,000 clinics, along with hundreds of health plans, health data analytics and life sciences companies, government agencies and academic bodies.

The fragmentation of data is a big problem facing healthcare, and making it easier to share health information holds the potential to improve patient outcomes, foster drug development, advance value-based models and contribute to medical research. That's why HHS has made improving interoperability a key prong of its healthcare agenda over the last few administrations.

But rising data-sharing is creating a lucrative third-party data market, giving rise to worries about patient privacy as medical datasets rapidly expand. There are real risks to aggregated, de-identified patient data, which is largely unregulated by the HIPAA privacy law, and could be subject to various types of monetization once it's wiped of patients' names and other identifying information, and leaves a covered healthcare entity.

Ciox, which was created by the merger of HealthPort, IOD Inc., Care Communications Inc. and ECS in 2015, and Datavant, which was founded in 2017, say they don't sell patient data to any third parties.

​The merger is supported by a group of investors including investment firm New Mountain Capital, Labcorp and Roivant Sciences. Pharma giants Merck and Johnson & Johnson also invested, as did payer Cigna's venture arm.

The deal is the latest in a flurry of tie-ups and partnerships in the health data connectivity space. In December, EHR giant Cerner snapped up the health division of Kantar Group for $375 million to advance its clinical research development.​ In February, 14 health systems formed Truveta, a company working on aggregating and selling de-identified data from their combined millions of patients; while just last month, several health data aggregators formed an industry coalition to advance the use of real-world data in regulatory decisions.

For their part, Datavant's closed two acquisitions, of IT company Highland Math in 2020 and data connectivity player Health Data Link in 2019, while Ciox bought AI company Medal last year.

The combined Datavant will be led by Coix CEO Pete McCabe, while Datavant CEO Travis May will be president and join the board of directors.

https://www.healthcaredive.com/news/health-data-giants-ciox-datavant-merge-in-7b-deal/601595/

Biogen now has 10 years to confirm approved Alzheimer's drug works

 Biogen will have until the end of the decade to complete another clinical trial confirming its newly approved Alzheimer's treatment can actually benefit patients. 

The Food and Drug Administration mandated the follow-up study as a requirement of the conditional clearance it granted Biogen's drug, called Aduhelm, on Monday. According to an approval letter from the regulator, the biotech company has until next August to finalize a plan for the study, until 2029 to finish testing and until 2030 to submit a final report to regulators. 

If Biogen fails to complete the study, or results are negative, FDA officials said the agency would pull Aduhelm from market. In the meantime, however, Biogen will be able to sell the drug widely, potentially generating tens of billions of dollars in revenue without convincing proof of clinical effectiveness. 

"We believe that the data supports accelerated approval while holding the company accountable for conducting an additional study to confirm the benefits observed in one of the trials, which we fully intend to do," Patrizia Cavazzoni, head of the FDA's main drug review office, told reporters Monday. "We acknowledge that it will take some time to conduct a confirmatory trial." 

The agency hopes to accelerate testing, however, by incorporating "opportunities" for earlier study results while the overall trial continues, an FDA spokesperson told BioPharma Dive in a statement after this story was published.

"We consider the nine-year timeline a conservative estimate, which is an appropriate starting point for development of the draft protocol from the sponsor for its global confirmatory study," the spokesperson wrote in an email. STAT News previously reported the FDA viewed the trial timeline as conservative, citing an unnamed official. 

Yet, in a Monday interview with CNBC, Biogen CEO Michel Vounatsos emphasized that nine-year timeline, although he acknowledged the specific trial plans were not yet set. 

As things stand now, Aduhelm is backed by two nearly identical Phase 3 studies as well as an earlier Phase 1 trial. But the results are highly controversial, as data from those two late-stage studies were conflicting. In one, treatment appeared to modestly slow cognitive and functional decline among patients given a high dose of Aduhelm. In the other, treatment had no effect. Patients on the high dose even seemed to decline slightly faster than those given placebo. 

The discordant data has stirred significant doubts among experts whether Aduhelm truly slows disease progression, and whether data from the one successful trial was a false positive. Both questions are made more complicated by Biogen's March 2019 decision to halt the trials early, thinking then that the drug was unlikely to succeed. The company's subsequent reversal was highly unorthodox and muddied the statistics used to determine treatment benefit. 

Accordingly, in the run-up to Monday's decision, many experts had urged the FDA to reject Aduhelm and ask Biogen to complete a third large, well-controlled study before granting approval. 

"No number of post hoc analyses of these two trials can substitute for the value that could be generated by a new trial," said Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health, in an April interview. Alexander was a member of an FDA advisory committee that rejected Biogen and the agency's case for Aduhelm in a contentious November meeting. 

The FDA dismissed the committee's advice, choosing after a long review a middle-ground approach that it hadn't discussed at the meeting. Even though Biogen requested a full approval for Aduhelm, based on the signs of clinical benefit in the one trial, the agency instead granted an accelerated approval, based on the drug's effect in reducing a toxic plaque found in the brains of Alzheimer's patients. 

Aduhelm does that very well, but it's not clear whether plaque reductions directly correlate to slower cognitive and functional declines. At the November meeting, even the head of the FDA's neuroscience division said the agency was not using amyloid reduction as a surrogate of efficacy — a position the regulator seemingly reversed. 

Unlike full approvals, accelerated approvals require a confirmatory study, which Biogen will now have to complete in order to keep its drug on the market. But the long timeline allowed by the FDA gives the company more than eight years to do so, even if opportunities for interim results are built in. Aduhelm's two Phase 3 trials ran for about four years to complete, although they were stopped early.

"We expect the sponsor to commit all resources needed to move this trial forward as effectively as possible, with the aim of completing the trial as soon as is feasible, while assuring the quality of the data and the robustness of the results," the FDA spokesperson told BioPharma Dive. 

In its letter, the agency didn't specify whether the study must use a placebo as a comparison, asking instead for "an appropriate control for the treatment of Alzheimer's disease." 

Experts previously questioned whether an approval of Aduhelm would make other clinical trials testing Alzheimer's drugs much harder, as patients would be less willing to receive a placebo. 

https://www.biopharmadive.com/news/biogen-aduhelm-confirmatory-study-fda-approval/601422/