The Covid-19 pandemic is considered by many experts to be a mass disabling event. Though most people fully recover from a battle with the highly infectious coronavirus, a significant chunk of patients develop lingering, sometimes debilitating symptoms—aka long Covid. Estimates of how many Covid patients endure long-term symptoms vary considerably. But the US Centers for Disease Control and Prevention recently estimated that nearly one in five Covid patients report persistent symptoms. With hundreds of millions of Covid-19 cases reported around the globe, even the more modest estimates still suggest that tens of millions have lasting effects.
Yet, as those patients seek effective care, researchers are scrambling to define, understand, and treat this new phenomenon. Many patients have reported uphill battles for finding care and relief, including long waits at clinics and few treatment options when they see a care provider.
Cue the quacks. This situation is ripe for unscrupulous actors to step in and begin offering unproven products and treatments—likely at exorbitant prices. It’s a tried-and-true model: When modern medicine is not able to provide evidence-based treatment, quacks slither in to console the desperate, untreated patients. Amid their sympathetic platitudes, they rebuke modern medicine, scowl at callous physicians, and scoff at the slow pace and high price of clinical trials. With any ill-gotten trust they earn, these bad actors can peddle unproven treatments and false hope.
There are already reports in the US of such unproven long-Covid treatments, such as supplements, vitamins, infusions, fasts, ozone therapy, and off-label drug prescribing. But, a British investigation published this week highlights a growing international trend of pricey “blood washing” treatments.
The investigation, carried out by the British outlet ITV News and The BMJ, revealed that thousands of long-Covid patients are traveling to private clinics in various countries—including Switzerland, Germany, and Cyprus—to receive blood filtering, or apheresis, which is not proven to treat long Covid.
Apheresis is an established medical therapy, but it’s used to treat specific conditions by filtering out known problematic components of blood, such as filtering out LDL (low-density lipoprotein) in people with intractable high cholesterol, or removing malignant white blood cells in people with leukemia.
In the case of long-Covid patients, it seems apheresis treatments are used to remove a variety of things that may or may not be problematic. That includes LDL and inflammatory molecules, a strategy initially designed to treat people with cardiovascular disease. Internal medicine doctor Beate Jaeger, who runs the Lipid Center North Rhine in Germany and has started treating long-Covid patients, touts the method, which involves filtering blood through a heparin filter. She also prescribes long-Covid patients a cocktail of anticoagulant drugs.
Jaeger hypothesizes that the blood of people with long Covid is too viscous and contains small blood clots. She suggests that thinning the blood with drugs and apheresis can improve microcirculation and overall health. But there’s no evidence that this hypothesis is correct or that the treatment is effective. When Jaeger tried to publish her hypothesis in a German medical journal, it was rejected.
Robert Ariens, professor of vascular biology at the University of Leeds School of Medicine, told The BMJ and ITV that the treatment is premature. For one thing, researchers don’t understand how microclots form, if apheresis and anticoagulation drugs reduce them, and if a reduction would even matter for disease. “If we don’t know the mechanisms by which the microclots form and whether or not they are causative of disease, it seems premature to design a treatment to take the microclots away, as both apheresis and triple anticoagulation are not without risks, the obvious one being bleeding,” Ariens said.
Jaeger, meanwhile, defended treating patients despite a rejected hypothesis and a lack of evidence. She expressed anger over “dogmatism” in medicine and claimed to have treated patients in her clinic who arrived in wheelchairs but walked out. “If I see a child in a wheelchair suffering for a year, I prefer to treat and not to wait for 100 percent evidence,” she said.
And Jaeger isn’t alone; other clinics have also started offering apheresis for long Covid. The British investigation interviewed a woman in the Netherlands, Gitte Boumeester, who paid more than $60,000—nearly all her savings—for treatment at a new long-Covid clinic in Cyprus after seeing positive anecdotes online. The woman, desperate for relief from her long-Covid symptoms, signed a dubious consent form filled with spelling mistakes, grammatical errors, and half-finished sentences that waived her rights.
Daniel Sokol, a London barrister and medical ethicist, said the form would be invalid under English and Welsh law. “You can’t say, ‘By the way, you agree not to sue us if we cause you horrible injury or kill you, even if it’s through our own negligence,’” he told the investigators. “You can’t do that.”
At the Cyprus clinic, Boumeester received a battery of other unproven treatments along with the apheresis, including vitamin infusions, hyperbaric oxygen treatment, anticoagulants, and hydroxychloroquine, which is notoriously ineffective against Covid-19. After two months in Cyprus, subjecting herself to various treatments and draining her bank account, Boumeester said, she’d seen no improvement in her debilitating symptoms, which include heart palpitations, chest pain, shortness of breath, and brain fog.
“I do think they should emphasize the experimental nature of the treatments more, especially because it’s so expensive,” Boumeester said. “I realized before I started that the outcome was uncertain, but everyone at the clinic is so positive that you start to believe it too and get your hopes up.”
Allison Guy was having a great start to 2021. Her health was the best it had ever been. She loved her job and the people she worked with as a communications manager for a conservation nonprofit. She could get up early in the mornings to work on creative projects. Things were looking “really, really good,” she says—until she got Covid-19.
While the initial infection was not fun, what followed was worse. Four weeks later, when Guy had recovered enough to go back to work full-time, she woke up one day with an overwhelming fatigue that just never went away. It was accompanied by a loss of mental sharpness, part of a suite of sometimes hard-to-pin-down symptoms that are often referred to as Covid-19 “brain fog,” a general term for sluggish or fuzzy thinking. “I spent most of 2021 making decisions like: Is this the day where I get a shower, or I go up and microwave myself a frozen dinner?” Guy recalls. The high-level writing required for her job was out of the question. Living with those symptoms was, in her words, “hell on earth.”
Many of these hard-to-define Covid-19 symptoms can persist over time—weeks, months, years. Now, new research in the journal Cell is shedding some light on the biological mechanisms of how Covid-19 affects the brain. Led by researchers Michelle Monje and Akiko Iwasaki, of Stanford and Yale Universities respectively, scientists determined that in mice with mild Covid-19 infections, the virus disrupted the normal activity of several brain cell populations and left behind signs of inflammation. They believe that these findings may help explain some of the cognitive disruption experienced by Covid-19 survivors and provide potential pathways for therapies.
For the past 20 years, Monje, a neuro-oncologist, had been trying to understand the neurobiology behind chemotherapy-induced cognitive symptoms—similarly known as “chemo fog.” When Covid-19 emerged as a major immune-activating virus, she worried about the potential for similar disruption. “Very quickly, as reports of cognitive impairment started to come out, it was clear that it was a very similar syndrome,” she says. “The same symptoms of impaired attention, memory, speed of information processing, dis-executive function—it really clinically looks just like the ‘chemo fog’ that people experienced and that we’d been studying.”
In September 2020, Monje reached out to Iwasaki, an immunologist. Her group had already established a mouse model of Covid-19, thanks to their Biosafety Level 3 clearance to work with the virus. A mouse model is engineered as a close stand-in for a human, and this experiment was meant to mimic the experience of a person with a mild Covid-19 infection. Using a viral vector, Iwasaki’s group introduced the human ACE2 receptor into cells in the trachea and lungs of the mice. This receptor is the point of entry for the Covid-causing virus, allowing it to bind to the cell. Then they shot a bit of virus up the mice’s noses to cause infection, controlling the amount and delivery so that the virus was limited to the respiratory system. For the mice, this infection cleared up within one week, and they did not lose weight.
Coupled with biosafety regulations and the challenges of cross-country collaboration, the security precautions required by the pandemic created some interesting work constraints. Because most virus-related work had to be done in Iwasaki’s laboratory, the Yale scientists would take advantage of overnight shipping to fly samples across the country to Monje’s Stanford laboratory where they could be analyzed. Sometimes, they would need to film experiments with a GoPro camera to make sure that everybody could see the same thing. “We made it work,” Monje says.
Spector sees this current version of the Zoe app as a giant citizen science project. Users can sign up to different studies, which involve answering questions through the app. Current studies include investigations into the gut microbiome, early signs of dementia, and the role of immune health in heart disease. Before the pandemic, recruiting hundreds of thousands of people for a study would be nearly impossible, but the Zoe app is now a huge potential resource for new research. “I’d love to see what happens when 100,000 people skip breakfast for two weeks,” says Spector.
People who reported Covid symptoms aren’t automatically included in these new studies. Some 800,000 people have agreed to track their health beyond Covid through the Zoe app, while a smaller proportion of people have signed up to specific trials. But it’s hard to imagine these huge sign-up figures without the app having played such a prominent role during the pandemic.
“These emergency situations become catalysts and create a very unique environment,” says Angeliki Kerasidou, an ethics professor at the University of Oxford. “Something we need to be thinking a bit more carefully about is how we use these situations and what we do with them.”
There’s also a question about the line between providing care and conducting research, Kerasidou says. At the height of the pandemic, the National Health Services of Wales and Scotland directed people to track their symptoms through the Zoe app. Tracking Covid symptoms that way might have seemed like the socially responsible thing to do, but now that the app’s emphasis is on wider health tracking and clinical studies, should people feel the same obligation to take part?
The German app Luca is undergoing an even more dramatic about-face. In spring 2021, 13 German states had signed contact-tracing contracts with the app, worth a total of €21.3 million ($22.4 million). Back then, people would use the app to check into restaurants or other businesses by scanning a QR code. If they crossed paths with someone who shortly afterward tested positive for the virus, the app would tell them to isolate.
But as Germany’s vaccination rates improved, state contracts began to evaporate. In response, Luca’s CEO, Patrick Hennig, looked around for a new business model. In February 2022, Luca revealed it would transform into a payments app, with its new payments function launching in early June.
This was a bold business decision in notoriously cash-friendly Germany. Around 46 percent of Germans still prefer to use cash, according to a 2021 study by British polling company YouGov, compared to just over 20 percent in the UK. But Hennig is hoping to change entrenched habits by leveraging the Luca brand—and user base of 40 million registered people—that the company has built throughout the pandemic.
The idea is that people can use Luca as an alternative to card terminals. At the end of a meal, restaurant-goers scan a QR code that shows them their bill and enables them to pay through the Luca app, using either Apple Pay or their card details. Hennig is attempting to incentivize restaurants to use his system by undercutting the 1–3 percent fee they’re usually charged for using a card terminal. Right now, Luca is free for restaurants and shops to use, but that will shift to a 0.5 percent fee at the end of the year, Hennig says. Over 1,000 restaurants and shops have signed up so far.
“At that point I started texting everyone I’d come in contact with over the week,” he says. Realizing how many people visit Provincetown from across the country, he posted about being infected on Twitter and Instagram too. DMs flowed back, from people who thought they’d picked up some summer crud as they traveled. “They thought they were fine,” he says. “Then they tested themselves, and it turned out they also had Covid.”
One of the people Holihan texted was Donnelly. This might seem odd, because Donnelly isn’t an epidemiologist. He is a policy geek who has done macroeconomic forecasting at the Federal Reserve Board and data analysis at Spotify and Facebook. But since early 2020, Donnelly had also been applying his skills to forecasting what Covid might do in the US, a way of making sense for himself of the data flowing from other countries and explaining to others why they ought to be more worried than they were. “Essentially, I wanted to convince my friends it was bad,” he says.
Donnelly’s analyses, which he initially published on Medium, had been solid. He had foreseen that federal action would be needed two days before President Donald Trump declared a national emergency. He had warned that New York City would have to shut down six days before Governor Andrew Cuomo announced that the whole state would be put “on pause.” That prediction led to a consulting gig with New York state (forecasting possible case counts, bed needs, and ventilator orders) and then to founding a site called CovidOutlook.info, a home for reports and predictions that he spun up with Michael LeVasseur, an epidemiologist at Drexel University.
So by the time the Delta variant began creeping through Provincetown, Donnelly was an informal but thoroughly informed expert in what Covid was doing in the US. “I had been tracking variants over the previous six months and, broadly, thought concerns about them were overblown,” he says. When his friends started testing positive, he was surprised, and nettled. He didn’t like being wrong.
Rumors about people testing positive were zipping through group chats: most of this house, everyone in that cottage; the Pennsylvania group, the California group, that couple from DC; 10 people positive, or 15, or 25. Text by text, Donnelly began verifying the stories, asking people about the symptoms they had and the tests they had taken, when they were vaccinated and which shot they got, and all the details of their visits to Provincetown—where they stayed, who they hung out with, which bars and restaurants and shows they went to. He started collecting information on Saturday afternoon, and by Monday he had more than 50 names in a spreadsheet.
The list represented a shocking number of breakthrough infections for a young, healthy, affluent population, a group that should have been at the lowest risk. Donnelly felt an itch to do a study, but LeVasseur persuaded him to turn the project over to a bigger institution than their team of two. Donnelly got in touch with Demetre Daskalakis, the former head of the infectious disease programs in New York City’s health department, who was now at the CDC. On Monday night, Donnelly texted, offering the spreadsheet. Daskalakis asked for it immediately.
Within 24 hours, Daskalakis set up calls between Donnelly, the CDC, and the Massachusetts health department. By the end of the week, the agencies had created a task force, set up a phone number and an email for people to self-report, reached out to other states that visitors had gone home to, and gotten mobile testing units rolling toward Provincetown. “It’s the most accelerated response I’ve ever seen in public health,” Daskalakis says. “And Michael pretty much started that outbreak investigation himself.”
A committee of independent, expert advisers for the Food and Drug Administration voted overwhelmingly to authorize the two-dose Novavax Covid-19 vaccine yesterday, with 21 of 22 committee members voting in favor of the vaccine and one member abstaining.
The endorsement is only for a two-dose primary series in adults, not for boosters. The FDA is not obligated to follow the advice of its committee—the Vaccines and Related Biological Products Advisory Committee (VRBPAC)—but the agency typically heeds its advice. If the FDA authorizes the vaccine, the Centers for Disease Control and Prevention will need to sign off on use before it becomes available.
The decision regarding the Novavax vaccine, which is already authorized in dozens of other countries, is not a straightforward one in the US. The vaccine has some advantages over currently approved vaccines but has several strikes against it.
In terms of design, the vaccine follows a more traditional recipe than the two mRNA-based Covid-19 vaccines or Johnson & Johnson’s adenovirus vector-based design. Both of those designs are relatively new and work by delivering genetic code for the SARS-CoV-2 spike protein to our cells, which then translate the code. The Novavax vaccine, on the other hand, is a protein subunit-based vaccine that directly delivers the SARS-CoV-2 spike protein to cells, along with an adjuvant—which is an additive used in vaccines to enhance immune responses to the vaccine. In this case, the adjuvant is derived from saponin compounds found in the Chilean soapbark tree, which have been used in FDA-approved vaccines previously.
Generally, the protein-subunit vaccine design is tried and trusted; it’s already used in vaccines against flu, pertussis (whooping cough), and meningococcal infection, for example.
Who Would Get It?
Novavax leaned hard into the traditional design in its pitch to the FDA. Now that we’re more than two years into the pandemic and mRNA vaccines are readily available in the US, most people who want to get vaccinated have already gotten their shots. This raises a key question of what role Novavax’s vaccine has left to play and how it warrants “emergency use” authorization given the availability of other vaccines.
The company firmly aimed its traditional shots at vaccine holdouts, which the CDC estimates to number around 27 million. They may be wary of the more innovative mRNA vaccines but could finally be swayed to get vaccinated if offered an alternative that is perceived as more conventional, Novavax argued.
“Millions of Americans today are still unvaccinated,” said Greg Poland, director of the Mayo Vaccine Research Group, who spoke on behalf of the Novavax vaccine at yesterday’s meeting. “For those individuals who are not fully vaccinated and are waiting for another option, having a vaccine platform that multiple stakeholders—including regulators, physicians, and the public—are familiar with can help mitigate some of the challenges we’re facing today.”
Though some committee members were skeptical that another option would sway holdouts, top FDA vaccine regulator Peter Marks seemed to buy it. “We do have a problem with vaccine uptake that is very serious in the United States, and anything we can do to get people more comfortable to be able to accept these potentially life-saving medical products is something that we feel we are compelled to do,” Marks said. He also noted that some Americans aren’t able to get mRNA vaccines due to adverse reactions, thus the protein-based vaccine would be a welcome new option.
Efficacy, Variants, and Safety
Novavax’s vaccine had solid efficacy estimates in a clinical trial published in February in The New England Journal of Medicine. In the trial of more than 29,000 participants, the vaccine had an overall efficacy estimate of 90.4 percent against symptomatic Covid-19. Safety data for the vaccine suggests it’s generally safe and well tolerated, though there may be a link to rare cases of heart inflammation (myocarditis) seen with the mRNA vaccines.
That said, the trial was completed last year before Delta and Omicron (with all its subvariants) came along. It’s unclear how the vaccine’s efficacy will stand up to those newer variants.