For a formidable adversary with plenty of secrets up its sleeve, the coronavirus presented one bright bull’s-eye for the world’s response. Scientists, in record time, developed vaccines based on the virus’s spike protein that in turn have saved millions of lives.
Yet more than two years after SARS-CoV-2 appeared, as documented deaths in the U.S. near 1 million and estimated global deaths reach as high as 18 million, there are still many mysteries about the virus and the pandemic it caused. They range from the technical — what role do autoantibodies play in long Covid? Can a pan-coronavirus vaccine actually be developed? — to the philosophical, such as how can we rebuild trust in our institutions and each other? Debate still festers, too, over the virus’s origins, despite recent studies adding evidence that it spilled over from wildlife.
Some of these questions defy answers entirely or can only be resolved over time. Here, STAT examines six mysteries that scientists are beginning to unravel. The eventual answers will determine our relationship with Covid and and how we’ll fight a future pandemic.
1. How will the virus evolve next?
It seems painfully naive now, the early thought that the SARS-CoV-2 virus would not mutate all that quickly. Instead, scientists have churned through more than half the letters of the Greek alphabet to label the unexpected array of mutation-laden variants that have emerged. The Delta variant was such an efficient spreader that some speculated that the virus was approaching its maximum transmissibility, and then along came Omicron — one of the most infectious respiratory viruses we’ve ever seen.
Which is to say, experts are humble about forecasting the evolution of the virus.
Any predictions rest on a guiding principle: All viruses want to do is replicate and spread, and strains will outcompete others by either becoming more inherently contagious or by managing to infect even people who have some level of protection, or both. Going from the Alpha variant to Delta to Omicron, we’ve witnessed the virus make leaps using both strategies. Now, given how many people have acquired immunity through vaccination or previous infection, it’s possible that the virus’ better strategy is through variants that can “escape” immunity to a degree. In face of such variants, we may need to update vaccine formulas.
As they accumulate mutations, viruses can pick up new traits but may have to sacrifice others. It’s possible, for example, that a variant could become even more adept at infecting the cells in our noses and throats, but not cause severe disease very often. There are also limits to how much a virus can change if it still wants to be able to hack into our cells and use them to churn out copies of itself.
But yet another SARS-2 surprise has been how much change the virus can “tolerate” in its spike protein, while still being able to infect our cells, proliferate, and make us sick.
“It opens the question of, well, if SARS-CoV-2 was able to tolerate so many mutations in Omicron, could it tolerate more?” said Jacob Lemieux, an infectious diseases physician at Massachusetts General Hospital who’s been tracking variants. “Could it tolerate mutations in other places? A completely different set of 30 to 50 mutations?”
SARS-2 also showed it can land a sucker punch. Both Alpha and Delta were so dominant globally that experts figured that the next “variant of concern” would be a descendant of theirs. But then, from somewhere rooted further back in the evolutionary family tree, came an entrant that surged ahead — first Delta to replace Alpha, and then Omicron to replace Delta.
“While we’re all watching Omicron and BA.2, there could very well be another curveball to come at us yet,” said Bronwyn MacInnis, the Broad Institute’s director of pathogen genomic surveillance. For now, scientists are tracking sublineages of BA.2 that have started cropping up around the world.
Another curveball would be the merging of two existing variants, which can occur when two viruses infect the same cell. There have already been documented cases of these “recombinant viruses” — including hybrids of Delta and Omicron, and of different Omicron sublineages — but they haven’t changed the course of the pandemic.
While the virus will almost certainly evolve to get better at spreading in a given setting, experts can’t predict whether it will get more or less dangerous on an individual level. “One of the most persistent myths surrounding pathogen evolution” is that viruses change over time to be less virulent, three experts wrote in a commentary last month. Omicron happened to be less virulent than Delta, but viruses can pick up random mutations that instead make them nastier. The possibility of a variant emerging, the experts warned, that features “the potentially disastrous combination of the ability to reinfect” along with “high virulence is unfortunately very real.”
— Andrew Joseph
2. What will future waves look like?
Many predictions have been made during the pandemic; many have turned out to be dead wrong. We’d like to avoid adding to that list. But here are some things we feel we can say with some certainty.
From the point of view of the virus, the pandemic isn’t over. But from the point of view of many humans, it is yesterday’s news.
People are bone weary of Covid-19 and the disruption it has inflicted on their lives. Many are done — done with not traveling, done with not socializing, done with the sense of powerlessness that permeated the earlier stages of the pandemic. Consequently, they are now determined to make their own calls, calibrating the concern they associate with a particular activity, like going to a concert or traveling for spring break, against their sense of vulnerability to the virus.
Political and public health leaders know that — especially the former. Even those who were slower to lift restrictions understand there is very little appetite for across-the-board measures that would be seen as concessions to the virus at this point.
There may still come a time (or times) when the Centers for Disease Control and Prevention or state or local authorities urge renewed caution — as the city of Philadelphia did this month by reinstating an indoor mask mandate that it had lifted just a month earlier. But it seems unlikely most jurisdictions will reach for big-hammer measures unless there is no other option. Even then, authorities in some states (think red) would probably object on philosophical grounds.
Will the SARS-CoV-2 virus put us in that spot?
What we’ve seen so far suggests that as people have acquired more immunity to SARS-2, through vaccination, infection or both, we’ve become less vulnerable to the virus. Yes, it can still infect us, even if we’re vaccinated. Yes, it will reinfect us. But rates of serious disease, hospitalization and deaths have dropped sharply. And at this point, the people who are dying are, in the main, people who have refused to be vaccinated.
Hopefully, that protection against serious diseases will hold up. If it does, we’ll still see waves of infections. We’ll also see hospitalizations and deaths. But not at the scale we saw before the vaccines were rolled out.
“I don’t think we’re going to get a clean ending, where suddenly the virus, in the immortal words of Donald Trump, vanishes,’’ said John Moore, a virologist at Weill Cornell Medical College. “But it may become a nuisance, rather than a crisis.”
Trevor Bedford, a computational biologist at the Fred Hutchinson Cancer Research Center, thinks it could be a bigger nuisance for us going forward than the annual flu season, even though Covid is now killing far fewer of the people it infects. Because of its high infectiousness, he thinks Covid-19 could cause about 60,000 deaths a year in the U.S., which is the equivalent of a very bad flu season. To put that in context, we’ve had more than 90,000 Covid deaths since early February.
Then there’s the question of the shape of future Covid curves. Some experts see SARS-2 eventually becoming like other respiratory viruses, which spike in the autumn and winter and then fall to very low levels for the rest of the year. Or it could be that seasonal patterns have geographic divides, with summertime surges in the South as in the past two summers, and more standard spikes in the northern part of the country when temperatures drop.
While the spread of viruses like flu falls to very low levels in the off season, it’s also possible that SARS-2 is so infectious that the country never sees waves truly bottom out. If there’s a floor of several thousand cases a day, that means “we’re going to kind of be dealing with this at some level at all times of the year,” with “substantial ebbs and flows in different places at different times,” said Stephen Kissler, an epidemiologist at the Harvard T.H. Chan School of Public Health.
A lot of the experts we’ve spoken to about Covid see this type of eventual move to a still-bad-but-manageable virus as the likeliest of scenarios. But in mid-February, STAT published a submitted commentary that gives us pause. In it Donald Burke, former dean of the University of Pittsburgh’s Graduate School of Public Health, laid out several more troublesome paths the SARS-2 virus could take. They include evolving to attack other organs rather than the respiratory tract, or using the SARS-2 antibodies we have developed against us, triggering more severe disease on future exposures to the virus (or Covid vaccines), a phenomenon known as antibody dependent enhancement. Burke is someone other experts pay attention to and there were groans on Twitter as people absorbed his cautionary words. “I don’t like reading those,” said Marion Pepper, associate professor and interim chair of the department of immunology at the University of Washington.
“I think on top of just the layers of immunity, we know how to handle it better,” she said.
So: We’re in a better place. We hope we’re heading towards a detente with SARS-2. But future skirmishes or worse cannot be ruled out.
— Helen Branswell and Andrew Joseph
3. If you’ve never had Covid, how worried should you be right now?
Pepper, the University of Washington professor, caught Covid about seven weeks ago during the Omicron wave; her husband and two kids did too. Fully vaccinated and boosted, she experienced what she described as the equivalent of a head cold. As someone who thinks we’re all destined to catch Covid sooner or later, Pepper admitted she thought, “At least I’m getting this over with.” She acknowledged, though, that putting off Covid infection till even later might be a better idea. “Not being able to predict the future, maybe there would be an even milder strain that you could be exposed to that would give you even better immunity,” she said.
With the enormous back-to-back Delta and Omicron waves, many, many people are in Pepper’s position. They have so-called hybrid immunity, acquired through a combination of vaccination followed by breakthrough infection, or infection followed by vaccination. The thinking is that the arsenal of immune system weapons protecting these folks is broader than those protecting people who have only been infected or only been vaccinated.
Research by Pepper and her team has demonstrated this, at least in terms of people whose first exposure to SARS-2 was through infection. The paper, which has been accepted for publication by the journal Cell, showed that the infected-first people generate higher levels of a cytokine called interleukin 10, which dampens the damaging immune response that Covid infection can sometimes trigger. In effect, this positions people to better handle Covid infections, Pepper said. The work was done, though, before the Omicron wave, and it’s not clear that a first infection with Omicron would elicit the same response. Pepper said her group plans to study this, and will look to see if the same effect occurred in people who were vaccinated first, then had a breakthrough infection.
If people who have hybrid immunity are better armed than people who are only vaccinated, should the latter be worried at this point? Several experts STAT spoke to said they saw no reason for them to be.
“So much of this is personal attitudes,” said Moore, from Weill Cornell Medicine in New York. “Common sense. Knowledge of your own health. I see no reason to go out and get infected to ‘boost your immunity.’ It’s not an efficient way of doing it and the side effects are going to be worse than any vaccine dose.”
John Wherry, director of the Institute for Immunology at the University of Pennsylvania, said that Omicron as a first infection might not give people the immunity weapons that would be helpful later. “Omicron infection in previously unvaccinated, previously uninfected individuals seems to do quite poorly in inducing antibodies that can efficiently cross-neutralize other variants,” he said.
There’s also the SARS-2 wild card: long Covid. There is currently no way of knowing who among the people who contract the virus could go on to develop this perplexing condition. The only way not to risk developing long Covid is to avoid catching Covid in the first place.
While we’re talking about immunity, you may be wondering about how long it will last. This is among the unanswerable questions at the moment. It’s been clear for some time now that antibody levels decline pretty quickly after vaccination, especially with the messenger RNA vaccines. And those lower levels of antibodies can permit breakthrough infections. But for the most part, the other facets of the immune responses generated by vaccination — the protection generated by B cells and T cells — appear to be holding up against serious illness. As Moore put it, “I think preservation against the worst consequences of Covid is going to last quite a long time.”
— Helen Branswell
4. How, exactly, does the virus transmit from person to person?
Remember the pandemic’s early months of ceaseless surface-sanitizing and hand-scouring? It’s now clear that contaminated surfaces are rarely, if ever, the culprit. Rather, SARS-CoV-2 is primarily transmitted through the streams of mostly invisible respiratory particles that everyone emits when they’re talking, singing, sneezing, coughing, and breathing. It can survive in even the tiniest particles, called aerosols, which can linger in still indoor air for hours and be inhaled into the deepest recesses of one’s lungs.
But exactly how much Covid-19 is caused by these aerosols, versus larger particles that don’t float, so much as spray and splatter and get trapped on mucous membranes further up in the respiratory tract, is a question that continues to defy easy answers. “If two people are close to each other and one becomes infected, there’s no way of telling whether it was from touching each other, breathing in the aerosols, or getting sprayed by bigger droplets,” said Linsey Marr, an environmental engineer at Virginia Tech and one of the world’s leading scientists on airborne viruses.
Disentangling the various transmission routes requires experiments that are expensive, technologically daunting, and ethically complicated. But getting to the bottom of how the virus spreads is critically important for determining the most effective ways to curb it.
“A more profound understanding of the mechanisms driving transmission will be extraordinarily useful in trying to design better working countermeasures,” said Vincent Munster, chief of the virus ecology section at the National Institute of Allergy and Infectious Diseases’ Rocky Mountain Laboratories. “Answering these questions not only has an impact on how we deal with SARS-CoV-2, but with any seasonal respiratory virus.”
In March 2020, Munster and his team provided some of the first evidence that SARS-CoV-2 could stay suspended in the air for hours. Later, they showed that these aerosols more easily infected hamsters and made them sicker than virus the animals picked up from surfaces. In a study published in January, his team proved for the first time that the smallest aerosols — those less than 5 microns — contain enough virus to infect other animals at distances up to 6 feet after just one hour.
It was time-consuming and meticulous work. One of the lab’s postdocs, Julia Port, had to design a novel caging system capable of filtering out all but the smallest aerosols. The equipment they use to generate, collect, and measure different sizes of aerosols costs millions of dollars. And they have to conduct their experiments in specialized, biosecure facilities.
Marr and her collaborators are among the few other labs with the means and expertise to do such work. In a study published last October, her team measured the different sizes of particles coming out of sick hamsters’ lungs. They found that SARS-CoV-2 congregated in the smallest aerosols; particles smaller than 5 microns contained the majority of airborne virus. “It’s a little counterintuitive because we think, ‘Oh, well, larger particles have a lot larger volume and should carry a lot more virus,’ but that doesn’t seem to be the case.”
Now, humans aren’t hamsters. But an aerobiologist at the University of Maryland, Don Milton, has been using a medieval-looking device he invented called the Gesundheit II to measure the amount of SARS-CoV-2 inside the breath of infected college students and staff. In a study published in September, his team found more virus inside smaller versus larger particles.
They also discovered that SARS-CoV-2 was evolving to be even better at getting into those smaller particles. People infected with the Alpha strain (previously known as B.1.1.7, which first emerged in the U.K.) shed 18 times more viral material into fine aerosols than people infected with older strains, after controlling for overall differences in viral load. Milton’s team is now looking at newer, even more contagious variants like Delta and Omicron.
Producing virus-laden particles is just the first step of transmission, though. Ultimately you want to know where those particles wind up and which ones caused any resulting infections. Not every place along your respiratory tract is equally vulnerable to serious infection, and different interventions are more effective against some sizes of particles than others.
Ventilation and air filtration clear out the smallest aerosols that can travel across rooms, but they have less of an impact on larger, heavier particles that are typically expelled over several feet by a person. Surgical masks block those larger particles, but aren’t as good at blocking aerosols. N95 and similarly rated masks (like KN95 and KF94 masks) block both, but are more expensive, and it’s not sustainable for everyone to wear them at all times.
However, that final step of transmission, deposition, is a much harder thing to study, especially with a virus that carries the risk of long Covid. So some of the best-equipped research teams are now turning their attention back to an older respiratory scourge — influenza.
Last month, Flu Lab announced it was funding an $8.8 million initiative led by Virginia Tech to try to find these answers for a virus that has plagued humankind for much longer than SARS-CoV-2. As part of the effort, Marr’s lab will be placing kid-friendly air-sampling robots around a day care center and measuring the germs that wind up inside and on their surfaces as the children interact with them.
Other teams will be using a molecular barcoding technology developed at Emory University to infect ferrets with clouds of artificially generated particles — with different-sized particles containing uniquely traceable versions of the virus. The idea is to be able to track which sizes of particles are best able to infect ferrets and capable of forward transmission, said Seema Lakdawala, a microbiologist at the University of Pittsburgh School of Medicine who is leading the project. “That’s just something you cannot do in humans,” she said.
But you can put a bunch of people who’ve been recently diagnosed with influenza into a quarantine hotel with healthy volunteers for two weeks and watch what happens. That’s something Milton’s team in Maryland is preparing to do, as part of a five-year randomized controlled trial supported by a $15 million grant from the National Institutes of Health.
“The hope is that this will allow us to clearly identify to what extent the transmission among young adults is via inhalation of aerosols versus spray-borne transmission of drops versus touching contaminated surfaces,” said Milton. At least for flu. And better understanding how flu spreads and how to manage it will almost certainly benefit efforts to curb the coronavirus. Especially if it, as expected, evolves from a pandemic pathogen to a more seasonally active endemic virus.
“These studies will allow us to develop a framework to examine the efficiency of each mode of transmission for a respiratory virus,” said Lakdawala. Such a framework could also help the scientific community respond faster the next time a novel respiratory pathogen emerges and avoid the early confusion that still haunts our response to SARS-CoV-2.
— Megan Molteni
5. Will we get a new, better generation of vaccines, therapeutics, and tests?
What do you want first: the good news or the bad news?
The good news is that the state of emergency created by the pandemic allowed researchers to quickly develop multiple different types of vaccines, effective treatments for the virus, and new types of rapid tests. The bad news is that new alternatives to this first rush of technologies may be more difficult to bring to market — unless major changes are made to the way society funds research, or SARS-CoV-2 evolves so much that existing remedies no longer work.
Whether we’ll get much better tools differs, as you might expect, for each category. It’s hardest to imagine diagnostics being revolutionized further. Tests that use new technologies from CRISPR or nucleic acid amplification systems other than PCR were developed during the pandemic, but for most people the two options remained PCR, which is much slower in the U.S. than it needs to be, and the rapid antigen tests that flooded drugstore shelves. In order for there to be something better, someone would have to want to do better and spend a lot of money to change the way our testing system works. There is no sign that there is a market for that. Yes, there will be new technologies, such as the recent SARS-CoV-2 test that can detect the virus on someone’s breath. But the big issues with testing have to do with infrastructure, not technology.
For vaccines, the picture is more complicated, but the same basic idea applies. The currently available vaccine technologies are backed by gigantic clinical trials, and they have been injected into millions and millions of people, which gives doctors a good idea about their safety and side effects. Some entrants missed the first wave of vaccination, such as the Sanofi-Glaxo vaccine and the one from Novavax, which is currently awaiting approval by the Food and Drug Administration. But new vaccines will face an uphill climb in approval and demand. Would a drugmaker need to conduct a new, 30,000-patient trial comparing the new vaccine to the old one? Would enough people, or their insurance companies, pay a premium for the new shot?
Still, there is a big effort to develop other, better, more durable vaccines. At a recent meeting of the FDA’s advisory panel, Ofer Levy, director of the Precision Vaccines Program at Boston Children’s Hospital, made a plea for society to realize that the vaccines we have, miraculous as they are, should not be seen as the vaccines we will need in the end. He hoped for vaccines that would give much broader immunity against new Covid strains. The World Health Organization does track more than 150 different Covid vaccines in various stages of testing. But their path to market may not be quick or easy unless we reach a point where they are desperately needed.
The news is perhaps brightest when it comes to therapeutics. It’s true, the monoclonal antibodies that were the first effective medicines developed against SARS-CoV-2 have lost their efficacy as new strains have emerged. But companies like Eli Lilly and Regeneron are developing new monoclonals. More importantly, Pfizer’s oral treatment, Paxlovid, should become much more widely available in the second half of the year. So far, it’s effective against all the strains we’ve seen.
A number of medicines have been found to be effective at tamping down the overactive immune system that does damage in the worst Covid cases, including the steroid dexamethasone and the arthritis medicines Actemra and baricitinib. And there are new treatments that are gathering evidence, including a drug called peginterferon lambda and the antidepressant fluvoxamine. Molecular Partners and Novartis are developing a treatment that is somewhat similar to monoclonal antibodies, but that may be less likely to fail as new strains emerge.
So, simply: We’ll probably get more treatments. We might get more vaccines. But getting better testing is much more a question of societal and political will than of research and development.
— Matthew Herper
6. How long before we understand long Covid?
Almost everything about the mystery of long Covid remains opaque, but we’ve at last reached what one researcher calls breadcrumbs on the trail to its root cause.
Scientists from many disciplines are tackling the collection of symptoms that persist in as many as one-third of people after a Covid-19 infection. Virologists are turning their HIV expertise to this coronavirus, neurologists are trying to explain the cognitive and physical disruptions they see in rehab clinics, and immunologists are teasing out inflammatory and autoimmune responses.
“What’s encouraging is that we’re starting to see these breadcrumbs,” David Putrino, director of rehabilitation innovation at Mount Sinai Health System, told STAT. “What is challenging is that we need to rapidly accelerate research efforts to actually create actionable treatments for these breadcrumbs that we’re seeing. And the therapeutics pipeline takes a very long time.”
The trail has three main branches that may or may not converge. One underlying theory is autoimmunity, in which the body starts to attack itself after infection. People who study — or live with — myalgic encephalomyelitis or other post-viral syndromes see parallels in the symptoms long Covid people report. They hope the attention to long Covid will spill over into progress for their conditions.
Another likely suspect in the long Covid lineup is chronic inflammation, a persistent, over-the-top response to infection. Clotting abnormalities, microclots in particular, fall on the inflammation path. Doctors noticed unusual blood clots when the first wave swept hospitals in New York City and Italy, prompting them to start giving hospital patients anticoagulants upon arrival. Last August, a South African scientist, Etheresia Pretorius, documented persistent clotting problems in people with long Covid, based on an analysis of proteins in blood samples.
The third suspected cause is viral persistence, in which the coronavirus still lurks in hidden reservoirs after the body has fought off acute infection. In a few patients with Ebola, for example, viral particles were found years later in the central nervous system, the testis, or the eye.
“The extent to which it’s one of these theories or the other, or a mix of all three, we’re still not sure,” Putrino said. “That’s something that we’re testing.”
Blood specimens taken from patients dating back to the spring of 2020 are being queried for inflammatory cytokines and other clues about long Covid, more formally known as post-acute sequelae of SARS-CoV-2 infection, or PASC. At Yale, Akiko Iwasaki has identified specialized biomarkers of T-cell immunity and B-cell immunity that could illuminate immune function and autoantibody production. Yapeng Su of the Fred Hutchinson Cancer Research Center has taken a multi-omics approach to look at the development of autoantibodies dating to the initial viral load at the time of the acute infection, taking into account preexisting conditions like diabetes or the reactivation of Epstein-Barr virus.
“The T-cell responses were different in people who went on to develop these different PASC phenotypes,” Ingrid Bassett, an infectious diseases physician at Massachusetts General Hospital, said about Su’s work. Bassett is also a site principal investigator of the Recover trial, a national, 15-member effort sponsored by the NIH whose mission is to understand, prevent, and treat long Covid. “Those are tantalizing and I think that approach of trying to look deeply at the immune response from multiple different angles is compelling.”
Steven Deeks, an HIV expert at University of California, San Francisco, said he has freezers full of biomarkers from Covid patients.
“We’re at that point in the scientific adventure where we have these big cohorts of people who have long Covid or don’t,” he said. “There are studies coming out left and right with various different biomarkers. You have to figure out which ones are real and which ones are noise.”
With no agreed-on biomarkers, no imaging tests to order, there are only measurements of how people feel and function. Both Putrino and Deeks believe it’s time for drug companies to test their compounds against long Covid. Reuters first reported that GlaxoSmithKline, Vir Biotechnology, and Humanigen had discussed trials using their current treatments against long Covid with researchers. Pfizer and Roche said they were also interested.
“I’ve been trying to drag companies into this business,” Deeks said. “I believe we need to start doing experimental medicine. You do that because you hope the medications will help, but you also do it because it will untangle the biology.”
How long, then, before we understand long Covid?
“The pace of progress is pretty impressive compared to what we experienced for the study of HIV,” Deeks said. “People want an answer now in terms of how to make people feel better. We don’t have that, but we certainly are making more rapid progress now than I would have expected.”
— Elizabeth Cooney
Correction: A previous version of this story misidentified the antidepressant that has shown promise against Covid.
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