Since a new coronavirus launched the global pandemic that has now killed more than 6.5 million people - 16 percent of them in the United States alone - scientists in record numbers have devoted themselves full time to unraveling its mysteries.
In less than three years, researchers have published more than 200,000 studies about the virus and COVID-19. That is four times the number of scientific papers written on influenza in the past century and more than 10 times the number written on measles.
Still, the virus has kept many of its secrets, from how it mutates so rapidly to why it kills some while leaving others largely unscathed - mysteries that if solved might arm the world’s scientists with new strategies to curb its spread and guard against the next pandemic. Here are some of the most pressing questions they are trying to answer:
Where did the virus come from, and why has it been so successful?
Scientists have found very similar viruses in horseshoe bats living in remote caves in Laos, southern China, and other parts of southeast Asia. So far, though, no one has succeeded in drawing a line between the viruses in bats and the Huanan Seafood Market, which sold and butchered live animals in Wuhan, China, and where many scientists believe the virus first spilled over into people.
That theory is backed by multiple lines of evidence, including the clustering of early COVID cases around the market - documentation laid out in two peer-reviewed papers published this summer. But key details remain elusive. We do not know where in the market the leap from animals to humans took place, or which animals were involved. Nor do we know the precise steps in the process.
“What particularly drove that spillover?” asked Vincent Munster, chief of the virus ecology section at Rocky Mountain Laboratories, a research facility in Hamilton, Mont., that is part of the National Institute of Allergy and Infectious Diseases. “We’ve now identified 20 or 30 of these viruses that all look very similar, but they are not the same. What is the true hideout place of the progenitor of SARS-CoV-2?”
Several investigations have not been able to categorically rule out the possibility the virus escaped from a laboratory in China, although many scientists believe that is far less likely than that it jumped from animals as part of a natural process.
Escape from a lab could involve at least two scenarios: one, in which the virus evolved in nature and was being studied by scientists; another in which the virus was created in the lab by researchers examining factors that might cause a coronavirus to become more deadly or more transmissible.
Scientists working at the Wuhan Institute of Virology, a major research center that studies coronaviruses, have denied ever having the virus in their laboratories, but that has never been corroborated by outside investigators since Chinese authorities limited access.
Whatever its origins, SARS-CoV-2 has proved far more successful at infecting large numbers of people than other coronaviruses, including the one that surfaced in Asia 20 years ago causing severe acute respiratory syndrome, a less contagious though also sometimes fatal illness. Both coronaviruses invade human cells through a spike protein that attaches to the ACE2 receptor on the surface of human cells. Yet the trajectories of the two pathogens could hardly be more different.
The original SARS, which emerged in China in late 2002, sickened 8,098 people, killing 774. But that outbreak was over within a year due in large part to 19th century public health measures such as social distancing and isolation of the infected - many of the same steps public health officials have urged during the current pandemic.
However, SARS patients, unlike those in this pandemic, “are most likely to be contagious only when they have symptoms, such as fever or cough,” according to the Centers for Disease Control and Prevention. That made it easier to identify and isolate them.
Resolving the uncertainties surrounding how SARS-CoV-2 was first transmitted to people and why it has thrived are “extraordinary questions,” Munster said, “because they would actually tie back to preparation for the next pandemic which everybody is worried about.”
How is the virus evolving, and will there be new variants?
Early on, scientists delivered a seemingly comforting message about coronaviruses, the family to which SARS-CoV-2 belongs: Other viruses acquire mutations more frequently, making them more difficult to keep up with and raising the possibility they will develop more contagious or deadly versions. Coronaviruses have their own proofreading system that helps limit mutations as the virus makes copies of itself.
But the reassuring message was soon followed by a parade of Greek letters - alpha, beta, delta, now omicron - signifying new, more contagious and occasionally more lethal variants of the virus. These variants are able to dodge the disease-fighting antibodies that protect people after being infected or vaccinated.
At least some of the virus’s rapid evolution has occurred inside the bodies of severely immunocompromised patients, where it was able to linger, replicate and mutate for months.
“We know that unfortunately immunocompromised people are a major breeding ground for these noxious variants because of the accelerated evolution of the virus inside them,” said Eric Topol, a professor of molecular medicine at Scripps Research Institute in La Jolla, Calif. “With all of the tens of millions of immunocompromised people around the world, the one that gave birth to omicron - what was it about that person?”
Because vaccination can pose a risk to some people with weakened immune systems, some did not take the vaccine, leaving them vulnerable to the virus and especially to long illnesses. The longer the virus remains inside a person, the more copies of itself it makes, each one offering a fresh chance to develop a mutation.
“But the language of the virus, the way it really comes up with ways to hurt us and infect us, and hijack our cells,” said Topol, “It’s always ahead of us and then we say, ‘Oh, that’s how it did it.’
“But we haven’t cracked its code.”
It is unlikely the virus has finished mutating or churning out new variants. Scientists believe it will continue evolving to become better at escaping the human immune system. But researchers are uncertain what future variants might look like.
“The virus is becoming more infectious, but less dangerous for the majority of people,” said Bill Powderly, co-director of the Division of Infectious Diseases at the Washington University School of Medicine in St. Louis. “But we’ve no guarantee that the virus wouldn’t develop additional mutations that would eventually make it more virulent in the future.”
An additional concern is whether animals infected with the coronavirus might become reservoirs for the evolution of new variants that might jump back into humans. According to a report last January, the virus had already been found in 29 other mammals. To date, incidents of animals infecting humans are rare. But some scientists fear that if the virus continues to spread to new species, it might pick up mutations as it adjusts to the environment inside those animals and then, transmit potentially more dangerous variants back to humans.
Can we develop a coronavirus vaccine that will protect against future variants?
The swift development of vaccines to protect against severe illness and death from COVID-19 has been hailed as one of the great scientific achievements of this century. But the vaccines did not, as some had hoped, bring the pandemic to an end. They provided protection against severe illness and death, but not infection and transmission, especially after the arrival of the more transmissible delta and omicron variants.
“They’ve been extremely effective, but they also have their shortcomings,” said Mark Siedner, an infectious-disease doctor at Massachusetts General Hospital. “Immunity wanes, and their ability to protect us against newer variants has been variable - in some cases quite strong, in other cases, not as good as we’d like.”
Even people who were fully vaccinated have become infected with the latest iterations of the virus. The United States still records more than 50,000 new daily infections and 400 deaths daily, according to seven-day averages compiled by The Washington Post.
While a new booster shot targeting both the original strain of the virus, as well as the now-dominant omicron subvariants, was authorized in late August by the U.S. Food and Drug Administration, some argue that reconfiguring vaccines to match the last variant will always put us one step behind the virus.
Jeffrey Shaman, director of the climate and health program at the Columbia Mailman School of Public Health, said the goal should be to develop a comprehensive vaccine that could protect against every version of SARS-CoV-2 - those we know about and those still to come.
“Can we develop a universal vaccine, effective across all existing and forthcoming variants, that confers sterilizing immunity, in other words that prevents infection altogether?” he said.
Developing such a vaccine poses challenges, acknowledged Stuart Cohen, chief of infectious diseases at UC Davis Health. In the meantime, “the beauty of [existing] RNA vaccines is that they can modify them very quickly,” he said.
Scientists developed the mRNA vaccines by examining the part of the virus that has the most contact with the cells in our immune system - commonly referred to as the spike protein. “But the problem with these variants is that this is the exact part of the virus that is changing the most,” Siedner said.
The newly configured booster shots focus on the spike protein, too, but use two versions of it: one from the original strain identified in Wuhan; and another from the omicron variant.
One strategy researchers are hoping will improve vaccines is to target them not only to the virus’s spike protein, but to other viral proteins as well.
Another potential improvement in the pipeline is development of a nasal-spray vaccine inhaled through the nose. “Maybe these will work on the respiratory tract more,” said Bernard Camins, medical director for infection prevention at the Mount Sinai Health System. “But we don’t know that yet.”
For the near-term, Siedner said, we may need to modify vaccines the way we do with influenza, by changing them each year.
That idea was recently shared by White House coronavirus coordinator Ashish Jha, who said Americans should prepare to receive an annual booster shot against COVID just as they do with the flu. Ideally people could be immunized against COVID and flu during the same medical visit, he said.
Why do some people develop long COVID?
About 1 in 5 COVID-19 survivors in the United States, including some who were never very sick as a result of their infections, go on to develop long COVID, according to the Centers for Disease Control and Prevention.
The condition itself is one huge question mark - a persistent illness marked by a variety of symptoms including fatigue, fever, shortness of breath, chest pain, pounding heart, headaches, difficulty thinking or concentrating, dizziness and joint pain.
“What are the drivers, and what are the causes?” said Gary Gibbons, director of the National Heart, Lung and Blood Institute, part of the National Institutes of Health. “We see the phenomenon in terms of all these symptoms, but why? What’s generating them?”
To develop treatments, researchers must answer such questions. For example, the condition may be caused by virus hiding out in the body, even after acute infection passes. If that is the case, Gibbons said, the answer may be using antivirals to clear more or all of the virus from the body.
Another theory is that minute blood clots, remaining after the viral assault or fueled by the body’s response, continue to have a punishing effect on different parts of the body.
A third notion is that the symptoms are caused not by the virus, but by an immune system gone haywire.
The disease “has a hidden burden,” said Maria Elena Bottazzi, associate dean of the National School of Tropical Medicine at Baylor College of Medicine. She said the long-term effects on the brain, including brain fog and mental health complications, bear some similarity to those of Lyme disease, which is transmitted by infected ticks.
In December 2020, Congress approved spending more than $1.1 billion to study long-term effects and possible treatments for COVID-19 and long COVID. So far, the project has awarded $37 million to 40 research studies, but millions of sufferers say they have yet to find meaningful treatments.
Why does COVID severity differ by age and from one person to another?
When deaths from COVID-19 are charted by age they form a ladder. The younger the patient, the less risk of severe illness or death.
Worldwide, children and adolescents under the age of 20, account for just .4 percent of all the deaths from COVID-19, according to UNICEF.
“Young kids, even really young kids, are much less susceptible to severe disease than older people,” said Stephen Goldstein, a postdoctoral fellow studying coronaviruses at University of Utah.
“If you’re 40, your absolute risk is still pretty low, but it’s much higher than somebody who’s 5. Why is it better to be 1 than 50? I mean, a 1-year-old with influenza, that’s bad.”
The opposite was true in the 1918 flu pandemic when the highest mortality rates were in children 5 and under, adults 20 to 40 and seniors 65 and older. In the 1957 flu pandemic, the highest death rates were among children 5 and under and seniors 65 and over.
Even within the same age group, SARS-CoV-2 can have vastly differently outcomes, killing one patient while sparing another of the same age who appears to have a similar health profile. Scientists believe that genetic factors and the amount of virus someone has in their body may influence the severity of their illness but how some of those factors play out is still largely unknown.
What is clear is that the human immune system declines as we age, leaving older people more vulnerable to pathogens. Also, COVID-19 presents a greater risk for severe illness to people already afflicted with some of the most common diseases of aging such as cancer, chronic lung diseases, heart disease and stroke.
Goldstein said the differing responses to the virus of young and old may have something to do with interferon, a protein that alerts the body’s natural immune system. “Maybe kids make more interferon, and maybe they make it earlier,” Goldstein speculated. “I think that’s probably the key.”
A report in Nature examined differences between the immune systems of adults and children, and found that cells in the airways of healthy children were already in an “interferon-activated state,” and ramped up further after infection with the coronavirus.
The researchers suggested that those innate interferon responses in children restrain the virus and progression of the disease.
Other scientists have suggested that children’s developing immune systems have lower levels of the proteins that can cause the potentially deadly immune response known as a cytokine storm. Another possible explanation is that children have more of the master cells capable of repairing damaged lungs.