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Virginia Hospital Center outpatient lab specialists open a drive-through coronavirus testing site in Arlington, Virginia, on March 18, 2020.
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The 9 most important unanswered questions about Covid-19

Is reinfection possible? Will it be seasonal? How prevalent is it really? These are some of the top questions on researchers’ minds.

Brian Resnick is Vox’s science and health editor, and is the co-creator of Unexplainable, Vox's podcast about unanswered questions in science. Previously, Brian was a reporter at Vox and at National Journal.

It’s easy to forget that just a few months ago, the virus that is causing the Covid-19 pandemic around the world was not known, at all, to science.

In the months and weeks since, researchers have been learning as much as they can about this pathogen — and at breakneck speed. Scientists have sequenced its genome and begun to create vaccines in the hope of making people immune to it. They’ve also learned, critically, that people can pass the virus on to others before they get symptoms themselves. That makes the virus hard to contain. But it also makes it clear that severe actions — like the social distancing measures in place in the US and around the world — are necessary in the fight to save lives.

We still don’t know how this pandemic will play out. That’s in large part because there are crucial unanswered questions about this virus and the disease it causes. For example, researchers don’t yet have precise estimates of how deadly the virus is or an exact understanding of how it spreads. The answers to these questions will provide key insights into stopping this pandemic in the least disruptive way possible.

It may be too easy to look at these uncertainties and the lack of data and feel cavalier: Maybe this all isn’t as bad as people are saying.

Do not take comfort in these uncertainties. Take caution.

“The way we deal with the uncertainty is we have to cover all of our bases,” Peter Hotez, the dean of the National School of Tropical Medicine at Baylor College. “A year from now we’ll realize some of the things that we did may not have been necessary.” But we have to proceed with extreme vigilance due to the many unknowns of this virus and the serious risk it poses to so many around the globe.

These are the nine most important unanswered questions about Covid-19 that will help determine the course of this outbreak. Be humbled by this list. We are. And take care.

1) How, exactly, does Covid-19 spread?

The virus — known as SARS-CoV-2 — that causes Covid-19 has infected more than 222,000 people since its emergence. (Of them, at least 9,000 have died.) That’s just the confirmed cases. A great many more may have occurred (more on that later).

Why has it spread so fast? “The best explanation for this rapid spread is that the virus is being passed through droplets from coughing or sneezing,” Vox’s Julia Belluz explains. “When these virus-laden droplets from an infected person reach the nose, eyes, or mouth of another, they can transmit the disease.”

But it’s still unknown how significant other modes of transmission are in spreading the disease.

Hand-washing instructions posted in a restroom on Capitol Hill in Washington, DC, on March 19, 2020.
Alex Wong/Getty Images

It’s possible that the virus can spread through feces. (The CDC says, though, “the risk is expected to be low based on data from previous outbreaks of related coronaviruses.” But if you weren’t already washing your hands vigorously after defecating, please do so now.). There are also uncertainties over how long the virus can linger in the air after a person coughs or sneezes.

You may have heard that the new coronavirus isn’t “airborne” — meaning that unlike extremely contagious diseases like measles, it’s unlikely to linger in the air for hours on end. But that doesn’t mean the virus can’t linger in the air for some amount of time.

As Wired explains, although some experts say the new coronavirus isn’t airborne, that’s based on a narrow scientific definition of the term. The virus can possibly still linger in the air for some time and under some conditions. As the journal Stat reports, we don’t yet know precisely what those conditions are. It will definitely be in the air in the moments after an infected person sneezes or coughs, but it’s unclear when the particles eventually come to rest on the ground (or surrounding surfaces).

“The studies suggesting that [the virus] can be aerosolized [i.e., linger as small particles in the air] are only preliminary, and other research contradicts it, finding no aerosolized coronavirus particles in the hospital rooms of Covid-19 patients,” Stat reports. More research is needed.

So all three transmission routes — droplets, airborne, and fecal — are still possible contributors to the spread of the virus. “Almost certainly, one of these is probably the predominant one, and the others might be minor modes of transmission, but we don’t really understand this,” Hotez says. Some good news is that scientists are figuring out how long the virus can live on some surfaces. Here’s the latest: It’s around three days for plastic and steel, about a day for cardboard, and less than a day for copper. This information helps direct sanitation efforts to where they are needed most.

2) Can people become reinfected? And, if so, after how long?

Another huge unknown: Can people become reinfected with Covid-19 after they’ve had it? There are some reports of people in China and Japan testing positive after recovering from the infection. Though, to be clear, it’s unknown whether those people were truly reinfected or still just had low levels of the virus in their systems after they felt better.

“I would say that the biggest unknown is how potent is the immune response generated in an infected person,” Akiko Iwasaki, an immunobiologist at the Yale School of Medicine, writes in an email. “How long would [immune] protection last? ... The answers to these questions are key to understanding whether herd immunity is effective.“

Herd immunity is when enough people have contracted the virus and become immune that its spread can be slowed and potentially stopped. If reinfection is possible, however, herd immunity may not be an option. (Also, stopping the virus via herd immunity is not an ideal scenario. It would first mean millions upon millions of infections and potentially millions of deaths.)

Right now, there’s limited research on the question of reinfection in humans. It’s just too early. Angela Rasmussen, a virologist at Columbia University, points to a hopeful, if small, study in Macaque monkeys. The monkeys had been infected with the virus and then, after they got better, exposed again to the virus. Good news: They didn’t get reinfected. The study, Rasmussen says, “bodes well for vaccine development, because that suggests the virus — or viral proteins — can elicit an immune response,” and protect monkeys at least from reinfection.

The last group of patients leave a gymnasium turned temporary hospital in Wuhan, China, on March 10, 2020.
Costfoto/Barcroft Media via Getty Images
A woman who recovered from the coronavirus hugs a medical staff member before leaving a temporary hospital in Wuhan, China, on March 10, 2020.
Stringer/AFP via Getty Images

Studies on humans will come in time. Researchers will be able to test the blood of people who have recovered from Covid-19 in the weeks and months following their infection and see if they still are immune.

But even if people do become immune, “one thing we don’t know about that still is how long that immunity would last,” Rasmussen says. “And that’s unfortunately not something we can determine until we wait months or years in the future, and test again and see if those antibodies are still there.”

For coronaviruses that cause the common cold (in the same family of viruses as the one that causes Covid-19), she says, reinfection is possible, but on a timescale of years, not weeks or months. Again, we’re going to have to wait and see if this also applies to Covid-19.

For now, at least, Rasmussen says, “I have not seen any data that is convincing that reinfection occurs.”

3) How many cases of Covid-19 are in the US, and where are we on the curve?

This is one of the scariest unknowns. Due to the continued lack of Covid-19 diagnostic testing in most of the US, we just don’t know how many cases are in the US.

“There’s speculation that there may be many mild infections who aren’t seeking care — or, even if they are, can’t be tested due to insufficient testing capacity,” says Harvard epidemiologist Maimuna Majumder. This obfuscates our knowledge of where the virus is, and how many vulnerable people may be in its path.

As of March 19, the CDC said there were 10,442 confirmed cases of Covid-19 in the US. But viral genetic data suggests the real number could be much higher. Here is one estimate from a computational virologist at Fred Hutchinson Cancer Research Center in Seattle (with a very wide range) from nearly a week ago;

Another problem with insufficient testing is that we don't know where we are on the epidemic curve. How do we know when the worst spikes in the number of cases are coming? It seems we’re early, but we don’t know how early or how big the wave of future cases is. We need to know this to make sure hospitals are prepared for a surge of patients.

If we know how many people are getting the disease without symptoms or getting it at a level that does not warrant medical attention, scientists can make better estimates for how deadly the virus is and for whom, and they can refine their assumptions about how contagious the virus is. More testing can also help researchers determine the true role asymptomatic transmission plays in the outbreak, and what factors make a person likely to transmit the virus before they feel sick.

4) How deadly, exactly, is Covid-19?

Knowing the true number of infections that exist in the US or around the globe (or at least getting a better estimate of the true number) will help researchers determine another crucial metric about Covid-19: its case fatality rate, meaning how deadly it is.

Right now, it’s looking like some countries have higher death rates for Covid-19 than others. These rates also keep changing. Now, the estimated death rate for Wuhan, China — the city where the outbreak began — is 1.4 percent, per a new study in Nature Medicine. In late February, the World Health Organization estimated the rate in Wuhan was 5.8 percent. South Korea, on the other hand, was estimated to have a death rate of less than 1 percent. Italy’s seems to be, for now, several percentage points higher.

Are these estimates different because the citizens of these countries are at different levels of risk for some yet-to-be-determined variables? Are their caregivers better at treating the virus? Or are their health care systems falling short in the testing of cases? All of these questions may be in play.

It’s also the case that the fatality rate can change over time, as Belluz explains:

CFRs do change over time. That’s exactly what happened in China, as you can see in this figure from the WHO. Even the first and hardest-hit province, Hubei, saw its death rate tumble as public health measures were strengthened and clinicians got better at identifying and treating people with the disease:

Crucially, it’s not just the overall CFR that matters but also the knowledge of who is most at risk for death. It does seem clear that older people — particularly those older than 80 — and those with chronic medical conditions are in the riskiest group for dying of Covid-19. But we need more knowledge on other subgroups so we can better protect them.

5) Is it seasonal?

For a variety of reasons, some viruses — but not all — become less transmissible as temperatures and humidity rise in the summer months. The viruses themselves may not live as long on surfaces in these conditions. The droplets that transmit the virus also may not spread as far in humid air. (When the air contains more water vapor, those virus droplets will collide with water molecules more frequently and may not travel as far. The humid air is kind of like a shield for virus-containing droplets.) Also, human behavior changes, and we spend less time in confined spaces.

“A lot of how the outbreak ends or at least how things progress in the next few months really depends on if this is seasonal,” Nathan Grubaugh, an epidemiologist at the Yale School of Public Health, says.

There are actually two important questions here. The first: Will Covid-19 show seasonal effects? The second: Will those seasonal effects make a meaningful difference in slowing down the spread of the pandemic?

The answer to the first question, right now, is maybe.

Boston Public School workers help to load boxes of homework to be distributed to students on March 19, 2020.
Jessica Rinaldi/The Boston Globe via Getty Images

Mauricio Santillana, the director of the Machine Intelligence Lab at Boston Children’s Hospital, has been studying the potential seasonality of Covid-19 by looking at the best available data from China.

Before China instituted massive lockdowns, “we saw a signature that places that were colder and drier showed slightly larger transmissions before interventions,” Santillana says. Though he admits the data is limited, and it’s hard to analyze the exact impact temperature and humidity have on transmission. That’s because, once China locked down, it became hard to disentangle the effects weather has on transmission from the mitigation policies from the government. Santillana and his colleagues are still working out what exact effect the weather may have on transmissibility, and he says it’s too soon to report a specific number.

But be prepared to be disappointed on this. On the second question, Santillana is firmer: “We cannot rely on weather alone to take care of the outbreak,” he says, pointing to warmer and more humid climates — like in Singapore — where the virus has spread. “We think the spring temperatures will not be enough to mitigate the outbreak.”

It’s just too contagious — and too few people are immune.

That said, it’s not futile to keep studying seasonality effects. “This virus may be with us for the coming years,” Santillana says. Predicting spikes based on weather, however small, will give us “a more precise way to deploy resources around the world.”

6) What role do children play in the spread of Covid-19? And why aren’t they getting very sick with it?

“When there’s an influenza epidemic, kids are often some of the biggest community spreaders,” Hotez explains.

But with Covid-19, kids generally don’t seem to be getting severely ill. Which is leading researchers to ask: Are kids a big source of transmission of this virus? “When we’re talking about closing schools, we’re doing that under the assumption that kids are significant community transmitters,” Hotez says. “If we knew that one way or another, we could make a more informed decision.”

On this, the data is slowly coming in.

“We do know that children tend to have more mild infection, have more mild disease, but we have seen [at least one child] die from this infection,” Maria Van Kerkhove, the Covid-19 technical lead at the World Health Organization, said in a press conference on March 16. “We can’t say universally that it’s mild in children, so it’s important that we protect children as a vulnerable population.”

While kids usually seem to be spared the worst, so many questions remain, as Vox’s Umair Irfan explains: “A small percentage of younger people, from babies to young adults, have also suffered serious harm,” he writes. “Few children are being tested for the virus, so there still isn’t much good information about how many children are getting infected overall. And from there, it’s hard to gauge the rate of severe illness for the young.”

7) What leads some people to be at higher risk for the worst symptoms of Covid-19?

On the question of risk factors, there seems to be one clear answer for the most prominent factor: age. Older people appear to be dying in much higher numbers from Covid-19 than younger people.

But we still don’t know a lot about what else contributes to risk. Even among older people, there are unanswered questions. Like why do men appear to be dying at higher rates than women?

Though the risks to older people are being emphasized, young people are also being hospitalized. New data from the CDC now shows that while Covid-19 is currently less than 1 percent fatal among those ages 20 to 54, this group makes up 38 percent of the hospitalizations so far (with 20 percent of the hospitalization occurring among those ages 22 to 44).

“It’s really an open question to try to figure out why some of these younger people are getting really, really severe disease, and if there are other risk factors that we are not appreciating,” Rasmussen says. “Some of that will just have to wait until we have really detailed clinical data on all the cases that are coming out now in Italy and in the United States.” Knowing who is most at risk, she says, “will help in terms of flattening the curve.” If we learn how to protect the young people most at risk and keep them out of hospitals, we can decrease strain on our health care system.

And a big part of keeping the health care system working well is ensuring its workers — who are often in this 20- to 54-year-old group — remain healthy. “We don’t understand why hospital workers also seem to be at higher risk for severe disease than you would expect based on their age,” Hotez says. “Is it just that they get exposed to a large dose of the virus? Do they have some type of susceptibility that we don’t understand?”

Currently, we don’t know.

8) How, exactly, did it start?

This is still a little bit of a mystery. Scientists know this virus jumped from an animal to a human, but they are not sure exactly how or where. “If you don’t understand where it came from, then it’s hard to make policies, procedures, to prevent it from happening again,” says Krutika Kuppalli, an infectious disease physician and Emerging Leader in Biosecurity fellow at the Johns Hopkins University Center for Health Security.

It likely started with a bat — the genetics of the novel coronavirus suggest that it did. As Vox’s Eliza Barclay reported:

What researchers have to figure out now is how exactly the coronavirus jumped to humans: perhaps through a human eating an infected animal, or through humans being exposed to infected feces or urine. “All we know [is] its likely distant source was bats, but we don’t know who was between bats and people,” said Vincent Racaniello, a professor of microbiology and immunology at Columbia and host of the This Week in Virology podcast. “It could be a direct infection [between bats and humans] as well.”

A lot of the evidence points toward the outbreak either starting or significantly gaining steam at a live animal market in Wuhan, China. The more we know about how this virus made the jump from animals to humans, the more authorities can help make sure an outbreak with this origin doesn’t happen again.

9) When will it end? And how? Will it become endemic?

The response to the Covid-19 pandemic is infiltrating every aspect of life, and we’re already longing for it to end. But this fight may not end for months or a year or even more. It’s also possible that Covid-19 will become endemic, meaning it becomes a disease that regularly infects humans and never really goes away.

But there are so many unknowns that will determine how long we have to live with this:

  • Could a pharmaceutical treatment emerge that will prevent people from dying from Covid-19? (Many drugs, including HIV-fighting antivirals, and common, cheap ones — like those to ward off malaria — are being tested right now, or may be tested soon.)
  • Will one of the many vaccine formulations that have been created in recent weeks (some of those trials are already underway) prove to be safe and effective?
  • If no drug works to treat the virus or stop its spread, we may need to live with strict social distancing for many months, if not a year or more, to prevent hundreds of thousands from dying. Will governments support that level of sustained disruption to the economy? Or could we find an alternative, like aggressive testing coupled with relentless contact tracing, quarantines of those exposed, and isolation of the sick?

As we learn more about this disease, our approach to fighting it will become more precise. We may be able to find a balance between protecting the vulnerable and letting our economy and society function again. But for now, we have to confront the possibility that this virus will disrupt life for a long while.

A closed playground in Wyomissing, Pennsylvania, on March 19, 2020.
Ben Hasty/Reading Eagle via Getty Images

“I think this idea … that if you close schools and shut restaurants for a couple of weeks, you solve the problem and get back to normal life — that’s not what’s going to happen,” says Adam Kucharski, an epidemiologist at the London School of Hygiene & Tropical Medicine and author of The Rules of Contagion, a book on how outbreaks spread. “The main message that isn’t getting across to a lot of people is just how long we might be in this for.”

But given that scientists have only known about this virus for a few short months, “it’s actually quite remarkable how much we’ve learned,” Hotez says. “We’ve learned more information about this virus in this short period of time than any other virus.”

The learning won’t stop. And because of that, hopefully, the spread of this pandemic someday will.


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