Even now, more than 16 months into this pandemic, "many key questions about SARS-2 and the disease it causes, Covid-19, continue to bedevil scientists," Helen Branswell writes for STAT News.

To learn which questions "topped scientists' lists," Branswell writes that STAT News surveyed more than 24 virologists, epidemiologists, immunologists, and evolutionary biologists to shed light on "how far we have left to go to solve the mysteries of SARS-2 and Covid-19."

1. Why do people respond so differently to the virus?

According to Branswell, one question scientists continue to grapple with is why some people who contract the coronavirus "never know they're infected," while others have fairly mild, flu-like symptoms, and still others suffer "debilitating" illness.

Angela Rasmussen, a virologist affiliated with the Georgetown Center for Global Health Science and Security, said two initial explanations—the amount of virus people are exposed to when they are infected and/or any preexisting health problems they may have—don't fully explain the variability in outcomes. "To me the data (and all the virus research I've ever done) suggests the host response is a major determinant, if not THE major determinant, of disease severity," she said.

2. What's a sufficient level of immunity?

According to Branswell, several experts want to know what blend of factors—whether antibodies alone or other physiological factors—establishes the right level of immunity to fend off not just symptomatic Covid-19 infection, but also asymptomatic cases.

"It would be nice to know exactly what we should measure and how to interpret it," said Sarah Cobey, associate professor of viral ecology and evolution at the University of Chicago. "Knowing how well a partially immune population could transmit the virus at any time could dramatically improve forecasting and the potential for effective policy responses."

3. How common will reinfection be? (Or, how long will immunity last?)

Although Covid-19 reinfection has been rare so far, experts want to know whether it will become more common and—if so—how severe will those infections be and how will variants affect the risks, Branswell writes.

"Are we headed for a situation akin to what occurs with the seasonal coronaviruses where the virus and reinfection is common but associated with only mild disease, with periodic reinfection providing boosts to immunity?" Paul Bieniasz, head of the retrovirology laboratory at Rockefeller University, asked. "Alternatively, will infection in those with waning immunity be associated with an unacceptable disease burden, necessitating a constant ongoing battle, with updated vaccines to keep viral prevalence and disease low." 

Put another way, Branswell writes, experts want to know how long immunity after infection or vaccination will last—which will inform how achievable herd immunity is and whether vaccine booster shots will be needed.

"It could be that protection against infection is comparatively short-lived, but protection against severe disease is longer lasting," said Natalie Dean, a biostatistician at the University of Florida. "It could be that vaccine-induced protection has a different durability than infection-induced protection."

4. How will variants affect efforts to curb Covid-19?

Several experts said variants—especially those that make the virus more transmissible, vaccine-resistant, or otherwise more dangerous—are top of mind, Branswell writes.

"My question is: What impact will these variants have on vaccine-related protection, effective treatment and what the ultimate impact this virus will be on our world for years to come?" asked Michael Osterholm, director of the University of Minnesota Center for Infectious Diseases Research and Policy.

More broadly, experts want to know how the virus could mutate in the future. "Are there many more 'large-effect' mutations that the virus could make to significantly change transmission," asked Emma Hodcroft, a molecular epidemiologist at the Institute of Social and Preventive Medicine in Switzerland, "or will mutations in the future be in smaller 'steps' as we see with many endemic viruses?"

5. What is 'long Covid,' and who is most at risk? Can it be prevented?

According to Branswell, several experts said they are interested in learning more about "post-acute sequelae of SARS-CoV-2 infection," which is the formal name of what many call "long Covid"—the experience of Covid-19 patients who've reported "debilitating and varied symptoms weeks and months after recovering."

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"My top 'I wish we knew' about Covid is by far what drives long Covid," Akiko Iwasaki, a virologist and immunologist at Yale University, said. "I think we have a unique opportunity to understand once and for all how acute viral infection can lead to long-term symptoms so we can design better therapy against this debilitating disease and potentially other viral-induced chronic fatigue syndrome."

6. How does Covid-19 interact with children?

Though most children appear to be spared severe cases of Covid-19, experts told Branswell they are curious whether the disease is particularly transmissible among children with asymptomatic infections and how frequently such transmission may occur.

"I think the disease dynamics in children are still not well understood," Caitlin Rivers, an infectious disease epidemiologist at the Johns Hopkins Center for Health Security, said.

7. What proportion of transmission do asymptomatic people account for?

Because asymptomatic and pre-symptomatic people may unknowingly infect others, a few experts voiced interest in figuring out precisely how infectious these patient populations really are, Branswell writes.

"We have few studies truly doing continued testing to identify asymptomatic infection right when it happens and then doing follow up analysis into how infectious that might be," said Saskia Popescu, an infectious disease specialist and assistant professor in George Mason University's biodefense program.

8. Can we pinpoint who may become a superspreader?

Experts also want to know whether it's possible to identify which people are at risk of becoming so-called "superspreaders," the minority of infected individuals who account for the majority of viral transmission, Branswell writes. 

"If we can decipher what makes a person a superspreader, I think it could change the dynamics of outbreaks and how we deal with them, now and in the future," said Vineet Menachery, a coronavirus expert at the University of Texas Medical Branch.

9. What can genetic sequencing tell us about the virus?

According to Branswell, several experts wonder if it’s possible to use genetic sequencing to predict how the virus might change in the future.

"Is it possible to find genomic markers for key properties that should raise a flag?" asked Marion Koopmans, head of virology at Erasmus Medical Center in the Netherlands.

10. What's the effect of nonpharmaceutical interventions?

Experts also said they wanted to learn more about the efficacy of various nonpharmaceutical interventions (NPIs) used to curb the spread of the coronavirus, such as social distancing, mask-wearing, and school closures, Branswell writes.

"Because many interventions were implemented simultaneously, it is challenging to disentangle the individual contribution of different NPIs," said Müge Çevik, a clinical lecturer in infectious diseases and medical virology at the University of St. Andrews School of Medicine in Scotland. "Therefore, we still struggle to make evidence-based decisions regarding which NPI to implement or lift, the importance and magnitude of certain NPIs in reducing transmission, and the associated harms."

11. How does SARS-CoV-2 differ from its cousin, SARS-1?

Relatedly, experts want to know how SARS-CoV-2 differs from its cousin, SARS-1, Branswell writes.

For instance, Stanley Perlman, a microbiologist at the University of Iowa, wants to figure out why SARS-2 can replicate in people's upper airways, making it more easily transmissible than SARS-1, which replicates in cells deeper in the lungs. According to Perlman, answering that question could help drug manufacturers learn how to prevent upper airway replication of the virus—and also help researchers determine the pandemic risks posed by other coronaviruses that may jump from an animal species

12. Where did SARS-CoV-2 come from?

Although experts largely agree that the source of the virus "is almost certainly a bat," Branswell writes, they are curious how a bat virus managed to find its way into humans—information that experts say could help the world prepare for any future outbreaks of coronaviruses we haven't yet met.

And experts say the question needs to be addressed quickly. "The longer we get away from the start of the pandemic the harder it will be to find out these answers," said Krutika Kuppalli, an infectious diseases physician at the Medical University of South Carolina (Branswell, STAT News, 4/20).