A Blog by Jonathan Low


Apr 20, 2021

The Most Urgent Questions Still To Be Answered About Covid

As much as science and medicine have learned in the last year, the list of questions still to be answered definitively reveals how much is still not known. JL

Helen Branswell reports in Stat:

What accounts for the wide variety of human responses to this virus? How much immunity is enough immunity? How often will reinfections happen and what will they be like? How long will immunity last? How are viral variants going to impact the battle against Covid? What is long Covid, who is at risk of developing it, and can it be prevented? What is the deal with Covid and kids? What does the future hold for SARS-2, evolutionarily and otherwise? How big a role do asymptomatically infected people play in SARS-2 transmission? Can we figure out who might become a superspreader? The impact of nonpharmaceutical interventions? Can we learn more quicker from the genetic sequences of SARS-2 viruses? Where did SARS-2 come from?

Less than a year and a half ago, the world was blissfully, dangerously ignorant of the existence of a coronavirus that would soon turn life on earth on its head.

In the 16 months since the SARS-CoV-2 virus burst into the global consciousness, we’ve learned much about this new health threat. People who contract the virus are infectious before they develop symptoms and are most infectious early in their illness. Getting the public to wear masks, even homemade ones, can reduce transmission. Vaccines can be developed, tested, and put into use within months. As they say, where there’s a will, there’s a way.

But many key questions about SARS-2 and the disease it causes, Covid-19, continue to bedevil scientists.


STAT was curious which questions topped scientists’ lists. So, we asked a bunch. More than two dozen virologists, epidemiologists, immunologists, and evolutionary biologists shared with us their top question. (Some … cheated, submitting several.)

There was surprising diversity in the questions, though many cluster around certain themes, such as the nature of immunity or the impact of viral variants. Knowing what scientists still want to learn shows us how far we’ve come — and how far we have left to go to solve the mysteries of SARS-2 and Covid-19.

What accounts for the wide variety of human responses to this virus?

Some people who contract SARS-2 never know they’re infected. Others have flu-like symptoms — some mild, some more debilitating. Some recover completely, others go on to suffer from the puzzling condition that’s come to be known as long Covid. Some die.

What predisposes individuals to those various and varied outcomes? That’s the question that perplexes Angela Rasmussen, a virologist affiliated with the Georgetown Center for Global Health Science and Security.

An obvious answer might be how much virus individuals are exposed to when they get infected. In other words, lots of virus equals more severe disease. But Rasmussen said animal studies don’t show dose as being a factor here. Some preexisting health problems, like diabetes, seem to put people at higher risk of getting more severely ill, but even they don’t explain all the variability. Some people without comorbidities, as they’re called, become profoundly ill.

“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,” Rasmussen wrote. She wants to know why some immune systems handle the virus with ease while others get swamped.

How much immunity is enough immunity?

Florian Krammer, a professor of vaccinology at the Icahn School of Medicine at Mount Sinai Hospital in New York, submitted only one question and it was very specific: He wants to know the exact measurements of antibodies needed to fend off asymptomatic Covid and symptomatic disease. “I guess you could say that I want to know which type of immune response indicates protection,” said Krammer. “It is likely indicated by a single antibody titer for each of the types of protection.”

Nahid Bhadelia, medical director of the special pathogens unit at Boston Medical Center, is also eager to quantify how much immunity is enough, so we can determine who is protected and who needs to have their immunity boosted. “We do this for measles now, for example — if there is an exposure, we check antibodies,” said Bhadelia.

Sarah Cobey, associate professor of viral ecology and evolution at the University of Chicago, thinks the issue might be more complicated. In her view, beyond specific antibody levels, physiological factors that vary from individual to individual are probably also part of the equation. “It would be nice to know exactly what we should measure and how to interpret it,” she said.

This could be among the factors that help explain why there’s so much variability in people’s susceptibility to the virus, and the severity of disease they experience if they contract it. “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,” Cobey added.

How often will reinfections happen and what will they be like?

So far, the vast majority of people who contracted Covid haven’t caught it again. If this coronavirus is like its cousins — four human coronaviruses that cause colds — reinfections will occur. How often will they happen? Will they be milder? What’s the impact of the variants — viruses that have acquired significant mutations — on reinfections, asked Kristian Andersen, an immunologist at the Scripps Research Institute.

Paul Bieniasz, head of the laboratory of retrovirology at Rockefeller University, has similar questions. “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?” he 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, how long will immunity last?

Soumya Swaminathan, the World Health Organization’s chief scientist, would like to know how long immunity lasts — immunity after infection and after vaccination. Knowing this would allow for better use of scarce vaccines, she suggested.

Natalie Dean, a biostatistician at the University of Florida, also listed this as her question, noting that the answers will tell us how achievable herd immunity is, and whether and when 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,” Dean said. “It could be that vaccine-induced protection has a different durability than infection-induced protection.”

How are viral variants going to impact the battle against Covid-19?

Variants have changed the virus in disadvantageous ways. Some, like B.1.1.7, have made it substantially more transmissible. Another, B.1.351, appears to be able to at least partially evade the immune protections generated by previous infection or immunization. The variants are top of mind for a number of experts.

“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,” said Michael Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy.

John Moore, a professor of microbiology and immunology at Weill Cornell Medical College, is of the same mindset.

“I wish I knew the outcome of the ongoing battle between the vaccines and the variants, both here in the USA and globally,” he said. “Will the more troubling … antibody-resistant variants reduce vaccine efficacy to an extent that compromises national and international efforts to control the pandemic via the current generation of vaccines?”

What is long Covid, who is at risk of developing it, and can it be prevented?

“My top ‘I wish we knew’ about Covid is by far what drives long Covid,” said Akiko Iwasaki, a virologist and immunologist at Yale University. The condition has been given a formal name, post-acute sequelae of SARS-CoV-2 infection, or PASC. (Sequelae is a fancy word for after effects.)

Significant numbers of people who contract the disease report debilitating and varied symptoms weeks and months after recovering. Brain fog. Deep fatigue. Shortness of breath. Why this happens is a mystery.

Iwasaki noted that other chronic syndromes are triggered by viral infections. “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,” she said.

Krutika Kuppalli, an infectious diseases physician at the Medical University of South Carolina, wonders if factors that put people at risk of developing long Covid can be identified, so that the risk can be lessened. And Andersen, of Scripps Research Institute, would like to know the frequency at which long Covid occurs and how cases break down by age and severity of symptoms during the initial infection.

What’s the deal with Covid and kids?

Children are largely — but not entirely — spared Covid’s wrath. Younger children especially seem to have few or mild symptoms in most cases. A few develop a Kawasaki disease-like syndrome a few weeks after infection.

Caitlin Rivers, an infectious disease epidemiologist at the Johns Hopkins Center for Health Security, wants to know more about the disease in children — for instance, are kids who have asymptomatic infection likely to transmit the virus, and how frequently? “I think the disease dynamics in children are still not well understood,” she said, noting that while many studies have looked at symptomatic illness in children, few have used study designs that would find asymptomatic infections in this age group.

How big a role do asymptomatically infected people actually play in SARS-2 transmission?

The fact that some portion of infected people never develop symptoms but do transmit the virus really threw a monkey wrench into efforts to contain and control the virus. A further complication: Infected people can transmit a day or two before they know they are sick, when they are pre-symptomatic.

Saskia Popescu, an infectious disease specialist and assistant professor in George Mason University’s biodefense program, wishes we had a clearer picture on how infectious asymptomatic and pre-symptomatic people actually are. “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,” she said. Popescu wonders how often the virus picked up from these people on swabs taken for polymerase chain reaction testing (you know it by now as PCR) is actually infectious virus, or whether there’s a period of shedding of non-infectious viral junk. “Is this person truly infectious and needs isolation and contact tracing or am I just getting viral fragments?” she wondered.

What does the future hold for SARS-2, evolutionarily and otherwise?

Emma Hodcroft, a molecular epidemiologist at the Institute of Social and Preventive Medicine in Bern, Switzerland, would like to know how many more mutational tricks the virus has up its sleeve. “Are there many more ‘large-effect’ mutations that the virus could make to significantly change transmission … or will mutations in the future be in smaller ‘steps’ as we see with many endemic viruses?” she wondered.

Adam Kucharski had a related question. Kucharski, an associate professor of infectious diseases epidemiology at the London School of Hygiene and Tropical Medicine, would like to know what the impact of evolutionary pressure will be on the virus as immunity to it grows. As increasing numbers of people have some protection, either from previous infection or vaccination, the virus will have to evolve to continue to be able to infect people. Knowing more about this will help with decisions on when and how to update vaccines, he said.

Rivers wondered about the near term: What will the autumn look like? “Vaccine coverage will (hopefully) be high in the U.S. by the fall, but that will not be the case for much of the world. Knowing whether we can expect a winter wave would help countries to prepare,” she said.

Can we figure out who might become a superspreader?

SARS-2 shares a bizarre feature with its older cousins, SARS-1 and MERS, a camel virus that occasionally triggers small outbreaks on the Arabian Peninsula. The majority of people who catch this bug don’t infect anyone else. Most of the transmission is done by a small number of people, potentially fewer than 20% of those who become infected. A lot of experts don’t like the term superspreader; some prefer to talk about superspreading events. Any way you slice it, though, a minority of people are responsible for a majority of cases.

Last summer Ben Cowling, a professor of infectious diseases epidemiology at the University of Hong Kong, co-wrote an opinion piece in the New York Times on the phenomenon, arguing that if authorities focused on preventing the types of activities that allow superspreading to occur — crowded events, sharing close spaces with others — more onerous measures wouldn’t be needed.

Now Cowling wonders if there is a way to figure out the types of people who are more likely to be superspreaders.

It’s the question that weighs on Vineet Menachery’s mind, too. “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 Menachery, a coronavirus expert at the University of Texas Medical Branch.

There aren’t obvious clues to pursue. “We know the virus that comes from superspreaders is not different in terms of its genetic sequence. We know there is no link with disease severity. There is no evidence for age, sex, or co-morbidities in driving this phenomena,” Menachery said.

Can we learn more quicker from the study of the genetic sequences of SARS-2 viruses?

When genetic sequencing picks up evidence of viruses that have acquired combinations of mutations, they are initially designated “variants of interest.” If any of these variants displays worrisome behavior, they get upgraded to “variants of concern.” That only happens, though, when epidemiological investigations — which can take some time — show that the changes are giving the viruses new powers. The ability to spread faster. The ability to cause more severe disease. The ability to evade the immunity generated by previous infection or vaccines.

Marion Koopmans, head of virology at Erasmus Medical Center in Rotterdam, the Netherlands, wonders if that process could be flipped. “Is it possible to find genomic markers for key properties that should raise a flag?” she asked.

Better yet, can science predict where the virus is heading, asked Ali Ellebedy, an associate professor of pathology and immunology at Washington University School of Medicine in St. Louis. “Knowing the answers to these questions now would greatly help us prepare for next winter by readying the appropriate interventions,” he said.

The impact of the nonpharmaceutical interventions

In the mid-2000s, when concern ran high that the deadly bird flu virus H5N1 appeared poised to trigger a pandemic, public health experts began a desperate search for mitigation tools to use until vaccines and drugs could be developed to deal with the threat. These tools took on the apt moniker nonpharmaceutical interventions — NPIs for short. Examples included closing schools, halting in-person church services, and banning mass gatherings.

These were largely thought to be Hail Marys — unlikely to have a big impact, but the best options in a time of few options. Yet with SARS-2, these measures, which included social-distancing in virtually all facets of life, clearly slowed transmission. They also came with enormous economic and societal costs.

Müge Çevik, a clinical lecturer in infectious diseases and medical virology at the University of St. Andrews School of Medicine in Scotland, would like to know: Which worked best and which were the most cost-effective?

“Because many interventions were implemented simultaneously, it is challenging to disentangle the individual contribution of different NPIs. 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,” she wrote.

Ran Balicer, director of Israel’s Clalit Research Institute, has a related question. “What is the level of transmission to be expected in a mostly vaccinated population (in different uptake levels), if some or all NPIs are dropped?” he asked. Knowing the answer would help countries figure out how to safely choreograph their pandemic exit strategies. Balicer, who with colleagues who have been researching the real-world effectiveness of Covid vaccines, said Israel is trying to come up with answers, removing NPIs layer by layer to see if the impact can be measured.

These tools have proven to be so extraordinarily effective at stopping transmission that some countries that implemented them quickly have managed to prevent the virus from taking hold. People in South Korea, Australia, and New Zealand, for instance, have led fairly normal lives throughout the pandemic. But elsewhere, people and politicians have bristled at tools perceived to be an infringement on individual liberties.

Maria Van Kerkhove, the WHO’s leading coronavirus expert, has preached repeatedly during the WHO’s frequent Covid press conferences that spread of SARS-2 can be stopped — if only countries would use the tools. Her question: What are the barriers to compliance of proven public health interventions and how can that problem best be addressed?

The differences between SARS-2 and its older cousin, SARS-1

The 2002-2003 SARS outbreak showed the world the disruptive power of coronaviruses. Ever since, scientists have worried about this large family of viruses, found in bats and others animals. The camel coronavirus, MERS, which was first spotted in 2012, underscored the threat: Coronaviruses are species jumpers.

But the virus that caused the original SARS outbreak, now called SARS-1, did not know some of the tricks SARS-2 has in its repertoire. Some coronavirus experts marvel at the differences between the two.

Stanley Perlman, a microbiologist at the University of Iowa, would like to know: Why is it SARS-2 can infect and make copies of itself — a process called replication — in the cells of the upper airways, something that SARS-1 did not do? SARS-1 replicated in cells deep in the lungs, which is why people who contracted that virus were only infectious when they were really sick — limiting how many people they could infect. SARS-2 has a huge advantage, because it replicates in the upper airways. People infected with SARS-2 — even those whose symptoms are so mild they don’t know they are infected — have opportunities to transmit the virus every time they sneeze, cough, even speak.

Adding to the puzzle: Both viruses infect by attaching to ACE-2 receptors on human cells, yet they choose cells in different parts of the body.

Finding out why SARS-2 can replicate in the upper airways could help drug developers figure out how to prevent it from happening, Perlman said. It would also help scientists assess the pandemic risks posed by other coronaviruses that might jump from an animal species.

Susan Weiss, who like Perlman is a longtime coronavirus researcher, is also interested in learning why people infected with SARS-2 can transmit to other people if they are asymptomatic or pre-symptomatic. That didn’t happen with SARS-1 or MERS, she noted.

Last but not least: Where did SARS-2 come from?

Analysis of the genetic sequences of SARS-2 viruses retrieved from some of the earliest people known to have been infected suggests the virus started transmitting among people sometime in the autumn of 2019. The original source of the virus is almost certainly a bat, but how did a bat virus find its way into humans? Were pangolins or mink or other wild animals sold as exotic foods in China’s wet markets the spark for the worst pandemic in a century?

Inquiring minds want to know — and not just for curiosity’s sake. Knowing the virus’ route will help the world prepare for future outbreaks. Research shows there are lots of bat coronaviruses we haven’t yet met.

A panel of international experts traveled to China earlier this year to dig into the question, but so far hasn’t come to a firm conclusion. Whether it ever will remains to be seen. Koopmans, of Erasmus Medical Center, was a member of the commission. She submitted several questions, the last of which was simply “The origin … of course.”

Kuppalli, the infectious diseases physician at the Medical University of South Carolina, said the opportunity to answer this key question could slip away, noting: “The longer we get away from the start of the pandemic the harder it will be to find out these answers.”


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