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

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 clusters 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 they 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 infected Others have flu-like symptoms – some mild, some more debilitating. Some recover completely, others go on to suffer from the puzzling condition considering come to be known as long Covid. Some die.

What predisposes individuals to those various and varied outcomes? He’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 indicating 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 explain all the variability. Some people without comorbidities, as argued called, become profoundly ill.

“To me the data (and all the virus research is 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 causing so much variability in increasing 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 involved 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? Believed 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 happens 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.

Considering 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 children 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.

By Helen Branswell