Coronavirus questions we haven't answered, six months later

On Dec. 20, 2019, a 61-year-old man from Wuhan, China, presented to the Wuhan Jinyintan Hospital with a fever and a strong cough. He'd previously been diagnosed with chronic liver disease but was exhibiting a new, pneumonialike illness. The cause was unknown. Over the next week, his respiratory distress worsened. He was placed on mechanical ventilation on Dec. 29, but died on Jan. 9, 2020. 

He was the first recorded death in the COVID-19 pandemic. On the same day, CNET reported on a "mystery illness" that had infected dozens of citizens in Wuhan, a city of over 11 million people. The patients were sick with pneumonia-like symptoms: Their lungs filled with fluid, and their temperatures soared. On Jan. 20, the first coronavirus case was recorded in the US. 

Six months later, the coronavirus that causes COVID-19 has killed over 600,000 people, and the World Health Organization warns that the pandemic may get "worse and worse and worse."

In the intervening months the coronavirus, SARS-CoV-2, has become the most studied microbe on the planet -- and the pace of science and scientific discovery has dramatically accelerated. The microbe is no longer a complete and utter mystery: We know how it gets into cells and how it makes people sick, its genetics and the methods that prevent it from spreading. Scientists and researchers I spoke to lauded the progress, calling it "inspiring" and "impressive."

Read more: 7 face mask myths debunked: What to know about coverings, COVID-19 and your health

But there's still just as much we don't know. Coupled with an increasing level of "pandemic fatigue" and the uncontrollable spread of misinformation, understanding the coronavirus feels as difficult as scaling Everest. 

For all the progress made, we've just barely limped into base camp. "We're just still scratching the surface," says Bruce Thompson, a respiratory expert at Swinburne University in Australia. "There's just so many questions."

The most pressing are some of the most basic. The science isn't settled on how the virus spreads, who is most effective at spreading it and why it behaves differently in different populations, for instance. But other questions are more complex, intertwined with social inequality, economic policy and pervasive politicization. From conversations with a range of scientific experts and researchers, it's clear we still have a long climb ahead of us. 

What is COVID-19?

Since its discovery, COVID-19 has been identified as a pneumonialike illness that wreaks havoc on the respiratory system, and its effect on the lungs are well-described. Some health authorities refer to COVID-19 as a respiratory illness. But scientists are beginning to realize the disease is much more complicated than that.

"I think it is taking us all some time to appreciate that this is not just another respiratory virus," says Vally. "It has the ability to affect many organs in the body and can cause a diverse range of symptoms."

We're still coming to grips with the varied symptoms and responses to COVID-19 seen in different populations. Some people feel nothing more than a slight fever and sore throat, others end up in intensive care, where mechanical ventilation is used to keep them breathing. The spectrum of COVID-19 responses is huge -- and it may come down to genetics.

The COVID-19 Host Genetics Initiative lists over 200 registered studies, examining various genes that may make us more or less susceptible to the worst effects of COVID-19. The initiative is a data-sharing agreement that could speed up the process of finding genetic variations that are risk factors for disease. 

For instance, scientists have documented how COVID-19 disturbs blood vessels and causes clotting in some patients. In June, a study published in the New England Journal of Medicine detailed a cluster of genes that might make patients more susceptible to COVID-19 respiratory failure and also suggested the ABO blood-group system may play a role in disease severity.

Nutritional status could also play a role, according to Richard Head, emeritus professor at the University of South Australia. There is clear evidence obesity is, at least partly, associated with poorer outcomes. For instance, one small study published in April, looking at 124 patients at a French hospital, found that those with a higher body-mass index were more likely to require mechanical ventilation. A much larger UK report found that nearly 75% of patients admitted to the ICU had a BMI that would put them in the overweight or obese range.

Six months into the pandemic, it's clear COVID-19 is a much more formidable foe than we anticipated. The diverse range of symptoms and complications could present significant hurdles when it comes to treatments and vaccines, and it's clear that age and sex are contributing to severity, too. 

"This is an incredibly complicated disease," Head notes.

How does the virus spread?

Since the earliest days of the pandemic, the WHO has maintained that the chief mode of transmission occurs via respiratory droplets blasted into the air by infected patients when they sneeze, cough or talk. However, recent scientific evidence has challenged this notion. A growing chorus of scientists believe the virus may spread via aerosol -- tiny particles much smaller than droplets which persist in the air for long periods of time.

This airborne route of transmission was recently raised in an open letter to the WHO, signed by over 200 experts, suggesting the threat of the virus spreading through the air was being overlooked. The WHO, which had said the airborne route is only important in COVID-19 spread in the case of some medical procedures, then clarified its position on July 9, suggesting it is possible, but "urgent high-quality research" is required to establish its role in spreading COVID-19. 

One commonly cited preprint study analyzed the dynamics of transmission in a restaurant in Guangzhou, China, hypothesizing that spread through one section of the restaurant using recirculated air caused a handful of new infections. Other researchers have noted that the evidence is shaky, but admit it seems likely aerosols play a role in the spread of disease in poorly ventilated, indoor spaces. 

Another open question is when, exactly, infected individuals can infect someone else. And there's another, more insidious problem: COVID-19 could be spread by people who never show any symptoms at all -- so-called asymptomatic cases.

These patients may not feel sick and may never even know they have the disease, but they could still spread COVID-19 unknowingly. In early June, Maria Van Kerkhove, WHO's technical lead in the COVID-19 response team, said it's "very rare" for asymptomatic cases to spread the virus. This caused a bit of a stir in the scientific community, as several studies have demonstrated asymptomatic spread could account for anywhere between 15% and 80% of all cases.

Van Kerkhove later clarified that the WHO does not know how common asymptomatic spread is. But the confusion was largely a lesson in semantics showing how important it is to differentiate between asymptomatic individuals and pre-symptomatic individuals. Both groups are infected with SARS-CoV-2, but only the latter eventually develops the symptoms associated with COVID-19, such as fever and respiratory distress.

The question experts are racing to answer is: How important are these two groups in spreading the virus? If they only account for a small percentage of cases, then it may not greatly affect the public health messaging. But if this kind of spread is rampant, then it becomes increasingly important for the public to wear masks and social distance even if they don't feel sick. 

The confusion surrounding transmission has led to a misunderstanding by the public that their own behavior can't have drastic effects, according to Mary-Louise McLaws, an epidemiologist at the University of New South Wales and member of the WHO's COVID-19 advisory panel. 

"One person's breach in infection control (e.g. going to work with symptoms) can have long-term consequences for the course of the pandemic and on others' health," she says. McLaws adds that social inequity -- like an employee having to attend work, even when sick -- helps amplify the spread of COVID-19 and that authorities should be thinking about how to address social problems in conjunction with providing health advice.

How does the immune system respond?

The immune system forms the first line of defense against COVID-19. To combat infection, it produces antibodies, Y-shaped proteins that stop the coronavirus from hijacking human cells. Recent evidence suggests this response may be short-lived and differs greatly from person to person.

"This has huge implications for the spread of the virus and also how effective a vaccine may be," says Hassan Vally, an infectious diseases epidemiologist at Australia's La Trobe University.

A recent preprint study, yet to undergo peer review, shows around 60% of patients were able to generate a "potent" antibody response to natural infection -- but within three months, only 17% of patients maintained that potency. In another preprint study, of COVID-19 patients in New York, the level of antibodies in a cohort of 370 patients varied greatly. Some had very low levels, while others showed a much stronger response. 

And that poses problems for potential vaccines. If a vaccine can only stimulate antibodies in the same way natural infection does, we may not be able to achieve long-lasting immunity.

"It's key to get an understanding of what level of immunity is required for protection from reinfection, which is difficult to assess right now," says Jennifer Juno, an immunologist at the Doherty Institute in Australia. 

Juno and her colleagues published a study in the journal Nature Medicine on June 13 detailing the importance of particular cells of the immune system in responding to a COVID-19 infection. Her team looked at patients who had recovered from a bout of COVID-19 and discovered that a subset of immune cells, known as T-follicular helper cells, were associated with the best immune responses. 

As Juno -- and others -- are showing, antibodies form one branch of the immune system's armed forces, but they may not be enough to stop COVID-19 from invading. To understand how the body eliminates SARS-CoV-2 and protects against future infection, researchers are turning their attention to responses in other branches of the system, from immune cells to proteins and cytokines. 

Where did the coronavirus come from?

One of the more puzzling mysteries is where the coronavirus originated. Researchers sequenced the genetic code of SARS-CoV-2 only weeks after the virus was first discovered and have attempted to work backward to a starting point ever since. The most likely scenario is SARS-CoV-2 jumped from bat to human sometime in late 2019, possibly through an intermediate species.

"The search for the origin is incredibly important to prevent reemergence of SARS-CoV-2-like viruses," said Alina Chan, a scientist at the Broad Institute of MIT and Harvard, in May.

Studies have shown it's closely related to a group of coronaviruses isolated from Chinese horseshoe bats sharing significant genetic similarities with a virus known as RaTG13. But that virus was found in 2013, and a direct ancestor of SARS-CoV-2 has not been discovered. In its absence, conspiracy theories and speculation have run rampant. 

The first cases of COVID-19 were clustered around a wet market in Wuhan, where a menagerie of wildlife and animal meat was sold. Chinese scientists recently ruled it out as a starting point. However, it clearly facilitated the spread of the disease in late December 2019 through Wuhan. 

The market is critical for the conspiracy theories that have been shared across social media, because it is in close proximity to the Wuhan Institute of Virology. The laboratory was known to hold coronaviruses related to SARS-CoV-2. That has led to speculation the coronavirus may have accidentally been carried out of the lab unknowingly. The lab director, Yuan Zhiming, in April told CGTN, a Chinese state-run media outlet, that the virus "definitely" did not come from the lab but most scientists agree it cannot be ruled out as a source.

Complicating matters is how politically charged the origin story has become. In May, US Secretary of State Mike Pompeo, suggested there was "enormous" evidence the virus originated from a lab. Chinese officials quickly demanded he back up those claims, and Pompeo later walked them back. Similarly, a war of words between Australia and China flared after the Australian government pushed for an independent inquiry in the origins of COVID-19. 

On May 18, the World Health Organization pledged it would launch an independent evaluation of the global response to the pandemic. In early July, it sent two scientists to Beijing to begin preliminary investigations into the virus' origin, though it has been criticized for coming "six months too late"

Some scientists have argued that the search for a starting point is ultimately of little value and won't halt the pandemic. But without understanding where the virus came from, or which species it may lurk in, there's a chance we may see a recurrence. 

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What's next?

The scientific questions are numerous, but it's clear the pandemic is a source of confusion and worry. The public holds numerous concerns: when restaurants and bars will open, when international travel might resume, when a vaccine might arrive. The list goes on. But each question, at its core, is asking the same thing: When can things go back to normal? 

"I think we need to come to that realization that this is going to be around for a very long period of time," says Bruce Thompson, respiratory expert at Swinburne University. Potentially, he says, we will be living through the pandemic until 2022, even with a successful vaccine.

It's a sobering thought, Thompson says, but recalibrating our new normal is necessary to prepare for the future and be more preemptive in combating the spread of disease. "This is how it's going to be, and it's OK," he says. "We're just going to have to adapt."

There is reason to be hopeful. Over two dozen vaccines are in human clinical trials, and dozens more are in the preclinical testing phase. There has been an unprecedented effort to develop a safe and effective vaccine, and some of the clinical trials are beginning to bear fruit. By the end of the year, it's unlikely we'll have something ready to roll out on a global scale, but we likely will have homed in on the most promising candidates.

"In six months, we should have some good data from human vaccine trials to evaluate their immunogenicity and see which approaches drive strong immune responses," says Juno. 

With our increasing knowledge of the disease, its severity and how it affects different populations, scientists will be in a position to tease out which treatments will be most effective -- and for whom. In recent months, two candidates, remdesivir and dexamethasone, have attracted a lot of media attention, but there are opportunities to repurpose other medications which could improve patient outcomes, too.

As we move into the final six months of the year, it will also be important to address pandemic fatigue within the community, says McLaws. The exhaustion is compounded by rolling lockdowns that isolate many and weigh heavily on mental health. Accepting this as the new normal, public health authorities will need to pivot, providing support not just for the current impacts of the pandemic, but to those that will be felt for years to come. 

And though we might think a pandemic is a freak, once-in-a-century event, there are ways to mitigate and prevent future outbreaks. Alina Chan believes the public misunderstands the "level of agency" they have in preventing future pandemics. Increasing the surveillance of pathogens in agriculture, in workplaces like mines and in villages bordering wildlife habitats could help us stamp out a pandemic before it has the chance to get started. 

To do so requires timely and transparent communication of potential threats. Funding more research programs and sampling pathogens is one way to do that, but without international cooperation we will continue to run the risk of new, highly infectious and deadly diseases spreading across the globe.

"We were unprepared for this pandemic," says Chan. "We have to think of new ways to be vigilant and prepared for future outbreaks."