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5 mysteries about COVID-19 that scientists must solve to end the pandemic

Bridget Balch, Staff Writer
February 16, 2021

Scientists have spent more than a year studying the coronavirus. Here’s what they’ve learned about how it spreads, why its symptoms and severity vary, what to expect from vaccines and variants, and why there's still more to learn.

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When health authorities in Wuhan, China, first reported a cluster of mysterious pneumonia cases in December 2019, very little was known about the novel virus that would soon alter the lives of the entire world’s population.

In the following months, as the virus tore through communities across the globe, the mysteries became even more confounding. How was the virus spread? What symptoms indicated infection? Why was the virus no more than a mild flu for some and a deadly pathogen for others?

Scientists across a broad spectrum of specialties quickly turned their focus to decoding COVID-19, from studying the effectiveness of masks at curbing transmission to better understanding the disease process to developing vaccines.

Now, more than a year into the pandemic, experts are taking stock of how far their understanding of the virus has come and how much further it has to go.

Transmission

Asymptomatic spread: SARS-CoV-2, the virus behind the pandemic, is remarkable in its ability to transmit from person to person. Unlike other related viruses — such as Severe Acute Respiratory Syndrome (SARS), which is transmitted when an infected person is showing symptoms — SARS-CoV-2 can spread through asymptomatic people. It took months for the global health community to confirm the role asymptomatic transmission plays in the spread of the virus. As late as June 2020, that the prevalence of asymptomatic spread remained a mystery.

But researchers have conducted numerous studies of real-life outbreaks and lab simulations over the past year, revealing that of all COVID-19 cases are spread from people who are asymptomatic or pre-symptomatic.

The reason the virus can spread asymptomatically is still unknown, says Ross McKinney Jr., MD, chief scientific officer at the AAMC and an infectious disease specialist.

“Symptoms are primarily due to the immune reaction,” McKinney explains. “With SARS-CoV-2, some people must be getting infected, but their immune reaction is not sufficient [to trigger symptoms].”

Whatever makes the virus able to transmit through asymptomatic people has given it an advantage. It’s not sufficient to ask people who are feeling sick or have a fever to stay home, which was one of the key public health strategies early in the pandemic.

Mode of transmission: The ways that the virus spreads further complicate containment efforts. Respiratory viruses are spread in three modes: contact transmission, which comes from touching an infected surface (called a “fomite”); droplet transmission, which occurs when a person inhales droplets coming from an infected person’s nose or mouth; and airborne transmission, which occurs when smaller droplets containing viral particles that are suspended in the air are inhaled.

Since the beginning of the pandemic, public health messages have emphasized the importance of staying six feet away from other people and frequent hand-washing, but some scientists are convinced that SARS-CoV-2 is also spread through aerosols — the tiny particles that are expelled when a person speaks, sings, or breathes.

These particles can float in the air farther than six feet and can remain suspended in poorly-ventilated rooms for hours, says Kimberly Prather, PhD, an atmospheric chemist, distinguished chair in atmospheric chemistry, and distinguished professor at the Scripps Institution of Oceanography and the Department of Chemistry and Biochemistry at the University of California, San Diego.

She compares the airborne virus particles to smoke.

“Smoke floats and behaves in the air very much like virus-containing aerosols produced in speech,” Prather says. “If you’re in a poorly-ventilated room with someone who is smoking, they could be sitting 50 feet from you and you can still see the smoke floating and accumulating in the air over time.”

While the that airborne spread can happen — particularly in enclosed spaces, where there is prolonged exposure, and where there is inadequate ventilation — it also contends that current available data suggests that the virus is mostly spread through close contacts and droplets rather than through airborne transmission.

Still, like Prather are urging public health authorities to take airborne transmission more seriously and encourage mitigation measures that address this form of transmission, such as universal masking, improving ventilation indoors, and moving activities outdoors as much as possible.

Masks: The quality and fit of masks is also particularly important when considering airborne transmission, says Linsey Marr, PhD, a professor of civil and environmental engineering at Virginia Tech in Blacksburg.

“Masks help protect others and they help protect you,” she says, noting that early messaging about masks not being protective for the wearer was misleading.

The two keys to mask effectiveness are its quality and its fit. In a for Med, a journal by Cell Press, Marr laid out the specifics that can make for good masking precautions, such as wearing a surgical mask under a well-fitted cloth mask or wearing a three-layer cloth mask that includes a filter. The its mask guidance to reflect similar recommendations last week.

As far as fit goes, the masks should not have any gaps around the face that allow leakage. For example, foggy glasses are an indication that air is escaping around the mask rather than filtering through it.

“Having people work together from completely different fields, you can move the needle very quickly.”

Kimberly Prather, PhD
Atmospheric chemist at the University of California, San Diego

Though the evidence for asymptomatic and airborne transmission and the efficacy of masks is substantial, there are still questions that scientists have yet to answer about transmission.

Marr says more research is needed to know which size particles contribute the most to transmission.

“That would enable us to hone our message on what types of masks would work best,” she says.

Prather adds that there is still much to learn about why a small percentage of infected people seem to be “” and account for the bulk of infections.

But she is also optimistic that the increased attention on the role aerosols play in infectious disease will result in a focus on improving ventilation and indoor air quality, which will protect against several diseases and health issues.

“Having people work together from completely different fields, you can move the needle very quickly,” Prather says.

Testing

In addition to precautionary measures like masking and social distancing, the best way to curb the spread of a virus like SARS-CoV-2 is to isolate people who are infectious. To do this effectively, tests that are accurate and provide quick results are essential. But in the United States, testing got off to a particularly slow start early in the pandemic and continues to face hurdles.

McKinney says that the global scientific community was quick to understand the biology of the virus, and many countries developed highly sensitive polymerase chain reaction (PCR) tests early in the pandemic. But in the United States, the CDC on the tests it initially sent to labs — setting the country’s testing and surveillance back for months. Many private and academic medical center labs stepped up and created their own tests, but even stretching into the second year of the pandemic, many people are not able to be tested regularly enough to identify and stop outbreaks early.

Some public health experts argue that making at-home rapid tests widely available as soon as possible would curtail the pandemic as millions of people wait to be vaccinated.

Michael Mina, MD, PhD, assistant professor of epidemiology at Harvard T.H. Chan School of Public Health and a faculty member at the , has advocated for the U.S. government to approve and distribute at-home testing kits.

Although rapid antigen tests are not as sensitive as PCR tests, they are designed to detect the virus when a person is most contagious, he explained in for Time magazine last November.

“If only 50% of the population tested themselves in this way every 4 days, we can achieve vaccine-like ‘herd effects’ (which is when onward transmission of the virus across the population cannot sustain itself—like taking fuel from a fire—and the outbreak collapses),” Mina wrote.

The White House COVID-19 Response Team that the U.S. government is finalizing contracts with six companies to provide at-home coronavirus tests, which could bring 60 million of these tests to the United States by the end of the summer.

Symptoms and disease

In the early weeks of the pandemic, the CDC listed three symptoms of COVID-19: cough, fever, and shortness of breath. Now, and notes that the list is not comprehensive.

that loss of smell is a common symptom of mild COVID-19. While most people regain their sense of smell within weeks, some patients report a warped sense of smell or a total loss for months.

And while it’s clear that older people are more susceptible to serious disease and death from COVID-19, with people over age 65 accounting for more than in the United States as of Feb. 3, a significant number of younger people have experienced adverse effects from the disease. On the other hand, very few pre-adolescent children suffer from the severe complications associated with the virus.

Some patients have experienced ; some have such as memory loss and inability to focus; and an of COVID-19 patients, known as long-haulers, have persistent symptoms for weeks or months after initial infection. All of this is in addition to the typical respiratory symptoms that can send severe cases to the hospital.

of disease caused by the virus than women, but from long-term symptoms than men. People with underlying health conditions — such as hypertension and diabetes — are at higher risk of developing serious cases, and Black and Hispanic people experience bad outcomes at than White and Asian people.

The wide range of symptoms and disease processes that COVID-19 patients experience is another of the great mysteries of this virus, McKinney says.

And, so far, available therapies and treatments are mediocre, he adds.

Convalescent plasma, which is taken from the blood of previously infected people, was authorized for emergency use in the United States last August, but studies into its effectiveness have had mixed results. The Food and Drug Administration its authorization to only recommend the treatment in hospitalized patients who are early in the course of the disease or can’t make sufficient antibodies. One found that convalescent plasma may have pushed the virus to mutate in a patient who was chronically ill and had a weakened immune system.

Doctors have had some success using monoclonal antibodies — proteins made in a lab and designed to mimic the body’s immune response — and some drugs, such as the anti-inflammatory steroid dexamethasone, have been helpful in patients whose immune systems overreact to the virus and threaten the body’s function.

Still, researchers and doctors have a lot of work to do to discover more helpful treatments, such as an effective antiviral medication.

Mukesh Kumar, PhD, an assistant professor of biology at Georgia State University, and his team have studied COVID-19 infection in genetically modified mice and have developed a theory for why the symptoms and disease associated with the virus are so boggling.

“The vaccine is here, and in a few months, people will get vaccinated. That is a very good thing, but the people who are already infected — a lot of people … they don’t know where to find help. There’s no protocol for how to manage and treat the long-term symptoms in these patients.”

Mukesh Kumar, PhD
Assistant professor of biology at Georgia State University

Kumar’s team had high viral levels in the brain. This could trigger an ongoing inflammatory response that might explain the array and longevity of symptoms in some people.

“Our data very clearly said early on [the virus] is in the lungs, but that is not why they’re dying,” Kumar says. “That may solve some of the mystery.”

Although studies done in genetically modified mice don’t equate to humans, Kumar hopes that his team’s research will help scientists understand the disease processes of COVID-19 and identify therapies that can be helpful for the people who experience long-term symptoms.

“The vaccine is here, and in a few months, people will get vaccinated. That is a very good thing,” Kumar says. “But the people who are already infected — a lot of people … they don’t know where to find help. There’s no protocol for how to manage and treat the long-term symptoms in these patients.”

Vaccines

For as many missteps and setbacks as the world — and particularly the United States — has had throughout the pandemic, the development of highly effective vaccines in a matter of months was a remarkable achievement for science, according to McKinney.

“We had been building a platform for several years to be ready for a novel pathogen,” he says.

The first vaccines to be approved in the United States use messenger RNA (mRNA), which instructs tissue cells to build a harmless copy of the spike protein that SARS-CoV-2 uses to infect cells. The presence of the foreign protein prompts an immune response and creates antibodies that will be quick to respond to the intruder in the future.

This is a new and promising concept for vaccines that has been in development for years, and it has proven highly effective in clinical trials. by Pfizer-BioNTech and Moderna had a 95% efficacy rate and prevented deaths and serious illness in all trial participants, which was far higher than optimistic projections from public health officials early in the pandemic.

are in various stages of development and testing, many of which use different kinds of technology. A vaccine made by which is in the process of seeking approval from the U.S. government, showed a 66% efficacy in clinical trials and was 85% effective at protecting against severe disease. It was created by engineering a harmless adenovirus to carry the genetic code for the SARS-CoV-2 spike protein into the body and prompt an immune response.

As of Feb. 11, nearly 35 million people in the United States had received at least one vaccine dose and ongoing studies continue to inspire optimism among public health officials.

President Joseph R. Biden that vaccines should be available to any person in the United States who wants one by the end of July.

Variants

The great challenge the vaccines face now — apart from distribution — is the emergence of several SARS-CoV-2 variants that have begun spreading across the globe, appear to be more contagious and more virulent, and may be able to evade the vaccines.

At least three concerning variants — first detected in the United Kingdom, South Africa, and Brazil, respectively — seem to be more contagious than the more common strain. Some initial studies indicate that the variant dominant in the United Kingdom may and the could evade antibodies.

Public health experts say that the emergence of the variants is all the more reason to ramp up vaccination efforts as vaccine developers are already working on that could make the vaccines more effective against variants.

Still, the longer the pandemic continues to spread mostly unchecked, the more opportunities the virus has to mutate and create more challenging variants for vaccines to keep up with.  

“We’re going to be perfecting vaccines and dealing with the mutants,” McKinney says. “SARS is 80% genetically the same as SARS-CoV-2, and SARS was incredibly lethal, but not very transmissible. … We could end up with something that has the worst of both: the lethality of SARS and the asymptomatic spread of SARS-CoV-2. That could happen. We’re going to have to watch. But even if this worst-case scenario happens, the ability to rapidly develop vaccines leaves me very optimistic for the long term.”

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