One Year In, Our Biggest Lessons and Unsolved Mysteries about COVID-19
A leading virologist reflects on the past year and the unknowns about COVID-19 that we still need to solve.
On the one-year anniversary of the World Health Organization declaring SARS-CoV-2 a global pandemic, it's hard to believe that so much and yet so little time has passed. The past twelve months seem to have dragged by, with each day feeling like an eternity, yet also it feels as though it has flashed by in a blur.
Nearly everyone I've spoken with, from recent acquaintances to my closest friends and family, have reported feeling the same odd sense of disconnectedness, which I've taken to calling "pandemic relativity." Just this week, Ellen Cushing published a piece in The Atlantic about the effects of "late-stage pandemic" on memory and cognitive function. Perhaps, thanks to twelve months of living this way, we have all found it that much more difficult to distill the key lessons that will allow us to emerge from the relentless, disconnected grind of our current reality, return to some semblance of normalcy, and take the decisive steps needed to ensure the mistakes of this pandemic are not repeated in the next one.
As a virologist who studies SARS-CoV-2 and other emerging viruses, and who sometimes writes and publicly comments on my thoughts, I've been asked frequently about what we've learned as we approach a year of living in suspension. While I always come up with an answer, the truth is similar to my perception of time: we've learned a lot, but at the same time, that's only served to highlight how much we still don't know. We have uncovered and clarified many scientific truths, but also revealed the limits of our scientific knowledge.
The Most Important Lessons Learned
The dangers of false dichotomies.
From the early days, we have been guilty of binary thinking, and this has touched nearly every aspect of the pandemic. The following statements are not true, but the narratives are all too common: The only outcomes of COVID-19 are full recovery or death. Masks either work perfectly or they don't work at all. Transmission only occurs entirely by droplets or is entirely airborne. Children are either complete immune or they are equally as susceptible as adults. Vaccines either completely protect against infection and illness or they are completely useless. Any true student of biology can tell you that there are very rarely binary certainties that apply to every situation, but sensible public health advice can be rapidly derailed by discussing biological realities that exist on a continuum as if they are all categorically true or false.
It's a natural impulse to reduce complex systems to a choice of two options, and also to seek absolute certainty. A challenge for all scientists is how to communicate uncertainty when many people are understandably frustrated at this point and sick of hearing "we don't know." If we don't know now, when will we know? How much do we need to know to make good decisions? When will we get back to "normal"? In trying to simplify complex scientific concepts, we've made them hopelessly complicated. An important lesson going forward is that we should move away from black and white conversations about the emerging science and embrace the shades of gray, with all the nuance and uncertainty that entails.
Novel pandemic viruses can be controlled without a vaccine or effective antiviral therapeutics, and there is no one right way to do so.
Coronaviruses are very different from influenza.
Since the beginning of the pandemic, the superficial similarities between SARS-CoV-2 and influenza viruses have inevitably led to comparisons: both are primarily respiratory viruses with some symptoms in common, both have a relatively low overall mortality rate, both are zoonotic viruses that spilled over into the human population from animals, both are enveloped viruses that use RNA, rather than DNA, as their genetic material.
But these similarities disguise the fact that these are two fundamentally different pathogens. They have very different biology at virtually every step of the viral replication cycle, or the process that a virus goes through when it infects a cell and transforms it into a virus factory. SARS-CoV-2 enters cells by interacting with a protein on cell surfaces called ACE-2, while influenza viruses interact with a sugar molecule called sialic acid that "decorates" cell surface proteins. This means the viruses infect different types of cells in the respiratory tract and throughout the body. They also encode vastly different types of viral proteins meant to subvert and hijack the cells they infect: the genome of influenza virus is less than half the size of the genome of SARS-CoV-2, and encodes fewer than half as many viral proteins that can interact with the host cell.
As a result, these viruses each interact with host cells in unique ways and induce different responses to infection. The host response to infection is critically important for determining disease severity in both influenza and COVID-19, with the most severe disease associated with an uncontrolled inflammatory response that results in damaging the lungs and other affected tissues. Indeed, comparative studies have now shown that COVID-19 and influenza infection induce very different host response profiles in infected cells, leading to fundamentally different diseases. Our early reliance on pandemic response plans and public health strategies designed for influenza virus was a mistake, and this will be critical to preparedness and improved response plans going forward.
Transmission is situational.
Another way in which SARS-CoV-2 is very different from influenza is how it spreads through a population, which is relevant to how it is transmitted. Early on, many people focused on the fact that the basic reproduction number (R0) of SARS-CoV-2 was between 2 and 4, similar to the 1918 influenza pandemic. R0 describes the number of people that an infected person will transmit the virus to, but this is an average.
Another key measurement epidemiologists use to look at spread is dispersion, or patterns of transmission. If R0 is 2, and you have a population of 10 people, does that mean that all 10 people transmitted the virus to exactly 2 people? Or did 4 of the people each transmit to 5 people, with the other 6 of the 10 transmitting to nobody? In both situations, the average number of new infections is still 2, but the latter situation is described as overdispersion. While influenza is typically not very overdispersed, SARS-CoV-2 is heavily overdispersed. This is reflected in the high frequency of "superspreading events", where many people are infected at the same time.
Superspreading events are highly dependent on circumstances that need to align to create a conducive environment for transmission. SARS-CoV-2 is primarily transmitted by either inhalation of infectious aerosols (smaller respiratory particles suspended in the air) or direct contact with infectious droplets (larger respiratory particles that can be transferred from the body to the nose or mouth). This means that transmission is more likely to occur in situations with increased exposure risk. The risk is additive, with the likelihood of transmission being higher with more potential sources of virus (people from different households), higher respiratory particle emissions (lack of masks and/or shouting or singing), a physical environment that concentrates potentially infectious particles (an enclosed, poorly ventilated indoor space), close physical proximity (crowding), and increased exposure time.
We have seen repeatedly that when these conditions are met, such as in crowded bars or restaurants, gyms, cruise ships, buses, or weddings, superspreading can occur. The good news, however, is that identifying all these different risk factors has also allowed us to identify methods to mitigate transmission, and these are also additive: masks, physical distancing, avoiding enclosed spaces, limiting interactions with people outside your household, improving ventilation, and practicing good hand hygiene all reduce exposure risk.
Presymptomatic and asymptomatic transmission are critical to controlling a pandemic.
Another critical early mistake was assuming that SARS-CoV-2 would be transmitted only by symptomatic people. This was an understandable assumption to make, as people infected with "classic" SARS-CoV reliably developed fevers and could be identified based on body temperature and symptom screening. However, by March 2020, it was apparent that symptom-based screening was inadequate. The symptoms of COVID-19 fall along a very broad spectrum, ranging from completely asymptomatic infection to lethal pneumonia, with everything from loss of taste and smell to "COVID toes" to diarrhea to kidney failure to strokes in between.
Furthermore, last spring several studies showed that viral loads in the nose and throat were highest at the time of symptom onset, suggesting that people were likely to be contagious before they would be aware that they were sick. This created a tremendous challenge that repeatedly thwarted efforts to control community transmission in many countries, including the U.S. Without sufficient testing and surveillance, and with prevalence too high to enable robust contact tracing, efforts to identify and quarantine exposed people were unsuccessful. While the percentage of cases resulting from silent asymptomatic or presymptomatic transmission is still not precisely determined, it may account for nearly half of new infections and has been observed repeatedly. However, our policies have not caught up, and overeager reopening and blanket lifting of mask mandates often fail to account for contagious people who don't realize they are infected. Unfortunately, it's now also well-established that prematurely letting up on precautions can drive new surges in case numbers.
There's more than one way to stop a pandemic. While we've certainly seen examples of failed pandemic responses by looking at the U.S. and most of Western Europe, there have been a number of other countries that have very effectively controlled the pandemic within their borders. This hasn't been a one-size-fits-all approach, either. China infamously instituted a draconian lockdown in late January after the pandemic quickly spread from Wuhan to the rest of the country. A number of other countries, including Taiwan, Hong Kong, South Korea, Vietnam, Australia, New Zealand, and Japan, have implemented various combinations of policy measures (travel restrictions, lockdowns), epidemiological approaches (contact tracing, isolation and quarantine), data collection (testing capacity and surveillance), and mitigation measures (mask availability and mandates, exposure risk reduction education campaigns), that have effectively kept prevalence low and in some cases eliminated COVID-19 altogether. It shows that novel pandemic viruses can be controlled without a vaccine or effective antiviral therapeutics, and also that there is no one right way to do so.
We can develop safe, effective vaccines in record time.
Last March, Dr. Anthony S. Fauci estimated that a vaccine might be available in 12 to 18 months. At the time this was thought to be an extremely optimistic estimate, given that vaccines typically take years to design, develop, and test to ensure they are safe and effective. So how did we go from the drawing board to authorized vaccines, which so far appear to be very safe and effective, in less than a year? In part this is due to streamlining the clinical trial process, allowing previously sequential steps in the pipeline to occur simultaneously, such as phase 3 clinical trials and manufacturing.
The expedited trial process also built upon previous studies with the vaccine technologies, including extensive preclinical studies and clinical trials that tested mRNA (Pfizer/BioNTech and Moderna) and adenovirus-vectored (Johnson and Johnson and AstraZeneca) vaccines against other viruses, including MERS-CoV, a cousin of SARS-CoV-2. Prior to the phase 3 clinical trials "reading out" (amassing enough data to enable a statistically robust appraisal of their safety and efficacy), our expectations were modest, hoping for 50 to 60% protection against COVID-19. Thus far, all the vaccines that have completed phase 3 trials have exceeded that expectation. While future vaccines will likely still take years to fully evaluate, we can apply the achievements of the SARS-CoV-2 vaccines to make the regulatory process more efficient for other vaccines, as well as develop ways to further expedite the process in emergencies without compromising safety or effectiveness. A more efficient regulatory environment could improve access to other technologies, such as promising new tests and therapeutics, as well.
The Biggest Unknowns
While we have made extraordinary strides forward in better understanding SARS-CoV-2 and both the triumphs and the failures of the response to the greatest public health challenge of our lifetime, the lessons we've learned have highlighted the many questions that remain. We will be studying many aspects of the pandemic for decades. Long after SARS-CoV-2 is finished with humanity on a global scale, we will not be finished with it. Some of these remaining questions won't have easy answers, and in fact may not even be answerable. But it is critical to engage with these questions as we move into a post-pandemic future.
The origin of SARS-CoV-2.
This topic is as confusing and murky as it is contentious, proving to be as confounding to science as it is disruptive to geopolitics. Multiple hypotheses abound: SARS-CoV-2 emerged into the human population naturally, passing from an infected animal to an unlucky human in the wrong place at the wrong time in a process called zoonotic spillover. This natural origin hypothesis is considered the most likely, as this is overwhelmingly the most common path for novel viruses to emerge in the human population.
Tracing SARS-CoV-2 back to its source is critical for both understanding how this pandemic began and preventing the emergence of SARS-CoV-3, which almost certainly is circulating in wildlife along with a frighteningly large number of other potential pandemic pathogens.
However, the evidence supporting this hypothesis is scant, and limited to genetic analyses that don't indicate anything artificial or engineered about the SARS-CoV-2 genome, as well as some very small studies suggesting that people who live close to bat caves in southern China have antibodies to closely related viruses. Such uncertainty has led to several other hypotheses, including that the virus emerged from a laboratory at the Wuhan Institute of Virology, either through accident or design. While there is far more speculation than evidence affirming any laboratory origin hypothesis, neither can be definitively excluded and both should be fairly investigated. In addition, the Chinese government has suggested that SARS-CoV-2 was imported via frozen seafood from Europe or North America. This hypothesis strains credulity, given that the most closely related viruses have been identified in China and transmission by indirect contact (with contaminated objects, or fomites, is thought to be uncommon), but it still should be ruled out objectively.
About the only thing most experts agree on is that SARS-CoV-2 evolved from an ancestral betacoronavirus that likely was circulating in bats. However, because we have not yet found that ancestral virus in nature, we are left still looking. Sometimes origin investigations into zoonotic origins can take decades, since we live in a big world, with many wild animals carrying many different viruses at different times in their lives. Trying to find the immediate forbear of SARS-CoV-2 in wildlife is like seeking a very specific tiny needle in a planet-sized haystack that is also littered with other tiny needles.
To further complicate matters, there is the possibility that SARS-CoV-2 did not spill over from bats to humans directly, but stopped off in another species along the way. Intermediary species have been involved in the transmission of both SARS-CoV and MERS-CoV, and we already know that SARS-CoV-2 can infect other animal species, including minks, dogs, and cats.
And if the science weren't complex enough, conducting any type of origin investigation, but particularly a rigorous independent investigation of lab origin theories, depends on other countries maintaining a productive diplomatic relationship with the Chinese government. That relationship erodes every time another piece is published outside China that treats laboratory origin as a foregone conclusion. Tracing SARS-CoV-2 back to its source is critical for both understanding how this pandemic began and preventing the emergence of SARS-CoV-3, which almost certainly is circulating in wildlife along with a frighteningly large number of other potential pandemic pathogens. But it won't be easy and we need to prepare ourselves for the possibility of a very long and arduous search for answers.
The long-term consequences of COVID-19.
While it is not clear how common "long COVID" is, one thing is certain: it has impacted a substantial number of COVID-19 survivors' lives. It remains unknown what predisposes a person to this outcome, now dubbed post-acute sequelae of COVID-19 (PASC). Nor does anyone truly know how long it lasts, or even what the most common presentation of it looks like. Many patients have reported a diverse array of symptoms, some very severe, that have persisted for months.
PASC can range from recurring neurological problems to hair and tooth loss to permanent lung injury. Some people have reported relapsing pain and severe fatigue similar to myalgic encephalomyelitis or chronic fatigue syndrome. Even more troubling, PASC can be severe in patients who reported having extremely mild acute COVID-19. Last month, the National Institutes of Health announced plans to study PASC in detail, but it may be some time before we know the cause (or causes) of PASC, much less how to treat it and ameliorate its impact on those suffering from it. But the potential for long-term debilitating illness persisting long after the resolution of acute SARS-CoV-2 infection suggests that even when the pandemic is behind us, public health will continue to struggle with the legacy of COVID-19.
Immune correlates of protection and durability.
While vaccine trials were designed to sacrifice little in the way of assessing short-term efficacy, they did not assess the length of time that protective immunity will last. This was because of the urgency of the situation, and allowed us to begin vaccinating as soon as we learned that the vaccines were safe and effective in the short term. Durability studies are one reason why normally vaccine trials can take over a decade, as unfortunately the only way to assess how long a vaccine lasts is to wait and see when protection begins to wane.
Furthermore, because the virus is novel and the technologies underlying the vaccine platforms are being used for the first time at population scale, we haven't yet defined correlates of protection for the vaccines. Correlates of protection are easily measurable features, such as antibody levels or cell counts, that can be used as surrogates for vaccine function. In other words, what we are missing is the knowledge of how many antibodies, or T-cells, does your immune system actually need to protect you from infection? We know that a high number is protective, but the question is how high.
Until we have enough data to define these correlates, we have to continue to follow trial participants and analyze observational studies of vaccinated individuals, which can be tedious as well as time-consuming. So it may be some time before we can advise people confidently about how long vaccine protection will last beyond a year or so, based on the duration of immune function in people who have recovered from natural SARS-CoV-2 infection. The good news is that protective immune responses can be easily restored with a booster shot, but that will present major logistical challenges if needed while global immunization efforts are still underway.
What price will we pay for nationalizing vaccine responses?
Finally, one of the biggest questions as we move into the post-pandemic future in the developed world is what the decision to respond nationally, rather than as a cooperative global community, will cost us in terms of truly ending the pandemic. Without question, in countries like the U.S., which will have enough vaccine doses in the next few months to vaccinate every American who wants one, the pandemic will end for most people's daily lives. But globally, the reality is very different. Many countries have yet to administer a single dose of any vaccine. While this may not seem relevant to people who do not intend to travel to those countries, it is relevant to every human being on earth. None of us are safe until all of us are safe.
Viruses infect their hosts regardless of what passport they carry. Pandemics, by definition, are global epidemics, and thus impact the global population. If people are vaccinated only in certain countries, SARS-CoV-2 can continue to circulate in populations with less immunization and fewer barriers to infection. As the U.S. today reaches this grim anniversary along with the rest of the world, we would do well to remember the lessons we've learned as we forge ahead with filling the remaining gaps in our knowledge.
This man spent over 70 years in an iron lung. What he was able to accomplish is amazing.
Paul Alexander spent more than 70 years confined to an iron lung after a polio infection left him paralyzed at age 6. Here, Alexander uses a mirror attached to the top of his iron lung to view his surroundings.
It’s a sight we don’t normally see these days: A man lying prone in a big, metal tube with his head sticking out of one end. But it wasn’t so long ago that this sight was unfortunately much more common.
In the first half of the 20th century, tens of thousands of people each year were infected by polio—a highly contagious virus that attacks nerves in the spinal cord and brainstem. Many people survived polio, but a small percentage of people who did were left permanently paralyzed from the virus, requiring support to help them breathe. This support, known as an “iron lung,” manually pulled oxygen in and out of a person’s lungs by changing the pressure inside the machine.
Paul Alexander was one of several thousand who were infected and paralyzed by polio in 1952. That year, a polio epidemic swept the United States, forcing businesses to close and polio wards in hospitals all over the country to fill up with sick children. When Paul caught polio in the summer of 1952, doctors urged his parents to let him rest and recover at home, since the hospital in his home suburb of Dallas, Texas was already overrun with polio patients.
Paul rested in bed for a few days with aching limbs and a fever. But his condition quickly got worse. Within a week, Paul could no longer speak or swallow, and his parents rushed him to the local hospital where the doctors performed an emergency procedure to help him breathe. Paul woke from the surgery three days later, and found himself unable to move and lying inside an iron lung in the polio ward, surrounded by rows of other paralyzed children.
Hospitals were commonly filled with polio patients who had been paralyzed by the virus before a vaccine became widely available in 1955. Associated Press
But against all odds, Paul lived. And with help from a physical therapist, Paul was able to thrive—sometimes for small periods outside the iron lung.
The way Paul did this was to practice glossopharyngeal breathing (or as Paul called it, “frog breathing”), where he would trap air in his mouth and force it down his throat and into his lungs by flattening his tongue. This breathing technique, taught to him by his physical therapist, would allow Paul to leave the iron lung for increasing periods of time.
With help from his iron lung (and for small periods of time without it), Paul managed to live a full, happy, and sometimes record-breaking life. At 21, Paul became the first person in Dallas, Texas to graduate high school without attending class in person, owing his success to memorization rather than taking notes. After high school, Paul received a scholarship to Southern Methodist University and pursued his dream of becoming a trial lawyer and successfully represented clients in court.
Paul Alexander, pictured here in his early 20s, mastered a type of breathing technique that allowed him to spend short amounts of time outside his iron lung. Paul Alexander
Throughout his long life, Paul was also able to fly on a plane, visit the beach, adopt a dog, fall in love, and write a memoir using a plastic stick to tap out a draft on a keyboard. In recent years, Paul joined TikTok and became a viral sensation with more than 330,000 followers. In one of his first videos, Paul advocated for vaccination and warned against another polio epidemic.
Paul was reportedly hospitalized with COVID-19 at the end of February and died on March 11th, 2024. He currently holds the Guiness World Record for longest survival inside an iron lung—71 years.
Polio thankfully no longer circulates in the United States, or in most of the world, thanks to vaccines. But Paul continues to serve as a reminder of the importance of vaccination—and the power of the human spirit.
““I’ve got some big dreams. I’m not going to accept from anybody their limitations,” he said in a 2022 interview with CNN. “My life is incredible.”
When doctors couldn’t stop her daughter’s seizures, this mom earned a PhD and found a treatment herself.
Savannah Salazar (left) and her mother, Tracy Dixon-Salazaar, who earned a PhD in neurobiology in the quest for a treatment of her daughter's seizure disorder.
Twenty-eight years ago, Tracy Dixon-Salazaar woke to the sound of her daughter, two-year-old Savannah, in the midst of a medical emergency.
“I entered [Savannah’s room] to see her tiny little body jerking about violently in her bed,” Tracy said in an interview. “I thought she was choking.” When she and her husband frantically called 911, the paramedic told them it was likely that Savannah had had a seizure—a term neither Tracy nor her husband had ever heard before.
Over the next several years, Savannah’s seizures continued and worsened. By age five Savannah was having seizures dozens of times each day, and her parents noticed significant developmental delays. Savannah was unable to use the restroom and functioned more like a toddler than a five-year-old.
Doctors were mystified: Tracy and her husband had no family history of seizures, and there was no event—such as an injury or infection—that could have caused them. Doctors were also confused as to why Savannah’s seizures were happening so frequently despite trying different seizure medications.
Doctors eventually diagnosed Savannah with Lennox-Gaustaut Syndrome, or LGS, an epilepsy disorder with no cure and a poor prognosis. People with LGS are often resistant to several kinds of anti-seizure medications, and often suffer from developmental delays and behavioral problems. People with LGS also have a higher chance of injury as well as a higher chance of sudden unexpected death (SUDEP) due to the frequent seizures. In about 70 percent of cases, LGS has an identifiable cause such as a brain injury or genetic syndrome. In about 30 percent of cases, however, the cause is unknown.
Watching her daughter struggle through repeated seizures was devastating to Tracy and the rest of the family.
“This disease, it comes into your life. It’s uninvited. It’s unannounced and it takes over every aspect of your daily life,” said Tracy in an interview with Today.com. “Plus it’s attacking the thing that is most precious to you—your kid.”
Desperate to find some answers, Tracy began combing the medical literature for information about epilepsy and LGS. She enrolled in college courses to better understand the papers she was reading.
“Ironically, I thought I needed to go to college to take English classes to understand these papers—but soon learned it wasn’t English classes I needed, It was science,” Tracy said. When she took her first college science course, Tracy says, she “fell in love with the subject.”
Tracy was now a caregiver to Savannah, who continued to have hundreds of seizures a month, as well as a full-time student, studying late into the night and while her kids were at school, using classwork as “an outlet for the pain.”
“I couldn’t help my daughter,” Tracy said. “Studying was something I could do.”
Twelve years later, Tracy had earned a PhD in neurobiology.
After her post-doctoral training, Tracy started working at a lab that explored the genetics of epilepsy. Savannah’s doctors hadn’t found a genetic cause for her seizures, so Tracy decided to sequence her genome again to check for other abnormalities—and what she found was life-changing.
Tracy discovered that Savannah had a calcium channel mutation, meaning that too much calcium was passing through Savannah’s neural pathways, leading to seizures. The information made sense to Tracy: Anti-seizure medications often leech calcium from a person’s bones. When doctors had prescribed Savannah calcium supplements in the past to counteract these effects, her seizures had gotten worse every time she took the medication. Tracy took her discovery to Savannah’s doctor, who agreed to prescribe her a calcium blocker.
The change in Savannah was almost immediate.
Within two weeks, Savannah’s seizures had decreased by 95 percent. Once on a daily seven-drug regimen, she was soon weaned to just four, and then three. Amazingly, Tracy started to notice changes in Savannah’s personality and development, too.
“She just exploded in her personality and her talking and her walking and her potty training and oh my gosh she is just so sassy,” Tracy said in an interview.
Since starting the calcium blocker eleven years ago, Savannah has continued to make enormous strides. Though still unable to read or write, Savannah enjoys puzzles and social media. She’s “obsessed” with boys, says Tracy. And while Tracy suspects she’ll never be able to live independently, she and her daughter can now share more “normal” moments—something she never anticipated at the start of Savannah’s journey with LGS. While preparing for an event, Savannah helped Tracy get ready.
“We picked out a dress and it was the first time in our lives that we did something normal as a mother and a daughter,” she said. “It was pretty cool.”