"I hope that the epidemic will end as soon as possible and that things will get better as soon as possible."
文 | STAT Staff
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More than two years after the emergence of the new coronavirus, with the number of recorded deaths in the United States approaching 1 million and the estimated global death toll reaching 18 million, there are still many unsolved mysteries about the virus and the pandemic it caused.
Technically, what role do autoantibodies play in the long-term sequelae of COVID-19? Can a pan-coronavirus vaccine really be developed to help us fend off colds, flu and coronavirus once and for all?
Philosophically, how do we rebuild trust in our institutions and each other? While recent studies have added to the evidence that the virus came from wild animals, the debate over the origin of the virus continues to intensify.
Some of these questions are completely unanswered or can only be solved over time. Professional medical media STAT investigated six mysteries that scientists began to solve. The ultimate answer will determine our relationship with COVID-19 and how we will fight future pandemics. The six questions are as follows:
1. How will viruses evolve next?
2. What will the wave summit of the future epidemic look like?
3. If you've never had COVID-19, do you need to worry now?
4. How exactly does the virus spread from person to person?
5. Will we get better vaccines, treatments and tests?
6. When will a better understanding be established about the after-effects of COVID-19?
How the virus will evolve next
The early idea that the coronavirus wouldn't suddenly mutate so quickly now seems naïve. Scientists have turned over more than half of the letters in the Greek alphabet to name the mutant. When the Delta variant came out, it was already speculated that the virus was close to its maximum capacity to spread, and then came out of Theomy Kerong, one of the most contagious respiratory viruses we've ever seen.
Any prediction is based on a guiding principle: all viruses want to do is replicate and spread, and strains will win the race by becoming more intrinsically contagious, or managing to infect people with some level of protection, or both. From Alpha to Delta to the Aumicon variant, we've seen the virus make a leap forward using both strategies. Now, given that a large number of people already gain immunity through vaccination or infection, a better evolutionary strategy for viruses may be to "escape" immunity to some extent through mutation. If this variant does occur, the vaccine formulation needs to be updated.
The coronavirus also showed that it could punch a combo punch. When Alpha and Delta dominate the world, experts believe the next "worry variant" will be their descendants. But then, somewhere deeper in the evolutionary genealogy, there was a "demon fist"—first delta replacing alpha, then opalon replacing delta.
"When we're all looking at Omicron and its BA.2 subtree, it's likely that another curved ball will hit us," said Bronwyn MacInnis, director of pathogen genome surveillance at the Broad Institute.
It is almost certain that the evolutionary direction of the new coronavirus is still to spread better in specific environments, but experts cannot predict whether its level of danger will increase or decrease at the individual level. Last month, three experts wrote in a review published in the journal Nature, "There is a persistent but unproven legend that evolution around pathogens says that viruses change over time and their toxicity decreases." Experts warn that the low severity of Omilon may be just a coincidence, "Unfortunately, future variants can both be reinfected by immune escape and have high virulence, and the prospect of having such a catastrophic combination is very real." ”
In short: Omi kerong may just be an accident, and it is still unknown whether the future virulence of the new crown virus is strong or weak.
What will the wave summit of the future epidemic look like
During the pandemic, many predictions were made; as it turned out, many were wildly wrong. We want to avoid adding another false prediction, but perhaps this is certain: from a viral standpoint, the pandemic is not over.
What is currently seen shows that as people gain more immunity to COVID-19 through vaccination, infection or both, the incidence of serious complications, hospitalization rates and mortality rates drop dramatically. At this stage, it is mainly those who refuse to be vaccinated who are dying. If this continues, hospitalizations and deaths will continue, even if there will still be waves of infections in the future, but it will not be able to reach the scale before the vaccine was introduced.
John Moore, a virologist at The Well Cornell School of Medicine, said, "I don't think we're going to get a clean ending, in Trump's words, 'the virus will suddenly go away,'" but it could be a nuisance rather than a crisis. ”
For reference, more than 90,000 people in the United States have died of COVID-19 since the beginning of February.
Because of its highly contagious nature, he believes the future of COVID-19 could lead to about 60,000 deaths a year in the United States, which is equivalent to the number of deaths caused by a very severe flu season.
There is also the question of the shape of the future coronavirus curve. Some experts believe that COVID-19 will eventually become like other respiratory viruses, surging in the fall and winter before falling to very low levels in the remaining seasons. It is also possible that there will be geographical differences in this seasonal pattern, with the South experiencing one wave of peaks in the summer, as in the past two summers, and more peaks in the North as temperatures drop.
Although the spread of viruses like the flu drops to very low levels in the off-season, there is a frightening possibility: the new crown virus is too contagious and may not stop at all times of the year. Stephen Kissler, an epidemiologist at the Harvard School of Public Health, said that if there are thousands of cases a day, it means "we're going to be dealing with this all the time of the year, except that there are noticeable ups and downs in different places at different times."
Many of the experts we interviewed agreed that the most likely evolution of COVID-19 is its eventual transformation into a still-bad but manageable virus. But in mid-February, Donald Burke, former dean of the University of Pittsburgh's Graduate School of Public Health, listed several trickier paths the coronavirus could take, including evolving to attack other organs rather than the respiratory tract, or the emergence of so-called ADE (antibody-dependent enhancement) effects, in which antibodies produced in the body may enhance the body's ability to infect after natural immunization or vaccination, resulting in a heavier virus. Burke is the kind of expert that other experts will pay attention to, but not very pleased, and when people hear his warnings, there will always be people on Twitter who complain. "I don't like to read the stuff he said," said Marion Pepper, an associate professor and interim chair of the Department of Immunology at the University of Washington.
"I think now in addition to having a few layers of immunity, we know how to deal with it better," she said.
In short: we are safe for the time being, but we cannot rule out that there will be worse situations in the future.
If you've never had COVID-19,
How worried should you be right now?
University of Washington professor Marion Pepper contracted COVID-19 about seven weeks ago; so did her husband and two children. She had been fully vaccinated and given booster injections, and she described the symptoms she had as the equivalent of a cold or flu. As someone who thinks we're all going to get COVID-19 sooner or later, Pepper admits, she thought, "At least I don't have to pay attention to it anymore." But she also said that if it is really inevitable, then the later the infection, the better. "Since the future can't be predicted, maybe a milder strain can emerge that you can get better immunity while exposing to that strain," she said. ”
Pepper and her team's research also found that if infected with COVID-19 before being vaccinated, it can bring a so-called "mixed" immunity, which is more extensive than infection alone or vaccination. However, this work was done before the Opmi-Kron outbreak, and it's unclear whether infecting the Ami-Keron variant before vaccinating it will cause the same reaction. Pepper said her team plans to study this and will see if the same effect can occur in people who develop breakthrough infections after being vaccinated first.
If people with mixed immunity are stronger than those who only get vaccinated, should the latter be worried now? Several experts interviewed by STAT said that there is no need to worry.
"It's very much a matter of personal attitudes, and I see no reason to go out and get the virus for the sake of 'boosting immunity,' which is not an effective method, and its side effects will be more severe than any vaccine dose," said Moore from The Cornell School of Medicine in Weill, New York.
John Wherry, director of the University of Pennsylvania's Institute of Immunology, said that if it was Aumicron who was infected first, it may not give people a useful immune weapon later. "In previously unvaccinated individuals, Omilon infection seems to have a hard time inducing antibodies that can effectively cross neutralize and other variants," he said. ”
When we talk about immunization, you might be wondering how long it can last. This question cannot be answered for the time being. What can be seen is that the levels of antibodies brought about by the mRNA vaccine can drop rapidly, and these low levels of antibodies can lead to breakthrough infections. But vaccines don't just neutralize antibodies; in most cases, other aspects of the immune response produced by vaccines — the protection produced by B cells and T cells — seem to be fighting off serious diseases. As Moore puts it, "I think the protection against the worst consequences of COVID-19 will last for quite some time." ”
In summary: If both infection and vaccination are given, immunity may explode for a period of time, but how long immunity can last is still uncertain.
How the virus spreads from person to person
Remember the first few months of the outbreak, you washed your hands frequently, and thoroughly disinfected when you received takeaways and couriers? It is now clear that contaminated surfaces are rarely to blame. Instead, COVID-19 is spread primarily through most invisible streams of respiratory particles that are released by everyone as they talk, sing, sneeze, cough, and breathe. It can survive in the tiniest particles, called aerosols, that can stay in stationary indoor air for hours and be sucked into the deepest parts of the lungs.
But how much of the coronavirus is caused by these aerosols, and how much is caused by the large particles that spew out, is a question that still cannot be answered simply. Linsey Marr, an environmental engineer at Virginia Tech and one of the world's leading scientists studying airborne viruses, said: "If two people are close to each other and one of them is infected, it is impossible to tell whether it is due to contact with each other, inhalation of aerosols, or being sprayed by larger droplets." ”
What is certain is that aerosols are small in size, but their virulence should not be underestimated. Malr and her collaborators, as well as the University of Maryland, found that there are more viruses inside small particles than inside larger particles. They also found that the coronavirus evolved to be better at getting into smaller particles.
It's not ethical to let people actively contract COVID-19, but a recent trial is looking at how the flu spreads, hoping to provide more explanation for COVID-19 as well. In the trial, a group of people recently diagnosed with the flu stayed in quarantine hotels with healthy volunteers for two weeks to see what would happen. The main purpose of the experiment was to understand the extent to which the virus was transmitted by inhalation of aerosols and to what extent it was through splashing and touching contaminated surfaces.
Knowing this can help people better protect against various respiratory infectious diseases such as colds, flu and new crown. Devices such as ventilation and the installation of fresh air or air purifiers can remove the smallest aerosols from the room, but they have less effect on larger, heavier particles. Surgical masks can block those larger particles, but not very well against aerosols. N95 and similar grade masks (such as KN95 and KF94 masks) can block these two particles, but they are more expensive, and not everyone can wear them all the time, nor may they be tightly worn.
In short: it may have been wrong for people to focus on sanitize; now people are focusing on avoiding the large particles of coughing from speech, which may not be comprehensive.
We're going to get better vaccines,
Treatments and tests
Do you want to hear good news or bad news first?
The good news is that the emergency caused by the pandemic has enabled researchers to rapidly develop many different types of vaccines, effective viral treatments, and new rapid testing methods. The bad news is that new alternatives to the first wave of technology may be harder to bring to market unless there is a major change in the way society funds research, or the coronavirus evolves to the point where existing therapies no longer work.
It is hard to imagine further innovation in diagnostics. Yes, there will be new technologies, such as the recent coronavirus test that can detect the virus by breathing. But the big problem with testing has to do with infrastructure, not technology.
In the case of vaccines, the situation is much more complicated, but the rationale is the same. The vaccine technologies currently available are supported by large-scale clinical trials, and they have been injected into hundreds of millions of people, giving doctors a good idea of their safety and side effects. There are vaccines that failed to catch up with the first batch, such as Sanofi-Gramson's vaccine and Nova Vacus's vaccine, which is currently awaiting approval from the U.S. Food and Drug Administration. But new vaccines will face a difficult process in terms of approval and demand.
Still, developing other better, longer-lasting vaccines is a major effort. At a recent meeting of the FDA's advisory panel, Ofer Levy, director of the Precision Vaccine Program at Boston Children's Hospital, called on society to recognize that the vaccines we have, while miraculous, should not be considered the ultimate vaccine. He hopes the vaccine will create broader immunity to the new coronavirus strain.
When it comes to therapeutics, this piece of news is perhaps the brightest. Indeed, with the advent of new strains, monoclonal antibodies have lost their potency as the first effective drugs developed against the new coronavirus. But companies like Eli Lilly and Regeneron are developing new monoclonal drugs. What's more, Pfizer's oral drug Paxlovid will be more widely used in the second half of this year. So far, it has been effective against all the strains we've seen.
Many drugs have been found to be effective in suppressing an overactive immune system, including the steroid dexamethasone and the arthritis drugs Actemra and baricitinib. Evidence is also being gathered for a number of new treatments, including a drug called peginterferon and the antidepressant fluvoxamine.
In short: there may be more drugs and vaccines in the future, but whether more tests will emerge is more of a question of social and political will.
Regarding the sequelae of COVID-19,
When will a better understanding be built?
Scientists from multiple disciplines are understanding why some people continue to develop symptoms after contracting COVID-19. Virologists are turning their HIV expertise to the coronavirus, neuroscientists are trying to explain the cognitive and physical disruptions they see in rehabilitation clinics, and immunologists are combing through inflammation and autoimmune responses.
The trail has three main branches that may or may not converge. A basic theory is autoimmunity, where the body begins to attack itself after infection. Studies or people with myalgic encephalomyelitis or other post-viral syndromes have found that people with COVID-19 sequelae experience symptoms similar to their symptoms.
Another possible suspicion is chronic inflammation, which is a persistent, overreactive response to infection. Abnormal blood clotting, especially microclots, is caused by inflammation. When the first wave of flu swept through hospitals in New York City and Italy, doctors noticed unusual blood clots that prompted them to start giving anticoagulants to admitted patients.
The third suspected cause is the persistence of the virus, which remains dormant in a hidden reservoir after the body has defeated the acute infection. For example, in some Ebola patients, viral particles are still found in the central nervous system, testicles, or eyes years later.
Since there are no recognized biomarkers and no imaging tests, only people's sensations and functions are measured. Many experts agree that it is time for pharmaceutical companies to test their compounds against the sequelae of COVID-19. Reuters first reported that GlaxoSmithKline, Vir Biotechnology and Humanigen discussed with researchers trials to treat the sequelae of COVID-19 using their current treatments. Pfizer and Roche have also expressed interest.
So, how long will it take for us to learn about COVID-19?
Steven Deeks, an AIDS expert at the University of California, San Francisco, said, "We're at this stage of scientific adventure where we have a large group of people with sequelae, but there are also many who don't." The rate of progress compared to what we have experienced in AIDS research is quite impressive. People now want an answer on how to make themselves feel better. We haven't yet, but we're certainly making progress now faster than I expected. ”
In short: there are not many answers as to who has sequelae, why they do, and how to treat them.
Source of this article: STAT; Translation: Juan