COVID Variants Are Like “a Thief Changing Clothes” – and Our Camera System Barely Exists
Being able to track variants of concern in real time is crucial to our ability to stay ahead of the virus.
Whether it's "natural selection" as Darwin called it, or it's "mutating" as the X-Men called it, living organisms change over time, developing thumbs or more efficient protein spikes, depending on the organism and the demands of its environment. The coronavirus that causes COVID-19, SARS-CoV-2, is not an exception, and now, after the virus has infected millions of people around the globe for more than a year, scientists are beginning to see those changes.
The notorious variants that have popped up include B.1.1.7, sometimes called the UK variant, as well as P.1 and B.1.351, which seem to have emerged in Brazil and South Africa respectively. As vaccinations are picking up pace, officials are warning that now
is not the time to become complacent or relax restrictions because the variants aren't well understood.
Some appear to be more transmissible, and deadlier, while others can evade the immune system's defenses better than earlier versions of the virus, potentially undermining the effectiveness of vaccines to some degree. Genomic surveillance, the process of sequencing the genetic code of the virus widely to observe changes and patterns, is a critical way that scientists can keep track of its evolution and work to understand how the variants might affect humans.
"It's like a thief changing clothes"
It's important to note that viruses mutate all the time. If there were funding and personnel to sequence the genome of every sample of the virus, scientists would see thousands of mutations. Not every variant deserves our attention. The vast majority of mutations are not important at all, but recognizing those that are is a crucial tool in getting and staying ahead of the virus. The work of sequencing, analyzing, observing patterns, and using public health tools as necessary is complicated and confusing to those without years of specialized training.
Jeremy Kamil, associate professor of microbiology and immunology at LSU Health Shreveport, in Louisiana, says that the variants developing are like a thief changing clothes. The thief goes in your house, steals your stuff, then leaves and puts on a different shirt and a wig, in the hopes you won't recognize them. Genomic surveillance catches the "thief" even in those different clothes.
One of the tricky things about variants is recognizing the point at which they move from interesting, to concerning at a local level, to dangerous in a larger context.
Understanding variants, both the uninteresting ones and the potentially concerning ones, gives public health officials and researchers at different levels a useful set of tools. Locally, knowing which variants are circulating in the community helps leaders know whether mask mandates and similar measures should be implemented or discontinued, or whether businesses and schools can open relatively safely.
There's more to it than observing new variants
Analysis is complex, particularly when it comes to understanding which variants are of concern. "So the question is always if a mutation becomes common, is that a random occurrence?" says Phoebe Lostroh, associate professor of molecular biology at Colorado College. "Or is the variant the result of some kind of selection because the mutation changes some property about the virus that makes it reproduce more quickly than variants of the virus that don't have that mutation? For a virus, [mutations can affect outcomes like] how much it replicates inside a person's body, how much somebody breathes it out, whether the particles that somebody might breathe in get smaller and can lead to greater transmission."
Along with all of those factors, accurate and useful genomic surveillance requires an understanding of where variants are occurring, how they are related, and an examination of why they might be prevalent.
For example, if a potentially worrisome variant appears in a community and begins to spread very quickly, it's not time to raise a public health alarm until several important questions have been answered, such as whether the variant is spreading due to specific events, or if it's happening because the mutation has allowed the virus to infect people more efficiently. Kamil offered a hypothetical scenario to explain: Imagine that a member of a community became infected and the virus mutated. That person went to church and three more people were infected, but one of them went to a karaoke bar and while singing infected 100 other people. Examining the conditions under which the virus has spread is, therefore, an essential part of untangling whether a mutation itself made the virus more transmissible or if an infected person's behaviors contributed to a local outbreak.
One of the tricky things about variants is recognizing the point at which they move from interesting, to concerning at a local level, to dangerous in a larger context. Genomic sequencing can help with that, but only when it's coordinated. When the same mutation occurs frequently, but is localized to one region, it's a concern, but when the same mutation happens in different places at the same time, it's much more likely that the "virus is learning that's a good mutation," explains Kamil.
The process is called convergent evolution, and it was a fascinating topic long before COVID. Just as your heritage can be traced through DNA, so can that of viruses, and when separate lineages develop similar traits it's almost like scientists can see evolution happening in real time. A mutation to SARS-CoV-2 that happens in more than one place at once is a mutation that makes it easier in some way for the virus to survive and that is when it may become alarming. The widespread, documented variants P.1 and B.1.351 are examples of convergence because they share some of the same virulent mutations despite having developed thousands of miles apart.
However, even variants that are emerging in different places at the same time don't present the kind of threat SARS-CoV-2 did in 2019. "This is nature," says Kamil. "It just means that this virus will not easily be driven to extinction or complete elimination by vaccines." Although a person who has already had COVID-19 can be reinfected with a variant, "it is almost always much milder disease" than the original infection, Kamil adds. Rather than causing full-fledged disease, variants have the potiental to "penetrate herd immunity, spreading relatively quietly among people who have developed natural immunity or been vaccinated, until the virus finds someone who has no immunity yet, and that person would be at risk of hospitalization-grade severe disease or death."
Surveillance and predictions
According to Lostroh, genomic surveillance can help scientists predict what's going to happen. "With the British strain, for instance, that's more transmissible, you can measure how fast it's doubling in the population and you can sort of tell whether we should take more measures against this mutation. Should we shut things down a little longer because that mutation is present in the population? That could be really useful if you did enough sampling in the population that you knew where it was," says Lostroh. If, for example, the more transmissible strain was present in 50 percent of cases, but in another county or state it was barely present, it would allow for rolling lockdowns instead of sweeping measures.
Variants are also extremely important when it comes to the development, manufacture, and distribution of vaccines. "You're also looking at medical countermeasures, such as whether your vaccine is still effective, or if your antiviral needs to be updated," says Lane Warmbrod, a senior analyst and research associate at Johns Hopkins Center for Health Security.
Properly funded and extensive genomic surveillance could eventually help control endemic diseases, too, like the seasonal flu, or other common respiratory infections. Kamil says he envisions a future in which genomic surveillance allows for prediction of sickness just as the weather is predicted today. "It's a 51 for infection today at the San Francisco Airport. There's been detection of some respiratory viruses," he says, offering an example. He says that if you're a vulnerable person, if you're immune-suppressed for some reason, you may want to wear a mask based on the sickness report.
The U.S. has the ability, but lacks standards
The benefits of widespread genomic surveillance are clear, and the United States certainly has the necessary technology, equipment, and personnel to carry it out. But, it's not happening at the speed and extent it needs to for the country to gain the benefits.
"The numbers are improving," said Kamil. "We're probably still at less than half a percent of all the samples that have been taken have been sequenced since the beginning of the pandemic."
Although there's no consensus on how many sequences is ideal for a robust surveillance program, modeling performed by the company Illumina suggests about 5 percent of positive tests should be sequenced. The reasons the U.S. has lagged in implementing a sequencing program are complex and varied, but solvable.
Perhaps the most important element that is currently missing is leadership. In order to conduct an effective genomic surveillance program, there need to be standards. The Johns Hopkins Center for Health Security recently published a paper with recommendations as to what kinds of elements need to be standardized in order to make the best use of sequencing technology and analysis.
"Along with which bioinformatic pipelines you're going to use to do the analyses, which sequencing strategy protocol are you going to use, what's your sampling strategy going to be, how is the data is going to be reported, what data gets reported," says Warmbrod. Currently, there's no guidance from the CDC on any of those things. So, while scientists can collect and report information, they may be collecting and reporting different information that isn't comparable, making it less useful for public health measures and vaccine updates.
Globally, one of the most important tools in making the information from genomic surveillance useful is GISAID, a platform designed for scientists to share -- and, importantly, to be credited for -- their data regarding genetic sequences of influenza. Originally, it was launched as a database of bird flu sequences, but has evolved to become an essential tool used by the WHO to make flu vaccine virus recommendations each year. Scientists who share their credentials have free access to the database, and anyone who uses information from the database must credit the scientist who uploaded that information.
Safety, logistics, and funding matter
Scientists at university labs and other small organizations have been uploading sequences to GISAID almost from the beginning of the pandemic, but their funding is generally limited, and there are no standards regarding information collection or reporting. Private, for-profit labs haven't had motivation to set up sequencing programs, although many of them have the logistical capabilities and funding to do so. Public health departments are understaffed, underfunded, and overwhelmed.
University labs may also be limited by safety concerns. The SARS-CoV-2 virus is dangerous, and there's a question of how samples should be transported to labs for sequencing.
Larger, for-profit organizations often have the tools and distribution capabilities to safely collect and sequence samples, but there hasn't been a profit motive. Genomic sequencing is less expensive now than ever before, but even at $100 per sample, the cost adds up -- not to mention the cost of employing a scientist with the proper credentials to analyze the sequence.
The path forward
The recently passed COVID-19 relief bill does have some funding to address genomic sequencing. Specifically, the American Rescue Plan Act includes $1.75 billion in funding for the Centers for Disease Control and Prevention's Advanced Molecular Detection (AMD) program. In an interview last month, CDC Director Rochelle Walensky said that the additional funding will be "a dial. And we're going to need to dial it up." AMD has already announced a collaboration called the Sequencing for Public Health Emergency Response, Epidemiology, and Surveillance (SPHERES) Initiative that will bring together scientists from public health, academic, clinical, and non-profit laboratories across the country with the goal of accelerating sequencing.
Such a collaboration is a step toward following the recommendations in the paper Warmbrod coauthored. Building capacity now, creating a network of labs, and standardizing procedures will mean improved health in the future. "I want to be optimistic," she says. "The good news is there are a lot of passionate, smart, capable people who are continuing to work with government and work with different stakeholders." She cautions, however, that without a national strategy we won't succeed.
"If we maximize the potential and create that framework now, we can also use it for endemic diseases," she says. "It's a very helpful system for more than COVID if we're smart in how we plan it."
Catching colds may help protect kids from Covid
A new study shows that the immune system's response to colds can help prepare it to defend against COVID-19 - but only in the very young.
A common cold virus causes the immune system to produce T cells that also provide protection against SARS-CoV-2, according to new research. The study, published last month in PNAS, shows that this effect is most pronounced in young children. The finding may help explain why most young people who have been exposed to the cold-causing coronavirus have not developed serious cases of COVID-19.
One curiosity stood out in the early days of the COVID-19 pandemic – why were so few kids getting sick. Generally young children and the elderly are the most vulnerable to disease outbreaks, particularly viral infections, either because their immune systems are not fully developed or they are starting to fail.
But solid information on the new infection was so scarce that many public health officials acted on the precautionary principle, assumed a worst-case scenario, and applied the broadest, most restrictive policies to all people to try to contain the coronavirus SARS-CoV-2.
One early thought was that lockdowns worked and kids (ages 6 months to 17 years) simply were not being exposed to the virus. So it was a shock when data started to come in showing that well over half of them carried antibodies to the virus, indicating exposure without getting sick. That trend grew over time and the latest tracking data from the CDC shows that 96.3 percent of kids in the U.S. now carry those antibodies.
Antibodies are relatively quick and easy to measure, but some scientists are exploring whether the reactions of T cells could serve as a more useful measure of immune protection.
But that couldn't be the whole story because antibody protection fades, sometimes as early as a month after exposure and usually within a year. Additionally, SARS-CoV-2 has been spewing out waves of different variants that were more resistant to antibodies generated by their predecessors. The resistance was so significant that over time the FDA withdrew its emergency use authorization for a handful of monoclonal antibodies with earlier approval to treat the infection because they no longer worked.
Antibodies got most of the attention early on because they are part of the first line response of the immune system. Antibodies can bind to viruses and neutralize them, preventing infection. They are relatively quick and easy to measure and even manufacture, but as SARS-CoV-2 showed us, often viruses can quickly evolve to become more resistant to them. Some scientists are exploring whether the reactions of T cells could serve as a more useful measure of immune protection.
Kids, colds and T cells
T cells are part of the immune system that deals with cells once they have become infected. But working with T cells is much more difficult, takes longer, and is more expensive than working with antibodies. So studies often lags behind on this part of the immune system.
A group of researchers led by Annika Karlsson at the Karolinska Institute in Sweden focuses on T cells targeting virus-infected cells and, unsurprisingly, saw that they can play a role in SARS-CoV-2 infection. Other labs have shown that vaccination and natural exposure to the virus generates different patterns of T cell responses.
The Swedes also looked at another member of the coronavirus family, OC43, which circulates widely and is one of several causes of the common cold. The molecular structure of OC43 is similar to its more deadly cousin SARS-CoV-2. Sometimes a T cell response to one virus can produce a cross-reactive response to a similar protein structure in another virus, meaning that T cells will identify and respond to the two viruses in much the same way. Karlsson looked to see if T cells for OC43 from a wide age range of patients were cross-reactive to SARS-CoV-2.
And that is what they found, as reported in the PNAS study last month; there was cross-reactive activity, but it depended on a person’s age. A subset of a certain type of T cells, called mCD4+,, that recognized various protein parts of the cold-causing virus, OC43, expressed on the surface of an infected cell – also recognized those same protein parts from SARS-CoV-2. The T cell response was lower than that generated by natural exposure to SARS-CoV-2, but it was functional and thus could help limit the severity of COVID-19.
“One of the most politicized aspects of our pandemic response was not accepting that children are so much less at risk for severe disease with COVID-19,” because usually young children are among the most vulnerable to pathogens, says Monica Gandhi, professor of medicine at the University of California San Francisco.
“The cross-reactivity peaked at age six when more than half the people tested have a cross-reactive immune response,” says Karlsson, though their sample is too small to say if this finding applies more broadly across the population. The vast majority of children as young as two years had OC43-specific mCD4+ T cell responses. In adulthood, the functionality of both the OC43-specific and the cross-reactive T cells wane significantly, especially with advanced age.
“Considering that the mortality rate in children is the lowest from ages five to nine, and higher in younger children, our results imply that cross-reactive mCD4+ T cells may have a role in the control of SARS-CoV-2 infection in children,” the authors wrote in their paper.
“One of the most politicized aspects of our pandemic response was not accepting that children are so much less at risk for severe disease with COVID-19,” because usually young children are among the most vulnerable to pathogens, says Monica Gandhi, professor of medicine at the University of California San Francisco and author of the book, Endemic: A Post-Pandemic Playbook, to be released by the Mayo Clinic Press this summer. The immune response of kids to SARS-CoV-2 stood our expectations on their head. “We just haven't seen this before, so knowing the mechanism of protection is really important.”
Why the T cell immune response can fade with age is largely unknown. With some viruses such as measles, a single vaccination or infection generates life-long protection. But respiratory tract infections, like SARS-CoV-2, cause a localized infection - specific to certain organs - and that response tends to be shorter lived than systemic infections that affect the entire body. Karlsson suspects the elderly might be exposed to these localized types of viruses less often. Also, frequent continued exposure to a virus that results in reactivation of the memory T cell pool might eventually result in “a kind of immunosenescence or immune exhaustion that is associated with aging,” Karlsson says. https://leaps.org/scientists-just-started-testing-a-new-class-of-drugs-to-slow-and-even-reverse-aging/particle-3 This fading protection is why older people need to be repeatedly vaccinated against SARS-CoV-2.
Policy implications
Following the numbers on COVID-19 infections and severity over the last three years have shown us that healthy young people without risk factors are not likely to develop serious disease. This latest study points to a mechanism that helps explain why. But the inertia of existing policies remains. How should we adjust policy recommendations based on what we know today?
The World Health Organization (WHO) updated their COVID-19 vaccination guidance on March 28. It calls for a focus on vaccinating and boosting those at risk for developing serious disease. The guidance basically shrugged its shoulders when it came to healthy children and young adults receiving vaccinations and boosters against COVID-19. It said the priority should be to administer the “traditional essential vaccines for children,” such as those that protect against measles, rubella, and mumps.
“As an immunologist and a mother, I think that catching a cold or two when you are a kid and otherwise healthy is not that bad for you. Children have a much lower risk of becoming severely ill with SARS-CoV-2,” says Karlsson. She has followed public health guidance in Sweden, which means that her young children have not been vaccinated, but being older, she has received the vaccine and boosters. Gandhi and her children have been vaccinated, but they do not plan on additional boosters.
The WHO got it right in “concentrating on what matters,” which is getting traditional childhood immunizations back on track after their dramatic decline over the last three years, says Gandhi. Nor is there a need for masking in schools, according to a study from the Catalonia region of Spain. It found “no difference in masking and spread in schools,” particularly since tracking data indicate that nearly all young people have been exposed to SARS-CoV-2.
Both researchers lament that public discussion has overemphasized the quickly fading antibody part of the immune response to SARS-CoV-2 compared with the more durable T cell component. They say developing an efficient measure of T cell response for doctors to use in the clinic would help to monitor immunity in people at risk for severe cases of COVID-19 compared with the current method of toting up potential risk factors.
In this week's Friday Five: The eyes are the windows to the soul - and biological aging?
Plus, what bean genes mean for health and the planet, a breathing practice that could lower levels of tau proteins in the brain, AI beats humans at assessing heart health, and the benefits of "nature prescriptions"
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on new scientific theories and progress to give you a therapeutic dose of inspiration headed into the weekend.
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Here are the stories covered this week:
- The eyes are the windows to the soul - and biological aging?
- What bean genes mean for health and the planet
- This breathing practice could lower levels of tau proteins
- AI beats humans at assessing heart health
- Should you get a nature prescription?