Should We Be Worried About the Coronavirus Mutating?
A study looks at one mutation that might make it more transmissible. Overall, it appears that SARS-CoV-2 mutates less than influenza.
On July 2, researchers from Los Alamos Laboratory released a new study in Cell—a highly influential journal in the scientific community—that examines whether a particular mutation of the coronavirus increases the virus’ transmission rate. Of primary concern to the study’s authors is the G614 mutation on the spike protein of the coronavirus, the protein responsible for invading host cells. The authors contend that this mutation began circulating throughout Europe in early February and began displacing the D614 form of the virus that originated in Wuhan, China. According to the study, this G614 variant possesses a higher transmission rate, results in a higher viral load, and consistently becomes the dominant form of the virus wherever it spreads.
Understanding how a virus is mutating is important for several reasons. Do mutations make the virus more dangerous, as described above? If there are different strains, will they respond to treatments differently, or target different segments of the population? And what does it all mean for having an effective vaccine?
While some researchers immediately embraced this study as a clear indicator that this particular mutation is increasing the virus’ transmissibility rate, others are less convinced. Dr. Raul Andino-Pavlovsky, a professor of microbiology and immunology at the University of California at San Francisco, called the spike protein mutation findings “intriguing,” but told The Dispatch “it may be a little too early to say that [these mutations] are being selected.” Dr. William Schaffner, an infectious disease specialist at the Vanderbilt University Medical Center, told us “it is too early to draw those conclusions.”
Other scientists suggest that gene sequencing studies focus too much on singular mutations when there’s so much about the virus we still don’t know. “People who are writing papers about sequence variation want to highlight the variation that they find because that’s how they’re going to publish the paper,” said Dr. Colin Parrish, a professor of virology at Cornell University. Excessive gene sequencing for the coronavirus has already become the norm, meaning that moving forward, researchers will continue talking about mutations “as if they're more important than they may well be.”
According to Parrish, “There are a hundred people doing sequencing for every one person that’s doing biology or actually going back and testing mutations for their real effect on the virus’ replication.” But even if particular mutations are unlikely to change viral behavior, tracing a virus’ lineage—or phylogeographic variation—can be helpful from a public health point of view. “There are sufficient mutations so that virologists can track the lineage of the virus,” Schaffner said, meaning “they can distinguish the viruses that probably came to the U.S. from Europe from those that came to us from Asia.”
What makes this mutation worth highlighting? According to Bette Korber, the study’s leading author, the coronavirus is shifting toward the “G clade” form (which refers to the particular descendant of SARS-CoV-2 that contains the G614 mutation on the virus’ spike protein). This mutation, she claims, is not due to random chance, but rather a fitness advantage.
She explains that random things, like superspreader events or human hosts moving into new regions, “are by definition just that, random.” So, if the two forms were equally likely to propagate,” she said, “you wouldn’t expect such a shift to almost always go in one direction, towards higher frequency G clade.” The repetition of this particular pattern in nearly all of the locations they studied—with few exceptions—is what Korber and her colleagues “found to be compelling evidence of positive selection,” meaning a mutation that improves the overall fitness of the virus.
Before jumping to conclusions, it’s worth mentioning that viral mutations are a normal part of the evolutionary process. Every time a virus infects a new host, it takes over the host’s replication machinery to reproduce billions of genetic copies of itself so that the virus can spread to other cells. When viruses reproduce, they will inevitably make mistakes—mutations—that become incorporated into the viral genome. Whereas DNA viruses—such as smallpox and HPV—have a low mutation rate, RNA viruses regularly mutate. According to Parrish, most of these RNA mutations “decrease the fitness of the virus and so they generally get purged from the virus over time.”
But some phylogenetic patterns accumulate over time, creating new lineages within the virus’ evolutionary tree. In a process called genetic drift, some mutations cause the frequency of an existing gene variant within a particular population to change over time by chance alone. Of course, not all of these fixed mutations from genetic drift confer evolutionary benefits to the virus.
If, however, mutations do provide an advantage to the virus, then they will be selected for, meaning they will be more likely to replicate and transmit over time. These adaptive mutations—which are essentially happy accidents from a virus’ point of view—often take the form of improving transmissibility and resistance to antiviral drugs like remdesivir. Selective mutations can also change a virus’ antigenic properties, allowing it to cause disease in formerly resistant hosts, or its “pathogenicity,” meaning its ability to infect and harm its host in the first place.
But how do we know when a new mutation constitutes a new viral strain? “In our original preprint we used the word ‘strain’ to refer to viruses that carried the G614D,” Korber told The Dispatch. She said this term was rejected by many other scientists who said the word “strain” should be used more judiciously. For example: Only if the genetic variant is associated with unique phenotypic characteristics that are different from the compared reference virus.”
“If you call it a new strain then there’s zillions of new strains out there because almost every virus will have some mutation that may or may not be of any importance,” said Dr. Diane Griffin, a professor in the department of molecular microbiology and immunology at the
Johns Hopkins Bloomberg School of Public Health. Typically, a strain refers to a mutation that is similar enough to be part of the same species of virus but deserves some degree of differentiation because it behaves differently. One way to determine whether a mutation constitutes a strain is to see if it confers functional differences in terms of its virulence, resistance, or transmissibility. Scientists can also look at phenotypic variation between mutations, including its reproductive capabilities, increased titers, or survival rate.
“We don’t have any evidence for greater or lesser virulence,” said Dr. Paul Offit—director of the Vaccine Education Center at Children’s Hospital of Philadelphia—regarding G614 mutation, “but I think there is reasonable evidence for increased transmissibility.” Still, this functional difference does not necessarily constitute a new strain. “It’s tricky because essentially you're always making strains,” he added.
Looking beyond the specific mutation the study’s authors cite, it’s important to consider how often a virus mutates. Whereas some viruses—like polio, HIV and influenza—are constantly mutating, other viruses remain stable over long stretches of time. Influenza is a single stranded RNA virus that serves as a perfect example of what scientists call a very “plastic” virus. The flu mutates so much from one year to the next that natural infection or immunization from the previous year does not typically protect individuals from the functional mutation of the new virus, hence the need for a new vaccine each year. Sometimes there is a carry-over effect, although this is quite rare.
But other viruses, like measles, hardly mutate at all. “The essential measles virus is the same virus that was around in 1934, just to pick a number out of the hat,” said Schaffner. “It’s pretty darn stable, and that’s why we have one measles vaccine. It works around the world, it’s worked for 50 years, and it’s going to keep working because this is a very stable virus.”
SARS-CoV-2 is somewhere in the middle. According to Diana Griffin, coronaviruses “have some editing function, but they still have an error prone polymerase.” This means that unlike most other RNA viruses, coronaviruses have some capacity to identify errors while copying nucleic material, thus reducing the mutation rate. Because of its low mutation rate, SARS-CoV-2 has remained generally stable, which is a good sign for vaccine research.
“This is very important.” Schaffner said, “particularly as regards the now notorious spike protein on its surface, because that means all this vaccine work that’s going on around the world is more likely to result in successful vaccines, because the virus, unlike flu, is not mutating in its essence.” Whereas many vaccines undergoing trial tests are targeting the coronavirus’ spike protein in particular, scientists are also developing RNA vaccines, DNA vaccines, viral vector vaccines, and recombinant vaccines, among others, which target other parts of the virus.
It is possible that after a long period of time—say, 10 to 20 years—the virus may vary sufficiently such that it can start to evade the vaccines that we make now. But there is some good news about the mutation that is the subject of the Cell study. As much as it might be increasing transmission rate, “the G614 form is actually more sensitive to neutralizing antibodies,” said Korber. This means that even if the G614 mutation continues to spread, a vaccine targeting it will likely be extremely effective.
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