When the pharmaceutical industry scrambled to develop the first COVID vaccines back in 2020, it made sense that developers focused on the part of the virus that allows it to grab onto and infect our cells: the spike proteins.
The best vaccines contain a piece of the spike, or genetic data about the spike, either of which can spur an immune response. Not to be outdone, the virus has been mutating—with many of the changes occurring on that same spike.
But other parts of the virus are changing, too. Now, for the first time, a team of scientists has scrutinized these changes—and voiced a warning.
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“With each major variant that has been identified, we are seeing mutations outside of [the] spike that we are trying to figure out,” Matthew Frieman, a University of Maryland School of Medicine immunologist and microbiologist and lead author of the new study, told The Daily Beast.
It’s possible the virus is accumulating non-spike mutations in an attempt to gain some advantage over our collective immunity as the COVID pandemic grinds toward its fourth year. These new mutations might not make the virus more infectious the way spike mutations do, but they could be associated with longer infections.
If this trend continues—and there’s no reason to believe it won’t—we might eventually need new antiviral drugs and new vaccine formulations that aren’t so specifically focused on the spike.
Vaccine developers weren’t wrong to focus their initial efforts on the spike protein, Frieman and his co-authors explained in their peer-reviewed study, which was published in Proceedings of the National Academy of Sciences and appeared online on Tuesday. “The spike protein is the immunodominant antigen,” they wrote. In other words, it’s the part of the virus most likely to produce a strong immune response.
Moreover, the major variants and subvariants of SARS-CoV-2—Delta then the various forms of Omicron including BA.4 and BA.5—have piled up mutations on the spike. As the spike evolves, the virus gets better and better at grabbing onto our cells despite the presence of antibodies.
That’s one reason why the vaccines have been getting somewhat less effective, and we’re seeing more and more breakthrough cases in vaccinated people. And it should come as no surprise that one of the leading contenders for the next dominant subvariant, a spinoff of Omicron called BA.4.6, features a particularly worrying mutation on the spike called R346T.
But there have been hints that non-spike mutations are becoming a bigger factor, too. Geneticists noted that BA.5, currently the dominant subvariant, doesn’t just have mutations along its spike—it features changes all across its structure.
There had to be a reason for those mutations, Frieman explained. “Viruses don’t do things by accident.” Instead, they try out small changes, over and over, until some combination of changes helps it survive and spread. The resulting variant or subvariant then outcompetes other forms of the pathogen until it becomes dominant—and the likely basis for the next set of mutations.
To understand the reason for, and effects of, the non-spike mutations, Frieman’s team cloned SARS-CoV-2 then started deleting the spike proteins and testing the resulting “deletion viruses” on mice, assessing how contagious the viruses were and how severe the infections were.
Their conclusion? “Mutations outside of [the] spike may be driving critical phenotypes of SARS-CoV-2 infection and disease.” That is to say, changes beyond the spike are beginning to define the virus.
For now, it seems the spike and non-spike mutations are working together. The spike mutations make the virus steadily more contagious. “Mutations in [the] spike have been identified in every major variant that then out-competes the previous variant,” Frieman explained.
Meanwhile, the non-spike mutations appear to prolong infection. This in turn gives the pathogen more time to mutate inside a particular person, and also spread to other people. “We hypothesize that this balance is critical for further evolution of SARS-CoV-2,” Frieman’s team wrote.
As the virus continues trying out mutations in order to stay ahead of our spike-focused immunity, it might further emphasize changes beyond the spike. BA.5, with its wide breadth of mutations, is a sign that’s already happening.
Take this as an urgent call for further study of non-spike mutations. “As more variants emerge, we will identify additional mutations outside of [the] spike that contribute significantly to viral replication, transmission and pathogenesis,” Frieman and his coauthors wrote.
Frieman said his goal is to scrutinize these non-spike mutations in order to “figure out what they do, how they do it [and] why they make the virus better at being a virus.” “Then we can use that information to make drugs,” including new antiviral therapies and vaccine formulations.
Speed matters. The Omicron variant and its rapid-fire subvariants, each coming just a couple months after the last, was a warning that our pharmaceutical research-and-development processes might be too slow. Note that the U.S. Food and Drug Administration just last week green-lit Omicron-specific vaccine boosters—a full 10 months after the initial Omicron variant first became dominant. “Omicron and its lineages”—another term for subvariants—“taught us a lesson for the need to be more agile in modifying the vaccine,” Ali Mokdad, a professor of health metrics sciences at the University of Washington Institute for Health, told The Daily Beast.
That problem could get worse if the rate of non-spike mutations accelerates. Our vaccine R&D is too slow even when it’s narrowly focused on the spike. What happens when it needs to broaden its scope to combat a virus that’s learning to mutate across its structure?
There’s another wrinkle. These accumulating mutations across the novel-coronavirus—on the spike and not on the spike—could start to mess with the polymerase chain-reaction tests we use to detect and track the virus.
PCR tests and sequencing use primers tailored for a certain range of viral characteristics. Too many mutations “can mess with the PCR test,” Niema Moshiri, a geneticist at the University of California-San Diego, told The Daily Beast.
Pay attention, but don’t panic. It’s really no surprise that SARS-CoV-2 is trying out mutations on different parts of the virus. That’s what viruses do—adapt. The trick for us, the novel-coronavirus’s host, is to adapt at least as quickly.
We did it before by rapidly developing vaccines and therapies targeting the most dangerous part of the virus. We can do it again as the virus finds new ways to evolve. It just takes political will… and money.
