A new study has identified several possible mutations that could allow the virus to escape immune defenses, including natural immunity acquired from virus infection or vaccines, and antibody-based treatments.
The findings, published this week, could help researchers predict how SARS-CoV-2 may change as it continues to adapt to its human hosts, allowing public health officials and scientists to plan for possible future mutations.
Indeed, as the study was about to be published, a new strain of concern, Omicron, appeared on the scene and was later discovered to possess some of the antibody-evading changes anticipated by the researchers in the newly released report. Omicron has been found in 25 different countries across Africa, Asia, Australia, Europe, North and South America. The list is growing on a daily basis.
The research suggests that the outcomes are not directly applicable to Omicron because how this specific variant behaves will depend on the interaction of its own unique set of mutations — at least 30 in the viral spike protein — as well as how it competes with other active strains circulating in populations around the world. Nonetheless, the study provides vital insights regarding specific areas of concern with Omicron, as well as a primer on potential mutations that may occur in future versions, according to the researchers.
“Our findings suggest that great caution is advised with Omicron because these mutations have proven quite capable of evading monoclonal antibodies used to treat newly infected patients and antibodies derived from mRNA vaccines,” says Jonathan Abraham, study’s senior author.
The study did not look into viral protection against antibodies generated in response to non-mRNA vaccinations.
The more the virus replicates in humans, the more likely it may generate unique mutations that discover new methods to spread in the face of existing natural immunity, vaccinations, and therapies, according to Abraham.
This means that public health efforts to restrict the virus’s spread, including mass immunizations as quickly as possible around the world, are critical both to prevent illness and to reduce opportunities for the virus to mutate, according to Abraham.
According to the researchers, the findings underscore the need of continuous research into the potential future evolution of not only SARS-CoV-2 but also other diseases.
“To get out of this pandemic, we need to stay ahead of this virus, as opposed to playing catch-up,” says Katherine Nabel, co-lead authory.
“Our approach is unique in that instead of studying individual antibody mutations in isolation, we studied them as part of composite variants that contain many simultaneous mutations at once — we thought this might be where the virus was headed. Unfortunately, this seems to be the case with Omicron.”
Several studies have been conducted to investigate the mechanisms that have evolved in emerging dominant strains of SARS-CoV-2 that allow the virus to resist the protective capability of antibodies in order to prevent infection and serious sickness in persons who have been exposed to the virus.
Rather than waiting to see what the next new variant might bring, Abraham set out this summer to determine how potential future mutations might impact the virus’s ability to infect cells and evade immune defenses, working with colleagues from HMS, Brigham and Women’s, Massachusetts General Hospital, Harvard Pilgrim Health Care Institute, Harvard T.H. Chan School of Public Health, Boston University School of Medicine, and AbbVie Bioresearch Center.
The researchers investigated signs in the virus’s chemical and physical structure, as well as unusual mutations seen in immunocompromised people and in a global database of virus sequences, to predict how the virus would transform itself next. The researchers discovered combinations of several complicated alterations in lab-based investigations employing noninfectious virus-like particles that would allow the virus to infect human cells while lowering or neutralizing the protective ability of antibodies.
The study concentrated on the receptor-binding region of the coronavirus spike protein, which the virus uses to hook onto human cells. The spike protein permits the virus to enter human cells, where it begins self-replication and eventually infects.
Most antibodies work by attaching to the same spots on the virus’s spike protein receptor-binding domain to prevent it from latching onto cells and infecting them.
Mutation and evolution are natural parts of a virus’s life cycle. Every time a virus is replicated, there is a chance that a copy error – a genetic typo — may be introduced. When a virus is subjected to selective pressure from the host’s immune system, copy mistakes that allow the virus to avoid being inhibited by existing antibodies have a better chance of surviving and replicating.
Escape mutations are those that allow a virus to elude antibodies in this manner.
The researchers proved that the virus could generate a huge number of simultaneous escape mutations while still being able to bind to the receptors required to infect a human cell. To put this to the test, the researchers created pseudotypes, which are lab-made virus stand-ins formed by mixing harmless, noninfectious viruslike particles with portions of the SARS-CoV-2 spike protein harboring the probable escape mutations. The researchers discovered that pseudotypes with up to seven escape mutations are more resistant to neutralization by therapeutic antibodies and serum from mRNA vaccination recipients.
At the time the researchers began their work, this amount of sophisticated development had not been observed in common strains of the virus. With the emergence of the Omicron mutation, however, this level of complicated mutation in the receptor-binding domain is no longer speculative. The Delta variant has only two alterations in its receptor-binding region, but the pseudotypes studied by the team had up to seven mutations, and Omicron looks to have 15, according to Abraham, including several of the specific mutations that his team studied.
The researchers used biochemical assays and pseudotype testing to evaluate how antibodies would attach to spike proteins with escape mutations in a series of trials. Several alterations, including several reported in Omicron, allowed the pseudotypes to totally avoid therapeutic antibodies, even those used in monoclonal antibody cocktail therapy.
The team also discovered one antibody that efficiently neutralized all of the tested variations. They did remark, however, that if the spike protein developed a single mutation that added a sugar molecule at the place where the antibody binds to the virus, the virus would be able to bypass that antibody. In essence, this would prohibit the antibody from doing its function.
They highlighted that circulating strains of SARS-CoV-2 have been shown to acquire this mutation in rare cases. When this occurs, it is most likely due to immune system selection pressure, according to the researchers. Understanding the role of this unusual mutation, they added, is crucial for being better prepared before it becomes a dominant strain.
While they did not directly evaluate the pseudotype virus’s capacity to circumvent natural infection immunity, recent work by the team with variants containing fewer mutations suggests that these newer, highly altered forms will likewise adeptly elude antibodies acquired through natural infection.
The pseudotypes were also exposed to blood serum from people who had received an mRNA vaccine in another experiment. Serum from single-dose vaccine recipients completely lost the capacity to kill the virus for some of the highly altered strains. The vaccine retained at least some effectiveness against all variations, including some substantially altered pseudotypes, in samples taken from individuals who had received a second dose of vaccine.
The authors emphasize that their findings show that recurrent immunization, even with the original spike protein antigen, may be necessary to combat highly altered SARS-CoV-2 spike protein variants.
“This virus is a shape-shifter,” Abraham adds. “The great structural flexibility we saw in the SARS-CoV-2 spike protein suggests that Omicron is not likely to be the end of the story for this virus.”
Source: DOI: 10.1126/science.abl6251
Image Credit: Getty
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