“This Virus Is a Shape-Shifter!” – New Research Details How COVID Variants Are Evolving New Ways To Evade Vaccines

New study models future SARS-CoV-2 mutations and predicts their ability to evade immune defenses developed by vaccines and antibody-based treatments. Since the study was completed, several of the predicted mutations have appeared in omicron, the most recently identified SARS-CoV-2 variant, providing insight into how omicron may be able to escape the immune defenses generated by mRNA vaccines and monoclonal antibody treatments for COVID-19 . The researchers modeled their predictions of future mutations using a combination of variables, including rare mutations documented in immunocompromised patients, existing SARS-CoV-2 genotypes, and the current molecular structure and behavior of the virus. Findings highlight SARS-CoV-2’s ability to change shape, underscoring the likelihood of new variants harboring multiple high-risk mutations and being able to evade antibody-based treatments and vaccines. The study highlights the urgent need to curb viral evolution and future mutations through mitigation measures and ensure global immunity through mass vaccination.

In an effort to predict SARS-CoV-2’s future evolutionary maneuvers, a research team led by researchers at Harvard Medical School has identified several likely mutations that would allow the virus to evade immune defenses, including natural immunity that is acquired through infection and developed through vaccination and antibody-based treatments.

The study, published Dec. 2, 2021 in the journal Science as an accelerated release for immediate release, was designed to measure how SARS-CoV-2 might evolve as it continues to adapt to its human hosts while helping public health officials and scientists are preparing for future mutations.

Indeed, as the study neared publication, a new variant of concern called omicron came on the scene and was subsequently found to contain several of the antibody-evasive mutations the researchers predicted in the newly published paper. Since December 1, ommicron has been identified in 25 countries in Africa, Asia, Australia, Europe and the Americas, a list that is growing daily.

The researchers caution that the study results don’t directly apply to omicron, because how this particular variant behaves will depend on the interplay between its own unique set of mutations — at least 30 in the viral spike protein — and how it competes with others. active strains circulate in populations around the world. Nevertheless, the researchers said, the study provides important clues about certain areas of focus with omicron, as well as serving as a primer on other mutations that may appear in future variants.

“Our findings suggest that great caution should be exercised with omicron, as these mutations have been shown to be very capable of producing monoclonal antibodies used to treat newly infected patients and antibodies derived from mRNA vaccines,” said senior author Jonathan Abraham, assistant professor of microbiology in the Blavatnik Institute at HMS and an infectious disease specialist at Brigham and Women’s Hospital. The researchers did not study the response to antibodies developed from non-mRNA vaccines.

The longer the virus continues to multiply in humans, Abraham noted, the more likely it is to continue developing new mutations that develop new ways of spreading in the face of existing natural immunity, vaccines and treatments. That means public health efforts to prevent the spread of the virus, including mass vaccinations worldwide as soon as possible, are critical, both to prevent disease and to reduce the chances for the virus to develop. said Abraham.

The findings also highlight the importance of ongoing anticipatory research into the possible future evolution of not only SARS-CoV-2, but other pathogens as well, the researchers said.

“To get out of this pandemic, we need to stay ahead of this virus, rather than catch up,” said lead author Katherine Nabel, a fifth-year student at the Harvard/MIT MD-PhD program. “Our approach is unique in that instead of studying individual antibody mutations individually, we studied them as part of compound variants that contain many simultaneous mutations at once — we thought that might be the direction of the virus. Unfortunately, this seems to be the case with ommicron.” to be.”

Many studies have looked at the mechanisms developed in newly dominant SARS-CoV-2 strains that allow the virus to resist the protective power of antibodies to prevent infection and serious disease.

Last summer, instead of waiting to see what the next new variant might bring, Abraham set out to determine how possible future mutations could affect the virus’ ability to infect cells and evade immune defenses – work he did. did in collaboration with colleagues from HMS, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Pilgrim Health Care Institute, Harvard TH Chan School of Public Health, Boston University School of Medicine and National Emerging Infectious Diseases Laboratories (NEIDL), and AbbVie Bioresearch Center.

To estimate how the virus might then transform itself, the researchers followed clues in the chemical and physical structure of the virus and looked for rare mutations found in immunocompromised individuals and in a global virus sequence database. In lab studies using non-infectious virus-like particles, the researchers found combinations of multiple, complex mutations that would allow the virus to infect human cells while reducing or neutralizing the protective power of antibodies.

The researchers focused on part of the coronavirus’s spike protein, the receptor-binding domain, which the virus uses to attach to human cells. The spike protein allows the virus to enter human cells, where it initiates self-replication and eventually leads to infection. Most antibodies work by sticking to the same locations on the virus’s spike protein receptor binding domain to prevent it from entering cells and causing infection.

Mutation and evolution are a normal part of a virus’s natural history. Every time a new copy of a virus is made, there is a chance that a copy error – a genetic typo – will be introduced. Because a virus experiences selective pressure from the host’s immune system, copying errors that ensure the virus is not blocked by existing antibodies have a greater chance of surviving and continuing to replicate. Mutations that allow a virus to escape antibodies in this way are called escape mutations.

The researchers showed that the virus can develop large numbers of simultaneous escape mutations, while retaining the ability to connect to the receptors it needs to infect a human cell. The team worked with so-called pseudotype viruses, lab-created stand-ins for a virus constructed by combining harmless, non-infectious virus-like particles with pieces of the SARS-CoV-2 spike protein that contains the putative escape mutations. . The experiments showed that pseudotype viruses containing up to seven of these escape mutations are more resistant to neutralization by therapeutic antibodies and serum from mRNA vaccine recipients.

This level of complex evolution had not been seen in widespread virus strains when the researchers began their experiments. But with the emergence of the omicron variant, this level of complex mutation in the receptor binding domain is no longer hypothetical. The delta variant had only two mutations in its receptor-binding domain, and the pseudotypes Abraham’s team studied had up to seven mutations, omicron appears to have fifteen, including some of the specific mutations his team analyzed.

In a series of experiments, the researchers performed biochemical tests to see how antibodies would bind to spike proteins containing escape mutations. Several of the mutations, including some of those found in omicron, allowed the pseudotypes to completely evade therapeutic antibodies, including those found in monoclonal antibody cocktail therapies.

The researchers also found one antibody that could effectively neutralize all variants tested. However, they also noted that the virus could evade that antibody if the spike protein developed a single mutation that adds a sugar molecule where the antibody binds to the virus. That would essentially prevent the antibody from doing its job.

The researchers noted that in rare cases, circulating strains of SARS-CoV-2 have been found to acquire this mutation. When this happens, it’s likely the result of selective pressure from the immune system, the researchers said. Understanding the role of this rare mutation, she added, is critical to being better prepared before it emerges as part of dominant strains.

Although the researchers did not directly study the ability of the pseudotype virus to escape immunity to natural infection, findings from the team’s previous work with variants with fewer mutations suggest that these newer, highly mutated variants would also skillfully evade antibodies. obtained by natural infection.

In another experiment, the pseudotypes were exposed to blood serum from individuals who had received an mRNA vaccine. For some of the highly mutated variants, serum from single-dose vaccine recipients completely lost the ability to neutralize the virus. In samples taken from people who had received a second dose of vaccine, the vaccine retained at least some efficacy against all variants, including some highly mutated pseudotypes.

The researchers note that their analysis suggests that repeated immunization, even with the original spike protein antigen, may be critical to counteract highly mutated SARS-CoV-2 spike protein variants.

“This virus is a shape-shifter,” Abraham said. “The great structural flexibility we saw in the SARS-CoV-2 spike protein suggests that omicron is probably not the end of the story for this virus.”

Reference: December 2, 2021, Science.
DOI: 10.1126/science.abl6251

Funding: This research was supported by the Massachusetts Consortium on Pathogen Readiness; US Centers for Disease Control and Prevention (U01CK000490); National Institutes of Health (T32GM007753); Harvard Clinical and Translational Science Center, of the National Center for Advancing Translational Science (1UL1TR002541-01); Barbara and Amos Hostetter; and the Chleck Family Foundation.

Disclosures: Jonathan Abraham, Lars Clark and Sarah Clark are inventors of a provisional patent application filed by Harvard University that contains antibodies mentioned in this work. Sarah Turbett receives monetary compensation from UpToDate, which provides clinical decision support.