Revealing the Details of Changes in Spike Proteins of SARS-CoV-2 Omicron Mutant Strains

The interesting SARS-CoV-2 omicron mutant strain evades immunity mediated by antibodies from vaccination or infection with early mutants due to the accumulation of a large number of spike mutations. Recently, in a research report titled "Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement" published in Science, scientists from institutions such as the University of Washington have determined the precise structural changes on the spike protein of the Omicron mutant strain through research, and the researchers' observations may help explain how the virus evades antibodies against previous mutants and can still remain highly infectious.

Researcher David Veesler said the findings in this study provide a blueprint that may help researchers design new strategies, whether vaccines or treatments, to deal with the potential emergence of mutant strains of Omicron and other coronaviruses. The Omicron mutant strain was first discovered in South Africa in November 2021, and its infection and transmission worldwide are currently expanding. In addition to being highly infectious, the mutant can also evade antibodies against other mutant strains at an early stage, which may lead to breakthrough infections in individuals who have been vaccinated or have been previously infected.

The infectivity of the Omicron mutant strain is thought to be at least partially due to a large number of mutations in the amino acid sequence on the viral spike protein, which can be used to lock and enter the cells it infects, and the spike protein of the Omicron mutant strain has 37 mutations, which makes it different from the first SARS-CoV-2 isolates in 2020. Previous researchers Veesler and colleagues found that antibodies produced by the six most commonly used vaccines and all but one of the monoclonal antibodies currently used to treat infections had the ability to reduce or abolish Omicron mutant strains.

However, many mutations in the mutant strain can affect the structure of the region responsible for adsorbing and entering the spike protein of the host cell, which is called the receptor-binding domain. Many researchers predict that the change in the structure of the receptor-binding domain may damage the ability of the mutant strain to enter the cellular target, which is the protein called angiotensin-converting enzyme-2 (ACE2). However, in this study, researchers Veesler and colleagues found that this change actually increases the ability of the receptor-binding domain to bind to ACE2 by 2.4-fold.

In order to understand why Omicron mutant strains accumulate so many mutations when retaining effective interaction with the host receptor ACE2, the researchers used cryo-electron microscopy and X-ray crystallography to unveil the 3-D organization of the spike protein of Omicron mutant strains, which may achieve a resolution of about 3 Å. At this resolution, the researchers may dissect the shape of the single amino acid and basic components that make up the spike protein. In addition, the researchers revealed how the structural changes of the spike protein affect the ability of antibodies that effectively protect against previous strains to bind to Omicron mutant strains. Using this technology, the researchers reveal how mutations change the way proteins interact with antibodies, which reduces the ability of almost all monoclonal antibodies against the mutant strain, and at the same time, the ability of spike receptor-binding domains to bind to ACE2 is also enhanced, and the resulting overall effect allows the receptor-binding domains to have the potential to evade targeted antibodies and bind more tightly to ACE2.

The researchers say the viruses have incredible plasticity, can change a lot, and still maintain all the functions needed for their infection and replication, and can ensure that the Omicron mutant strain is not the last mutant strain seen by scientists. In the future, researchers aim to study and identify other regions on spike proteins that may not be changed without causing the protein to lose its function, and due to the importance, these regions tend to remain conserved even if other parts of the protein are mutated.

Therefore, this conserved region of the viral protein is likely to remain unchanged in the presence of new mutant strains, and these regions may become ideal targets for novel vaccines and therapeutic means, and these vaccines or therapeutic strategies may not only be effective against new mutant strains, but also remain effective against new sarbecoviruses. In summary, the results of this study suggest that the researchers provide a blueprint that may help understand that a significant decrease in the binding level of other therapeutic monoclonal antibodies can lead to a weakening of neutralizing activity; the remodeling of the interaction between the receptor-binding domain of Omicron mutant strains and human ACE2 may help explain the results of the enhanced affinity of host receptors relative to ancestral viruses.