How did the BA.5 omicron subvariant become a master of disguise and what is its current relevance to COVID-19?

The omicron subvariant, called BA.5, was first identified in South Africa in February 2022 and has spread rapidly worldwide. By the second week of July 222, BA.5 accounted for nearly 80% of the COVID-19 variants in the United States.

Soon after, South African researchers reported the original omicron variant (B.1.1.529) in November. As of March 24, 2021, many scientists, including myself, have speculated that the omicron may become the dominant variant worldwide if multiple mutations in the omicron make it more infectious or better at immune evasion than the earlier delta variant.

The Omicron variant really took off in early 2022, and since then several sublines or subvariants of the Omicron have appeared: BA.1, BA.2, BA.4 and BA.5, among others. With the emergence of such highly transmissible variants, it appears that SARS-CoV-2, the virus that causes COVID-19, is effectively using classical techniques used by viruses to evade the immune system. These evasion strategies range from changing the shape of key proteins recognized by your immune system’s protective antibodies to camouflaging its genetic material so that human cells treat it as part of itself instead of an invader.

I’m a virologist who studies emerging viruses like SARS-CoV-2 and viruses that jump from animals to humans. My research group followed the spread and evolution of SARS-CoV-2, assessing how well omicron subvariants evade the immune system and the severity of disease they cause after infection.

The BA.5 subvariant is more capable of evading the body’s immune system than previous subvariants.

How is the transmissibility of a virus measured in a population?

The basic reproduction number, R0—pronounced “R-none”—measures the transmission of the virus in a population that is not yet infected.

Epidemiologists use the term effective reproduction number, called Re or Rt, to measure the transmission of a virus after a proportion of people in a population have acquired immunity due to prior infection or vaccination. The Re of the Omicron option is estimated to be 2.5 times higher than the delta option. This increased throughput likely helped the micron become the dominant delta variant, outperforming the competition.

The bigger question is, what is driving the evolution of omicron sublineages? The answer is a process known as natural selection. Natural selection is an evolutionary process in which traits that confer a reproductive advantage on a species are passed on to the next generation, while unobserved traits are eliminated by competition. As SARS-CoV-2 continues to circulate, natural selection favors mutations that give the virus the greatest survival advantage.

What causes Omicron and its branches to spread?

Several mechanisms contribute to the increased infectivity of SARS-CoV-2 variants. One of them is the ACE2 receptor, a protein in the body that primarily helps regulate blood pressure, but also helps SARS-CoV-2 enter cells. The latter omicron sublines contain mutations that evade antibody protection while retaining the ability to bind effectively to ACE2 receptors. The BA.5 sublineage may evade antibodies from both vaccination and prior infection.

Omicron sublines BA.4 and BA.5 share several mutations with previous omicron sublines, but also have three unique mutations: L452R, F486V, and R493Q reversion (or lack of mutation). L452R and F486V in the Spike protein help to evade BA.5 antibodies. In addition, the L452R mutation helps the virus bind more efficiently to its host cell membrane, an important feature associated with the severity of the COVID-19 disease.

The BA.5 subtype is responsible for two-thirds of the current cases of COVID-19 in the United States.

Another mutation in BA.5, F486V, may help the sublineage evade certain types of antibodies, but may reduce its ability to bind to ACE2. Surprisingly, another mutation that restores the lost affinity of BA.5 for ACE2, the R493Q reversion, appears to compensate for ACE2 binding strength. The ability to successfully evade immunity while retaining the ability to bind to ACE2 may have contributed to the rapid global spread of BA.5.

In addition to these immune mutations, SARS-CoV-2 has evolved to suppress the innate immunity of its hosts—in this case, humans. Innate immunity is the body’s first line of defense against pathogens, consisting of antiviral proteins that help fight viruses. SARS-CoV-2 has the ability to suppress the activation of some of these key antiviral proteins, meaning it can effectively defeat many of the body’s defenses. This explains the spread of infection among vaccinated or previously infected individuals.

Innate immunity exerts strong selective pressure on SARS-CoV-2. Delta and omicron, the two most recent and highly successful SARS-CoV-2 variants, share several mutations that help the virus subvert innate immunity. However, scientists do not fully understand what changes in BA.5 allow this.

What is next?

BA.5 will not be the last game. As viruses continue to circulate, this evolutionary trend may lead to the emergence of more transmissible variants capable of immune evasion.

Although it is difficult to predict what options will emerge, we researchers cannot rule out the possibility that some of these options may lead to increased morbidity and increased hospitalization rates. As the virus continues to evolve, most people will get COVID-19 multiple times, regardless of their vaccination status. This can be confusing and frustrating for some and can contribute to vaccine refusal. Therefore, it is important to understand that vaccines do not necessarily protect against infection, but rather against severe disease and death.

Research over the past two and a half years has helped scientists like me learn a lot about this new virus. However, many unanswered questions remain as the virus continues to evolve and we are working towards a constantly moving target. While updating vaccines to match the ones in circulation is an option, this may not be practical in the short term because the virus evolves so quickly. Vaccines that generate antibodies against a wide range of SARS-CoV-2 variants and a cocktail of broad-spectrum treatments, including monoclonal antibodies and antiviral drugs, will be essential in the fight against COVID-19.

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