Professor and Chair of Emerging Infectious Diseases, Penn State
The omicron subvariant known as BA.5 was first detected in South Africa in February 2022 and quickly spread worldwide. As of the second week of July 2022, BA.5 accounted for nearly 80% of COVID-19 variants in the United States.
Shortly after researchers in South Africa reported on the original version of the omicron variant (B.1.1.529) on November 24, 2021, many scientists, including myself, speculated that if the numerous mutations of omicron made it more transmissible or better at immune evasion than the earlier delta variant, omicron could become the dominant variant worldwide.
In fact, the omicron variant became dominant in early 2022, and since then several omicron sublineages or subvariants have emerged: BA.1, BA.2, BA.4, and BA.5, among others. With the continued emergence of such highly transmissible variants, it is clear that SARS-CoV-2, the virus that causes COVID-19, is effectively using classic techniques that viruses employ to evade the immune system. These escape strategies range from altering the shape of key proteins recognized by the immune system's protective antibodies to camouflaging its genetic material to trick human cells into perceiving it as part of themselves rather than an invader to attack.
I am a virologist who studies emerging viruses and viruses that jumped from animals to humans, such as SARS-CoV-2. My research group has been tracking the transmission and evolution of SARS-CoV-2, assessing changes in how well omicron subvariants evade the immune system and the severity of the disease they cause after infection.
How is the transmissibility of the virus measured in a population?
The basic reproduction number R0, pronounced "R-naught", measures the transmissibility of a virus in a population not yet infected.
Once a proportion of individuals in a population become immune due to prior infection or vaccination, epidemiologists use the term effective reproduction number, called Re or Rt, to measure the transmissibility of the virus. The Re of the omicron variant has been estimated to be 2.5 times higher than that of the delta variant. This increased transmissibility likely helped omicron outcompete delta to become the dominant variant.
The most important question, then, is what is driving the evolution of omicron sublineages? The answer to that is a well-known process called natural selection. Natural selection is an evolutionary process in which traits that give a species a reproductive advantage continue to be passed on to the next generation, while traits that do not are eliminated through competition. As SARS-CoV-2 continues to circulate, natural selection will favor mutations that give the virus the greatest survival advantage.
What makes omicron and its derivatives so stealthy when it comes to spreading?
Several mechanisms contribute to the increased transmissibility of SARS-CoV-2 variants. One is the ability to bind more tightly to the ACE2 receptor, a protein in the body that primarily helps regulate blood pressure but can also help SARS-CoV-2 enter cells. Newer omicron sublineages have mutations that make them better at evading antibody protection while retaining their ability to bind effectively to ACE2 receptors. The BA.5 sublineage can evade antibodies from both vaccination and previous infection.
The Omicron BA.4 and BA.5 sublineages share several mutations with previous Omicron sublineages, but they also have three unique mutations: L452R, F486V, and the reversion (or lack of mutation) of R493Q. L452R and F486V in the spike protein help BA.5 evade antibodies. Additionally, the L452R mutation helps the virus bind more effectively to its host cell membrane, a crucial characteristic associated with the severity of COVID-19.
While the other mutation in BA.5, F486V, may help the sublineage evade certain types of antibodies, it could decrease its ability to bind to ACE2. Surprisingly, BA.5 appears to compensate for the decreased ACE2 binding strength through another mutation, the reversion of R493Q, which is thought to restore its lost affinity for ACE2. The ability to successfully evade immunity while maintaining its ability to bind to ACE2 may have potentially contributed to the rapid global spread of BA.5.
In addition to these mutations that evade the immune system, 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 invading pathogens, composed 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 overcome many of the body's defenses. This explains the spread of infections 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 could be key to helping the virus evade innate immunity. However, scientists still do not fully understand which changes in BA.5 might allow it to do so.
What's next?
BA.5 will not be the final game. As the virus continues to circulate, this evolutionary trend is likely to lead to the emergence of more transmissible variants capable of evading the immune system.
While it is difficult to predict which variants will emerge next, researchers cannot rule out the possibility that some of these variants could lead to more severe illness and higher hospitalization rates. As the virus continues to evolve, most people will contract COVID-19 multiple times despite vaccination status. This could be confusing and frustrating for some and may contribute to vaccine hesitancy. Therefore, it is critical to recognize that vaccines protect you from severe illness and death, not necessarily from infection.
The research of the past two and a half years has helped scientists like myself learn a great deal about this novel virus. However, many questions remain unanswered because the virus is constantly evolving, and we are still trying to target a constantly moving target. While updating vaccines to match circulating variants is an option, it may not be practical in the short term because the virus is evolving too rapidly. Vaccines that generate antibodies against a broad range of SARS-CoV-2 variants and a broad-spectrum cocktail of treatments, including monoclonal antibodies and antiviral drugs, will be critical in the fight against COVID-19.