Various COVID-19 variants have been discovered around the world during the nearly two years of the pandemic – the vast majority being expressions of random and insignificant changes in the virus's genome.
The reason the omicron variant – discovered in several South African countries and identified in Israel for the first time on Thursday – has attracted so much attention is that it includes a very large number of mutations in critical parts of its spike protein, some seen previously and others that are new. The number of mutations and their locations represent an ominous sign.
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How do we identify new variants and determine which might pose a serious problem?
A variant might have a single genetic change, a few isolated changes or dozens of them, like the omicron variant. “Variants are created all the time as a result of the replication of the virus. Many of them appear and disappear, emerge in a specific outbreak and then die down,” says Prof. Cyrille Cohen, the head of the tumor immunology and immunotherapy lab at Bar-Ilan University. According to Cohen, researchers begin to track the new variants in three cases – when the variant begins to spread, when it causes more severe illness, or when it has the ability to evade the immune system.
What are the characteristics of the new variant?
“This is a variant that includes over 30 mutations just in the spike protein, and about 50 mutations in the entire genome, and it seems it has the ability to evade the immune system and an increased capability to infect,” says Prof. Tomer Hertz of the microbiology, immunology and genetics department at Ben-Gurion University of the Negev in Be’er Sheva.
Hertz is a member of a research team of the National Institute for Biotechnology in the Negev, and is involved in mapping and assessing variants. If the new variant spreads quickly to other places, it could replace the dominant variant delta that caused Israel's fourth wave, he says. “At this stage, relatively little is known about it, but it is causing worry–justifiably.”
Why are the changes in the spike protein so critical?
In contrast to bacteria, fungi or other pathogens with the ability to live independently, viruses rely on their hosts' cells, which they penetrate and use to reproduce. The spike protein binds the virus to the host cell and serves as the basis for the coronavirus vaccines.
The spike protein of the coronavirus is a chain of 1,273 amino acids, with different areas along the protein fulfilling functional tasks for the virus, like binding to cells in the body and evading the immune system. A main function is the virus's use of the spike protein to bind to a receptor known as ACE2, on the surface of cells.
What is so worrying about the mutations in the omicron variant?
This is the highest number of mutations “that we know of in the spike protein. We already know some from other variants, and some are new and not known to us,” says Cohen.
It is not just the number of mutations that worries the scientists, but also their locations along the spike protein: the combination of the two helps the virus bind to the host cell. “The virus attaches much more strongly and this causes them to be much more infectious,” said Prof. Gideon Schreiber of the department of biomolecular sciences at the Weizmann Institute of Science in Rehovot.
As part of the research conducted by Schreiber and published in August in the scientific journal Nature Microbiology, Schreiber and his colleagues carried out an evolutionary simulation of the virus in a lab, with the goal of aiding in developing a drug for treating COVID-19. They carefully analyzed genetic changes and the strength of the protein's binding to the ACE2 receptors, noticing how the version of the virus produced in the experiments underwent an evolutionary process similar to the alpha, beta and gamma variants.
“We wrote in the article that we feared a variant would appear in the future with a combination of problematic mutations,” says Schreiber. “We feared a mutation in the amino acid in location 498 in combination with the known 501 mutation from the British variant. We saw how this combination was problematic and binds the virus to the receptor site much more strongly. When you add the mutations at locations 477 and 484 to this, too – it is even worse.”
The scientists identified the changes at these locations as critical, and a rapid spread of the new variant supports this. “After this research, we continued to track [variants] to see if such a combination appeared – and it did appear in variant B.1.1.529,” he added.
How protected are people who have been vaccinated or recovered from COVID-19 against the omicron variant?
It is still hard to estimate at this stage what the level of protection against the new variant provided by the existing COVID-19 vaccines is. But the higher the number of changes in the spike protein, the farther it moves away from the original version of the virus that the vaccine is designed to combat. As a result, the immune system has a difficult time recognizing the variant’s profile and is less prepared to identify and attack it. This is all the more significant when it comes to an especially infectious variant with the ability to become the dominant one.
The problem applies not just to vaccines, but also to antibodies among those who have recovered from a previous variant. The manufacturers of the vaccines will likely examine this and publish their findings soon.
As a rule, the extent of the damage from the variant depends to a great extent on its characteristics and ability to spread and become dominant. “The reason we are worried is that when you vaccinate someone today, you do it with a vaccine based on the original variant,” says Cohen. “Antibodies and T-cells can be very sensitive to changes, even if it is just a change or two. The more changes there are, there are less and less antibodies until you are left bare in terms of your ability to respond.”
Is it a coincidence that a variant with so many changes appeared in African countries?
“This variant is a classic example of the way in which variants with lots of mutations are created, so until they increase the vaccination rates and the access to vaccines in these countries, the problem won't be solved. Places where there are no vaccines and there is a large unvaccinated population, including among them people who are immunocompromised – those are incubators for the development of new variants,” says Cohen.
Why are the immunocompromised the ones linked to the potential emergence of variants with large numbers of mutations?
“When a healthy person is unvaccinated and infected, the immune system goes into operation and within five to 10 days – more or less – it overcomes the viral infection by damaging and reducing its replication ability. But for a vaccinated person, the system works and responds immediately to eliminate the virus much faster,” he said.
In contrast, Cohen explains, "in an immunocompromised person, the vaccination process is slower and can stretch over a month or a month and a half." He said, "The long period of time that the virus has to act in an immunocompromised person enables it to 'find solutions' to the immune system's activity. It gives it time for a longer evolutionary process to occur, in which it develops mutations in critical areas," Cohen explains.
Will the new variant become as dominant as delta?
"The range of variants does not always work in favor of the virus," Cohen says. "Too many or too extreme changes cause it to lose its original properties. In the end, "of all the variants we've talked about in recent months, like the lambda variant or the AY4.2 variant, which is a subtype of the delta variant – the one that remains the most dominant is the delta variant that exists today in Israel.
"It is not possible to know at this stage whether the variant discovered in South Africa will become as dominant as delta. I want to hope not, but we should be vigilant," he says.
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