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Suddenly everyone’s talking virus!
Throughout this SARS-CoV-2 pandemic, we’ve all become much more aware of viruses, how they behave, and how our immune system responds. The terms ‘mutations’, ‘variants’, ‘antigens’, and ‘antibodies’ are now overheard in supermarkets and cafés and are no longer limited to labs and academic conferences. So, we’ve all learned that viruses can easily (and sometimes rapidly) mutate, giving rise to new ‘variants’. But what are the important SARS-CoV-2 variants (so far), why do these variants arise, and what does this mean for immunity?

What are the SARS-CoV-2 variants of concern?
The term variant of concern is fairly self-explanatory. It’s used to indicate that we should be concerned about the potential of a newly mutated form of a virus (a variant) to harm human health.For example, the SARS-CoV-2 Delta (Δ) variant was first identified in India in October 2020 and was considered a variant of concern because of mutations in its spike-encoding gene. These genetic changes altered the spike protein in ways that affected the virus’s transmissibility and how well some antibodies could neutralize the virus.

Throughout 2020 and 2021, we’ve had five SARS-CoV-2 variants of concern, each of which is briefly described below:

• Alpha (B.1.1.7): The first variant of concern described in the United Kingdom in late December 2020. Alpha was estimated to be 40–80% more transmissible than the wild-type SARS-CoV-2 because of mutations in the spike protein.
• Beta (B.1.351): First reported in South Africa in December 2020. This variant was notable because of three worrying mutations in the virus spike protein. It was reported that the Beta variant had a relatively higher prevalence among healthy young people and was more likely to cause serious illness in this group.
• Gamma (P.1): Reported to be in circulation in Brazil in early January 2021, this variant has 17 amino acid substitutions, ten of which are in its spike protein. A study found that infections by Gamma can produce nearly ten times more viral load compared to other variants, with the same ability to infect both adults and older persons.
• Delta (B.1.617.2): First reported in India in December 2020, the Delta variant of SARS-CoV-2 has been described as one of the most transmissible respiratory viruses ever ..
• Omicron (B.1.1.529): First reported in South Africa in November 2021. Omicron is somewhat mysterious as it seems not to have developed from one of the recent variants of concern, but from earlier versions of SARS-CoV-2 that had been circulating more than a year prior (!!!). This left the scientists wondering “where, exactly, did Omicron come from?”. Some research has suggested the virus jumped from a human to an animal, where it evolved, before later jumping back into a human host. Or that this variant spent a long time evolving in the body of an infected immunocompromised human host. Omicron presents more than 50 mutations, of which at least 30 are in its critically important spike protein, altering how Omicron infects human cells.

OK, but why do viruses mutate?
In all life, mutations arise because of imperfect replication of genetic information. Natural selection then works with these mutations, and the result is evolution.

 RNA viruses accumulate mutations faster
Viruses can be classified as either DNA or RNA viruses. DNA viruses store their genetic information as DNA (which gets transcribed into RNA when a host cell is infected, then translated into protein), whereas RNA viruses store their genetic information as RNA. Relative to DNA viruses, many RNA viruses are “error-prone” when replicating their genomes. While most mutations give no advantage to the virus, beneficial mutations (to the virus) make the virus more infectious, help it evade the immune system, or allow it to jump to a new species. Viruses showing high mutation rates tend to be more efficient at evading immunity. For example, influenza constantly undergoes antigenic changes. This is why yearly vaccine updates are required and why influenza vaccines typically have limited efficacy (less than 50%).

Viruses’ delicate balancing act
Viruses are a special form of ‘life’. They cannot survive and replicate alone; they need a host, infecting the host cells and hijacking that cell’s machinery to produce more virus. This means that viruses must achieve a delicate balance: they need to adapt to host cells to enhance their opportunities for survival, but at the same time, they must maintain a replication-competent genome. The ideal scenario would be to evolve into a problem-free coexistence with the host. Viruses aim to maximize this survivability in a host by a variety of complex and fast-moving mechanisms, including:

• Becoming less harmful (a minimization of virulence) so that the virus can live in its host without causing major illness, and therefore proliferate and spread to other hosts more easily or for longer;
• Developing resistance to anti-viral drugs or to antibodies;
• Gaining the ability to jump from one host to another, as we have seen with coronavirus.

This delicate balancing act seems to have played out with SARS-CoV-2 over the last few years, with the virus mutating to become more transmissible but less virulent (more on this below).

What does this mean for our immunity (natural and vaccine) against SARS-CoV-2?
T-cells and antibodies
Protection against respiratory viral disease derives primarily from cellular immunity. Reactive lymphocytes limit viral multiplication at sites of infection. And because all viruses replicate within cells (and many of them spread directly between cells without fully re-entering the extracellular environment), resolution of infection is more reliant on T-cell function than on antibodies, which merely play supportive roles in preventing viral spread in the bloodstream. However, anti-viral antibodies are still important as an additional immunoprotective barrier against reinfection.

Coronaviruses are somewhat careful
SARS-CoV-2 is an RNA virus with a large genome (coronaviruses have the largest genomes among RNA viruses 30–33 kb). This makes SARS-CoV-2 especially susceptible to accumulating mutations. To cope with this, coronaviruses have evolved proofreading capacity: they encode a proofreading enzyme that can correct mistakes made during the process of replication. Coronaviruses that have this proofreading enzyme can keep their mutation rate in check. This proofreading mechanism and the constraints of the virus-host relationship put the brakes on SARS-CoV-2’s evolution.

What does mean for us? It’s not yet totally clear, but it’s hoped that this proofreading mechanism will help limit the risk that future variants of SARS-CoV-2 will suddenly and comprehensively escape the immunity (natural and vaccine) that has been built up since late 2019.

Blog by Chiara Mencarelli
Edited by Reckon Better Scientific Editing