After COVID-19 emerged in late 2019, SARS-CoV-2, a coronavirus, changed very little for about 11 months.1 Humans had minimal, if any, immunity to SARS-CoV-2. So, there was little pressure to alter. But the growing number of people who survived COVID-19 and, since December 2020, mass vaccination bolstered the population’s immunity,1 which, in turn, drove changes in SARS-CoV-2. Now after a a lull, the number of COVID-19 cases is on the up, driven by the two omicron ‘variants of concern’ known as BA.4 and BA.5.2
In June, BA.4 and BA.5 accounted for more than half (22.3% and 39.5% respectively) of COVID-19 cases in the UK.2 But how much do we know about these variants?
The tree of life
Charles Darwin famously sketched a tree of life showing how related species diverge from a single starting point. Over time, branches divide, eventually producing new species. Viruses also climb the tree of life.
Initially, there was one SARS-CoV-2 strain. The first isolates from Wuhan shared about 99.99% of their nucleotides, the building blocks of the genetic code.3 SARS-CoV-2 diverged into three large branches: the alpha, delta and omicron linages. Then smaller variant branches diverged. BA.4 and BA.5 may have branched off from BA.2.4
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Viruses are prone to high rates of mutation.5 So, they evolve rapidly in response to, for example, changes in the pattern of their host’s immunity.5 That’s because viruses replicate quickly, swapping accuracy for speed. As viruses copy the string of nucleotides that contains the genetic code they make a mistake in one of every 5000 nucleotides copied.6 (SARS-CoV-2 contains about 30,000 nucleotides).3 The error rate when replicating the human genome is some 6000 times lower.6
Mutations to the genetic code are random. Indeed, researchers identified about 30,000 nucleotide substitutions in SARS-CoV-2.5 The entire genome has not changed, however. Sequences of three nucleotides code for an amino acid, which join together to form a protein. Some amino acids must remain the same for the virus to survive. So, some mutations are highly deleterious to SARS-CoV-2 and rapidly die out. Most mutations have little if any effect. For example, some mutations change a nucleotide, but the amino acid remains the same. In other cases, the mutation changes the amino acid. But this does not alter the protein’s biological function.
Mutations to some other parts of the genome, such as the nucleotides encoding amino acids in the spike, are more worrying. BA.4 and BA.5 carry mutations that change the viral spike protein.4 A small proportion of mutations benefit the virus, affecting, for example: the severity of the signs and symptoms (pathogenicity); infectivity (ability infect an exposed person); transmissibility (ability to pass between people); and antigenicity (ability to stimulate the immune system).1
For instance, viral infections tend to begin with a single ‘founder’ event – an infected person going into an office, for example. The viruses spreads from person-to-person forming clusters of infection. Previous strains of SARS-CoV-2 differ in reproduction number, which varies from 2.2 to 5.9.5 So, depending on the variant, each person can infect, on average between two and six other people. BA.4 and BA.5 spread more rapidly than other circulating strains.4 BA.5 seems to show a growth advantage over BA.4 and will probably become the dominant strain in the UK.2
Neutralising antibodies triggered by vaccination and previous infections recognise areas in the spike.1,4,7 In laboratory studies, antibodies in response to older strains of SARS-CoV-2 block BA.4 and BA.5 less well. In one study, levels (titres) of neutralising antibody against BA.4 or BA.5 were 21 times lower that those evoked by an ancestorial strain from Wuhan.7 Titres against BA.4 or BA.5 were also 3.3 times lower than triggered by BA.1.7 This means that BA.4 and BA.5 can infect people who were previously immune to SARS-CoV-2.4
The future
COVID-19 mortality varies between 0.8% and 14.5% depending on the strain.5 (Obviously, medical care influences mortality.) The pandemic’s history, such as when a variant reached a country, and the relative success of the vaccination programme influence the population’s immune profile. Demographic factors, particularly the number of old and vulnerable patients, also influence a strain’s health impact. So, the size of the BA.4 and BA.5 waves will vary between countries.4
In South Africa, BA.4 and BA.5 became the dominant strains and the wave triggered by these variants is beginning to subside. But the increase in admission and deaths was less than the original omicron wave (BA.1).8 Other countries seem to follow a similar pattern. At the time of writing, the number of cases and hospital admissions is increasing in the UK, but the effect on mortality is not clear (see coronavirus.data.gov.uk for updates).
BA.4 and BA.5 may not be the last variants. Several areas in the spike protein that are recognised by antibodies induced by vaccination and previous infections could mutate. This could, in turn, produce new variants.4 In addition, repeated exposure to omicron strains could induce a broad immunity to this linage. This ‘cross immunity’ may be one reason BA.4 and BA.5 seem less likely to trigger severe COVID-19 than the initial omicron wave. But robust immunity against omicron could allow a different linage to come to the fore.4 Vaccine selection should, therefore, reflect the dominant circulating variants,6 analogous to the approach for flu jabs.
The diversity of SARS-CoV-2 exemplifies evolution in action. SARS-CoV-2 is in a constant battle between its ability to pass on its genetic code to the next generation and the threat posed by our changing immunity. Optimally, a virus should evolve to maximise infectivity and transmissibility, while avoiding serious disease. If you are laid up with an infection you’re less likely to be up and about to spread the virus.
Apart from the Middle East Respiratory Syndrome and the severe acute respiratory syndrome, four coronaviruses cause common colds.3 In around 1890, a bovine coronavirus jumped from cattle to humans. Genetic analysis suggests that the human coronavirus OC43, which now circulates causing common colds, is the descendent of this bovine virus.3,9 SARS-CoV-2 seems destined for a similar fate. But how long that takes and how many variants we encounter along the way remains to be seen.
Mark Greener is a freelance medical writer
References
1. Harvey WT, Carabelli AM, Jackson B, et al. SARS-CoV-2 variants, spike mutations and immune escape. Nature Reviews Microbiology. 2021. 19 (7):409-24. https://doi.org.10.1038/s41579-021-00573-0
2. UK Health Security Agency. SARS-CoV-2 variants of concern and variants under investigation in England. Technical briefing 43. 24 June 2022. Available at https://www.gov.uk/government/publications/investigation-of-sars-cov-2-variants-technical-briefings. Accessed July 2022.
3. The Royal Society. The SARS-CoV-2 genome: variation, implication and application. 2020. Available at royalsociety.org/-/media/policy/projects/set-c/set-c-genome-analysis.pdf Accessed July 2022.
4. Callaway E. What the latest omicron subvariants mean for the pandemic. Nature. 2022. 606:848-9. https://doi.org.10.1038/d41586-022-01730-y
5. Hou Y, Zhao S, Liu Q, et al. Ongoing positive selection drives the evolution of SARS-CoV-2 genomes. Genomics, Proteomics & Bioinformatics. 2022. https://doi.org.https://doi.org/10.1016/j.gpb.2022...
6. Yewdell JW. Antigenic drift: Understanding COVID-19. Immunity. 2021. 54 (12):2681-7. https://doi.org.10.1016/j.immuni.2021.11.016
7. Hachmann NP, Miller J, Collier A-rY, et al. Neutralization escape by SARS-CoV-2 omicron subvariants BA.2.12.1, BA.4, and BA.5. New England Journal of Medicine. 2022. https://doi.org.10.1056/NEJMc2206576
8. Wise J. COVID-19: Omicron sub variants driving new wave of infections in UK. BMJ. 2022. 377:o1506. https://doi.org.10.1136/bmj.o1506
9. Vijgen L, Keyaerts E, Moës E, et al. Complete genomic sequence of human coronavirus OC43: molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event. Journal of Virology. 2005. 79 (3):1595-604. https://doi.org.10.1128/jvi.79.3.1595-1604.2005