Mutations

RNA Viruses, such as the SARS-CoV-2HIV and Influenza, tend to pick up mutations rather quickly, once they are copied inside the cells of our bodies. This happens because the little cell workers that copy the RNA (called enzymes) are sloppy workers and prone to make errors. 

The SARS-CoV-2 virus genetic code has just 30,000 nucleotides blocks of RNA, or letters that can spell at least 29 genes1; and, the most common mutations are single-nucleotide changes between viruses from different people, that have little effect on the overall performance of the virus infection rate, but that allow researchers to track the spread by linking closely-related viruses2

In fact, sequencing data actually suggests that coronaviruses change more slowly than most other RNA viruses, because they have “proofreading” mechanisms that correct potentially fatal copying mistakes, accumulating only two single-letter mutations per month in its genome — a rate of change about half that of Influenza and one-quarter that of HIV2.

The problem is, that scientists can spot mutations faster than they can make sense of them, or what problems they may cause. Many mutations will have no consequence for the virus’s ability to spread or cause disease, because they do not alter the shape of a protein; whereas those mutations that do change proteins are more likely to harm the virus than improve it2. For example, in the beginning of the pandemic in Singapore, the ∆382 deletion made the infection of the virus milder3. On the contrary, the G614 variant showed a fitness advantage of infection, where individuals had a higher concentration of pseudotyped virions, suggestive of higher upper respiratory tract viral loads, but not with increased disease severity4

If we think about it, the virus just wants to spread, but not actually kill – because, if it kills, it can no longer spread.

More recently, a new SARS-CoV-2 virus variant showed up in the UK, where multiple spike protein mutations are seen (deletion 69-70, deletion 144, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H)5. Changes are also seen in other genomic regions, inclusively in the receptor binding domain (N501Y, “Nelly”). 

The unusually high number of spike protein mutations suggests that the variant has not emerged through gradual accumulation of mutations6. Instead, one possible explanation for the emergence of the variant, is prolonged SARS-CoV-2 infection in a single patient, potentially with reduced immunocompetence, similar to what has previously been described7,8. Such prolonged infection in immunocompromised patients can lead to accumulation of immune-escape mutations at a higher rate. 

This explanation is also suggested to the current SARS-CoV-2 virus variant found in Brazil (P.1)9, and in South Africa (501Y.V2)10

Unfortunately, this shows that the emergence of successful variants with similar properties is not so rare6; and, just like the need to develop new influenza vaccines every season, that also might be the case for SARS-CoV-2. The persistence of the pandemic, may enable accumulation of immunologically relevant mutations in the population, even as vaccines are developed. 

But, because science tries to be one step ahead, this is exactly what manufacturers are already working on, specifically the ones using mRNA technology that can quickly adapt their platforms to the current mutations seen.

Mutation luck
Mutation of luck

References:

1          Naqvi, A. A. T. et al. Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach. Biochim Biophys Acta Mol Basis Dis 1866, 165878-165878, doi:10.1016/j.bbadis.2020.165878 (2020).

2          Callaway, E. The coronavirus is mutating — does it matter? Nature 585, 174-177, doi:https://doi.org/10.1038/d41586-020-02544-6 (2020).

3          Young, B. E. et al. Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study. The Lancet 396, 603-611, doi:10.1016/S0140-6736(20)31757-8 (2020).

4          Korber, B. et al. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell 182, 812-827.e819, doi:10.1016/j.cell.2020.06.043 (2020).

5          Andrew Rambaut, N. L., Oliver Pybus, Wendy Barclay4, Jeff Barrett5, Alesandro Carabelli6, et al. Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations: COVID-19 genomics UK consortium. https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563 December 2020 (2020).

6          ECDC. Rapid increase of a SARS-CoV-2 variant with multiple spike protein mutations observed in the United Kingdom. https://www.ecdc.europa.eu/sites/default/files/documents/SARS-CoV-2-variant-multiple-spike-protein-mutations-United-Kingdom.pdf December 2020 (2020).

7          Choi, B. et al. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. N Engl J Med 383, 2291-2293, doi:10.1056/NEJMc2031364 (2020).

8          McCarthy, K. R. et al. Natural deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape. bioRxiv, 2020.2011.2019.389916, doi:10.1101/2020.11.19.389916 (2020).

9          Kupferschmidt, K. New mutations raise specter of ‘immune escape’. Science 371, 329-330, doi:10.1126/science.371.6527.329 (2021).

10        Karim, S. S. A. The 2nd Covid-19 wave in South Africa. https://www.scribd.com/document/488618010/Full-Presentation-by-SSAK-18-Dec December 2020 (2020).

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