COVID-19 Update – Variations on a Theme

The news is filled with alarming stories about new variants of SARS-CoV-2 that were isolated in recent weeks. These variants are versions of the original SARS-CoV-2 virus that have acquired mutations. Mutations are a natural and regular occurrence that happens when the parental viral genome replicates during the process of making progeny viruses. In an infected cell, the parental viral genome makes hundreds to thousands of copies of itself and each copy is packaged into a new virus particle. To produce these many genome copies the virus uses an enzyme called a polymerase. The polymerase uses the original genome as a template and duplicates it over and over, like a copy machine printing multiple copies from an original document. However, unlike copy machines polymerases are never 100 percent accurate. All polymerases make mistakes during the copying process so errors inevitably occur in some of the newly made genomes, and these mistakes are the mutations. Fortunately for us, SARS-CoV-2 has a fairly accurate polymerase and accumulates mutations less frequently than most other RNA viruses.

The genome of SARS-CoV-2 is an RNA molecule. All RNAs, from viruses to humans, are composed of four ribonucleotides that are abbreviated as A, U, C, and G. These ribonucleotides form the alphabet of the genetic language and are used to compose the genes which are the “words” of the genome. Roughly 30,000 ribonucleotides are linked together in a long, unbroken string to form the SARS-CoV-2 genome. During genome replication, the polymerase starts at one end of the template genome and travels along the template progressively copying it to produce the new genome. At any point, the polymerase may incorporate an incorrect ribonucleotide into the growing copy, creating a random error similar to making a typo in a document. Many such genetic errors are neutral and cause no change in the viral proteins so they do not affect the virus’ properties. Other mutations can harm the virus and generally would be lost from the viral population as these mutants are less fit than the original virus. The mutants that concern us are the ones that improve viral fitness so that the mutant strains outcompete the parental virus and become the dominant strains in circulation.

This current set of significant variants arose in different countries and have begun spreading rapidly around the world. The most prevalent of the new variants originated in the United Kingdom (B.1.1.7), South Africa (B.1.351), and Brazil (P.1), all of which appear to have greater transmissibility than the original SARS-CoV-2 virus that triggered the pandemic. Because they are more easily transmitted from person-to-person, these variants are spreading rapidly and likely will replace the parental virus as the predominant strains in circulation. Importantly, all three variants have one or more mutations that change amino acids in the spike protein that protrudes from the surface of the virus. The spike protein is critical for infection because it is the component of the virus that interacts with the ACE2 receptor on our cells. This spike protein-receptor interaction allows the virus to bind to the cell and be taken up to initiate the infection. Without the spike protein-receptor interaction the SARS-CoV-2 would be harmless and unable to infect our cells. The spike mutations in the variants appear to improve their binding to the receptor which likely accounts for their increased infectiousness.

While increased disease severity hasn’t been confirmed for any of these variants, there is concern that the current vaccines may be less protective against these existing and potential future variants. All the approved vaccines work by inducing antibodies against the spike protein. These antibodies coat the spike proteins on the surface of viruses and block the spike-receptor interaction to prevent infection. Antibodies are exquisitely specific for the exact amino acid sequence and shape of their target protein. If the mutant spike proteins in the variants change significantly from the original spike protein, then the antibodies induced by the vaccines may fail to bind these altered spike proteins and won’t block infection. So far, the changes in the current three major variants don’t seem to reduce the Pfizer or Moderna vaccine efficacy greatly, but the danger is that additional mutations can arise that produce spike proteins that are not recognized by the vaccine-induced antibodies. This would necessitate booster vaccines or revaccination with newly constructed vaccines with all the logistical challenges that we are already facing. The best way to prevent new mutations from arising is to restrict viral replication by reducing the number of susceptible individuals as quickly as possible through our current vaccination efforts.

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