Dr. Marc-André Langlois and his team at the University of Ottawa analyzed mutations in SARS-CoV-2 from December 2019 to December 2020, including the impact on virus biology, therapeutics and vaccine effectiveness. This study was supported by the Canadian Institutes of Health Research (CIHR) and the COVID-19 Immunity Task Force (CITF).
In this pre-print, the authors present a retrospective metadata study of high frequency mutations, those represented in over 1% of all sequenced viruses globally. They specifically investigated the appearance of these mutations over time, where they emerged, and finally if they remained within the circulating viruses or if they faded away. Additionally, they focused on mutations in the spike protein of recent variants of concern. They highlighted how some mutations could strengthen the binding to the cellular receptor, making the virus more infectious, while reducing the binding of neutralizing antibodies, enabling immune surveillance escape. This study offers an integrative view of the emergence, disappearance, and sequence integration of successful mutations that constitute the latest circulating SARS-CoV-2 variants and their potential impact on neutralizing antibody treatments and vaccines.
Viruses that carry their genetic material in the form of RNA like SARS-CoV-2, the virus that causes COVID-19, are prone to make errors every time their genome is copied. These errors drive the evolution of the virus as they are the source of new mutations. If a mutation gives the virus a replicative advantage or allows it to evade immune recognition, it is often maintained and even enriched in the population, giving rise to new viral variants. Mutations are named to highlight the amino acid substitution that occurred. For example, the amino acid known as aspartic acid (abbreviated as D) in position 614 in the spike mutated to glycine (abbreviated as G), so the mutation was named D614G. This mutation was first reported in early 2020, and it was shown to increase the transmissibility of the virus. Together with P323L in the enzyme that makes copies of the viral genome, these two mutations are now present in over 90% of all SARS-CoV-2 sequences currently circulating worldwide. The authors also describe several other mutations. Some of these were stabilized in smaller subpopulations (representing less than 50% of the circulating viruses) while others rapidly faded out. Langlois’ team mapped the most widely distributed mutations across the globe. While many of the prevalent mutations appear to be predominantly present in developed countries, this could be attributable to overall higher sequencing rates. The most conserved regions of the genome included genes NSP8, NSP10, NS6, NS7a, and envelope. These genes did not have many mutations during the periods analyzed during this study.
Between October and December 2020, new coronavirus variants of interest arose worldwide, such as B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil). These variants have both an increased transmissibility and ability to escape antibody surveillance. Current vaccines may be less effective with these variants. Of the 24 mutations present in the B.1.1.7 SARS-CoV-2 variant, nine mutations are in the spike protein. The authors mapped these to the 3D structure of the spike protein. Of these mutations, N501Y was found in the region of the spike that binds the cellular receptor, human protein ACE2. This region is known as Receptor Binding Domain, or RBD for short. It was suggested that this mutation generates a new contact site between the spike and ACE2, enhancing infectivity and virulence. The mutations found in the B.1.1.7 SARS-CoV-2 variant can be found in over 70% of the genomes sequenced up to mid-February 2021. Likewise, B.1.351 and P.1 variants contain multiple mutations in its spike, including three shared mutations in the RBD: N501Y, E484K and substitutions in K417 (K417N and K417T, respectively). The authors predict that these mutations would be able to evade antibody surveillance. Unlike B.1.1.7, B.1.351 and P.1, variants have low frequency worldwide, under 2% as of mid-February 2021.
In conclusion, the analysis from Langlois and colleagues emphasises the natural fluctuations in mutation prevalence. They also illustrate how mutations can sometimes create favorable conditions enabling viral propagation. Tracking these mutations is critical for the development and deployment of effective treatments and vaccines. The authors conclude that it is the responsibility of all governing jurisdictions to increase virus sequencing and to upload SARS-CoV-2 genomes to databases in real-time. It is only then that we will have the most accurate information to convey to decisions-makers about interventions required to slow down the global transmission of the virus.
Castonguay N, Zhang W, Langlois M-A. Meta-analysis of the dynamics of the emergence of mutations and variants of SARS-CoV-2. MedRxiv preprint, 2021 March 08. DOI: 10.1101/2021.03.06.21252994