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Transmission and diversity of SARS-CoV-2

Like all viruses, and in particular RNA viruses, SARS-CoV-2 makes errors in the replication of its genome, which causes mutations and the appearance of new variants. These mutations can give the virus a selective advantage (increase in transmissibility or evasion of the immune response). This is case with the UK variant, which seems to be at least 50% more transmissible than the original Wuhan strain, and which has now become the dominant strain in many countries.

Sequencing the genome is the best technique for monitoring the appearance of new variants. Most studies analyse mutations observed in the consensus sequence, that is to say, representing only the majority variant in an infected individual. However, mutations appear when the virus replicates in an individual, and its viral population is not made up of a single variant. Researchers at the University of Oxford recently studied all the variants present in an individual (this is called intra-host diversity). They showed that diversity could be quite limited in the case of high viral charge, and that not all the variants are necessarily transmitted when a new individual is contaminated.

The researchers sequenced 1390 SARS-CoV-2 genomes from individuals infected in the UK during the 1st wave of the epidemic. Their first analysis examined the frequency of variants in an individual during the infection’s acute phase. They noticed a relation between the viral charge and the number of variants detected: the higher the charge, the smaller the number of intra-host variants. After an initial peak, the viral charge decreases gradually as the infection develops, whereas the number of mutations increases gradually as the virus replicates.

The scientists took two samples from each of 41 individuals, with a 6 day gap between samples. They observed an intra-host variant dynamic, especially where minority viruses were concerned. Some regions of the viral genome have a greater density of mutations than others. This is the case with the ORF3a, 7a and 8 proteins and the nucleocapsid. The region coding for the spike (S) surface protein does not seem to be subject to mutations. This explains the structural constraints that are necessary for its successful interaction with the ACE2 cellular receptor that enables entry of the virus into the cell.

The researchers also investigated the diversity of variants transmitted using the samples from the same people. The question was whether all the variants present in a person are transmitted. It appears that there is a “bottleneck” when the virus is transmitted and that only a limited number of variants are transmitted (between 1 and 8).

In conclusion, SARS-CoV-2 diversity does exist within an individual. However, during the infection’s acute phase, when the viral charge is high and when transmission between individuals is more likely, few mutations that might increase transmissibility or immune system evasion actually emerge. Nevertheless, mutations giving the virus advantages in replication, transmission or evasion were observed in minority variants. It is therefore essential to continue to monitor the appearance of variants, especially minority variants, within individuals.

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