When we speak of variants we refer to differences in the sequence of the genome due to mutations. Strain is a variant in which changes in its biology are demonstrated (antigenicity, transmissibility, virulence,…). For now, let’s talk about variants.

The evaluation of the new variants should answer these questions: Has the new variant appeared by a phenomenon of natural selection or by chance, by chance? If it has occurred by natural selection, what mutations have been selected? What is the adaptive advantage of these mutations? What effect do these mutations have on the transmissibility, diffusion, antigenic change, or virulence of the virus?

The D614G mutation

Change of the aspartic amino acid (D) for a glycine (G) at position 614 of the S protein. Detected in early March 2020, it has spread globally throughout the planet, becoming the dominant one the following month.

It initially appeared independently and simultaneously in several regions, suggesting natural selection and a possible beneficial adaptive effect. However, the mutation was found in various regions of China in some isolates from late January. This suggests that the global spread of this mutation has been the result of a chance phenomenon (non-adaptive) in which the viruses with the mutation initiated most of the first transmission events in multiple places (founder effect).

A recent analysis of more than 25,000 virus sequences in the UK has found that viruses with the 614G mutation spread faster than 614D. In animal models it has also been found that 614G viruses are transmitted more efficiently.

The N453Y mutation

In late spring 2020, an outbreak of SARS-CoV-2 was detected in mink farms in the Netherlands and Denmark. Early investigations demonstrated transmission of the virus from humans to minks, between minks and from minks to humans.

In November 2020, Danish authorities reported 214 human cases of COVID-19 associated with these mink farms. Many of the sequences of these shoots had a mutation in the gene encoding protein S, resulting in a substitution of an asparagine (N) for a tyrosine (Y) at position 453, the site of binding to the cellular ACE2 receptor. In addition, eleven individuals from the Danish outbreak had three additive mutations (del69_70, I692V and M1229I).

The adaptation of SARS-CoV-2 to mink is very worrying because it can favor the evolution of the virus in an animal reservoir of which, as we have seen, it can end up infecting humans or other mammals. For this reason, many countries have increased their vigilance and adopted mass slaughter policies on mink farms.

The B.1.1.7 lineage and the N501Y mutation

The B.1.1.7 lineage (also called 501Y.V1) is a phylogenetic group that is spreading very rapidly in south-east England. It has accumulated 17 mutations before its detection in early September, suggesting a rapid evolution, probably in a chronic patient.

On December 28, this variant was responsible for approximately 28% of infection cases in England and population genetic models suggest that it spreads 56% faster than other lineages.

This lineage is expanding when SARS-CoV-2 cases are very widespread and it appears that it becomes dominant by competition in a situation where there are several different variants circulating. This suggests a phenomenon of natural selection of the virus that is more transmissible at the population level. Controlling these types of more transmissible variants, in addition to masks, social distance and limitation of meetings, will probably require more restrictive measures.

Eight of the mutations of the B.1.1.7 lineage are in the gene for glycoprotein S. The most important are the substitution of an asparagine (N) by a tyrosine (Y) at position 501 in the receptor binding site, and deletion of the amino acid at position 69_70 and substitution of a proline (P) for a histidine (H) at position 681 at the furin cleavage site.

All these mutations most likely affect the ability of the virus to bind to the ACE2 receptor and its intracellular replication. The 501Y variants are likely to have higher affinity for the human ACE2 receptor. A different variant, also with the N501Y mutation, is spreading rapidly in South Africa. Although there are still no experimental data to affirm that these new variants are more virulent, the one that they can be more infectious and spread more quickly can also end up causing more cases, a sanitary collapse and in the long run greater mortality.

What effect can these mutations have on the antigenicity and effectiveness of vaccines?

Genomic surveillance of SARS-CoV-2 variants has largely focused on mutations in glycoprotein S, responsible for cell binding and the main target of neutralizing antibodies. Protein S is also the main antigen in most current vaccines.

If a variant has one or more mutations that increase its transmissibility, it could quickly compete and replace other circulating variants. Therefore, there is great interest in whether these mutations can cause changes in the glycoprotein that compromise the efficacy of vaccines.

Because current vaccines elicit an immune response against all protein S, effective protection is expected despite some changes in antigenic sites in SARS-CoV-2 variants. Although, obviously, it is an issue that will have to be watched very closely.

It should also be noted that viral glycoproteins are subject to evolutionary trade-offs. Sometimes a mutation that enhances one viral property, such as binding to a receptor, can reduce another property, such as escaping the host’s antibody. In fact, the evidence suggests that this could be the case for the D614G mutation.

Mutations that are “good” for the virus at this time may also make it less suitable in the context of population-level immunity in the future.

Understanding these dynamics and their possible influence on vaccine efficacy requires large-scale monitoring of the evolution of SARS-CoV-2 and host immunity over a long period of time. It is too early to know what effect these mutations will have, it should not be a cause for alarm, but it should be a cause for very close monitoring.