Almost no difference
The vaccine was predicted to be equally effective against all current variants of SARS-CoV-2
Vera Mukhina, N+1
A comparison of 18514 SARS-CoV-2 genomes showed that – contrary to fears – this virus is quite conservative and its variants should be equally recognized by the vaccines being developed. Most of the mutations found by researchers are neutral or negative for the virus, and the popularity of several mutations like D614G can be explained by the founder effect. The work was published in the journal PNAS (Dearlove et al., A SARS-CoV-2 vaccine candidate would likely match all currently circulating variants).
The coronavirus is based on an RNA molecule that is more prone to mutations when compared with DNA. It is this property of RNA viruses that does not yet allow us to create a universal vaccine against influenza, which has many different mutable strains that replace each other. Scientists have to predict every year which virus will be popular this season, and adapt the vaccine based on these predictions. Something similar was expected from the new coronavirus, but it turned out to be not so changeable, and the new work claims that it will not be necessary to change the coronavirus vaccine every year.
Bethany Dearlove and her colleagues from the Walter Reed Army Research Institute made this conclusion by analyzing 18514 SARS-CoV-2 genomes collected in the winter and spring of 2020 in 84 countries around the world. Initially, there were more genomes, but in order to make the selection more balanced, some were eliminated: the researchers selected one genome from groups of people who directly infected each other, and at the same time did not take into account all the dubious sequences and part of the genomes from the UK, because there were too many of them – almost half of the total.
To assess the variability of the virus, the researchers compared these sequences and found out that out of 29409 letters of the SARS-CoV-2 genome, 7559 turned out to be polymorphic, that is, confused at least in some of the genomes studied. At first glance, it seems that this is a lot, but most of these mutations occur only once (5085), and the difference between two randomly selected genomes is small with a median difference of seven positions. In the GISAID database, there are genomes that have accumulated, at first glance, many mutations, but usually they turn out to be technical artifacts. In total, seven mutations occur more often than in 10 percent of the studied cases, and three of them are related to each other.
Comparing the number of synonymous and non-synonymous substitutions, the authors of the article concluded that most of the positions in the SARS-CoV-2 genome are under purifying selection and mutations there are rather undesirable for the virus, especially at protein-coding sites. They especially carefully inspected the RBD domain of the S-protein, which plays a key role in infection and is known for its variability among coronaviruses. Nevertheless, they did not find a single mutation there, occurring in more than 0.2 percent of cases. Based on this analysis, one should not expect that individual strains of the virus will mutate quickly and become very different from each other.
Despite the fact that mutations occur relatively slowly, some of them can profitably adapt the virus to a new host or make it resistant to vaccines that are currently being developed around the world. To test these concerns, the researchers focused on the most popular mutations that, presumably, could help the virus spread quickly.
The most well–known candidates are two substitutions (D614G in S-protein and P4715L in ORF1ab), which occur together in 70 percent of sequences. They were first found in the earliest European genomes and – since the descendants of these viruses quickly became leaders in the number of infections – they were naturally suspected of helping the mutant virus spread faster. The popularity of this idea was added by studies that pseudoviruses with D614G more actively infect cell cultures in vitro, although this does not directly indicate the success of the virus and the speed of its spread. For example, the previous coronavirus SARS-CoV-1 infected cells in vitro even more effectively than any of the variants of SARS-CoV-2, but did not receive such a spread. Another version attributes their popularity to a coincidence – it just so happened that this version was one of the first to reach Europe and managed to spread unnoticed before the introduction of restrictive measures.
The authors of the article adhere to the second hypothesis and believe that the popularity of the D614G replacement is fully explained by the founder effect. This position turned out to be more variable than the others, but the researchers did not find evidence that mutations in these places help the virus spread faster. They suggested that D614G may affect the immune response, but T cells and neutralizing antibodies recognize SARS-CoV-2 from other protein sites and have no preference in this position. There was also no evidence that the frequent occurrence of this mutation is caused by its independent appearance from different sources.
Analysis of a large number of genomes showed that in five months only one mutation became widespread, and its role in the adaptation of the virus remains debatable. Such rates allow scientists to optimistically declare that the vaccines being developed should work equally well (or poorly) against all analyzed variants of the virus.
How effective the Russian vaccine being developed at the Gamalei Institute is will be found out by the results of the third phase of clinical trials that started a few days ago. About forty thousand people will take part in the tests, but even before the results are received, it is planned to begin vaccinating people from the risk group on the basis of temporary registration of the vaccine.
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