The term ‘double mutants’ doesn’t mean much

With reporting of the impact of the current wave of Covid-19 in India, there has been interest in the B1.617 variant of Covid-19 which was first identified there, and has been dubbed the ‘Indian variant’. 

It has often been described as a ‘double mutant’ but this terminology is unhelpful and doesn’t actually carry much scientific meaning.

It is normal for viruses to develop genetic mutations over time, and so mutations of SARS-CoV-2 (the virus that causes Covid-19) are to be expected. The number of mutations that a variant has is less relevant than what characteristics the mutation effects, and if the mutations could enhance each other's impact 

We have previously written about genetic mutations of Covid-19 and how they are classified here. 

What is a variant and what is B1.617?

When viruses replicate, they may mutate. Many of these mutations will have little impact on the way that the virus behaves but some may help the virus survive and so new variants of the virus with beneficial mutations may take root. 

These mutations may increase the variant’s transmissibility, how much harm it causes people who are infected (virulence), whether people can become reinfected, or how well vaccination can protect against them.

B1.617 is commonly called the “Indian variant”, and refers to a lineage of variants. The UK has recognised three closely related variants from this group to be closely monitored. These are B1.617.1, B1.617.2 and B1.617.3.  

They are sometimes collectively referred to as the B1.617 variants. However, they do each contain slightly different mutations. 

At the time of writing, B1.617.1 and B1.617.3 are variants under investigation which means that they possess “concerning epidemiological, immunological or pathogenic properties”, but have not yet been designated a variant of concern by an expert committee. 

B1.617.2 has been designated a variant of concern, after expert committee review.

Up until 5 May 2021, 235 cases of B.1.617.1, 509 cases of B1.617.2, and nine cases of B1.617.3 had been confirmed in England. 

What are the mutations and what do they do?

The B1.617.1 variant has at least thirteen different genetic mutations but it has been dubbed a ‘double variant’ because of two particular mutations (E484Q and L452R) which affect the genetic code which directs the building of the ‘spike’ protein on the coronavirus’ surface. This protein is important in allowing the virus to bind to and enter cells in the body. 

B1.617.3 has a slightly different make up, but also carries the E484Q and L452R mutations.  B1.617.2 is also genetically similar to the other B1.617 variants, but does not possess the E484Q mutation.

The E484Q mutation in B1.617.1 and B1.617.3 occurs at the same point in the genetic code, but is a slightly different version of the more well known E484K mutation in other variants. Lab studies have shown that the E484K mutation can make the immune system less able to recognise and respond to Covid-19, but work to explore what impact this will have on humans in the real world is ongoing. 

This also raises questions for how well vaccines can work against variants like these. E484Q has been less extensively studied than E484K, but initial lab studies have shown that the action by some, but not all types of antibodies were also reduced. 

The other genetic mutation of interest (L452R) may reduce the effect of antibodies, and potentially increase its infectivity.  

While E484Q and L452R are two potentially important mutations, the variant has quite a few others which demonstrate why the term "double mutant" isn't helpful, for example  P681R, which could alter the processing of the spike protein, and potentially therefore impact the way that the virus enters cells in the body. 

Professor Sharon Peacock, Director of COG-UK, and Professor of Public Health and Microbiology, University of Cambridge, said that the term ‘double mutant’ “is inaccurate, has no specific meaning and should be avoided.”

Professor Peacock said that whilst we do have some information about the individual mutations “more evidence is needed to understand the virus changes that result from the specific combination of mutations present in B.1.617”.

Dr Jeffrey Barrett, Director of the Covid-19 genomics initiative at the Wellcome Sanger Institute has said:

“This variant has a couple of potentially concerning mutations but these are probably not as serious as some of the mutations present in the variants first seen in Kent, South Africa and Brazil. This could be because we have had less time to study them, so these mutations should be watched carefully.” 

Is B1.617 behind the outbreaks in India?

There has been concern that the genetic mutations found in B1.617.1 (or the B1.617 variants more generally) may be contributing to the current Covid-19 crisis unfolding in India. 

They could be, but there are a number of other, human factors that may be driving the spike in cases. Because of this, experts such as Professor Peacock have said that “It is not clear at the present time whether B.1.617 is the main driver for the current wave.” 

She also said that we must be cautious of estimates that talk about the prevalence of different variants of Covid-19 in India, because relatively few cases are currently being sequenced, and this may be happening unevenly across different geographic regions of the country. 

Dr Jeffrey Barrett, Director of the Covid-19 genomics initiative at the Wellcome Sanger Institute, said:

“It is certainly possible that there is a cause and effect relationship but there have only been about 1000 sequences published from India out of about 4 million cases in this wave so far. So we only have a tiny window into which variants are becoming the most common and it’s not clear if they are fully representative.”