28 July 2020
Coronavirus SARS-CoV-2, the virus behind the COVID-19 pandemic, has been studied intensely since emerging in late 2019 – so far, researchers have sequenced tens of thousands of SARS-CoV-2 genomes to learn about the genetic variation of the virus. Monitoring the viral genome for mutations can give important clues as to how the biology of the virus is changing and the potential impact on transmission rates and disease severity. From a policy point of view, this can have huge impacts on reinstating or relaxing lockdown and social distancing measures.
Genetic variation is caused by mutations (or errors) arising randomly in the genome as the virus spreads through populations. This process happens at different rates in different viruses and the biological consequences of these mutations vary greatly.
Coronaviruses such as SARS-CoV-2 possess 'proof-reading' machinery that enables the virus to repair most mutations that occur in the genetic code. The genetic diversity of SARS-CoV-2 is therefore quite low and the virus mutates relatively slowly, accumulating around two mutations in its genome per month, around four times slower than the influenza virus.
The vast majority of mutations will be neutral, meaning that there will be no impact on the biology of the virus. Positive mutations could increase a virus’s ability to infect host cells, to replicate within a host cell more rapidly, to evade the host immune response, or increase virus transmissibility. These are likely to support spread of the virus through the human population. Negative mutations, on the other hand, inhibit these capabilities, and are unlikely to prevail.
There are currently investigations and debates underway as to whether there are different strains of SARS-CoV-2 circulating – in particular, there is a focus on whether a genetic mutation in the SARS-CoV-2 genome that emerged early in the pandemic rendered it more transmissible , which would allow the virus to spread to more people, more easily.
The interpretation of genomic data is still ongoing, but has important impacts for medical developments, public health and policy decisions. Recent analyses have suggested that a variant of the original virus isolated from patients in Wuhan, carrying a mutation in the viral spike protein, has dominated around the world.
The external shell of the virus is covered by the spike protein which enables the virus to attach to and enter host cells. This protein is of particular interest as it is one of the most likely targets for the immune system, and therefore, vaccines are being developed using the specific sequence of the spike protein.
A recent publication by Korber et al provided evidence that a specific mutation in the spike protein has dominated in viruses isolated from patients around the world – i.e. the mutation has been repeatedly found to dominate in different locations where the original and the mutated version co-circulated – suggesting that this mutation conferred a fitness advantage. They found that individuals infected with this variant of the virus had higher viral loads – i.e. more virus particles in their upper respiratory tracts – potentially meaning that they may be more effective at spreading the virus. In addition, laboratory tests in cells suggest that this variant could be better at entering human cells, though these tests cannot determine the impact on transmission within populations.
In addition to the Korber paper, the COVID Genomics UK (COG-UK) consortium’s most recent report echoes the finding that viruses containing the spike protein mutation are prevailing. However, COG-UK have been somewhat more reserved in their interpretation of the analyses, stating that the full impact of this finding is not yet clear.
Whilst there is still uncertainty around the importance of these findings, importantly, both analyses confirmed that there is not yet any evidence that there is a link with this mutation and more severe disease.
Many factors have contributed to the SARS-CoV-2 pandemic. External factors such as densely populated, globally mobile communities have contributed to disease spread, but virus biology also contributes.
SARS-CoV-2 is highly transmissible with estimates that each infected person will infect two to four individuals – as a comparison, those with seasonal influenza will infect one to two individuals. In humans, SARS-CoV-2 infection does not always cause symptoms or they can emerge up to two weeks after infection. Containing the spread of the disease is more difficult when individuals can be infected and pre- or asymptomatic, and pass on the virus without knowing it.
Changes to the viral genome that enable SARS-CoV-2 to infect individuals more efficiently and replicate faster but do not, for example, change the severity or timescale of symptoms could lead to more people being infected. Conversely, a mutation that leads to more people feeling ill could mean more people getting tested and either being advised to isolate or being hospitalised, thereby potentially reducing transmission.
From a policy point of view, changes to virus biology and our understanding of what is causing them can have huge impacts on reinstating or relaxing lockdown and social distancing measures.
In addition to impacting policy decisions, changes to the genome sequence can have consequences for other disease management initiatives. There are many efforts ongoing to develop diagnostics, vaccines and treatments, which rely on accurate genomic information. Should mutations arise in parts of the genome, such as the Spike protein gene, which are being targeted by these efforts, then this could undermine the development of vaccines or treatments based on a particular genetic sequence. For example, many groups are working on vaccines that use the specific structure of spike protein to evoke an immune response, bestowing immunity.
With only seven months’ worth of genetic data, gathered from only a small sample of the infected population, uncertainty is to be expected. The relative importance of mutations found so far in the SARS-CoV-2 genome is still unclear. But with what we know about the infectious disease genomics, the substantial sequencing efforts around the globe in response to the pandemic are clearly vital to reducing the spread of this disease and future pandemics.