Virulent Mutant of SARS-CoV-2 and the lingering questions

The genomic study on the virus is limited in India and there is, therefore, a need to study it so that any changes and its consequent implications are understood.

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Manipur is just coming out from the first wave of the COVID-19 pandemic and people seem to think that the problem is over. But the breathing space must be utilised to prepare for the second wave and it is hoped that the more virulent lineages are not the one which comes in the second wave.

In the initial stage of the pandemic, in March, Korber and her group observed that mutations are reoccurring several times in samples from people with COVID-19. Although SARS-CoV-2 mutates slower as compared to HIV, there is no doubt that mutations are happening. At the 614th amino acid position of the spike protein, the amino acid aspartate (D, in biochemical shorthand) was regularly being replaced by glycine (G) because of a copying error that changed the single nucleotide in the virus’s 29,903 letter RNA code. Virologists called it D614G mutation. The mutant is becoming the dominant lineage in Europe and had spread to the US, Australia and Canada. A paper in April by Korber et al suggested that it is a more transmissible form of the virus, one that had emerged from natural selection.

Some studies have shown that this variant infects human cells more easily. Other studies revealed some good news in that the variant might mean that vaccines can target the virus more easily. But many scientists were sceptical, saying that there is no solid proof that D614G has any significant effect on the spread of the virus. There are more questions than answers about coronavirus mutations. Scientists studied and analysed the viral samples and posting of the genetic codes online. Mutations most of which are single-letter alterations between the viruses from different people allowed tracking of the spread by linking closely related viruses and to estimate when SARS-CoV-2 started infecting people. In the SARS virus, there is the belief that a mutation called a deletion might have slowed its spread.

It was suggested that a typical SARS-CoV-2 virus accumulates only two single-letter mutations per month in its genome; a rate of change which is half of that of influenza and one-quarter of HIV. Two SARS-Cov-2 viruses from anywhere in the globe would differ by an average of 10 RNA letters out of the 29,903 letters. By September, despite the lower rate of mutation, researchers have catalogued 12,000 mutations in the virus genome. Mutations occur, however, much faster than scientists can make sense of it. Many mutations have no effect on the virus’s ability to spread or cause disease because they do not alter the shape of a protein, whereas those mutations that do change the proteins are more likely to harm the virus than to improve it. There are suspicions that mutation that helps to spread faster had happened earlier when the virus first jumped into humans or acquired the ability to move efficiently from a person to another. Logically when every human on earth is susceptible to infection, there is no reason for selection to do better.

D614G was first observed in samples collected in China and Germany in late January; making scientists believe that the mutation occurred in China. It was found that D614G is almost accompanied by three other mutations in other parts of the genome hinting that these share a common ancestor. There is the belief that changing from D to G make the virus more infectious.

The clearest sign that D614G has an effect on the spread of the disease in humans comes from the ambitious UK effort called the Covid-19 Genomics UK Consortium, which analysed more than 25,000 viral samples and from these data, researchers have identified more than 1,300 instances in which virus entered the UK and spread, including examples of D and G types of viruses. After the study, it was found that there are no clinical differences in people infected with either virus; though G virus tends to transmit slightly faster than lineages that do not carry the mutation and formed larger clusters of infections. In pseudovirus study on the spike protein, it was found that D614G loosens the spike protein. The spike protein is composed of three identical peptides in an ‘open’ and ‘closed’ orientation and it was suggested that at least two of the three peptides need to be open for viral particles to fuse with the cell membrane and it was further observed that the G variant was much more likely to be in this state.

Most available evidence tends to suggest that D614G does not stop the immune system’s neutralising antibody from recognising SARS-CoV-2. The reason may be that the mutation is not in the spike protein’s receptor-binding domain (RBD). RBD binds to the cell receptor protein ACE-2 and the target of the antibodies. There are other evidences that other mutations could help the virus avoid some of the antibodies.  Studies were carried out to predict what mutations are likely to occur. What worries scientists are that immune evading mutations may occur, especially when a large number of people is immune to the virus through either natural infection or through vaccination? Cocktails of monoclonal antibodies which Donald Trump was given may be an answer to meet the challenge in the future. Further body’s natural immune system produces a range of antibodies so that if the mutated virus is immune to one it will not be to the others.

The above paragraphs were to show that the virus continues to mutate and will continue to do so and that researchers are on their toes to study them and catalogue all such lineages and strains.

Recently UK had announced that a new lineage of SARS-CoV-2 which is 70% more infectious than the earlier lineages. The new linage named B.1.1.7 was detected from the Covid-19 Genomics UK Consortium data and in a report published in October expressed concern about this cluster. This cluster has been growing rapidly since September in UK. B.1.1.7 lineage has an unusually large number of genetic changes, particularly in the spike protein; very worrisome alterations. Three of the mutations have potential biological effects which are: mutation N501Y, spike deletion 69-70del and mutation P681H. Mutation N501Y is one of the six key contact residues within the RBD and has been identified as increasing binding affinity to human and murine ACE-2. Spike deletion 69-70 del was described in the context of evasion to the human immune response but has also occurred a number of times in association with other RBD changes and Mutation P681H is immediately adjacent to the furin cleavage site.

The response to the announcement was the ban of flights originating from the UK by various countries including India and the UK is now literally isolated. Despite the travel restrictions, this lineage will find its way to other countries and may already have travelled to other countries from September onwards and may become the dominant lineage of SARS-CoV-2. There will be a flurry of investigations as to whether the vaccines developed or under development will continue to have an effect on the virus or whether this lineage will require a new vaccine. There is as yet no report on the clinical manifestation of the new lineage though there seems to be hardly any difference. This is just an example of the mutations on the genome of the virus will have an impact on the prognosis of the disease and its treatment and protection.

The genomic study on the virus is limited in India and there is, therefore, a need to study it so that any changes and its consequent implications are understood. The virus will continue to mutate and thus the challenges will be there with us and it may finally become like that of the Spanish or Asian flu, where the humans adapted so that the outcome of the infection is not mortality but an inconvenience. In the meantime vaccines and drugs which can combat it will also be thrown up to meet the challenges.

First Published:Dec. 23, 2020, 1:41 p.m.

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