Social media is on the fire with ‘Supermax coronavirus’ scare. With the detection of seven patients with the new variant of a novel coronavirus, called B.1.1.7 among the passengers who had disembarked from the UK, one of them in Chennai, public anxiety is on the upswing.
Are we back to square one? From all the scientific evidence at our hand, the short answer is emphatic ‘No!’ This is a variant of the novel coronavirus. The disease caused, treatment required, public measures to be followed and the personal hygiene protocol remain the same. “This is not a super-virus. This is another variant of the same novel coronavirus causing COVID19 disease. It is not a new strain or species of virus. While we must exercise caution there is no reason for panic” says Dr Vinod Scaria, Senior Scientist, CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB)
Why is the UK variant in the news? The variant was first discovered in September 2020. By December, about 70% of the new cases in Kent region were affected by this new variant, causing alarm that this variant may be more infectious. December 19, the UK health secretary announced in the British parliament that the variant, dubbed B.1.1.7 is spreading rapidly in the UK. Keeping the Christmas and New Year holidays in mind, UK prime minister Boris Johnson announced stricter lockdowns.
What is new in the variant? This specific variant is named ‘B.1.1.7’. As compared to the first-ever genomic sequence of SARS-COV-2 virus sampled from a patient at Wuhan during last December, this one has in total 23 mutations. Eight of these mutations are in the part of the RNA corresponding to the spike protein. Spike protein enables the virus to enter human cells and is the critical targets for immune response. In particular, two of these mutations called N501Y mutation, and P681H mutation is expected to have a considerable impact on the virus’s cell entry. “Antigens, in the spike protein are the target region for vaccine, monoclonal antibody treatment, convalescent plasma treatment and hence alterations in the spike proteins are watched with caution,” says Dr Scaria.
What is a mutation? We can think of the genome of SARS-CoV-2, RNA, as a ‘book of life’ containing 30,000 nucleotides, that is the alphabets of life, adenine (A) and guanine (G) cytosine (C) and uracil (U). The ‘words’ of the genome are three lettered and code for 20 different types of amino acids. The ‘gene’ that is the ‘sentence’ in the book of life is a chain of amino acids goes to make a protein. The virus reproduces by replicating its genomic code. Just like spelling errors creep in as we copy the master text, mistakes may occur in the genome sequence during replication. These are called mutations. Most of the modifications are not sustainable, and those mutants that survive are called ‘variants’.
Are all mutations more dangerous? Not at all. The mutations may occur essentially in three ways; deleting an alphabet in the sequence, an additional one inserted or one nucleotide replaced with another. Most of these misspellings, mutations, are deleterious to the pathogen. It impairs the function of the virus, and the mutant variety may not survive at all. Each amino acid is coded by more than one sequence, and hence at times, the change in the genetic sequence may not result in the variance of the amino acid coded for. In such cases, the mutant is no way different from the earlier one. Only in rare instances the mutation result in non- synonyms change of amino acid and results in the modification of protein produced. Even when the protein now has a different amino acid, the protein’s biological function is more to do with the way it folds and creates a shape. As long as the form is sustained, there is no biological difference stemming from the altered protein. Only in a sporadic case, the change in amino acid may result in amended protein fold. Only such a mutant may show an altered behaviour with the host interaction.
Is the UK variant the only one? No. On an average, in novel coronavirus, one mutation occurs once in fifteen days. In India, as on December 24, 2020, we have sequenced more than 6370 genomes and found 5879 unique variants. World over the unique variants detected will be many times more. “Many many variants emerge, some thrive and some may even disappear completely,” says Vinod Scaria. “For example around June 2020 we noticed a new clade A3i dominant among the samples from certain states. Once it accounted for as much as 41 per cent of the genome sequenced in India. Today this clade has almost disappeared. On the other hand another mutation D614G in the spike protein has come to stay. It is widely prevalent all over the world.”
Mutations in B.1.1.7? This variant sport 23 mutations across five genes. Of these six mutations do not change the code for amino acid and hence practically do not alter the behaviour. However, 17 of these changes are non-synonymous, meaning that the amino acid coded gets modified. Eight changes are in the spike protein, which is a chain of 1273 amino acids. N501Y mutation replaces asparagine (N) to tyrosine (Y) at position 501 of the spike protein amino acid chain. Similarly, Proline (P) is replaced by Histidine (H) at the 681st position by the P681H mutation.
Why this is a cause for concern? The N501Y mutation is at a critical contact point of the receptor-binding domain (RBD) in the spike protein. This part of the spike protein comes into close contact with the ACE2 receptor in human respiratory cells. Computations show, this mutation, could boost the binding affinity of the spike protein to ACE2. The P681H mutation is at the cleavage site. This is the spike protein part that pries open the human cell, letting the viral genome enter. These two mutations together can make this variant possibly more contagious. “There is not much evidence that this variant will cause severe disease, though there is a possibility that it may evade detection in some cases, especially diagnostic kits using primers/probes for spike gene” observes Dr Scaria.
Is this the first mutation on the spike protein? No. World over 4000 mutations have been seen in spike proteins until now. “Even the variants carrying N501Y and P681H mutation are not new. N501Y mutation is already frond in a lineage in South Africa and Australia” says Dr Scaria. However this is the first time both these mutations are seen together in one single variant.
Is this variant more scary? The Public Health England, an executive agency of the Department of Health and Social Care, conducted a cohort study in which they compared the patients infected with this B.1.1.7 variant and other coronavirus variants. The preliminary results clearly indicate that there is no significant difference in hospitalisation, or mortality between the new variant and older ones.
Will this affect the vaccines? Around 120 vaccines are under development around the world. About five are in the last stage of human trail awaiting approvals. In India, two indigenously developed vaccines are in the third stage of human trials. “Vaccines target not one region of the spike protein but a range of antigens. Hence changes like these are unlikely to have serious impact on the efficacy of the vaccines” says Dr Scaria. A study conducted by Vineet Menachery, Department of Microbiology and Immunology, The University of Texas suggest that ‘the N501Y variant is just as susceptible to our defenses as the original virus’. Therefore the vaccines under development will be as effective against this variant as any other. “But the case of the monoclonal antibody treatments against the virus is different, the mutations may make some of the monoclonals ineffective against this variant” cautions Dr Scaria.
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Vigilance is needed: In a recent paper, which is yet to be peer reviewed, but available on a pre-publication server, Bani Jolly of CSIR-IGIB and others report on the global emergence of the ‘antibody and immune escape variants’. These variants have critical mutations in the spike protein and hence the monoclonal antibody therapeutics could fail when a person is infected with this variant. The study also points out, that including N501Y, a total of 20 such ‘antibody and immune escape’ variants are circulating in India. Of this N440K mutant in spike protein genome is around 2.1% in India and about 33.8% in Andhra Pradesh.
The N501Y mutation found in the B.1.1.7 is one such mutation. This mutation is found among the patients in United Kingdom, Australia, South Africa, USA, Denmark and Brazil, suggesting that perhaps this mutation has emerged independently in more than one location. This means, these variants need not be physically transmitted from one region to another; they can emerge at a distant location naturally. This is no surprise, as the natural selection is at work, and out of random mutations more adapt variant is bound to emerge sooner or later. Unless we eradicate novel coronavirus with global universal vaccination.
If many of these mutations evolve and blend into one variant, that could lead to emergence of a worrisome variant that could evade not only monoclonal antibody therapy, but some of the vaccine candidates too. That would be a disaster. This study once again under score the need to take the molecular surveillance seriously, and closely monitor the emergence of mutations in India.
What is to be done? Being vigilant about the emergence of new mutants is particularly important at this juncture of the pandemic. For example, analyses of more than 28,000 spike gene sequences in May 2020 revealed a D614G substitution that was rare before March 2020 but became more common as the pandemic spread, occurring in over 74% of all published sequences by June 2020.
With vaccines around the corner, and the end of the pandemic is in sight, what we can’t afford is new mutant that would evade the immune response of vaccines. The World Health Organisation (WHO) recommends that viral sample from one out of every 300 confirmed cases, which works out to 0.33%, is sequenced to catch the emerging new variant before it becomes viral. Australia has the highest rate of genomic sequence. They sequence the virus sample taken from about 50% of the confirmed cases. The UK has about 7 to 8 % coverage. US, South Africa cover about 3% very close to the suggested range
Spearheaded by the Centre for Cellular & Molecular Biology (CCMB) and IGIB, two institutions under CSIR, with foresight, India embarked upon the molecular surveillance, right at the beginning of the pandemic. Indian SARS-CoV-2 Genomics Consortium (INSACOG) has been put in place to obtain samples and sequenced genome. Vigilant watch over the virus mutations in India showed us the emergence of a new clade IA3i, which was once widely prevalent, but now practically disappeared. The work also brought to light asymptomatic healthcare workers reinfected with Covid-19, that the Coronavirus clade predominant in India originated in Europe, and about 4% of the variants circulating in India will evade the current test primers. These findings have implications for pandemic control. As the dominant clade in circulation from Europe, the vaccines and drugs developed in Europe will also be as effective in Indian patients. Keeping check on the viral mutation helps in updating the test kits and vaccine composition.
“We need to keep watching the mutations, in particular occurring in spike protein. As long as the virus is in circulation, over time, through natural selection a mutant viruses that can evade the immune system will evolve. Until now the mutations do not affect the vaccines under development, a tipping point may come when the existing vaccines may be become somewhat less effective due to cumulative effect of the accumulated changes” says Dr Scaria.
In India, at this point, our sequencing rate is about 0.05%, way below the WHO recommendations. Further experts say that most of the sample in India are collected from cities and metros. There is a need to ramp up the sequence rate with samples collected from wider geographical locations. Kerala, the only state to do so, has planned to collect 1400 samples from the state every month. Other states needs to dial up the samples for sequencing. For India, the UK variant is not so much a threat, but a wake-up call.