India reported 1,84,372 new Covid-19 cases in the last 24 hours, setting another grim one-day record, taking the overall tally to 13,87,825 on Wednesday, according to the data issued by the Union Health Ministry. The crowds at election rallies and religious gatherings are not thinning and the daily growth of infections and active cases are also growing consistently. India is also grappling with various variants of the coronavirus: the UK variant, South Africa variant, Brazil variant and the double-mutant, which combines mutations from two separate virus variants, found in samples from Maharashtra, Delhi and Punjab. The double-mutant has been classified as B.1.617 lineage, was found in 15-20 per cent samples in Maharashtra. In the backdrop of steep rises in cases, the government has allowed faster access to foreign-made vaccines by doing away with bridging trial studies prior to grant of emergency authorization.
Virologist Shahid Jameel, director of the Trivedi School of Biosciences at Ashoka University, said “we don’t yet know whether further mutations would make current vaccines useless, this is unlikely. However, the efficacy of vaccines may be reduced due to mutations.”
Excerpts from the interview
Q1: The genome sequencing carried out by Indian SARS-CoV-2 Consortium on Genomics identified two important mutations in the variant dubbed as “double mutant”. Is there a possibility that currently available vaccines may not work against double mutant?
Answer: The “double mutant” is a misnomer. This has now been defined as a distinct lineage called B.1.617 (just like the UK variant is called B.1.1.7). Viruses of this lineage have 15 mutations, of which 6 make changes to the Spike protein – and 3 are critical. The mutations L452R and E484Q are in the region of the Spike protein that binds to the ACE2 receptor – the first mutation increases ability of the virus to enter cells and the second one accounts for partial immune evasion. Another mutation called P681R also makes virus entry into cells more efficient. The combined effect is a virus that infects more (i.e. more infectious) and also partially evades some neutralizing antibodies. This inference is based on earlier studies of these mutations. The Indian B.1.617 variant has so far not been grown in labs to directly test its properties. That work is going on.
Q2: Virus are subject to mutations and with time, many more mutations will surface. How could vaccine technology adapt to these mutations?
Answer: Mutation is natural to a virus. Every time a virus multiplies, random copying errors take place. Most of these errors are deleterious to the virus and those mutants don’t survive. However, sometimes a mutation gives an advantage to the virus by binding and entering cells just a little better than its predecessor or by side stepping pre-existing immunity. These mutant viruses are selected and overtake the original virus. But there is a limit to how much a virus can mutate. Beyond a point, mutations will compromise essential steps in the virus multiplication and infection process.
Vaccines give rise to two types of responses – humoral, based on antibodies and cellular, based on T cells. Even if antibodies don’t protect as well, T cells are able to seek and destroy cells that do get infected by the virus that side steps the antibodies. The result is infection but no disease. Most vaccines protect against disease not infection, and Covid vaccines are no exception. There are very few vaccines that give sterilising immunity, i.e. no infection.
We don’t yet know whether further mutations would make current vaccines useless. This is unlikely. However, the efficacy of vaccines may be reduced due to mutations. This was observed in Phase 3 trials of the Johnson & Johnson and the Novavax vaccines. These were effective against the original virus and the UK variant, but showed reduced efficacy against the South African and Brazil variants. India’s Covaxin also seems to neutralise the UK variant well in laboratory tests, but results are not yet available from the population or for the B.1.617 variant.
Q3: One of the reasons for the steep rise in cases is due to emerging mutants – both imported and homegrown. Which is the most lethal homegrown mutant, is it the double mutant which was found in Maharashtra?
Answer: I do think that once the time series data coming in from states are epidemiologically correlated, emerging mutants are going to be an important factor in the surge. It is hard to say which is the most lethal mutant. To be able to say that we will need a large enough dataset of people infected with the original virus and the different mutants, and these people would have to be categorized into asymptomatic, mild, severe and fatal cases. Such data is not available. So, everything you hear is anecdotal and has no rigorous scientific basis.
What we do know from laboratory experiments is whether viruses with a particular mutation or variants of concerns (eg UK, South Africa, Brazil, etc) are able to evade certain therapeutic antibodies or antibodies present in the blood of recovered patients and vaccinated people. We also know the structures of the viral Spike protein, the ACE2 receptor and several therapeutic antibodies bound to the Spike protein. This allows us to know the important regions in the Spike protein and if the mutations change these regions enough to speed virus entry into cells or reduce the effects of antibodies. That in turn would lead to increased infectiousness and immune evasion, respectively.
Q4: Is there a possibility that due to mutants, one person is spreading the infection to many persons, and this may have led to the spike in cases in the second wave?
Answer: There is accumulating evidence that more “infectious” strains are in circulation. The UK variant was shown in that country to be about 50 per cent more infectious. The Indian B.1.617 variant also carries the signatures for being more infectious, although those tests have not been done so far. It is plausible that this increased infectious potential of mutant viruses is a strong reason for the surge.
Q5: The increase in number of cases in second wave is twice as fast as in the first wave? Is it largely due to the mutations?
Answer: That seems to be the most logical explanation. However, as mentioned above, those epidemiological correlations have not yet been made.
Q6: Is there a possibility of a third wave, in the backdrop of the ongoing vaccination drive?
Answer: That will depend on vaccine availability, coverage and duration of protection. It will also depend upon whether the virus can change further and continue to productively infect those who have already been infected or vaccinated. Essentially, it would depend upon the remaining pool of susceptible people. Pandemics also die out with waves that become progressively weaker and come farther apart. We will have to wait and see that.
(Sumit Saxena can be contacted at firstname.lastname@example.org )