The questions, as usual, are plenty and never too easy. Is the second wave over? When will the next wave of infections wash up ashore? Will it be as brutal as the previous one? How dangerous is the Delta plus variant? Take that first poser, for instance. The most likely answer: Yes and No. As Balram Bhargava, director general of the Indian Council of Medical Research (ICMR), put it at a press briefing in late June, the epidemic is under control in large parts of the country—about 535 districts at last count—where the test positivity ratio was less than 5 per cent. But not so in some pockets. “The second wave is not yet over in our country. We still have 75 districts which have more than 10 per cent prevalence,” he said. Averting a future wave, therefore, hinges on a variety of factors—foremost among them being Covid-appropriate behaviour and avoiding mass gatherings.
Even in regions where the two-month lockdowns have been lifted, the threat hasn’t gone—Pune, and other cities in Maharashtra, brought back last week strict curbs such as night curfew from 5 pm and ordered shops selling non-essential items closed during weekends following a state-wide alert on the Delta Plus virus variant that is being closely tracked now. This new variant is from the same family tree as Delta—first identified in India, this one we now know was the primary cause of infection in the country during the second wave.
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But first, a recap—given the difficult technical nomenclature of virus lineages, the WHO in June assigned a simpler naming system of Greek alphabets to the key SARS-CoV-2 virus variants which had so far been commonly referred to by the countries they were detected in. Hence the UK, South Africa, Brazil and India variants became Alpha, Beta, Gamma and Delta. As virologist Shahid Jameel explains it, the variants in circulation in India this year were mostly Alpha and Delta—the other two not having caught on in the country. “And wherever Alpha and Delta were present together,” says Jameel, “the former has been replaced by Delta which means Delta is more transmissible than Alpha.” Currently, reports suggest that Delta may be replacing other variants in other parts of the globe as well—it is now the dominant variant in the UK, and several Australian cities have locked down to control the Delta surge there.
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In mid-June, the Indian SARS-CoV-2 Genomics Consortium (INSACOG), a network of genomic sequencing labs that tracks the virus’s spread in the country, began tracking a Delta variant which had a further mutation in its spike protein—this mutation, called K417N, had been previously seen in the Beta lineage and has been associated with immune evasion. The new variant, which goes by the name Delta Plus was first reported by Public Health England in early June but very little is known so far about its clinical relevance. According to INSACOG, the first occurrence in India was detected during a retrospective analysis of a sample collected from Maharashtra in April. Up to this week, about 51 isolates of this variant have been detected in Maharashtra, Kerala, Madhya Pradesh and nine other states. The Delta plus variant has been detected in 12 countries so far.
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Jameel says there’s really no data at the moment to say anything conclusive about the Delta plus. “Everything that people are talking about is pure speculation. Let’s keep tracking it,,” he says. “But based on 50 sequences, for people to go out and say it is more infectious or lethal, that it would bring the third wave, that’s all baloney.” Authorities say the samples detected were mostly localised but the alert has been sounded across states and laboratory tests are on to know whether vaccines work against it. “Whether that virus is going to be significant or not we do not know yet but we have identified where it has suddenly emerged and isolated those people and ring vaccination has been initiated in those areas,” said Bhargava at the briefing.
The bigger worry, Jameel reckons, is people slipping up on precautionary measures as soon as lockdowns ease up. Indeed, cases have dipped—to less than 50,000 new infections this week while vaccination has picked up pace—averaging over 60 lakh most days by the third week of June.
“It’s definitely important to be ready for another wave. But at the same time it’s very hard to predict, no matter how sophisticated the model, that there is going to be a wave because so many things have to come right in order for it to be a nationwide phenomenon,” says Prof Sitabhra Sinha of the Chennai-based Institute of Mathematical Sciences. Even during the first wave last year, he says, there had been localised outbreaks in districts when overall nationwide cases had fallen. Currently, India’s reproductive number (an indicator of the speed of transmission) is around 0.78, which is the lowest it has ever been since the pandemic broke out last year, says Sinha. “But this is a national average, it won’t tell you much about whether things are going bad in particular states and so on.”
Biostatistician Bhramar Mukherjee of the University of Michigan, who had flagged early trends of the second wave in mid-February, recently told an interviewer: “I think it is very difficult to predict the timing and magnitude of the third wave at this moment as they depend on virus transmission, human behaviour, virus mutation and level of vaccination. Our models currently do not predict an imminent wave in the next six weeks but the reality can change rapidly.”
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Prof Manindra Agrawal of IIT Kanpur, who is currently working on a projection using a mathematical model called SUTRA, too reckons that predictions of a future wave can’t be made with any certainty. “The reason is that the characteristics of the virus itself keep changing. One has to just make some reasonable guesses. Effectively, what you can do is create some ‘what if’ scenarios, they are not really predictions.”
Recently, scientists from ICMR and Imperial College London simulated the potential conditions under which a serious third wave could occur in a mathematical model. Their results suggested that a new immune escape variant would need to fully escape at least 30 per cent of prior immunity, to cause a third wave, and that a more-transmissible variant would need a higher reproductive number of at least 4.5 to cause a third wave. “Overall, these results suggest that a third wave, if it should occur, is unlikely to be as severe as the second wave, given the extent of spread that has already taken place,” said the paper. “Consequently, for a virus to cause a major third wave in the face of this pre-existing immunity, extreme scenarios for the abrogation of that immunity are required, or for that matter, for the transmission fitness of any novel virus.”
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Many experts reckon that few places were left untouched by the brutal second wave this summer—a fresh serosurvey, which ICMR has proposed, could point to a clearer estimate of what fraction of the population has been exposed to infection. Epidemiologist Jayaprakash Muliyil says that all the scepticism about the immunity conferred by a previous infection have been proved wrong—meaning that adaptive immunity has been found to be long lasting. It is possible that a more infectious variant can emerge but that, again, means that only people not previously infected are susceptible, he points out. “We are doing a serosurvey, we’ll wait for the results,” he says.
Currently, the INSACOG network has around 300 sentinel sites from which samples are picked up for genomic sequencing to trace variants. “We have covered the entire country...all the districts, all the states have been covered,” said Dr Renu Swarup, secretary, department of Biotechnology at the briefing with Balram Bhargava . The sentinel sites include both labs—where transmission can be monitored—and hospitals, where severity of disease can be assessed. The INSACOG puts out a weekly bulletin which goes to the state governments so that immediate action can be taken.
Given the increase in centres and lower caseloads of late, the original target of sequencing 5 per cent of infection cases appears feasible now. But smart sequencing—whereby districts with higher infection rates are targeted—will probably yield better results, says Shahid Jameel. He points to the faster and cheaper genotyping assays being used by Public Health England to identify variants. “Perhaps some of our labs can deploy that as well to look at Delta plus in a more focused manner,” he says.
Surveillance on all fronts clearly is the way ahead. “We are rebuilding our capacities in order to analyse up to the taluk and primary health centre-level. And, if there is any trend in positivity picking up in a certain village, to try and adapt micro containment approaches,” says V Ponnuraj, nodal officer of the Karnataka Covid war room. The idea, he says, is to achieve the granularity of PHC- and village-level in Covid management, so that the officers on the ground can take quick decisions and the PHCs can become fulcrum of Covid management, which in turn will strengthen the physical triaging mechanism.
“Whether a third wave comes or not, or whether it will be a wave for the whole country or that different regions will peak and go down at different times remains to be seen,” says Jameel. “And it will depend on how people are behaving, on how much we are able to vaccinate our population and whether a more infectious variant emerges.”
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Constant Variables
The fact that the SARS-CoV-2 virus lineages now have easy to use labels says a lot about how common they have become in public discussions—surely B.1.617.2 sounds far more complicated than Delta.
Currently, the WHO lists four Variants of Concern which go by the first four letters of the Greek alphabet. Besides these, are seven Variants of Interest—Epsilon to Lambda.
Since virus naturally mutate—changes to their genetic sequence can happen practically every time they replicate inside a host—there’s a constant watch on what’s happening through genomic sequencing and the information is shared via repositories such as GSAID. A virus isolate gets flagged as Variant of Interest when it has genetic markers—like a change in the receptor binding domain—that could potentially affect transmission or immune escape. When there’s evidence of this happening, it becomes a Variant of Concern (Delta, for instance, was designated a VoC on May 11 this year).
As of last week, India had sequenced around 45,000 samples—typically these are picked up from various sites across the country and include samples from international travelers arriving in India, hospitals, testing labs and from high transmission areas. The sampling also looks for repeat infections and infections post vaccination.
So far, the variants with public health importance detected in community samples in India are Alpha (3969), Beta (149) and Gamma (1). The Delta lineage, meanwhile, was found in several states where it drove the surge in cases during the second wave, according to Sujeet Kumar Singh, director, National Centre for Disease Control (NCDC).
By Ajay Sukumaran in Bangalore
