India’s triple mutant Covid variant is sparking global concern. Why do we know so little about it?

As of April 20, India’s homegrown variant of the novel coronavirus has spread to at least 15 other countries, worrying health administrators and scientists across the world. Several countries, most recently the United Kingdom, have banned flights from India. There is a growing clamour in many other countries such as Canada to do the same.

Although there is lack of data, there is widespread speculation among Indian scientists that the country’s current surge – the worst since the outbreak of the pandemic – is fuelled by this variant, labelled B.1.617.

According to the global GISAID database, a free-to-access collaborative initiative of the German government and Friends of the non-profit GISAID, the variant accounted for 63.6% of coronavirus strains from India that underwent genome sequencing by GISAID participants in the last four weeks.

Apart from India, the variant is most prevalent in the United Kingdom, United States, Singapore and Australia.

“It is remarkable how far it has spread since it was first detected,” said Jeremy P Kamil, associate professor of microbiology and immunology at Louisiana State University in the United States.

Growing concerns

The B.1.617 variant was first detected in Maharashtra in October, show GISAID records. It was initially thought to comprise two mutations – E484Q and L452R – and hence, referred to as a “double mutant” variant. But now scientists believe the variant consists of more mutations: E154K, P681R and Q1071H.

Viruses mutate all the time, resulting in millions and millions of new variants. However, what has made scientists worry about B.1.617 is the presence of three mutations, E484Q, L452R and P6814 – the reason why some are now referring to it as a “triple mutant” variant. These mutations have been found in other “variants of concern”, a term currently being used for the variants from UK, South Africa and Brazil.

The E484Q mutation, for instance, is similar to the E484K that was previously seen in the fast-spreading Brazilian and South African variants.

The L452R, also found in a variant first reported in California, could have immune escape, which means it could dodge antibodies induced during a prior infection or a vaccine, and therefore, show greater virulence.

The P681R mutation is similar to a mutation seen in the highly-infectious United Kingdom variant and, according to Kamil, “possibly also similar” to the Q677H mutation seen in the South African variant.

Lack of data

Despite these red flags, there is surprisingly very little publicly available data on the extent of the variant’s spread. Consider this: as of Tuesday evening, there are over 384,000 sequences of the UK-origin B.1.1.7 variant on the GISAID database. In contrast, the count of B.1.617 sequences is only 660. Out of them, 298 are from India, 205 from the United Kingdom, and 69 from the United States.

This has exasperated scientists across the world. “India’s scientists have thus far not done a great job sharing the sequences that they generate, which is a shame because the sequences are most valuable to India and to scientists around the world when they are shared in real time,” said Kamil.

Kei Sato, a virologist affiliated to Japan’s University of Tokyo, expressed similar frustrations. The lack of data from India, Sato said, was “one of the biggest concerns in the virologist community worldwide”.

It is not that Indian scientists and research institutions have not tried to do more. But bureaucratic red tape and lack of resources have come as a stumbling block in every step of the way – as this report in The Wire documents with great clarity.

The Indian government stepped in only in late December when it launched the Indian SARS-CoV-2 Genomic Consortia. The consortia’s work, too, has suffered because of government inertia: it has been able to barely meet 20% of its target so far.

‘Sampling bias’

What this means is we still do not know for sure how much of a cause of concern the new Indian variant is.

Scientists warn that although over 60% of the sequenced variants from India in the last four weeks have thrown up the B.1.617, there was likely a “sampling bias”. In this period, India has submitted a mere 88 sequences.

This is reflective of a larger pattern. Ever since the beginning of the pandemic, India has submitted only around 8,800 virus sequences on the GSAID database. Of them, 247 of them are the UK variant and 298 are of B.1.617.

“I am concerned that these data are incomplete,” said Kamil.

Sato agreed: “It looks the proportion of B.1.167 may be just due to sampling bias.”

Consequently, research that may help answer some of the more burning questions around it such as immune escape and response to vaccination, is also hard to come by. “So far, nothing is public about who, where, infectivity or vaccine escape,” said Christina Pagel, head of the clinical operational research unit at University College London. “These are all crucial questions but right now we just don’t know the answer.”

How immune escape, really

There are at least two studies which suggest that the L452R mutation may evade some neutralising antibodies. One of them, however, is a pre-print which has not been academically peer-reviewed,

Sato was part of a third study, the results of which too have not been peer-reviewed yet. The pre-print contends that the L452R mutation increases viral infectivity and helps the virus evade a certain kind of “cellular immunity”.

Cellular immunity through T-cells is different from humoral immunity that antibodies provide. However, the cellular immunity in question is mediated by a part of the immune system that differs according to ethnicity.

Sato said the type of evasion he and his colleagues found may “not (be) related to the Indian situation”. Instead of worrying about the mutation’s immune escape potential, India’s energies should be directed more at dealing with the mutation’s higher infectivity potential, he said.

‘Huge exaggeration’

Kamil said concerns about the L452R mutation evading all immune responses seemed overblown. “There is no credible research that says the L452R mutation will escape all cellular immunity or antibodies,” he said. “That’s a huge exaggeration.”

Adaptive immune response, Kamal explained, is “polyclonal”. “Which means even if the thief (the virus) puts on a fake moustache or a wig, the immune system will still recognise the tattoo on his arm, or the scar on his hand,” he said.

So are some vaccines more adept at negotiating these mutations than others? “I think it is inevitable that some vaccines might perform better than others,” he said. “However, almost all of them could save your life… AstraZeneca, JNJ, Sputnik, Moderna, BioNTech/Pfizer… for most people these vaccines can mean the difference between little to no disease and ending up in the hospital with a risk of dying.”

But to keep the vaccines up to date, Kamil said, it was imperative that there was more genome sequencing. “The entire world needs to do a better job being transparent with the public about how valuable and important the genetic data of viruses that infect us are when these data are shared in real time,” he said. “What is amazing is that this technology has been around for at least 10 years but until the pandemic we didn’t realise how inexpensive it was compared to the economic costs of a pandemic.”