This 'double mutant' variant is adding fuel to India's COVID-19 crisis

While its spread in India is worrying, preliminary studies show vaccines are still effective against the viral newcomer.

Human behavior is probably more to blame for the second wave of the COVID-19 pandemic than the new mutants arising around the country. But the combination of these two is proving catastrophic.

Every day for a whole week, India has reported an average of 340,000 new coronavirus cases; on Wednesday deaths exceeded 3,300. Many experts suspect that numbers could be even higher. The country now accounts for one in every three infections reported worldwide daily.

“The major factor in the spread of the virus is the behavior of the people. Spread of the virus is largely because of us not taking care of each other. Variants are just taking advantage of our carelessness,” says Rakesh Mishra, director of the Indian Centre for Cellular and Molecular Biology.

This surge of COVID-19 cases comes three months after the Indian health minister announced "India has successfully contained the pandemic." He believed that studies based on a mathematical "Indian Supermodel" suggested the country “may have reached herd immunity” through natural infections. But the model was flawed, and the results skewed by the lack of accurate data. Now the number of daily new infections has crippled the healthcare system; oxygen and PPE supplies have run out, there are no hospital beds available, and patients are dying on sidewalks and streets as they wait outside hospitals.

Alarmed by the local outbreaks of B.1.1.7, the variant first discovered in the United Kingdom, the government formed a multi-laboratory network named the Indian SARS-CoV-2 Genomic Consortium (INSACOG) to monitor the evolution of SARS-CoV-2, the virus that causes COVID-19. On March 24, after sequencing less than one percent of coronavirus samples collected by its member laboratories across the country, INSACOG announced it had found “a new double mutant variant.” What alarmed scientists was that the variant carried features from two worrisome lineages; the variants first identified in California (B.1.427 and B.1.429), and those discovered in South Africa (B.1.351) and Brazil (P.1).

A variant emerges

Although it wasn’t noticed at the time, the mutant had in fact been sequenced and its genetic code deposited in the global database as early as in October 2020, but “it seemed like it just wasn't on anybody's radar screen,” says David Montefiori, who studies viral immunology and vaccine development at Duke Human Vaccine Institute. This new variant has spread fast, causing more than 60 percent of all coronavirus infections in the Indian state of Maharashtra alone, which reported the largest number of all COVID-19 cases in India.

The emergence of more transmissible variants highlights major limitations in the current state of global surveillance of not only SARS-CoV-2 but of all emerging diseases in far-flung areas. INSACOG was expected to sequence five percent of the positive samples from all states but managed far fewer: only 13,614 by April 15. “This is a global problem,” says Montefiori.

“Certainly, the world has lots and lots of genomic surveillance, and I feel very strongly that India needs to be doing a much higher proportion. Often people ask how much? The U.K. is the gold standard on genomic surveillance and maybe between five and 10 percent. India does far less than one percent,” says Dr. Ashish Jha, a public health policy expert at the Brown University.

What is a “double mutant”?

Viruses frequently mutate and these mutations occur randomly, says So Nakagawa of Tokai University who has been studying the variants first discovered in California. In fact, SARS-CoV-2, HIV, and influenza viruses, all of which encode their genetic instructions using the molecule RNA, mutate more frequently than other types of viruses due to copying errors introduced as viruses replicate in their host cells.

More than a million distinct sequences of SARS-CoV-2 have been reported to GISAID, the global public database. Many inconsequential mutations go unnoticed. But some mutations can change the amino acids, which are the building blocks of viral proteins, “which may change their characteristic,” Nakagawa says. When one or more mutations persist, instead of being evolutionarily cast off, they create new variants distinct from the ones already in circulation and are then given new names.

The new variant, now designated as B.1.617, carries two known mutations; the first at position 452 of the spike protein and the second at 484. “[But it] shouldn't be called double mutation, because that is just a misnomer,” says Mishra.

Actually, B.1.617 carries 11 other mutations—13 in total, of which seven are in the spike protein that punctuate the surface of SARS-CoV-2 and endow the virus with its signature “crown” structure. The virus uses spike proteins to anchor to the ACE2 receptor protein on the surface of lung and other human cells, and infect them. An eighth mutation in B.1.617 located at the midpoint of the immature spike protein—and also found in some New York variants—can increase the transmission of the virus, giving it an adaptive advantage.

“The mutations in the B.1.617 have been studied independently, but not in combination,” explained virologist Benjamin Pinsky. “What's important …there's a lot of mutations coming up in the spike protein.”

Location matters when it comes to mutations

“That's something that occurs quite a lot in viruses,” says Grace Roberts, a virologist at Queen's University Belfast. “Surface proteins evolve more rapidly, especially with a new virus, [as] it wants to evolve to bind cells better.”

Because the spike protein coats the surface of the SARS-CoV-2 virus, it is the primary target for immune system. Immune cells make antibodies that recognize and bind to the virus and “neutralize” it. That is why, all current COVID-19 vaccines also use the spike protein to train the body for immunity.

While random, the mutations in the spike protein that change its appearance and structure can help the virus evade the antibodies. These adaptations increase the ability of the virus to survive and replicate. “Any mutations in spike protein have potential to impact the neutralization phenotype of the virus and its infectivity, its transmissibility, and potentially pathogenesis,” Montefiori says. He has shown that the California variants with L452R mutations are two to three times less susceptible to antibodies from vaccines and convalescent serum samples.

Similar studies suggest that L452R mutation can increase the number of viruses that can infect a single cell, potentially promote viral replication, and help the virus bind more tightly to the ACE2 receptor on the surface of cells. However, Kei Sato, who led one such study cautioned that, “we are not sure whether that mutant can be more dangerous for human population.”

Just a mutation at the E484 site alone, which is the case in the B.1.351 and P.1 variants, can help the virus escape neutralizing antibodies, says Montefiori. Coupled with the L452R mutation, which is also likely responsible for helping the virus evade antibodies, the B.1.617 can be a very troublesome variant. “It's a …high priority to characterize this [B.1.617],” added Montefiori.

Global traveler

B.1.617 has quickly hitchhiked across the globe and spread worldwide. On April 3, the B.1.617 variant was identified in a U.S. patient. “We screen all of the positives that come through our laboratory for three mutations that are associated with variants of concern or variants of interest,” Pinsky says. “We were able to pick that mutant up because [it] really stood out to me.”

Could the variant have arisen independently in the United States? “The cases that we identified here did not arise independently, but rather were through global spreads,” says Pinsky. B.1.617 variant has now been identified in 16 countries on all continents, except Africa.

Since B.1.617 brings so many ominous mutations together, the additive effects seem to be “evidenced by the rapid increase in India at present,” Pinsky says.

Not everyone agrees.

“It should also be noted that the number of viral sequences analyzed in India [about 100 sequence per day] is much smaller than the number of infected people in India [about 300,000 per day]. Therefore, we are still not sure the current huge surge of COVID in India is due to B.1.617,” Sato wrote in an email.

“The so-called fast spreading variant still in the country is about 10 percent so that means 90 percent of the cases in the current sense are something else, not double mutant,” said Rakesh Mishra of the Indian Centre for Cellular and Molecular Biology.

Could genomic surveillance have reduced the second surge?

While genomic surveillance of the variants is critical, that alone cannot prevent new outbreaks, super spreader events, or stop the pandemic. Genomic surveillance can only help scientists track where infections are going, and how and where the virus is spreading.

“India was pretty blind to [this],” says Jha. He believes India needs to be doing more sequencing and that it would have been helpful. But he isn’t sure whether surveillance data would have prevented or reduced the second wave. “[This] is because, part of it, is you also have to act on that information. And there was enough information even without the genomic surveillance certainly by the end of March, and I would argue even by early to mid-March, that things were heading in the wrong direction,” says Jha.

“Getting as many people vaccinated as possible, as quickly as possible, is the key to controlling this pandemic,” says Pinsky, the virologist.

There is some preliminary evidence that existing vaccines are effective against B.1.167 and other variants. “And while that rollout continues, it is important that everyone follows all public health interventions that people are tired of hearing about, but still remain extraordinarily effective against the spread of this infectious disease,” Pinsky added. “And that's masking, social distancing, and washing one's hands. All of those things still work against the variants and we should continue to do that until, you know, more individuals are vaccinated.”

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