Are new Omicron sub-variants a threat? How researchers keep track

Speckled guinea fowl drift into the garden where Tulio de Oliveira sits as he describes two new members of the growing Omicron family of SARS-CoV-2 coronavirus. Called BA.4 and BA.5, the subvariants are now growing in prevalence in South Africa, where the virologist leads one of the world’s strongest genomic monitoring programs for SARS-CoV-2, at the Center for Epidemic Response and Innovation at Stellenbosch University in South Africa.

The virus is being targeted by the World Health Organization (WHO) because its mutations according to laboratory studies may enable them to avoid immunity from covid-19 vaccine or previous infections stronger than existing versions of Omicron. However, de Oliveira is clear that he is not panicked by BA.4 and BA.5. Although the sub-variants have rapidly gained ground in South Africa over the past month, the number of cases of covid-19 and hospital stays is stable in the country. He is also unaffected because he has been through this before – his team has made similar discoveries during the pandemic and knows the exercise. Right now, he says, “it’s just time to work carefully and diligently, but calmly.”

Researchers are now studying these subvariants, which have so far been discovered in nine countries, to determine if their effect is severe enough to justify intervention. SARS-CoV-2 will continue to mutate as it evolves, but not every variant will be newsworthy. To determine what deserves attention, Wendy Barclay, a virologist at Imperial College London, says researchers focus on two factors: “We care about differences in the severity of the disease, and we care about a variant that avoids vaccines – because even if we have the same severity, an increase in cases still has a major impact on life. “

At the same time, researchers are struggling with how to communicate their concerns and uncertainties about variants openly, while not provoking unnecessary government policy and concerns. Late last year, when the Oliveira team discovered the original Omicron, countries including the United States and the United Kingdom invoked a travel ban on South Africa. The bans failed to prevent the spread of the variant, but seriously damaged the already struggling South African economy. If it happens again, de Oliveira says, “I would stop sharing data in real time with the world, but would continue to share with my government, to guide our own response.”

The new variants

On April 1, Eduan Wilkinson, a bioinformatician on the Oliveira team at Stellenbosch, saw that researchers at the center’s lab and at the National Institute for Communicable Diseases in Johannesburg had flagged several abnormal SARS-CoV-2 genomic sequences in their latest database. The sequences had some notable mutations in the region of SARS-CoV-2 encoding its nail protein. Because the nail protein is the key to virus-invading cells, Wilkinson realized an urgent need to hunt for these mutations in every genome sequenced in the country in recent months to see if they had passed unnoticed.

Over the weekend, he and his colleagues discovered that they had it. One month earlier – during the first week of March – the BA.4 and BA.5 sequences accounted for about 5% of the approximately 500 genomes sequenced in South Africa. In the first week of April, the share had risen to 50%. That week, an international virus classification team determined that BA.4 and BA.5 were indeed their own separate lines on Omicron’s family tree and gave them their names.

In addition to the accumulating sequences from South Africa, a relatively small number of BA.4 sequences have been uploaded to the GISAID data platform from Botswana, Belgium, Denmark and the UK in the last two weeks, and BA.5 has appeared from China, France, Germany and Portugal. .

One thing that makes BA.4 and BA.5 stand out for virologists is an amino acid mutation in the parts called F486V. It is located on the nail’s nail protein near where the protein attaches to the ACE2 receptor on cells – an interaction that opens the door to infection. Important antibodies generated in response to covid-19 vaccines and to previous SARS-CoV-2 infections neutralize the virus by adhering to this site.

Since last year, virologists have begun to notice the vulnerability of this stain in laboratory experiments. For example, virologist Benhur Lee of the Icahn School of Medicine at Mount Sinai in New York City and his colleagues helped vet a promising monoclonal antibody treatment by exposing it to an artificial virus carrying many versions of the SARS-CoV-2 nail protein. Only one version of the nail protein avoided their antibodies. It had a mutation almost identical to F486V.

At the time, Lee was relieved that the mutation was vanishingly rare in real life, suggesting that it prevented the virus in some way. Only about 50 of the nearly 10 million SARS-CoV-2 sequences in GISAID contained the mutation, so Lee felt confident that the antibody treatment would still be widely used. But with the rapid increase of BA.4 and BA.5 in South Africa, it seems that the coronavirus has developed so that the mutation no longer holds it back, Lee explains.

Risk analysis

Lorenzo Subissi, a virologist at the WHO, says the agency tracks the two underlines. But before drawing any conclusions as to whether they pose an additional threat compared to other Omicron variants, it needs to learn more from epidemiological studies in humans. Immunologists also approach the issue of immune escape by exposing samples of BA.4 and BA.5 to blood taken from people previously infected with SARS-CoV-2 and people who have been vaccinated.

“That’s why we immediately gave samples to researchers around the world,” says de Oliveira. It included researchers in South Africa and the United Kingdom, as well as those at the US National Institutes of Health and the Chinese Center for Disease Control and Prevention.

Immediately after identifying BA.4 and BA.5, de Oliveira also met with the South African government and a consortium of about 200 researchers in the country to take strategy to the next level. Without any increase in the number of hospital admissions in South Africa – and only about 1,200 cases per day – he advised the government not to set stricter guidelines than the country already has. So far, the government has not changed its rules.

Mr Oliveira was particularly wary of communicating news of variants to health officials from other countries, urging them to keep an eye out while not triggering a largely meaningless policy, such as a travel ban, that could do more harm than good. “We have a lot of pressure on us,” said de Oliviera. “When we reported Omicron, my colleagues and I received death threats. We had to put security in front of the lab.”

In the face of such tensions, Barclay applauds South Africa’s surveillance work and transparency. Although this year’s SARS-CoV-2 variants on average cause less serious illness than previous versions of the virus, she says it is not a sign that the coronavirus will continue to weaken. In addition to acquiring common mutations, SARS-CoV-2 can develop rapidly by recombination and insert a piece of a sequence from one variant into the genome of another. If an Omicron variant recombines with another SARS-CoV-2 variant, it can produce a virus that both avoids immunity and makes people sicker, says Barclay. “It would be good if these new variants are part of a trend where the virus is getting milder, but there is no biological reason to believe that this will always be the case.”

This story was supported by the Pulitzer Center.

This article is reproduced with permission and was not published until April 15, 2022.

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