Subvariants of Ómicron BA.4 and BA.5: already detected in 9 countries and scientists are on alert

More than 500 million cases of people with COVID-19 have already been confirmed since the start of the pandemic and 6.1 million deaths. Although the number of deaths is falling globally, the Ómicron variant of the coronavirus, which causes most cases today, continues to circulate around the world. Its last identified subvariants, which are called BA.4 and BA.5 , have already been detected in nine countries and scientists say that there is watch them, but calmly.

One of the researchers is the Brazilian scientist Tulio de Oliveira, who works in South Africa. With his group, he was the one who spotted Ómicron last November. Since then, the sublineage BA.1 was first propagated and more recently BA.2. A few days ago, Dr. de Oliveira announced the discovery of sublinages BA.4 and BA.5 in his country.

De Oliveira leads one of the most powerful SARS-CoV-2 genomic surveillance programs in the world, at the Center for Epidemic Response and Innovation at the University of Stellenbosch. They have already revealed that subvariants BA.4 and BA.5 are increasing their prevalence in cases of COVID-19 detected in South Africa.

On April 1, Eduan Wilkinson, a bioinformatician with de Oliveira's team in Stellenbosch, observed that researchers at the center's laboratory and the National Institute for Communicable Diseases in Johannesburg had pointed out several anomalous sequences of the coronavirus genome in their latest batch of data.

The sequences exhibited some notable mutations in the region of the coronavirus that encodes its spike protein. As this protein is key for the virus to invade cells, Wilkinson recognized the urgent need to search for these mutations in all genomes sequenced in the country in recent months to see if they had gone unnoticed.

Working over the weekend, Wilkinson and his colleagues discovered that these sublineages were increasing in proportion in the samples analyzed. A month earlier, during the first week of March, the BA.4 and BA.5 sequences represented about 5% of the approximately 500 genomes sequenced in South Africa. By the first week of April, the proportion had increased to 50%. At that time, an international virus classification group determined that BA.4 and BA.5 did indeed constitute their own separate lineages in the Ómicron family tree and gave them their names.

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

The World Health Organization (WHO) also reported a few days ago that it has on its surveillance radar BA.4 and BA.5 which are part of a variant that is already classified as “of concern”. He pays attention to them because, according to laboratory studies, their mutations could allow them to evade immunity obtained with COVID-19 vaccines or previous infections more strongly than the other versions of Ómicron.

However, De Oliveira told the journal Nature that “you just have to work carefully and diligently, but calmly”. He is not afraid of BA.4 and BA.5. because while they have gained ground rapidly in South Africa over the past month, rates of COVID-19 cases and hospitalizations are stable in the country. He is also calm because his team has made similar discoveries during the pandemic and knows the surveillance procedure.

For the virologist of the Imperial College of London, in the United Kingdom, Wendy Barclay, we must focus on two main issues in the surveillance of subvariants: “We care about a difference in the severity of the disease, and we care about a variant that evades vaccines, because even if we are the same severity, an increase in cases continues to have a major impact on life,” he said.

One of the things that makes BA.4 and BA.5 stand out for virologists is a mutation of amino acids they share called F486V. This mutation is found in the virus spike protein, near where the protein binds to the ACE2 receptor of cells, an interaction that opens the door to infection. Antibodies generated in response to COVID-19 vaccines and previous coronavirus infections neutralize the virus by adhering to that point.

Since last year, virologists had begun to notice the vulnerability of this point in laboratory experiments. For example, virologist Benhur Lee, from the Icahn School of Medicine on Mount Sinai in New York, and his colleagues were helping to examine a promising monoclonal antibody treatment by exposing it to an artificial virus that had many versions of the coronavirus spike protein. Only one version of the Spike protein evaded its antibodies. It had a mutation almost identical to the F486V.

At the time, Lee was relieved to see that the mutation was incredibly rare in real life, suggesting that it hindered the virus in some way. Only about 50 of the nearly 10 million coronavirus sequences in GISAID contained the mutation. At that time he felt confident that antibody treatment would continue to be widely useful. But with the rapid rise of BA.4 and BA.5 in South Africa, it seems that the coronavirus has evolved in such a way that the mutation would no longer slow it down.

Lorenzo Subissi, WHO virologist, says the agency is following the two sublinages. But before you draw any conclusions about whether they pose an additional threat compared to other variants of Omicron, you need to know more about the epidemiological studies of people. Immunologists are also addressing the issue of immune escape by exposing samples of BA.4 and BA.5 to blood taken from people previously infected with the coronavirus and vaccinated people. Researchers from South Africa, the United Kingdom, the US National Institutes of Health and the China Centre for Disease Control and Prevention have provided patient samples for surveillance studies.

Today, researchers strive to openly communicate their concerns and uncertainty about variants, without causing unnecessary government policies or anxiety. At the end of last year, when Dr. de Oliveira's team detected the original Ómicron variant, there were countries such as the United States and the United Kingdom that invoked travel bans against South Africa. At that time, WHO came out to warn that travel restrictions to South Africa were measures that were taken hastily and disproportionately. In addition, researchers such as de Oliveira received death threats and had to put more security in the institute where he works.

The bans failed to prevent the spread of the variant, but seriously damaged the South African economy, which was already in difficulty. If that happens again, says de Oliveira, “I would stop sharing data in real time with the world, but I would continue to share it with my government, to guide our own response.”

Taking into account what happened last November and following the identification of the BA.4 and BA.5 sublinages, de Oliveira met with the South African government and a consortium of some 200 researchers in the country to strategize the next steps. In the absence of an increase in hospitalizations in South Africa — and only about 1,200 cases a day — he advised the government not to establish stricter guidelines than the country already has. At the moment, the government has not changed its rules.

De Oliveira was especially careful a few days ago with how he transmitted the news about the variants to health officials in other countries. He asked them to remain vigilant but without triggering largely useless policies, such as travel bans, which can cause more harm than good.

What could happen to the sublinages? This year's coronavirus variants cause, on average, a less serious illness than previous versions of the virus. But according to Dr. Barclay, that is not a sign that the coronavirus will continue to weaken. In addition to acquiring the usual mutations, coronavirus can evolve rapidly through recombination by inserting a piece of sequence from one variant into the genome of another.

If an Ómicron sublineage is recombined with another variant of the coronavirus, it could produce a virus that evades immunity and make people sicker. “It would be great if these new variants were part of a trend in which the virus would become milder, but there is no biological reason to believe that this will always be the case,” Barclay said.

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