1 diciembre, 2021

Patience is crucial’: Why we won’t know for weeks how dangerous Omicron is

At 7:30 a.m. on 24 November, Kristian Andersen, an infectious disease researcher at Scripps Research, received an instant message on Slack: “This variant is completely insane.” Molecular evolutionary biologist Andrew Rambaut of the University of Edinburgh was reacting to a set of new SARS-CoV-2 genome sequences shared on the global platform GISAID. Three came from samples collected in Botswana on 11 November that were sequenced by researchers there; one was picked up a week later in a traveler from South Africa to Hong Kong.

Andersen looked at the data and then replied: “Holy shit—that is quite something. The length of that branch …” A few minutes later he added: “Just had a look at the list of mutations—so nuts.”

They were talking about what is now called Omicron, a new variant of concern, and the long branch Andersen noticed refers to its distance to every other known virus on SARS-CoV-2’s evolutionary tree. The variant seemed to have picked up dozens of mutations, many of them known to be important in evading immunity or increasing transmissibility, with no intermediate sequences in the database of millions of viral genomes. On 23 November, after spotting the odd sequences in the GISAID database, Tom Peacock, a virologist at Imperial College London, had already posted his own verdict on GitHub: “This could be of real concern.”

Now, once again, the world is watching as researchers work nights and weekends to learn what a new variant has in store for humanity. Is Omicron more infectious? More deadly? Is it better at reinfecting recovered people? How well does it evade vaccine-induced immunity? And where did it come from? Finding out will take time, warns Jeremy Farrar, head of the Wellcome Trust: “I’m afraid patience is crucial.”

Researchers in South Africa were already on the trail of this new variant. Several teams were independently trying to figure out why cases were spiking in Gauteng, a northern province that includes Johannesburg and Pretoria. And a private lab called Lancet Laboratories had noticed that routine polymerase chain reaction (PCR) tests for SARS-CoV-2 were failing to detect a key target, the gene, in many samples, a phenomenon previously seen with Alpha, another variant of concern. When Lancet sequenced eight of these viruses, it found out why: The genome was so heavily mutated that the test missed the gene.

Lancet shared the genomes with the Network for Genomics Surveillance in South Africa (NGS-SA), which called an urgent meeting on 23 November. “We were shocked by the number of mutations,” says Tulio de Oliveira, a virologist at the University of KwaZulu-Natal and NGS-SA’s principal investigator. After the meeting, de Oliveira says, he called South Africa’s director general of health and “asked him to inform the minister and president that a potential new variant was emerging.” The team sequenced another 100 randomly selected sequences from Gauteng in the next 24 hours. All showed the same pattern. After informing the government, de Oliveira and his colleagues presented their evidence at a press conference on the morning of 25 November. On 26 November, the World Health Organization (WHO) designated the virus a “variant of concern” and christened it Omicron. (Variant names follow the Greek alphabet, but WHO skipped the letters Nu and Xi, it said, “because Nu is too easily confounded with ‘new’ and Xi was not used because it is a common surname.”)

One reason for concern about Omicron is that sequenced samples indicate it has rapidly replaced other variants in South Africa. But that picture might be skewed. For one, sequencing might have been focused on possible cases of the new variant in recent days, which could make it appear more frequent than it is. PCR data provide broader coverage and a less biased view, but there, too, samples with the gene failure indicate a rapid rise of Omicron.

The rising frequency could still be due in part to chance. In San Diego, a series of superspreading events at a university resulted in an explosion of one particular strain of SARS-CoV-2 earlier this year, Andersen says: “It was thousands of cases and they were all the same virus.” But the virus wasn’t notably more infectious. South Africa has seen relatively few cases recently, so a series of superspreading events could have led to the rapid increase of Omicron. “I suspect that a lot of that signal is explained by that and I desperately hope so,” Andersen says. Based on a comparison of different Omicron genomes, Andersen estimates the virus emerged sometime around late September or early October, which suggests it might be spreading more slowly than it appears to have.

The other reason to be concerned is Omicron’s confusing genome. Its spike protein, which latches on to receptors on human cells, has 30 amino acid differences from that of the original virus from Wuhan, China. In addition, amino acids have disappeared in three places and new ones appeared in one place. Many of the changes are around the receptor-binding domain, the part of the protein that makes contact with the human cell. “That is very troubling,” Farrar says. Structural biology mapping in 2020 showed some of these changes made the virus bind to the receptor much better.

It’s hard to tell how infectious a virus is based on mutations alone, says Aris Katzourakis, an evolutionary biologist at the University of Oxford. “But if we were looking out for mutations that do affect transmissibility, it’s got all of them,” he says.

The sequence also suggests the virus could excel at evading human antibodies, says Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Research Center. The human immune system produces a host of different antibodies that can neutralize SARS-CoV-2, but many of the most important ones fall into three categories that each target a slightly different site on the spike protein of the virus, simply called 1, 2, and 3. A mutation called E484K has long been worrying because it changes the shape of the site that class 2 antibodies recognize, making them less potent. Omicron carries a mutation called E484A in this site and similar changes in the sites for the other two classes of antibodies.

“It seems clear to me that our antibodies and the spike protein are sort of in a genetic arms race,” says virologist Paul Bieniasz of the Rockefeller University. “A week ago, I was more confident that antibodies were going to come out on top, and I’m a little less confident now.” Bloom thinks people who recovered from COVID-19 or were vaccinated are unlikely to completely lose their ability to neutralize the virus. “But I would expect, based on this particular combination of mutations, that the drop in neutralization is larger than for all the other major variants.”

Experiments in the laboratory will have to show whether he is right. Alex Sigal, an infectious disease researcher at the Africa Health Research Institute, says he received swabs with Omicron on 24 November and has started to grow the virus. Producing enough of it to test against sera from vaccinated and recovered individuals will take a week or two, he says. Other researchers will test viruses genetically engineered to carry just the spike protein of Omicron, a process that is faster than growing the variant itself, but a bit further removed from what happens in real life.

As such studies take place, it’s crucial to closely monitor the pandemic, Farrar says. “Do you see cases increasing not just in South Africa, but the broader South African region?” The same applies to the rest of the world. The virus has already been picked up in more than a dozen countries, many of which are not high on the list of the most connected places to Johannesburg. “My feeling is that Omicron has likely spread to many more places where it will soon be detected,” says Oxford epidemiologist Moritz Kraemer. Epidemiologists will also watch for changes in disease severity—how many people are hospitalized and die. All that will take time.

In the meantime, the European Union, the United States, and many other countries have restricted travel to and from southern Africa in a bid to protect themselves. Travel restrictions are unlikely to stop the variant, Farrar says, but they can buy some time. “The question is what you then do with the time.”

But the restrictions could, ironically, hamper science. “It is really difficult to get the needed reagents in a plane as the last 10 planes that I tried to get our reagents on got canceled,” de Oliveira says. And the economic and social cost could be a disincentive to report new variants: “I’ve heard through the grapevine that countries didn’t push sequences out very quickly [in the past] because they were worried about travel bans,” says Emma Hodcroft, a virologist at the University of Bern. “This is the opposite of what we want.”

Such considerations did not stop the South African researchers, de Oliveira says. “We do risk a massive backlash in case [Omicron] does not cause a massive wave of infection and can be controlled,” he wrote in a message. “But this is a risk that I am comfortable to live with as the pandemic has caused so many deaths and suffering. [Our] hope is that our early identification will help the world.”

Créditos: Comité científico Covid

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