Variant hunters race to find new strains where variant testing lags

Variant hunters race to find new strains where variant testing lags
Marina Dekhnik | Getty Images

In mid-February, three travelers were stopped at the airport in Luanda, Angola. Even during the pandemic, the country, a hub for the oil industry, had seen plenty of passengers from Europe and South Africa, where two concerning variants of the virus that causes Covid-19 hold sway. But the strains weren’t yet circulating widely in Angola, so this winter, health officials battened down the hatches. Before any passports get stamped, travelers receive a rapid antigen test and wait 30 minutes for a result. A negative test means self-quarantine, followed by another test a few days later. A positive test means a two-week stay at a quarantine hotel. For the three travelers, it was option two.

A few weeks later, samples taken from their noses arrived 2,000 miles south in South Africa, at the lab of Tulio de Oliveira, a geneticist at the University of KwaZulu-Natal. He was in for a surprise. The virus that had infected these three travelers didn’t resemble the strains circulating in most other places, including those labeled as “variants of concern” for their ability to spread faster and evade certain types of immunity. If those variants are like siblings, this one was more like a forgotten second cousin. It came from a lineage of the virus that emerged in the early days of the pandemic but had disappeared soon thereafter, apparently outcompeted by other variants. And yet here it was, a year later. And it had been busy. The virus had since accumulated dozens of mutations, including many of the same ones that made those other strains worrisome because of increased transmissibility and immune evasion. It had arrived at a similar genetic conclusion all on its own.

A scarcity of data

The new variant seemed to have stepped out of an epidemiological void. Which, in a way, it had, because the travelers had arrived from a country where the pandemic did not officially exist. Last June, the president of Tanzania, John Magufuli, declared the country Covid-free, having rid itself of the virus through three days of national prayer. Since then, reports from doctors and nonprofits within the country told of a “hidden epidemic” raging as fiercely as it was anywhere. But the government’s data had evaporated: no tests or case numbers or genome sequences. With so little information—just three genomes—it was hard to say what this new variant meant. Where had it come from, and where were its closer relatives? Was it spreading widely, or were these cases just a fluke? Were its mutations as worrisome in practice as on paper? De Oliveira and his colleagues are now racing to answer those questions.

Such surprises are somewhat common in de Oliveira’s line of work. Since the pandemic began, African labs have uploaded fewer than 12,000 genomes to GISAID, the leading database for viral sequences, compared with 280,000 from North America, a continent with less than half the population. About half of those African genomes come from South Africa, where de Oliveira’s lab is the centerpiece of a national sequencing effort. That means there are plenty of gaps to be explored. “It’s concerning,” says Emma Hodcroft, a molecular epidemiologist at the University of Bern. “It’s a huge continent, and we know that there are Covid outbreaks happening. But, apart from South Africa, we don’t have a good idea of what’s happening anywhere else.”

In recent months, De Oliveira has been working to change that. In early December, the lab’s genomic sleuthing amidst a surge of cases in South Africa led to the identification of a strain now known as B.1.351. That variant is now spreading globally, causing headaches because it is more resistant to the protection of some vaccines. It was also a wake-up call for South Africa’s neighbors. So earlier this year, de Oliveira’s lab, in partnership with the Africa Centres for Disease Control and Prevention, began receiving weekly or biweekly samples from 10 countries in southern Africa, part of an effort to track the newly uncovered variant and others around the continent. A second lab, Nigeria’s Africa Centre of Excellence for Genomics of Infectious Diseases, or ACEGIP, handles the northern half of the continent. The research from Angola, which was co-led by the country’s health minister, Silvia Lutucuta, appeared as a preprint Monday and has not yet been peer reviewed.

In the past year, emerging variants have changed the calculus of the pandemic, forcing countries back into lockdowns and to reconsider vaccine strategies. Basically, it’s now a race: Getting shots to more people will help quell the variants’ spread and slow the emergence of new ones. But in Africa, where only a few countries have so far received a trickle of vaccines, that process is expected to take longer. And as the virus continues to replicate and spread among people, it will also keep changing—with implications for the whole world.

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“It’s going to be bumpy,” says Christian Happi, ACEGIP’s director. “Within the continent, we have found a number of major variants, and there are likely many more.” It’s not unusual for African states to work together to stifle epidemics, he notes. Not every country has access to the sequencing machines that crunch these genomes quickly, and those that do are often relying on a single commercial lab. So governments and labs have learned to collaborate, forming networks that make use of advanced sequencing centers like his and de Oliveira’s to tackle emergent diseases, rather than sending samples overseas. So far in 2021, the initiative has helped double the number of viral genomes sequenced in Africa compared with all of 2020, with a goal of producing 50,000 genomes by year’s end.

Even as the capacity to sequence picks up, the process remains challenging, Happi says. A high rate of asymptomatic cases and limited health care access means the Covid-19 tests that lead to genome sequencing are limited in some areas. And it’s not easy to gather and store samples from across a country like Somalia and send them to Nigeria, via multiple planes and handlers, while keeping them perfectly intact. From a few hundred samples in a recent delivery from Mogadishu, the lab retrieved complete sequences from only 10 of them.

Epidemics within a pandemic

One way of thinking about SARS-CoV-2 variants is as a series of epidemics within the pandemic. When variants first emerge, or when they arrive for the first time in a new place, they’re like embers, ready to catch fire if the opportunity to spread arises and if their mutations make them competitive with other strains. But embers are also easier to extinguish than widespread conflagrations. Variants can be stopped at borders, and outbreaks in hot spots can be identified and quashed—provided variant hunters move fast and cast a wide net. “We need consistent and quick turnaround, because these variants tend to dominate quickly,” de Oliveira says. “You don’t want to discover six months late that you have an epidemic of a strain that escapes vaccines.”

The type of border checks being done in Angola, a response to surges linked to variants found in nearby countries, is a good example of putting surveillance into action, de Oliveira says. Samples from the airport have turned up not only the new strain, but plenty of examples of B.1.351 and B.1.1.7, the variants of concern first identified in South Africa and the United Kingdom and now circulating worldwide. He thinks catching those kinds of cases early is a crucial part of why Angola didn’t experience the same surge its neighbors did at the beginning of this year. Conducting surveillance at travel hubs also increases overall coverage; the researchers had no way of doing genomic surveillance in Tanzania, for example, until those three travelers happened upon the border check.

Even when worrisome variants take hold, the ability to track them has bearing on what public health measures officials can take. “Sequencing really helps because you understand the patterns of human migration for a variant,” Happi says. In Nigeria this winter, for example, the government grew concerned about a surge of unknown origin. It was impossible at first to tell if the virus was spreading faster, or if human behavior was the cause. Genome sequencing revealed it was driven by B.1.1.7, the variant that was first identified in the United Kingdom, allowing health officials to identify hot spots and, importantly, give the public an explanation for why it was necessary to hunker down. Similarly, when researchers at the Uganda Virus Research Institute identified a novel variant circulating there, surveillance led to more testing in prisons and on cross-country trucking routes, where the strain was found to be most densely concentrated.

What has shocked researchers about the variant identified in the Tanzanian travelers is that it is so distantly related to other variants of concern. It’s a member of the so-called “A lineage”—sometimes dubbed the “19 lineage” since it appeared in 2019—and is the closest known relative to the virus that first spilled into humans. “My postdoc sent me a Slack message saying, ‘WTF the A lineage??’” says Bill Hanage, an epidemiologist at Harvard University who studies viral evolution. Variants of the A lineage are still picked up from time to time, but by early 2020, most of them had been outcompeted by members of the still-reigning B lineage. The finding underlines the power of human networks in how viruses spread, Hanage adds. B-lineage variants clearly acquired mutations that made them fit to spread across the world, but what if they also got boosted by luck? It’s possible that viruses of the B lineage simply happened to take root early on in densely populated places like New York City and Italy, and from there they took over the world.

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Meanwhile, it appears A-lineage viruses continued to circulate with little detection in places where testing and sequencing was scant. Along the way, this variant acquired many of the same mutations identified in those worrisome strains. That’s another good piece of evidence that the virus is exhibiting what’s known as convergent evolution, says Jeremy Kamil, a microbiologist at Louisiana State University Health in Shreveport. That’s when certain mutations that help the virus thrive—to be better at replicating, perhaps, or better at finding its way into cells—emerge independently, because they help the virus eclipse other variants. “The convergence is so striking,” he says. In the case of this new strain, that convergence includes a mutation called E484K, nicknamed “Eek” by researchers studying it for how it helps the virus evade certain immune defenses. The mutation occurs on the virus’s receptor binding domain, which it uses to enter cells.

But at least one of those mutations hasn’t been seen in the other variants of concern: a mutation elsewhere on the binding domain, at a location called R346. Antibodies to SARS-CoV-2 are grouped into classes that refer to their ability to stick to different parts of the virus. Three of those classes are the most potent, and so far variants of concern have had mutations, like E484K, that hinder the effectiveness of two of them. According to research from the lab of Jesse Bloom at Fred Hutchinson Cancer Center in Seattle, R346 affects the third class. The next step is to see how those antibodies generated by vaccines and past infections perform against this virus in lab tests. “It is possible that R346 mutations will further erode antibody neutralization by some serum,” Bloom writes in an email. That kind of research is already happening in South Africa, where the variant was cultured within weeks of its identification in a biosafety level 3 lab.

There’s plenty of evidence to make the variant interesting to virologists, and worth tracking, but not yet cause for alarm. Lab studies to understand the functional effects of all those mutations are still to be done, and having three genetic samples is not enough to draw clear conclusions about how and where the variant is spreading. More sequences would help. But given the situation in Tanzania, they’re difficult to acquire.

There are signs that change is happening. In March, around the time de Oliveira’s team was communicating news of the strain to the Tanzanian government through diplomatic channels at the African Union, Magufuli reportedly fell ill and died. (Officially, the cause was a heart condition, though some observers suspect Covid-19.) On Tuesday, the day after de Oliveira’s preprint was posted online, Tanzania’s new president, Samia Suluhu Hassan, announced that the country was again acknowledging Covid-19 and would form a scientific committee to get a better grip on the pandemic.

In the meantime, de Oliveira is working with the Africa CDC to strengthen surveillance near the Tanzania border—in Malawi, for example, and in the northern reaches of Mozambique. “Our main dream is that this is a variant that can be extinguished as quickly as possible,” he says. And the broader surveillance effort will continue to grow, he says. The point isn’t to induce panic. It’s far from certain that new variants will cause more trouble than the ones we’ve already found. Even the nastiest variants identified so far only reduce the effectiveness of some vaccines; they don’t escape them entirely. But it will be important to remain vigilant, especially in places where the virus is going to keep moving for some time. “If we don’t vaccinate the whole world, the variants could spread quite quickly,” de Oliveira says.

New variants are also a reminder that world leaders can’t be lulled into complacency, even as their nations’ vaccination levels rise. They’ll need to keep testing and tracing, doing screenings at borders. But it will take a balanced approach. It may be tempting to treat new discoveries with alarm, and to ostracize people from nations where those strains are found to be circulating. But that could discourage those governments from participating in testing and sequencing efforts. The important thing is that those efforts keep growing. “A far worse outcome will be a variant of concern that we only discover too late because people weren’t looking for it,” Hanage says.

This story originally appeared on wired.com.


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