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Just over a week ago, Dr. Charles Chiu reviewed the latest batch of genomic sequencing results from his lab at UCSF. He was looking for the familiar model of a particularly infectious variant of the UK coronavirus known as B117.
He didn’t find it. What he found instead was alarming and unexpected: a rare variant that Chiu had only seen a handful of times suddenly made up 25% of his samples. California had a mysterious new enemy to face.
“It had slipped under our noses,” said Chiu, director of the UCSF-Abbott Center for Diagnosis and Viral Discovery.
Chiu’s team were the first to report the new variant, which the state calls L452R, but days later another group of Cedars-Sinai scientists reported that the same variant now accounts for more than a third. cases in Los Angeles.
The results underscore the urgent need to increase genomic sequencing across California and the country, according to scientists like Chiu. California has more labs capable of doing this work than many countries, but the state does not have the coordinated infrastructure to quickly identify new variants and determine if they pose a threat.
The same is true for the United States, which lags far behind almost every other major country in terms of sequencing, and lacks funding and national leadership to improve the situation, infectious disease experts say. As the nation rushes to vaccinate as many people as possible before the virus detects more mutations that could make management more difficult, it is essential that scientists understand what they are facing.
Without much larger-scale surveillance, Chiu said, anyone trying to control the pandemic is “flying blind.”
“We don’t know what variants may circulate or emerge. It becomes very difficult for us to fight an enemy if we don’t know what the enemy is, ”Chiu said.
Genomic sequencing is used to determine the order of the chemical elements that make up the virus. These building blocks move or mutate as the virus replicates. Genomic sequencing allows scientists to identify these mutations, providing a kind of genetic fingerprint for the virus.
This is important for several reasons. It helps scientists and public health officials understand how the virus behaves at the molecular level. It can also help infectious disease investigators track where the virus is spreading and identify outbreaks. And it can alert authorities to mutations in the virus that can cause behavioral change – making it more infectious or less susceptible to vaccines, for example.
The latter use is essential, but it requires a strong national surveillance program that involves frequent genomic testing of random samples taken from across the country. The UK has a program like this, and it tests around 10% of coronavirus cases. The United States tests far less than 1% of their cases.
“I know what this country can do. But there has to be a call to arms about it, and it has to come from the top, ”said Dr. Joe DeRisi, co-chair of the Chan Zuckerberg Biohub in San Francisco, which does about 45% of the genomic sequencing in California and 5% of the national total. “It can be done. The UK has done it. The UK has wonderful genomic surveillance for the country. Why are we so far behind? No national leadership.”
California’s genomic sequencing network is loosely coordinated, with a handful of labs across the state providing results but little guidance on what types of samples are collected and how they are reported. Most labs that do genomic sequencing do not focus on surveillance, which involves regular screening for mutations in the virus, but on analyzing specific cases and outbreaks.
And there is little to no funding, DeRisi said. The Biohub and UCSF pay for genomic sequencing with grants they have already obtained.
“We are trying to do what we can do. We’re going to try as hard as we can for that, ”DeRisi said. “But we’re a small, non-profit research institute, and we feel like we carry a very heavy burden.”
In addition to UCSF and Biohub, UC Berkeley and Stanford also perform genomic sequencing for the coronavirus. Stanford said last week it launched a monitoring program to quickly find new variants that could be circulating in northern California.
Chiu’s lab found two of the earliest cases of the B117 variant in California, which were reported in San Bernardino County. Scripps Research in La Jolla has identified a cluster of B117 cases in San Diego County. Another case in Los Angeles County was discovered by a federal lab.
This scattered approach to finding new variants, both state and national, does not capture their extent, said Dr Joel Ernst, an infectious disease expert at UCSF. The B117 variant has been found in 22 states to date, including 72 cases across California, according to the Centers for Disease Control and Prevention.
“We know for example that the British variant is there. We know it’s in multiple states, ”he said. “But we have no idea what fraction of infections in Colorado, Los Angeles, Seattle or Boston are caused by this variant.”
Increasing genomic sequencing will be more important than ever as more people get vaccinated, infectious disease experts have said. A small percentage of people vaccinated will develop COVID-19 anyway, and scientists need to be able to identify those cases and understand why the vaccine failed, Ernst said.
And as more and more people are vaccinated, the pressure will increase on the virus to mutate and try to escape. Public health experts will need to know very quickly if a new variant does not respond as well to vaccines.
The B117 variant appears to be fully covered by current vaccines. But a variant identified in South Africa – which, like the UK, has a strong genomic sequencing network – may be somewhat resistant to vaccines, studies show. There are similar concerns with a variant identified in Brazil.
“We are launching the largest evolutionary virology experiment ever carried out on the planet. We will put immune pressure on the virus which will force it to mutate or die. Chances are there are mutations that will allow him to avoid the vaccine, ”DeRisi said. “Wouldn’t we like to know that so that we can design a generation 2 and 3 vaccine?”
Chiu’s lab has already started studies on how the L452R variant responds to vaccines. Three days after reporting the variant to the state, he had started growing it in the lab. In about a week, he’ll be exposing the variant to antibodies taken from previously infected donors. This will tell it if the virus has a mutation that allows it to evade one or more of the antibody weapons the body uses to fight infection.
But the other important question is whether the variant is more infectious than other versions of the virus. “To show that it is more transmissible, you would need a robust community surveillance program, to see if the virus is increasing in frequency compared to other mutations,” Chiu said. “This can only be done with a very structured, organized and coordinated monitoring program, which we don’t have.”
Chiu is concerned that the L452R variant is indeed more contagious. His team found that it made up less than 5% of samples tested from November to mid-December, but 25% in a second batch from mid-December to January. That’s a worrying increase in a very short period of time. The variant was also linked to several large groups in Santa Clara County, including an outbreak at Kaiser Hospital in which more than 90 people were infected.
The variant also carries a mutation located in a precarious place on the virus, which can make it more infectious.
The Cedars-Sinai group suggested that the variant may have helped fuel the recent painful outbreak in Los Angeles County. But scientists like Chiu say they’re just not sure. All the evidence is circumstantial.
Regardless of the magnitude of the threat posed by L452R or any variant, the arrival of multiple mutations at once should raise a red flag, said Fyodor Urnov, a virologist at UC Berkeley Innovative Genomics Institute.
“It’s kind of like a quake on the San Andreas fault. Like a 3.5, ”said Urnov. “It’s not a major quake, but if we don’t start preparing for the big one, Mother Nature will say, ‘Didn’t I tell you? Which part did you not understand? “
Michael Williams, editor of the San Francisco Chronicle, contributed to this story.
Erin Allday is a writer for the San Francisco Chronicle. Email: [email protected] Twitter: @erinallday
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