San Francisco Chronicle - (Sunday)
‘Flying blind’: Scientists seek plan in hunting virus variants
A little over a week ago, Dr. Charles Chiu looked through the latest batch of genomic sequencing results from his lab at UCSF. He was scanning for the familiar pattern of an especially infectious coronavirus variant from the United Kingdom, 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 foe to contend with.
“It had slipped under our noses,” said Chiu, who’s director of the UCSFAbbott Viral Diag
nostics and Discovery Center.
Chiu’s team was the first to report the new variant, which the state is calling L452R, but days later another group of scientists at CedarsSinai reported the same variant was now making up more than a third of cases in Los Angeles.
The findings underscore the urgent need to increase genomic sequencing across California and the nation, scientists like Chiu say. California has more laboratories capable of doing that work than many countries, but the state lacks the coordinated infrastructure needed to quickly identify new variants and determine whether they’re a threat.
The same is true for the United States, which is far behind almost every other major country in the amount of sequencing it does, and lacks funding and national leadership to improve the situation, infectious disease experts say. As the nation races to vaccinate as many people as possible before the virus picks up more mutations that could make it harder to manage, it’s critical scientists understand what they’re up against.
Without much more largescale surveillance, Chiu said, everyone trying to control the pandemic is “flying blind.” “We don’t know what variants may be circulating or emerging. It becomes very challenging 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 building blocks that make up the virus. Those building blocks shift, or mutate, as the virus replicates. Genomic sequencing lets scientists identify those mutations, providing a sort of genetic fingerprint for the virus.
It’s important for several reasons. It helps scientists and public health officials understand how the virus behaves from a 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 may cause a change in behavior — making it more infectious or less susceptible to vaccines, for example.
That last use is critical, but it requires a robust national surveillance program that involves frequent genomic testing of random samples collected from around the country. The United Kingdom has a program like that, and it tests about 10% of coronavirus cases. The United States tests far fewer than 1% of its cases.
“I know what this country can do. But there has to be a call to arms on this, and it has to come from the top,” said Dr. Joe DeRisi, copresident 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 did 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 few directives for what types of samples are collected and how they’re reported. Most labs that do genomic sequencing are focused not on surveillance, which involves regularly screening for mutations to the virus, but on analyzing specific cases and outbreaks.
And there’s little to no funding, DeRisi said. The Biohub and UCSF pay for genomic sequencing with grants they’ve already obtained.
“We’re trying to do what we can do. We’re going to donate as much effort as we can to this,” DeRisi said. “But we are a small nonprofit research institute, and it feels like we’re shouldering a very heavy burden.”
In addition to UCSF and the Biohub, UC Berkeley and Stanford also do genomic sequencing of the coronavirus.
Stanford last week said it had started a surveillance program to quickly find new variants that may be circulating in Northern California.
Chiu’s lab found two of the first cases of the B117 variant in California, which were reported in San Bernardino County. Scripps Research in La Jolla identified a cluster of B117 cases in San Diego County. Another case in Los Angeles County was found by a federal lab.
That scattershot approach to finding new variants, both statewide and nationally, isn’t capturing how widespread they may already be, said Dr. Joel Ernst, an infectious disease expert at UCSF. The B117 variant has been found in 22 states so far, including 72 cases across California, according to the Centers for Disease Control and Prevention.
“We know for example that the UK variant is here. We know it’s in multiple states,” he said. “But we don’t have any idea what fraction of the infections in Colorado or Los Angeles or Seattle or Boston are caused by that variant.”
It will be more important than ever to increase genomic sequencing as more people get vaccinated, infectious disease experts said. A small percentage of people who are vaccinated will develop COVID19 anyway, and scientists need to be able to identify those cases and understand why the vaccine failed, Ernst said.
And as more people are vaccinated, pressure will mount on the virus to mutate and try to escape. Public health experts will need to know very quickly if a new variant doesn’t respond as well to vaccines.
The B117 variant appears to be fully covered by the 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 have found. There are similar concerns about a variant identified in Brazil.
“We are launching the largest evolutionary experiment in virology that’s ever been on the planet. We’re going to put immune pressure on the virus that will force it to mutate or die. Chances are there will be mutations that allow it to sidestep the vaccine,” DeRisi said. “Wouldn’t we want to know that so we can design a generation 2 and 3 vaccine?”
Chiu’s laboratory already has started studies of how the L452R variant responds to vaccines. Three days after reporting the variant to the state he’d started growing it in the lab. In a week or so he’ll expose the variant to antibodies sampled from previously infected donors. That will tell him if the virus has a mutation that lets it evade one or more of the antibody weapons the body uses to fight off infection.
But the other important question is whether the variant is more infectious than other ver
sions of the virus. “To show that it’s more transmissible you would need a robust community surveillance program, to see if the virus is increasing in frequency relative to other mutations,” Chiu said. “That can only be done with a very structured, organized, coordinated surveillance program, which we don’t have.”
Chiu is worried that the L452R variant may indeed be more infectious. His team found that it made up fewer than 5% of the samples they tested in November to midDecember, but 25% in a second batch from midDecember to January. That’s a concerning increase in a very short period of time. The variant also was tied to several large clusters in Santa Clara County, including a Kaiser hospital outbreak in which more than 90 people were infected.
The variant also carries a mutation that’s located in a precarious spot on the virus that may make it more infectious.
The CedarsSinai group has suggested the variant may have helped fuel Los Angeles County’s recent distressing surge in cases. But scientists like Chiu say they just don’t know for sure. All of the evidence is circumstantial.
Regardless of how big a threat L452R or any other variant poses, the arrival of multiple mutations at once should raise a red flag, said Fyodor Urnov, a virologist with the UC Berkeley Innovative Genomics Institute.
“It’s a bit like a tremor on the San Andreas fault. Like a 3.5,” Urnov said. “Not a major tremor, but if we do not start preparing for the big one, Mother Nature will say, ‘Didn’t I tell you? What part didn’t you understand?’ ”