Sun. Oct 2nd, 2022
People in protective clothing load a stretcher-bound patient into an ambulance.
enlarge KIRKLAND, Wash.: A patient is screened as they are placed in an ambulance outside the Kirkland Life Care Center on March 7, 2020. Several residents have died from COVID-19 and others have tested positive for the new coronavirus.

When cases of COVID-19 surfaced in Washington state in late February, researchers quickly delved into the genetics of the viruses infecting residents. Based on what they knew at the time, they hypothesized those cases in late February were genetically linked to the very first case found in the state — one in a person who arrived in Washington on January 15 after traveling from Wuhan, China, where the outbreak started. The case was also the first infection identified in all of the United States.

If correct, the genetic hypothesis linking the late February cases to that very first case meant that early efforts to contain the pandemic coronavirus — isolating the first patient, tracing contacts, etc. — had failed spectacularly. It also meant that the virus, SARS-CoV-2, circulating cryptically in the state for six weeks† And that would mean that, in addition to those early cases, there may be hundreds or thousands of others, undetected and potentially spreading the infection further.

The hypothesis played a part in state officials’ decision to issue some of the country’s earliest social distancing measures. But now that we know a lot more about the genetics of circulating SARS-CoV-2 viruses, that hypothesis seems wrong.

At present, researchers now have the complete genetic blueprints of more than 25,000 SARS-CoV-2 viruses isolated from patients. And with all that accumulated knowledge, a new analysis suggests the cases discovered in Washington in late February were: not related to that first case in January. Instead, the February outbreak in the Evergreen State was likely caused by additional introductions of SARS-CoV-2 strains. The analysis links the blazing release to February 13, two weeks before the cases came to light.

An important note: the new analysis is a preprint, meaning it has not yet been published in a scientific journal or has undergone the standard scientific scrutiny of peer review.

That said, several researchers accept the findings — in general, at least. And the analysis culminates in a growing stream of warnings and corrections about genetic analysis done early in an emerging outbreak.

Origin story

The kind of analyzes in question are particularly phylogenetic, that is, looking at genetic variation and evolution of individual organisms to understand how they relate to each other. All COVID-19 victims are of course infected with the new coronavirus, SARS-CoV-2. But not all SARS-CoV-2 viruses are exactly the same. When a person is infected, SARS-CoV-2 viral particles enter body cells and hijack the cells’ molecular machinery to make viral copies of themselves, which can then infect someone else. In all hectic viral clones, there can be small errors in the copies of the genetic code. And as virus particles move from person to person to person, the viral code can drift off, accumulate new sets of mutations or pick up other variations.

By looking at the genetic sequences of many SARS-CoV-2 viruses and identifying the differences between them, geneticists can try to figure out how they all relate to each other and how the virus develops in general. By doing so, researchers can also help understand the chains of person-to-person transmission. For example, if two patients are infected with viral strains that have very different sets of mutations, one of them is unlikely to have infected the other. If the viruses are nearly identical, it is possible, although not certain, that the infections are linked.

What those mutations might mean: Sometimes they are meaningless, sometimes they are not. In the worst cases, they can cause a virus, for example, to cause a more serious illness, or make it more likely to spread between people.

So far, there is no solid evidence that SARS-CoV-2 picks up creepy mutations. In fact, SARS-CoV-2 doesn’t seem to be evolving much at all. The dozens of genetic sequences that researchers have collected show that SARS-CoV-2 has a relatively slow evolution.

That may be good news for humanity in general, but it’s definitely bad news to understand phylogenetic data. The slow evolution means that many of the viruses are very similar, making it difficult to unravel exactly how they are related. That’s what led researchers to suspect that February’s COVID-19 cases in Washington state were linked to the first case in January.

In the new analysis, led by Michael Worobey, an expert on pathogen evolution at the University of Arizona, researchers took a closer look at the genetic data collected since late February. They note that although the SARS-CoV-2 from the first case in Washington, called WA1, is very similar to the other SARS-CoV-2 viruses found in the state, they differ by two nucleotides — represented by letters. in their genetic code.

†[D]despite hundreds of genomes sequenced in Washington State, no viruses have been sampled where the genome is identical to WA1 or has a transition phase between the genomes and the outbreak group (i.e., with a C at position 17747 or an A at position 17858, such as WA1),” the authors wrote.

To go further, Worobey and colleagues set up simulations with the latest estimate for SARS-CoV-2’s rate of evolution — the rate at which it picks up such changes. In all of their simulations seeded with WA1, none resulted in viral strains with the genetic changes similar to what was seen in the real outbreak viruses. However, other models strongly supported the possibility that additional introductions of SARS-CoV-2 into Washington from China led to the February outbreak. They estimate that another case arrived in the state on Feb. 13, with a possible spread from Feb. 7 to Feb. 19.

viral threads

While the analysis still needs to be thoroughly peer reviewed, other researchers seemed to accept the general conclusion that additional introductions of SARS-CoV-2 likely led to the Washington outbreak — not the first case in January.

So is Trevor Bedford, the researcher who first suspected WA1 was the source of the February outbreak in the state. Bedford, an expert on viral evolution at the Fred Hutchinson Cancer Research Center in Seattle, admitted on Twitter that his hypothesis did not hold up

“At this point, I don’t think we can rule out a WA1 launch as an impossibility,” he wrote in a lengthy thread on the topic. †[B]ut I think the most likely scenario is a separate, undetected release by a genetically identical virus or a virus that has the additional 17858G mutation.”

Bedford went on to say he still estimates there was a major, undetected outbreak at the time when outbreak cases surfaced in late February. “So I believe I was wrong in the original assessment of a WA1 introduction, but was correct in claiming that I had significant community distribution in Washington State on Feb. 29,” he wrote. “I’m sorry I caused confusion here. Although I think my original actions were justified given the evidence available at the time.”

William Hanage, an epidemiologist and expert on pathogen evolution at Harvard, also agreed with the overall conclusion of the analysis by Worobey and colleagues. “It’s pretty clear now that there were more introductions” in Washington, he wrote in a Twitter thread respond to Bedford’s comments.

Hanage and colleagues made a cautionary note about the matter in Nature Microbiology on May 19, before Worobey’s analysis appeared online. Hanage and his colleagues wrote:

Most viruses can be divided into strains and if two infections are caused by different strains, transmission can be ruled out. The oft-forgotten point is that phylogenies can rule out transmission, but if infections are caused by the same strains or identical viruses, it’s not definitive proof of transmission. During an emerging outbreak, when pathogens have not yet diverted into different strains, the phylogenetic information is too weak to make a hypothesis about transmission coupling…

While the link between WA1 and Washington’s subsequent outbreak may be tenuous, there may be a bright spot in all of this — that Washington state officials acted when they thought there could be a massive, covert outbreak. As Worobey and co-authors note, Washington was “one of the first in the US to impose restrictions on social distancing and the size of gatherings.”

“An irony,” they wrote, was that said action “was based at least in part on an assumption about the timing of community transmission that was not supported by the phylogenetic data (i.e., the belief that cryptic transmission had been going on since mid-January). This action may have closed the gap between the onset of sustained community transmission and mitigation action in Washington State, compared to other locations such as New York City, in ways that deserve careful re-evaluation.

On March 22, when New York issued a stay-at-home order, the state saw more than 17 newly confirmed cases per 100,000 people per day, according to IHME data. In April, that number reached a whopping 52 new cases per day per 100,000.

On March 23, when Washington issued its warrant, the state saw about three new cases per day per 100,000 — and the figure has not climbed above eight amid aggressive testing.

By akfire1

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