Enlarge /. KIRKLAND, Wash .: A patient is shielded when he is ambulance on March 7, 2020, outside Kirkland's Life Care Center. Several residents have died of COVID-19, others have tested positive for the novel corona virus.
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When cases of COVID-19 appeared in Washington State at the end of February, the researchers quickly looked into the genetics of the viruses that infect residents. Based on what they knew at the time, they hypothesized that in late February these cases were genetically related to the very first case in the state – one for a person who came to Washington on January 15 after traveling from Wuhan, China Outbreak began. The case was also the first infection found across the United States.
If true, the genetic hypothesis that linked the cases to the very first case in late February meant that the early efforts to contain the pandemic coronavirus – isolate the original patient, follow up contacts, etc. – had spectacularly failed. This also meant that the SARS-CoV-2 virus had been circulating cryptically in the state for six weeks. And that would mean that, in addition to these early cases, there might have been hundreds or thousands of others out there who went undetected and may have spread the infection.
The hypothesis played a role in government officials' decision to adopt some of the country's earliest socially distancing measures. But now that we know a lot more about the genetics of circulating SARS-CoV-2 viruses, this hypothesis seems to be wrong.
At this point, the researchers now have the complete genetic blueprints of more than 25,000 SARS-CoV-2 viruses isolated from patients. And with all the knowledge gathered, a new analysis suggests that the cases discovered in Washington in late February were not associated with this first case in January. Rather, the Evergreen State outbreak in February was probably triggered by the additional introduction of SARS-CoV-2 strains. The analysis provides for a sparking launch by February 13, two weeks before the cases became apparent.
An important note: The new analysis is a preprint, which means that it has not yet been published in a scientific journal or has been subjected to the peer review standard scientific review.
However, several researchers accept the results – at least in general. And the analysis flows into a growing stream of genetic analytical precautions and corrections that are done early in an emerging outbreak.
In particular, the nature of the analyzes in question is phylogenetic; H. Looking at the genetic variation and evolution of individual organisms to understand how they are related. All COVID-19 victims are of course infected with the novel coronavirus SARS-CoV-2. But not all SARS-CoV-2 viruses are exactly the same. When a person is infected, SARS-CoV-2 virus particles enter body cells and hijack the cell's molecular machinery to make viral copies of themselves that can then infect another person. With all frenetic clones of viruses, small errors can occur in the copies of the genetic code. And when virus particles move from person to person, the virus code can drift, collect new sets of mutations, or incorporate other variations.
By examining the genetic sequences of many SARS-CoV-2 viruses and identifying the differences between them, geneticists can find out how they are all related and how the virus develops overall. In this way, researchers can also help to understand the transmission chains from person to person. For example, if two patients are infected with virus strains that have very different mutations, one of them is unlikely to infect the other. If the viruses are nearly identical, the infections may be linked, if not certain, to one another.
What these mutations might mean: sometimes they are meaningless, sometimes not. In the worst case, they could, for example, allow a virus to cause a more serious illness or improve the spread between people.
So far, there is no clear evidence that SARS-CoV-2 picks up scary mutations. In fact, SARS-CoV-2 does not appear to be developing at all. The results of genetic sequences collected by researchers show that SARS-CoV-2 has a relatively slow rate of evolution.
This may be good news for humanity in general, but it is definitely bad news for understanding phylogenetic data. The slow development means that many of the viruses look very similar to each other, making it difficult to unravel how closely they are related. This led the researchers to suspect that the COVID-19 cases in February in Washington State were linked to the first case in January.
In the new analysis – led by Michael Worobey, an expert in pathogen evolution at the University of Arizona – the researchers looked closely at the genetic data that has accumulated since late February. They find that SARS-CoV-2 from the first case in Washington, WA1, is very similar to the other SARS-CoV-2 viruses found in the state, but differs by two nucleotides – represented by letters in their genetic code .
“(D) Despite hundreds of genomes sequenced in the state of Washington, viruses with genomes that are identical to WA1 or that pass between WA1 and the outbreak group (that is, with a C at position 17747 or an A at position 17858) have not been examined there like WA1) ", the authors wrote.
To go further, Worobey and colleagues created simulations with the latest estimate of the evolution rate of SARS-CoV-2 – the rate at which such changes are detected. In all of their simulations populated with WA1, none led to virus strains with similar genetic changes to those of the real outbreak viruses. However, other models strongly supported the possibility that additional SARS-CoV-2 launches in Washington from China would result in the February outbreak. They estimated that another case had arrived in the state on February 13, with a possible range from February 7 to 19.
Although the analysis still requires thorough peer review, other researchers seemed to accept the general conclusion that additional introductions of SARS-CoV-2 were likely to lead to Washington's outbreak – not the first case in January.
This includes Trevor Bedford, the researcher who first suspected that WA1 was the source of the February outbreak in the state. Bedford, an expert in viral evolution at the Fred Hutchinson Cancer Research Center in Seattle, admitted on Twitter that his hypothesis was not valid.
"At this point in time, I don't think we can rule out a WA1 introduction as impossible," he wrote in a long thread on the subject. "(B) But I think the most likely scenario is a separate undetected introduction by a genetically identical virus or a virus that has the additional 17858G mutation."
Bedford continued that he still estimates that there was a large, undetected outbreak at the time when outbreaks occurred in late February. "So I think I was wrong in the initial assessment of a WA1 launch, but right in claiming a significant expansion of the Washington state community on February 29," he wrote. "I am sorry to have caused confusion here. Although I believe that my original actions were justified given the evidence available at the time."
William Hanage, epidemiologist and pathogen development expert at Harvard, also agreed with Worobey and colleagues' general acceptance of the analysis. "It is now pretty clear that there have been more introductions," he wrote in a Twitter thread in Washington, responding to Bedford's comments.
Hanage and colleagues posted a warning comment on this topic in Nature Microbiology on May 19, before Worobey's analysis appeared online. Hanage and his colleagues wrote:
Most viruses can be broken down into strains, and if two infections are caused by different strains, transmission can be excluded. The often forgotten point is that phylogenies can rule out transmission, but if infections are caused by the same strains or identical viruses, this does not definitely prove the transmission. During an emerging outbreak where pathogens have not yet broken down into different strains, the phylogenetic information is too weak to suspect a transmission link …
While the connection between WA1 and the subsequent Washington outbreak may be weak, all of this can include a silver lining – Washington state officials acted while they thought it might be a massive, hidden outbreak. As Worobey and co-authors note, Washington was "one of the first in the United States to introduce restrictions on social distance and meeting size."
"An irony," they wrote, was that this action "was based, at least in part, on the assumption that the timing of the community transmission was not supported by the phylogenetic data (i.e., the assumption that the cryptic transmission had been in the middle This measure may have closed the gap between the establishment of a sustainable community transmission and pollution control measures in Washington State compared to other regions such as New York City in a way that deserves careful reassessment. "
On March 22, when New York issued an order to stay at home, the state saw more than 17 newly confirmed cases per 100,000 people per day, according to IHME data. In April, that number reached up to 52 new cases per 100,000 a day.
On March 23, when Washington issued its stay-at-home order, the state saw about three new cases per 100,000 a day – and the number did not exceed eight in aggressive testing.