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Bad news: a newly identified mutation makes SARS-CoV-2 more transmissible

Scientists published a preprint manuscript Thursday with genetic evidence that a new mutation of SARS-CoV-2, known as Spike D614G, is more transmissible than the original strain first identified in Wuhan in December.

Although a comparison of hospital records from English COVID-19 patients with the two strains did not yield any evidence that the new strain causes more hospitalizations or deaths among the infected, higher transmissibility makes SARS-CoV-2 harder to contain. This is terrible news.

The team also identified another mutation which, although it doesn’t appear to have the evolutionary advantages of Spike D614G, appears in a collection of lineages indicating that it probably spread by recombination, the first confirmation that this potent mutation mechanism is occurring in SARS-CoV-2 in humans.

How this study was performed

The sequencing of the SARS-CoV-2 genome in the first week of January definitively established that the outbreak in Wuhan was caused by a novel coronavirus. Since then, scientists have been sequencing samples from COVID-19 patients around the world and depositing them in a databank called GISAID, which was set up for influenza sequences and has expanded to coronaviruses. The team behind this research, based in Sheffield, Los Alamos, and Durham, has a software pipeline that ingests this database every day, checking the latest sequences and comparing them to prior ones.

This kind of comparison tracks where different strains of the virus are moving over time, which resulted in the news that most introgressions of SARS-CoV-2 to New York came from Europe. It also allows the identification of new mutations and assessment of their frequency over time, and assessment of whether they may matter clinically or in therapeutic development.

This kind of research has led to a lot of headlines in the mainstream press like “scientists identify [some number] strains of COVID-19 virus,” and a lot of speculation about whether the SARS-CoV-2 virus has an especially high mutation rate and whether more lethal or more transmissible strains are already out there.

However, experts have consistently said that the mutation rate of SARS-CoV-2 is relatively low and typical of coronaviruses, and that identified strains don’t have clinical significance. Until now.

What the D614G mutation is and why scientists think it makes SARS-CoV-2 more contagious

The D614G mutation is an alteration of a single amino acid on the Spike protein of SARS-CoV-2, at position 614, from aspartic acid (D) to glycine (G). The spike protein, which forms the “crown” appearance on an electron micrograph and gives coronaviruses their name, protrudes from the viral envelope and recognizes the ACE2 receptor on mammalian cells, allowing the virus to enter. While aspartic acid is a negatively charged polar residue with some bulk to it, glycine is neutral and is the smallest and simplest amino acid.

The D614G mutation appeared first in a single sample from Wuhan and then several more in Europe in February, and has become much more common since then, growing in prevalence over time. In theory, this could be because of “founder effects,” wherein the D614G doesn’t make a difference but was “carried along” with the rapid spread of a “founder” strain that wound up infecting many people. Because almost all strains carry some mutations, and some strains enjoy outsized reproductive success, founder effects driving some mutations to high prevalence are widely seen.

The team from Sheffield tested this hypothesis by looking at the pattern of increasing D614G prevalence over space and time. What they found was a repeated pattern of D614G strains of SARS-CoV-2 rising in prevalence over time in countries with both increasing and decreasing infection rates. This suggests that D614G is not just the beneficiary of a founder effect, but is actually making SARS-CoV-2 more transmissible. If so, it is the first known epidemiologically significant mutation in the COVID-19 pandemic.

Since its emergence, the D614G strain has become the dominant one around the world, and by the end of March made up about 75% of samples being submitted to GISAID in the USA, and the majority in other places.

How D614G might work

This leaves unanswered the question of how D614G makes SARS-CoV-2 more transmissible. Residue 614 on the spike protein is not a key recognition residue for ACE2, nor is it a key recognition residue for antibodies against the spike protein, which are two leading areas where scientists usually look for clinically significant mutations in coronaviruses.

However, the authors posit two possibilities. One, suggested by 3D modeling, is that the 614 residue has a hydrogen bond interaction with another nearby residue which alters the shape of the ACE2 recognition region, altering its activity. The second, suggested by limited immunological evidence, is that a nearby antibody recognition domain is larger than previously believed and the 614 residue is part of it. This could make it harder for the body to develop neutralizing antibodies against SARS-CoV-2, or easier for SARS-CoV-2 to function despite antibody binding in some circumstances.

Why D614G probably doesn’t make SARS-CoV-2 deadlier or harder to treat

All of this leaves unanswered an important question: does the Spike D614G mutation matter clinically? A person carrying this strain instead of another may be more contagious, but will they have different symptoms or a greater risk of death? Luckily, the answer appears to be no.

To answer this question, the Sheffield team consulted a database of 453 SARS-CoV-2 genomes matched with medical records from the donor patients, available at their university’s teaching hospital. Using a variety of statistical and machine-learning methods, they looked for evidence that COVID-19 patients who were carriers of the D614G mutation had a higher risk of hospitalization or death, and came up empty-handed.

In addition, Spike protein residue 614 does not currently appear to be a target of any known therapies.

Thus, while the D614G mutation is probably more transmissible, there’s currently no evidence that it’s more lethal or will frustrate current therapy efforts.

S943P: Evidence of SARS-CoV-2 recombination

In addition, the work presents evidence that another spike protein mutant, S943P, has been involved in recombination events. They conclude this because S943P is seen in multiple genetic backgrounds among samples in Belgium, but never seen outside Belgium (so far). The chance that it would independently arise multiple times in the same population, but never anywhere else, is considered remote, leading to the conclusion that this mutation has recombined in Belgium since it first emerged.

The S943P mutation doesn’t appear to have significance of its own, and it’s not common, but it’s important because it shows that recombination has been occurring in SARS-CoV-2 in humans. Recombination occurs when one cell is infected with multiple strains of a virus, and copies of their genomes undergo homologous recombination, creating a sequence with parts of both genomes which goes on to be incorporated into virions and form a new strain. It’s important because, like sexual reproduction, it allows mutations from multiple sources to be combined together. It’s known to be important in coronavirus evolution, but until now scientists had not confirmed it was happening in humans during the pandemic.

In theory, future recombination events could allow mutations with greater significance to combine together and form new, yet-worse strains of SARS-CoV-2.

What this and similar work will mean for the future of the pandemic

This is significant and very bad news, for a number of reasons:

  • A more transmissible strain of SARS-CoV-2 means the epidemic might be harder to contain. A strain with a higher R0 value will spread more rapidly when it’s not controlled, and take more stringent measures to contain. It will even resist vaccination more, taking a more effective vaccine or higher inoculation penetration to protect populations, not because a vaccine will be less effective but just because R must be reduced more from a higher starting point to get below 1. It’s going to be very important to get some estimates of how much more transmissible the D614G mutation makes SARS-CoV-2, so we can proceed accordingly.
  • This is the first epidemiologically important mutation discovered in SARS-CoV-2 so far, raising the prospect that we’ll see more such mutations in the future. We are only four months into the pandemic, and only a tiny percentage of humans have been infected so far, and we’ve already seen a harmful mutation emerge.
  • The confirmation that recombination is operating in humans means the potential impact of future damaging mutations is worse.

This news also reinforces a couple of points we’ve been making repeatedly for a long time, like the value of rapid and widespread genetics research and other recently-developed biotechnology methods in this pandemic, and the critical importance of keeping caseloads down everywhere in the world. Every additional case is another opportunity for damaging mutations to emerge.

If this pre-print passes peer review and the results hold up, it is very unfortunate news. Expect to hear more about this in the mainstream press soon.


  • 16 Comments

    • Hardened

      Well then!  Let me be the first to say thank you for your thoughtful analysis and g*d d*mn it!

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    • Margit Burmeister

      There is zero evidence the US will ever contain the virus – we will learn to live with it, not get rid of it or contain it. The US has not enough testing ability and not the willpower to restrict people’s movements or hire thousands of screeners or follow an app telling you to distance, as we have seen recently. So, it means we will get quicker through infection waves and/or vaccines through to herd immunity but as long as it is not getting  deadlier and our medical system is learning more about how to treat people, it’s not going to be disastrous.

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    • Cia

      An article about this at Thailand Medical News, May 1, said that this mutation represented an increase of function, the goal of the genetic manipulation funded by NIAID, which may be the source of this coronavirus pandemic. A specific nucleotide insertion has been identified as the novel technique enabling the virus to meld with host T cells, an insertion successfully carried out by genetic engineers. The article at Thailand Medical News said that the new mutation worsened clinical outcomes and made the development of a vaccine very unlikely. Any opinions on this? I said for months that coronavirus was the result of two natural zoonotic species leaps, but now I think it looks more likely that it was a lab accident. It seems unlikely that a pangolin sold at that wildlife market have interacted with a specific kind of horseshoe bat from a specific cave some distance away with a specific kind of coronavirus being studied at that lab. And that the lab, working on increase of function to increase the transmissibility and pathogenicity of the virus, was not involved in the virus binding not just to one, but to two receptor sites, and that its new spike protein, which enabled the unique increase of function of furin cleavage, was achieved naturally, with no connection to the lab doing such work just yards away.

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      • Hardened Cia

        Cynthia, it would be helpful if you include links to your sources.

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      • Cia Cia

        I’ll do it on the computer tomorrow. I don’t know how to give links on this cell phone. I thought those who were interested could google it by journal name and date.

         

        Here it is: https://www.thailandmedical.news/news/breaking-covid-19-warning-study-shows-of-spike-mutations-of-sars-cov-2,-making-it-more-transmissible-and-dangerous-the-reality-is-that-there-is-unlike

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      • Cia Cia

        https://www.google.com/amp/s/www.forbes.com/sites/williamhaseltine/2020/05/16/did-the-oxford-covid-vaccine-work-in-monkeys-not-really/amp/

        The rhesus monkeys in the Oxford vaccine trial developed neutralizing antibodies which turned out not to be protective. Even after having been vaccinated, when they were exposed to the virus, all of them became infected.

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      • Cia Cia

        https://www.google.com/amp/s/www.forbes.com/sites/williamhaseltine/2020/05/16/did-the-oxford-covid-vaccine-work-in-monkeys-not-really/amp/

        The rhesus monkeys in the Oxford vaccine trial developed neutralizing antibodies which turned out not to be protective. Even after having been vaccinated, when they were exposed to the virus, all of them became infected.

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      • Margit Burmeister Cia

        I don’t understand the logic if the Wuhan cases did not have this mutation, but later cases, particularly those in Europe and the US have this mutation. If it spreads faster, it easily can be 90% of cases now soon. It is pretty common for viruses to develop mutations that make it spread faster but I see no evidence that it makes the disease more severe, or why the Thai review claims to conclude that no vaccine would ever be developed – in my blog here, I venture to say that it may become a moving target with annual vaccines. But why never? It doesn’t mutate more than other viruses. I don’t get why this is an argument for the lab development – clearly the first Wuhan cases did not have this mutation

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      • Cia Cia

        I just put up another comment before seeing yours. I just found this, on the S and L strains: newscientist.com, March 5, 2020, Jessica Hamzelou, “Coronavirus: Are  There Two Strains and is one more deadly?” The answer is yes, the later L mutation is more deadly. I don’t know why they have said it seems to be stable and unchanging. A new mutation was identified in India in January and one in Brazil. There are said to be at least thirty strains, typical for a rapidly-mutating RNA virus. With many subtypes specific as to cities in Europe identified when analyzing samples in New York.

         

        But an overarching problem is the antibody-dependent enhancement, which can make subsequent exposure to the CV antibodies extremely dangerous or fatal, whether the antibodies are from exposure to the natural disease or to reaction to CV vaccine antigens. I read the other day that some of the fatal cases of CV may have been because the patients had previously been exposed to the four variants of CV which can cause colds (though rhino viruses are more common causes of colds).

         

        Since they are working on many potential CV vaccines, maybe they have a theoretical way to overcome this problem. But in addition to that problem, I think the numerous different strains, types, and subtypes may not be similar enough to provide cross-protection between types, either in vaccines or exposure to the natural diseases. There is no vaccine for the common cold, probably for similar reasons. It is uncertain whether recovery from one strain gives any long-lasting immunity either to that strain or other, similar ones. And with its appearing probable that this virus was the fruit of increase of function experiments, we can’t know yet the scope of what was achieved.

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      • Hardened Cia

        “Despite all the publicity and lies, it is impossible for a vaccine to be developed for a virus that has more complicated and far more potent attributes than the HIV virus …”

        This is an unsubstantiated claim that’s demonstrably false given that we have a vaccine that works in monkeys.

        The article you linked is speculative and fear-mongering.  Any time an article makes sweeping claims about the future such as “there is not going to be a single drug that can cure or treat COVID-19 as it evolves to become more complicated” you should take it with a large grain of salt.  The author doesn’t know this to be true and is being irresponsible by claiming that it is.

        The scientific paper is interesting but the interpretive article in the Thailand Medical News is not credible.  Ignore it.

        This is a scary situation and we need to keep educating ourselves about it.  Unfortunately, news publications such as Thailand Medical News use fear, both on purpose and by accident, as a means to generate attention.  It’s easy to get sucked into it but we must be disciplined and skeptical.  Fear takes too great a toll on the health of the body and we need to be smart about managing it.  Conveying accurate information about a scary topic while not adding unnecessary fear is a challenging task that requires skill.  I admire publications like The Prepared and The New York Times for being careful in striking an appropriate balance.

        On a personal note, here’s how I manage my own fear:  While reading news, for example, I’ll gradually notice my breathing becoming more shallow and a tightness in my abdomen.  Through practice I have learned to recognize these as signs that I’m feeling scared.  My mind is usually racing with thoughts along the lines of, “I have to DO something about this!”.  Instead, I stop whatever I’m doing and put all of my attention on the sensations in my body.  I observe the fear as it passes through.  Through lots of experience I have learned that when I am afraid like this, there is literally NOTHING I need to do nor should do other than to observe the fear as it passes through my body.  When it finishes I then go back to reading the news or whatever else I was doing.  It’s been very helpful.

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    • Cia

      They’ve said for several months that there were at least two major strains: the original S strain in China which was then carried over the Pacific to California and The Pacific Northwest, and the L strain, a more lethal mutation that was carried West to Italy, Iran, the rest of Europe, and New York, New Jersey, Massachusetts, etc. They announced several weeks ago that there were at least thirty strains, and that genetic analysis had been able to pinpoint the European cities strains from which had produced cases in the US. I don’t know the broader significance of this.

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    • Oly Pen Aaron

      Thanks for the information. Does your research indicate why we don’t see mainstream reports of recovered cases in a timely manner? For instance, my county (Jefferson, WA) now has — according to the link — two (2) “active” cases. https://www.jeffersoncountypublichealth.org/1429/COVID-19. However all I see on the major reporting websites is a glaring “28” cases: https://www.worldometers.info/coronavirus/usa/washington/ and the same stat is seen on the Johns Hopkins scary red death bubble app. I think it’s germane, esp. given where things seem to be heading with the phased-in reopening approaches I’ve seen where active-cases-per-some-capita-number will drive the tightening or relaxation of current measures. Any feedback or insight is appreciated.

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    • lemur

      “Scientists published a preprint manuscript Thursday with genetic evidence that a new mutation of SARS-CoV-2, known as Spike D614G, is more transmissible than the original strain first identified in Wuhan in December.”

      That’s what they concluded, but other scientists have found that the evidence in the article does not support that conclusion. Ars Technica has a pretty good write up about it:

      https://arstechnica.com/science/2020/05/draft-study-conclusions-on-sars-cov-2-mutation-overstep-data-grab-headlines/

      Everybody who trumpeted the article’s headline jumped the gun. Journalists and scientists can jump the gun only so many times before their credibility is shot beyond repair.

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      • Hardened lemur

        Nice find!

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      • Stephanie ArnoldContributor lemur

        All pre-prints jump the gun, so to speak–they’re not yet peer reviewed. Some expert peers will point out merits, others will point out flaws in the design. All feedback helps shape the future research that piggybacks on the findings. Repeated replication of findings or repeated failures to replicate findings are very telling, but take a lot of time to come to fruition. We need to see what happens with more data and perhaps with better design. That’s how it works.

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