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Wednesday, December 23, 2020

Here's what we know about the N501Y mutation in SARS-CoV-2 (updated Jan 02, 2021)

We're living in an age when a single nucleotide change can throw a continent into a state of utter panic

T his week a mutated form of the virus SARS-CoV-2 has thrown Europe into a state of panic and caused the governments of the UK to impose draconian lockdowns. Trucks are backed up at Dover as France has barred entry. What the heck is going on?

The new mutation is called VUI-202012/01. It is a mutation on the virus's S (spike) protein. The mutation is called N501Y. This means that an asparagine in the amino acid sequence has changed to a tyrosine.

The news media are claiming that this new mutation makes SARS-CoV-2 70% more infectious than the “normal” virus. However, most of these claims either come from political sources like Al Jazeera, The Guardian, and Wikipedia, or from sources like the COG Consortium that are too vague to be useful.

Here's what we know so far:

The Gu et al. paper is very interesting. Here are their main points:

It is important to note this does NOT mean the mutation was created in a lab. If anything, adapting it to mice would make the virus less dangerous to humans but more dangerous to mice. The fact that it spread slightly more rapidly in mice was entirely due to its adaptation in mice. I could find no source in the published literature or in any preprints for the claim that this mutation is more infectious in humans. This suggests that the figure is somebody's speculative guess.

It is remarkable that we're in an age when a car mechanic can talk about PCR Ct values, as mine did recently, and a trash collector talks about DNA mutations and actually understand them. Who says humans aren't interested in science? Whether it's due to the Last Man Standing principle or to the fact that we're in a panic, it shows there's a deep reservoir of interest in science out there.

Update (Dec 25 2020): A preprint has just appeared [2] describing the origin of the 70% figure. It seems the number comes from a series of computer models. The authors express their result as a ratio σ of two R0 numbers, which are derived from an epidemiological model. So, for example, σY1 is the ratio of the estimated transmissibility R0 for 501Y variant 1 to the normal variant; the same for variant 2, which they believe (on the basis of a molecular model) is more infectious. They write:

Using confirmed deaths (adjusted for the delay between onset and death [7]) as the proxy for the COVID-19 epidemic curve [8], we estimated that σY1 was 1.10 (95% CrI 1.06–1.13) and σY2 was 1.75 (1.70–1.80). That is, the basic reproductive number of the 501Y Variant 1 and Variant 2 was 10% (6–13%) and 75% (70–80%) higher than that of the 501N stain, respectively.

The fitted model was largely congruent with the observed proportions of the three strains over time, except in the last week of November 3–10 during which 501Y Variant 1 cocirculated with 501N and 501Y Variant 2 (Figure 2).

Here's their conclusion:

. . . [M]ore rapid and stringent control measures would be necessary to suppress spread, which is precisely what the UK government effected on December 19, including the addition of a new tier 4 set of restrictions.

Maybe those numbers will turn out to be correct and the new variant really is slightly more transmis­sible, but that political statement gives it away. It is a proxy model based on many assumptions. Most of their references are to websites and other preprints. I seriously doubt this paper will pass peer review.

Update (Jan 02 2021): The press are celebrating a new preprint from Imperial College London, saying that the mutation, now called B.1.1.7 / SARS-CoV-2 VUI 202012/01, (also called "Super-Covid" by the press) is 48% more transmissible. Imperial College is the source of a flawed epidemiological prediction that wildly overestimated the risk of SARS-CoV-2, so we need to be cautious, but an additional point is that the press is also misreporting what they are saying. Here is the authors' punch line:

Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility, but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H.[3]

At the risk of stating the obvious, D796H is not the same as N501Y, which they say was only "transiently" detected. The main point of the paper is that the virus might be mutating in such a way as to avoid existing antibodies. Viruses, as we all know, do things like that.

1. Gu H, Chen Q, Yang G, He L, Fan H, Deng YQ, Wang Y, Teng Y, Zhao Z, Cui Y, Li Y, Li XF, Li J, Zhang NN, Yang X, Chen S, Guo Y, Zhao G, Wang X, Luo DY, Wang H, Yang X, Li Y, Han G, He Y, Zhou X, Geng S, Sheng X, Jiang S, Sun S, Qin CF, Zhou Y. Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy. Science. 2020 Sep 25;369(6511):1603-1607. doi: 10.1126/science.abc4730. Jul 30. PMID: 32732280; PMCID: PMC7574913. https://pubmed.ncbi.nlm.nih.gov/32732280/

2. Leung K, Shum M, Leung G, Lam T, Wu J (2020). Early empirical assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom, October to November 2020. Preprint posted Dec 23, 2020 https://www.medrxiv.org/content/10.1101/2020.12.20.20248581v2

3. Kemp SA, Collier DA, Datir R, Ferreira IATM, Gayed S, Jahun A, Hosmillo M, Rees-Spear C, Mlcochova P, Ushiro I, Roberts DJ, Chandra A, Temperton N , The CITIID-NIHR BioResource COVID-19 Collaboration, The COVID-19 Genomics 5 UK (COG-UK) Consortium, Sharrocks K, Blane E, Briggs JAG, van Gils MJ, Smith KGC, Bradley JR, Smith C, Doffinger R, Ceron-Gutierrez L, Barcenas-Morales G, Pollock DD, Goldstein RA, Smielewska A, Skittrall JP, Gouliouris T, Goodfellow IG, Gkrania-Klotsas E, Illingworth CJR, McCoy LE, Gupta RK (2020). Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation https://www.medrxiv.org/content/10.1101/2020.12.05.20241927v3 Preprint posted Dec 29 2020

dec 22 2020, 11:20 am. updated jan 02 2021, 5:34 am

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