=====================================================================
[reminder] Issues with GISAID's SARS-CoV-2 sequencing data
https://virological.org/t/issues-with-sars-cov-2-sequencing-data/473
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>Mutations of Interest QRD/list:
https://github.com/emmahodcroft/cluster_scripts/blob/master/README.md
SARS-CoV-2 Mutation Tracker System
https://www.cbrc.kaust.edu.sa/covmt/
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[qrds on UK variant]
https://archive.4plebs.org/pol/thread/297625248/#297629894
S:N501 in a nutshell:
>Has appeared multiple times independently: each can be associated with different accompanying mutations
>Amino-acid changes are N501Y (nucleotide mutation A23063T), N501T (nucleotide mutation A23064C), and N501S (nucleotide mutation A23064G)
>Mutation is in the receptor binding domain (RDB), important to ACE2 binding and antibody recognition
>Associated with a recently reported 'new variant' announced in the South East of England on 14 Dec 2020
>This particular variant is associated with multiple mutations in Spike, including: N501Y, a deletion at 69/70 (as seen in S:N439K & S:Y453F), and P681H
>Clusters also seen in USA, South Africa, & Australia
>May be associated with adaptation to rodents and mustelids:
>N501T in ferrets https://archive.is/17oKa
>N501Y in mice https://archive.is/4paiC
>Some have speculated of risk of a persistent reservoir in wild rodents/mustelids
>Appears to increase ACE2 binding:
https://archive.is/X4tL8
https://jbloomlab.github.io/SARS-CoV-2-RBD_DMS/
[chinks already had the "UK" mutation(s) in their labs month(s) before]
https://archive.4plebs.org/pol/thread/297745390/#297762664
The protein adaptation at position 501, featured in the current mutation outbreak in the UK and South Africa is not an original feature of SARS-2, but SARS-1. The SARS-2 501 sequence aligns with the 487 sequence of OG SARS.
https://jvi.asm.org/content/94/7/e00127-20
>Second, residue 501 in 2019-nCoV RBD (corresponding to residue 487 in SARS-CoV) is an asparagine
>Alarmingly, our data predict that a single N501T mutation (corresponding to the S487T mutation in SARS-CoV) may significantly enhance the binding affinity between 2019-nCoV RBD and human ACE2.
>Thus, 2019-nCoV evolution in patients should be closely monitored for the emergence of novel mutations at the 501 position (to a lesser extent, also the 494 position).
This factor of SARS 1 originality is also confirmed to an extent by the mutation reference on github:
https://github.com/emmahodcroft/cluster_scripts/blob/master/cluster_tables/S.N501_table.md
>Note any pre-2020 Chinese sequences are from SARS-like viruses in bats (not SARS-CoV-2).
>China: first_seq 2013-07-24 num_seqs 2 last_seq 2019-06-25
The chinks deliberately modified the 501 protein and made the 501Y strain, precursor to the current mutant outbreak strain.
However the original 501Y had a distinct mutation: nucleotide mutation A23063T. Which they fully admit to creating here:
https://archive.is/4paiC
>To decipher the underlying mechanism for the increased virulence of MASCp6, the complete genome of MASCp6 was subjected to deep sequencing with an Ion Torrent S5Plus sequencer.
>The A23063T mutation resulted in a N501Y amino acid substitution in the RBD of the S protein, which is assumed to be responsible for receptor recognition and host range of SARS-CoV-2
And this mutation remains intact and detectable in modern S:N501Y
https://github.com/emmahodcroft/cluster_scripts/blob/master/README.md#sn501
>Amino-acid changes are N501Y (nucleotide mutation A23063T), N501T (nucleotide mutation A23064C), and N501S (nucleotide mutation A23064G)
=====================================================================
[Yusen Zhou's (died in-between 2 May and 30 July) research is related to the SARS-CoV-2 variants that popped up recently]
On May 2, 2020, as a co-corresponding author, Zhou uploaded a preprint, Rapid adaptation of SARS-CoV-2 in BALB/c mice: Novel mouse model for vaccine efficacy, on bioRxiv. And on July 30, Science Magazine published Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy, listing Zhou as a “Deceased” co-corresponding author.
>According to Lude Media, Zhou had a close tie with the defector who is “the second person from China to provide information about Chinese biological research with potential weapons applications”. Resources say many people related to this defector have been secretly arrested by the CCP. Besides, insiders told Lude, friends on WeChat found his wife, who works in the same area, appeared unusually silent and calm after his death.
https://archive.vn/xvQRZ
https://archive.4plebs.org/pol/thread/298253203/#298262536
https://archive.4plebs.org/pol/thread/298253203/#298264663
https://archive.4plebs.org/pol/thread/298253203/#298265453
[]
Did Fauci’s NIH Institute Financially Assist China’s Military?
>U.S. patent number 8933106 entitled “2-(4-substituted phenylamino) polysubstituted pyridine compounds as inhibitors of non-nucleoside HIV reverse transcriptase, preparation methods and uses thereof” is assigned to the Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences of China’s People’s Liberation Army.
>One of the inventors of that patent, Shibo Jiang, is a graduate of the First and Fourth Medical University of the People’s Liberation Army, Xi’an, China.
>Since 2004, Shibo Jiang has had scientific collaboration with Yusen Zhou, who was a professor at the State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences in Beijing.
>It is unclear whether Yusen Zhou also received his education at one of China’s military medical universities, but his early scientific work was associated with the Department of Infectious Disease, 81st Hospital of the People’s Liberation Army, Nanjing Military Command and the Fourth Medical University of People’s Liberation Army, Xi’an, Shibo Jiang’s alma mater.
>Shibo Jiang and Yusen Zhou are listed as co-inventors on at least eight U.S. patents, the references supporting those patents, for example, 9889194, was research funded by NIAID.
https://archive.vn/2r6x8
=====================================================================
[qrds on Brazil variant]
Brazil: Identifying a new coronavirus variant in Río de Janeiro
>it is not known if it is transmitted faster and if it is more aggressive
>the new variant is "partially restricted" to the city, which concentrates the largest number of cases and deaths per city in the region, but warned about a possible spread
>"The significant increase in the frequency of this design raises concerns about the management of public health and the need for genomic surveillance during the second wave of infections," the scientists expressed in the study.
>The new strain was discovered through the genetic sequence of line B.1.1.28, which has been circulating in Brazil since the beginning of the year, and it is estimated that the variant appeared in July .
>The researchers analyzed 180 genomes of SARS-CoV-2 and discovered five "exclusive mutations", which "emerged and quickly spread".
>The study, however, does not indicate if the new strain identified is the most transmissible or the most aggressive that is known in Brazil, one of the worst countries hit by the pandemic in the United States and India.
https://translate.google.com/translate?sl=pt&tl=en&u=https://www.pagina12.com.ar/313320-alerta-en-brasil-identifican-una-nueva-cepa-de-coronavirus-e
https://cov-lineages.org/lineages/lineage_B.1.1.28.html
https://www.mdpi.com/1999-4915/12/12/1414/htm
[]
>Regarding amino acid mutations, new evidence recently emerged showing a number of important amino acid changes in the Spike protein.
>An amino acid change (D614G) is of particular interest since G614 lineages have consistently replaced well established D614 strains and could confer a fitness advantage of the former strains leading to a higher viral load in infected patients and higher mortality rate
>Second, we attempted to isolate this virus after the third passage in VERO CCL-81 cells and we managed to detect 75% (620/816 reads) G23073T of the reads supporting the N501Y mutation (Table S7).
>The genomic analysis of 101 SARS-CoV-2 genomes from the beginning of the epidemic at Pernambuco state, Brazil, revealed at least five independent international importation events of SARS-CoV-2 strains, that effectively seeded community transmission, occurred from late February to mid-April which is in line with studies focusing on other Brazilian states.
[late February to mid-April, and another "rare" N501Y mutation]
>Interestingly, this sample was not clustered phylogenetically with other sequences containing this amino acid substitution.
[interestingly indeed]
=====================================================================
[qrds on South Africa variant]
S-variant SARS-CoV-2 is associated with significantly higher viral loads in samples tested by ThermoFisher TaqPath RT-QPCR
https://www.medrxiv.org/content/10.1101/2020.12.24.20248834v1.full
[]
Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa
>'20C/501Y.V2' is found in South Africa and was also announced in December 2020
>The K417N mutation would abolish key interactions with class 1 NAbs, and likely contributes toward immune evasion at this site.
>Class 2 antibodies bind to spike residue E484, and the E484K mutation has been shown to confer resistance to NAbs in this class, and to panels of convalescent sera, suggesting that E484 is a dominant neutralizing epitope
https://www.medrxiv.org/content/10.1101/2020.12.21.20248640v1
[]
>This variant is associated with multiple mutations in Spike, including: N501Y, K417N, and D80A.
>There is also an N mutation: T205I.
>It does -not- have the deletion at 69/70.
https://github.com/emmahodcroft/covariants/blob/master/README.md
[]
>E484K shows higher expression and higher binding
>K417N shows much lower binding
https://jbloomlab.github.io/SARS-CoV-2-RBD_DMS
[]
>You’ll note the N501Y is also in the UK strain, but the E484K is one that people are particularly watching, because that’s in a region that a number of antibodies seem to recognize.
https://blogs.sciencemag.org/pipeline/archives/2020/12/22/the-new-mutations
[]
[T205I]
>In contrast, when uBCEL sequence variability was inspected within an updated sampling (Last accession: 1 May 2020) of 1639 SARS-CoV-2 isolates with complete genome sequences, only four uBCELs demonstrated residue changes in more than 1% of isolates (Figure 3b and Table 2).
>Among these, the I68- deletion in uBCEL-S2, V483A in uBCEL-S5, and the S197L, R203K-G204R, and T205I in uBCEL-N4 variants were observed in 10 or more isolates.
>All these predominant lineages were detected for the first time in isolates obtained between 29 January 2020 and 15 March 2020.
https://www.mdpi.com/2076-393X/8/3/397/htm
=====================================================================
Variation analysis of SARS-CoV-2 complete sequences from Iran
>24 complete sequences were analyzed
>Seventeen sequences had amino acid changes in the spike glycoprotein. These sequences were sampled throughout the pandemic, although, we analyzed D614G mutation with or without other mutations A475V, L452R, V483A, and F490L that are related to the increasing virus infectivity and transmissibility potentials
https://www.biorxiv.org/content/10.1101/2021.01.23.427885v1.full.pdf
[]
https://www.sciencedirect.com/science/article/pii/S0092867420308771
>Ten mutations such as N234Q, L452R, A475V, and V483A was markedly resistant to some mAbs
https://elifesciences.org/articles/61312
>F490L forms from pressure from C121 mAb
>We show that Δ382 does not elicit a significantly different host response from infected cells compared to the wild-type strain, despite the absence of a large genome segment encompassing ORF8.
>This observation is particularly interesting when juxtaposed with the reduced incidence of severe outcomes and reduced systemic levels of certain cytokines in patients infected with Δ382.
>When taken together, this suggests the in-vivo differences associated with Δ382 infection are likely an emergent effect from interaction between infected cells and the host immune system, and not a direct consequence of virus strain-specific effects at the cell infection level.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009130
[]
>SARS-CoV-2 ORF3b suppresses IFN more efficiently than its SARS-CoV ortholog
https://doi.org/10.1016/j.celrep.2020.108185
[]
>This is in concordance with previous studies on SARS-CoV that although orf3b, orf6 and nucleoprotein of SARS-CoV can individually function as interferon antagonist, infection with orf6-null SARS-CoV triggered STAT1 nuclear translocation
https://www.tandfonline.com/doi/full/10.1080/22221751.2020.1780953
[]
>Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV
>This level of sensitivity is similar to MERS-CoV and suggests that the novel CoV lacks the same capacity to escape a primed IFN-I response as SARS-CoV (41, 42). Notably, the sensitivity to IFN-I does not completely ablate viral replication; unlike SARS-CoV 2’O methyl-transferase mutants (37), SARS-CoV-2 is able to replicate to low, detectable levels even in the presence of IFN-I.
>While SARS-CoV-2 may employ a similar mechanism early during infection, STAT1 phosphorylation and reduced viral replication are observed in IFN-I primed and post-treatment conditions indicating that the novel CoV does not block IFN-I signaling as effectively as the original SARS-CoV
>Together, the sequence homology analysis suggests that differences 235 in NSP3, ORF3b, and/or ORF6 may be key drivers of SARS-CoV-2 IFN-I susceptibility.
>For SARS-CoV ORF3b, a 154 amino acid (AA) protein known to antagonize IFN-I responses by blocking IRF3 phosphorylation (33), sequence alignment indicates that the SARS-CoV-2 equivalent ORF3b contains a premature stop codon resulting in a truncated 24 AA protein.
https://www.biorxiv.org/content/10.1101/2020.03.07.982264v4
=====================================================================
In silico investigation of the new UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 variants with a focus at the ACE2-Spike RBD interface
>Transmission of the UK and possibly South African SARS-CoV-2 strains appears substantially increased compared to other variants
>This could be due, in part, to increased affinity between the variant Spike proteins and ACE2
>We investigated in silico the 3D structure of the Spike-ACE2 complex with a focus on Spike K417N, E484K and N501Y
>The N501Y substitution is predicted to increase the affinity toward ACE2 (UK strain) with subsequent enhanced transmissibility and possibly pathogenicity
>Additional substitutions at positions 417 and 484 (South African strain) may pertub the interaction with ACE2 raising questions about transmissibility and pathogenicity
https://www.biorxiv.org/content/10.1101/2021.01.24.427939v1
SARS-CoV-2 receptor binding mutations and antibody mediated immunity.
>There were no SARS-CoV-2 mutations found at the Q498 residue of the RBD. This is perplexing as the Q498H, Q498Y, and Q498F all improve RBD expression and ACE2 binding, moreover, the Q498H mutation boasts the highest affinity for ACE2 of any RBD mutant. Furthermore, there were a number of mutations that could significantly improve RBD-ACE2 binding but were either completely absent in our data or of extremely low frequency, including N501F, Y453F, T385R, Q493M, and Q414A amongst others. These contradictions may be explained by the transmission-mortality trade-off theory. This theory suggests that fitness is not defined by a high mortality rate due to symptoms, but rather a high transmission rate or R0. It is possible that mutations at Q498 would negatively impact viral fitness by increasing mortality and reducing SARS-CoV-2 transmission. If correct, this theory suggests that the mortality rate of SARS-CoV-2 should decrease over time while transmission rate should improve to a yet unknown maximum. This may be the case with the recently increased frequency of a new spike deletion variant ΔH69/ΔV70
https://www.biorxiv.org/content/10.1101/2021.01.25.427846v1
E484K as an innovative phylogenetic event for viral evolution: Genomic analysis of the E484K spike mutation in SARS-CoV-2 lineages from Brazil
>The propagation of new lineages and the discovery of key mechanisms adopted by the virus to overlap the immune system are central topics for the entire public health policies, research and disease management. Since the second semester 2020, the mutation E484K has been progressively found in the Brazilian territory, composing different lineages over time. It brought multiple concerns related to the risk of reinfection and the effectiveness of new preventive and treatment strategies due to the possibility of escaping from neutralizing antibodies. To better characterize the current scenario we performed genomic and phylogenetic analyses of the E484K mutated genomes sequenced from brazilian samples in 2020. From October, 2020, 43.9% of the sequenced genomes present the E484K mutation, which was identified in three different lineages (P1, P2 and B.1.1.33) in four Brazilian regions. We also evaluated the presence of E484K associated mutations and identified selective pressures acting on the spike protein, leading us to some insights about adaptive and purifying selection driving the virus evolution.
https://www.biorxiv.org/content/10.1101/2021.01.27.426895v1
Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants
>Our results correctly model an increase in open-state occupancy for the more infectious D614G via an increase in flexibility of the closed-state and decrease of flexibility of the openstate.
>We predict the same effect for several mutations on Glycine residues (404, 416, 504, 252) as well as residues K417, D467 and N501, including the N501Y mutation recently observed.
>This is, to our knowledge, the first use of normal-mode analysis to model conformational state transitions and the effect of mutations thereon.
>N501Y mutant shows a doubling of the occupancy of the open state with the concomitant decrease of the occupancy of the closed state.
>Additionally, this mutation was shown to also increase binding affinity to the ACE2 receptor relative to the wild type with a Δlog10(KD,app) of 0.24.
>Therefore, we predict that N501Y has a strong potential to contribute to increased transmission.
>The calculations above were performed in the context of D614.
>However, the double mutant representing the N501Y mutation in the context of G614 has equally shifted occupancies with values of 35.06% and 64.04% for the open and closed state respectively.
>Our results explain the behaviour of the D614G strain, the increased infectivity of SARS-CoV-2 relative to SARS-CoV as well as offers a possible explanation for the rise of new strains such as those harboring the N501Y mutation.
https://www.biorxiv.org/content/10.1101/2020.12.16.423118v2
The SARS-CoV-2 S1 spike protein mutation N501Y alters the protein interactions with both hACE2 and human derived antibody: A Free energy of perturbation study
>we observed significant decrease of the binding between S1 RBD and STE90-C11 antibody by ΔΔG of 3.78kcal/mol.
>Thus, our calculations predict that the N501Y mutant will produce a decrease of the binding to ΔG=-8.92kcal/mol or 293nM.
>This is about 161 times lower than the wild type.
https://www.biorxiv.org/content/10.1101/2020.12.23.424283v1
[(((GISAID))) data btw] Paired SARS CoV-2 Spike Protein Mutations Observed During Ongoing SARS-CoV-2 Viral Transfer from Humans to Minks and Back to Humans
>In pdf, info/rundowns on:
>F486L
>L452M
>Q314K
>Y453F
>N501T
>V367F
https://www.biorxiv.org/content/10.1101/2020.12.22.424003v1
https://www.biorxiv.org/content/10.1101/2020.12.22.424003v1.full.pdf
[]
But beware:
>Competing Interest Statement
>Reid Rubsamen, Scott Burkholz, Richard T. Carback III, Tom Hodge, Serban Ciotlos, Lu Wang, and CV Herst are employees of Flow Pharma, Inc., currently developing a SARS-CoV-2 vaccine, and all receiving cash and stock compensation. Paul Harris is a member of Flow Pharma's Scientific Advisory Board. Daria Mochly-Rosen, Suman Pokhrel, and Benjamin R. Kraemer have nothing to declare
UK authorizes Astrazeneca vaccine - first non-experimental Western vector vax
https://archive.vn/aomD9
SARS-CoV-2 in Brazil shows gross genetic diversity
>this could reduce the efficiency of some of the interventions meant to contain the virus, due to the viral genetic diversity
https://archive.vn/1evLg
https://archive.vn/rBL6X
Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic
>In conclusion, our data show that >70% of the population has been infected in Manaus approximately seven months after the virus first arrived in the city. This is above the theoretical herd immunity threshold. However, prior infection may not confer long-lasting immunity (30, 31). Indeed, we observed rapid antibody waning in Manaus, consistent with other reports that have shown signal waning on the Abbott IgG assay (14, 32). However, other commercial assays, with different designs or targeting different antigens, have more stable signal (14), and there is evidence for a robust neutralizing antibody response several months out from infection (33). Rare reports of reinfection have been confirmed (34), but the frequency of its occurrence remains an open question (35). Manaus represents a “sentinel” population, giving us a data-based indication of what may happen if SARS-CoV-2 is allowed to spread largely unmitigated.
https://science.sciencemag.org/content/early/2020/12/07/science.abe9728
"Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant"
https://pubmed.ncbi.nlm.nih.gov/32321524/
"The D614G mutation in SARS-CoV-2 Spike increases transduction of multiple human cell types"
https://pubmed.ncbi.nlm.nih.gov/32587969/
Scientist suggests SARS-CoV-2 VUI-202012/01 variant could more easily infect children
>"There is a hint that it has a higher propensity to infect children... but we haven't established any sort of causality on that, but we can see that in the data."
>"What we've seen over the course of a five or six-week period is consistently the proportion of pillar two cases for the variant in under-15s was statistically significantly higher than the non-variant virus."
>More data would be needed to draw a conclusion.
>"We are not saying that this is a virus which specifically attacks children"
>"We know that SARS-CoV-2, as it emerged as a virus, was not as efficient in infecting children as it was adults, and here are many hypotheses about that.
>"And again, if the (new) virus is having an easier time of finding an entrance cell then that would put children on a more level playing field."
https://archive.vn/IQ5Di
Change of dominant strain during dual SARS-CoV-2 infection
>>Our findings suggest that the patient was infected by two genetically distinct SARS-CoV-2 strains at the same time. One of the possible explanations is that the second infection occurred in the hospital
https://www.medrxiv.org/content/10.1101/2020.11.29.20238402v1
Worrisome new data—new B117 variant is not only more infectious, it’s potentially more infectious in children 0-9 (+24%) and 10-19 (+14%), and less among 60-79, compared to common strains. More sobering—the R estimate is much higher.
https://twitter.com/DrEricDing/status/1345382699071102977
The newly introduced SARS-CoV-2 variant A222V is rapidly spreading in Lazio region, Italy
>A new SARS-CoV-2 clade (GV) characterized by S substitution A222V
https://www.medrxiv.org/content/10.1101/2020.11.28.20237016v1
Prospective mapping of viral mutations that escape antibodies used to treat SARS-2
>These complete maps uncover a single amino-acid mutation that fully escapes the REGN-COV2 cocktail, which consists of two antibodies targeting distinct structural epitopes. The maps also identify viral mutations that are selected in a persistently infected patient treated with REGN-COV2, as well as in lab viral escape selections. Finally, the maps reveal that mutations escaping each individual antibody are already present in circulating SARS-CoV-2 strains
https://www.biorxiv.org/content/10.1101/2020.11.30.405472v1
Time-lapse video was taken on the Etaluma LS620 by Tabb Sullivan and his group at Integral Molecular. HEK-293T cells expressing SARS-CoV-2 spike cells fusing to HEK-293T cells stably expressing hsACE2 forming giant syncytia
https://twitter.com/DNA_RNA_Uni/status/1338197228381483009
[]
Syncytia formation by SARS‐CoV‐2‐infected cells
https://www.embopress.org/doi/full/10.15252/embj.2020106267
[]
>SARS-CoV-2 infected cells express the viral Spike protein (S) at their surface and fuse with ACE2-positive neighbouring cells. Expression of S without any other viral proteins triggers syncytia formation
https://www.biorxiv.org/content/10.1101/2020.07.14.202028v1
Within-host genomics of SARS-CoV-2
>SARS-CoV-2 infections are characterised by low levels of within-host diversity across the entire viral genome, with evidence of strong evolutionary constraint in Spike, a key target of vaccines and antibody-based therapies
>potential vaccine-escape mutations are likely to be rare in infectious individuals. Nonetheless, we identified Spike variants present in multiple individuals that may affect receptor binding or neutralisation by antibodies. Since the fitness advantage of escape mutations in highly-vaccinated populations is likely to be substantial, resulting in rapid spread if and when they do emerge, these findings underline the need for continuedvigilance and monitoring
https://www.biorxiv.org/content/10.1101/2020.05.28.118992v4
https://www.biorxiv.org/content/10.1101/2020.05.28.118992v4.full.pdf
The Potential for SARS-CoV-2 to Evade Both Natural and Vaccine-induced Immunity
https://www.biorxiv.org/content/10.1101/2020.12.13.422567v1
Neutralising antibodies drive Spike mediated SARS-CoV-2 evasion
https://www.medrxiv.org/content/10.1101/2020.12.05.20241927v1
New SARS-CoV-2 variant in UK
>This variant carries a set of mutations including an N501Y mutation in the receptor binding motif of the Spike protein that the virus uses to bind to the human ACE2 receptor
https://www.cogconsortium.uk/news_item/update-on-new-sars-cov-2-variant-and-how-cog-uk-tracks-emerging-mutations/
>N501Y
Mouse-adapted strain from chink lab?
https://www.biorxiv.org/content/10.1101/2020.11.10.377333v1
https://science.sciencemag.org/content/369/6511/1603
https://systembio.com/shop/ppack-spike-n501y-sars-cov-2-s-pseudotype-n501y-mutant-lentivector-packaging-mix
First case of coronavirus detected in wild mink (US, Utah)
>"The virus strain detected in the wild mink was identical to the strain found in captive mink on a nearby mink farm, and no other animals have thus far tested positive despite surveillance efforts around infected farms in several areas of the US," he said.
https://archive.vn/1mrx9
On UK mutation
https://twitter.com/firefoxx66/status/1338533710178775047
SARS-CoV-2 in minks in Sweden not the same variant found in Denmark
http://outbreaknewstoday.com/sars-cov-2-in-minks-in-sweden-not-the-same-variant-found-in-denmark-55059/
New SARS-2 strain has 'striking' amount of mutations: Scientists discover 17 changes on crucial spike protein of evolved virus spreading through London and the South East
https://archive.vn/6Odeg
One Year of SARS-CoV-2: How Much Has the Virus Changed?
https://www.biorxiv.org/content/10.1101/2020.12.16.423071v1
>Investigation of novel SARS-COV-2 variant: Variant of Concern 202012/01
https://www.gov.uk/government/publications/investigation-of-novel-sars-cov-2-variant-variant-of-concern-20201201
Recurrent emergence and transmission of a SARS-CoV-2 Spike deletion ΔH69/V70
>Of particular concern is a sub130 lineage of around 350 sequences (Figure 6) bearing six spike mutations across the RBD (N501Y, A570D) and S2 (P681H, T716I, S982A and D1118H) as well as the H69/V70 in England (Figure 7).
>This deletion spanning six nucleotides, is mostly due to an out of frame deletion of six nucleotides, has frequently followed receptor binding amino acid replacements (N501Y, N439K and Y453F that have been shown to reduce >binding with monoclonal antibodies) and its prevalence is rising in parts of Europe, with the greatest increases since August.
>The detection of a high number of novel mutations suggests this lineage has either been introduced from a geographic region with very poor sampling or viral evolution may have occurred in a single individual in the context of a chronic infection.
>Given the emergence of multiple clusters of variants carrying RBD mutations and the H69/V70 deletion, limitation of transmission takes on a renewed urgency.
>Concerted global vaccination efforts with wide coverage should be accelerated.
https://www.biorxiv.org/content/10.1101/2020.12.14.422555v3
Del69/70 (with D796H) were selected for in an persistently infected immunocompromised patient given immune sera from different people
https://www.medrxiv.org/content/10.1101/2020.12.05.20241927v1
"There are around 4000 different genome sequences of #SARSCoV2 deposited in labs, hospitals, research institutes across the country. In India, we find only 6 out of the 10 different lineages found globally. There is an unique genetic lineage called 'I/A3i clade' in India"
https://twitter.com/PIBMumbai/status/1339913111856324608
SARS-CoV-2 Mutations including A222V and S477N Evade T Cell Immunity
https://www.thailandmedical.news/news/covid-19-news-study-by-university-of-vienna-shockingly-shows-variety-of-sars-cov-2-mutations-including-a222v-and-s477n-evade-t-cell-immunity
Brazil: Identifying a new coronavirus variant in Río de Janeiro
>it is not known if it is transmitted faster and if it is more aggressive
>the new variant is "partially restricted" to the city, which concentrates the largest number of cases and deaths per city in the region, but warned about a possible spread throughout the state and, consequently, , other areas of the country.
>"The significant increase in the frequency of this design raises concerns about the management of public health and the need for genomic surveillance during the second wave of infections," the scientists expressed in the study.
>The new strain was discovered through the genetic sequence of line B.1.1.28, which has been circulating in Brazil since the beginning of the year, and it is estimated that the variant appeared in July .
>The researchers analyzed 180 genomes of SARS-CoV-2 and discovered five "exclusive mutations", which "emerged and quickly spread".
>The study, however, does not indicate if the new strain identified is the most transmissible or the most aggressive that is known in Brazil, one of the worst countries hit by the pandemic in the United States and India.
https://translate.google.com/translate?sl=pt&tl=en&u=https://www.pagina12.com.ar/313320-alerta-en-brasil-identifican-una-nueva-cepa-de-coronavirus-e
https://cov-lineages.org/lineages/lineage_B.1.1.28.html
>Regarding amino acid mutations, new evidence recently emerged showing a number of important amino acid changes in the Spike protein.
>An amino acid change (D614G) is of particular interest since G614 lineages have consistently replaced well established D614 strains and could confer a fitness advantage of the former strains leading to a higher viral load in infected patients and higher mortality rate
>Second, we attempted to isolate this virus after the third passage in VERO CCL-81 cells and we managed to detect 75% (620/816 reads) G23073T of the reads supporting the N501Y mutation (Table S7).
>The genomic analysis of 101 SARS-CoV-2 genomes from the beginning of the epidemic at Pernambuco state, Brazil, revealed at least five independent international importation events of SARS-CoV-2 strains, that effectively seeded community transmission, occurred from late February to mid-April which is in line with studies focusing on other Brazilian states.
>Interestingly, this sample was not clustered phylogenetically with other sequences containing this amino acid substitution.
https://www.mdpi.com/1999-4915/12/12/1414/htm
Thread on calculating probability of B.1.1.7 variant spreading from UK to Switzerland
>Assuming k = 0.5, we obtain a probability of 58% (for Re = 1.05) and 79% (for Re = 1.1) that the 25 cases will initiate a sustained transmission chain in Switzerland
>However, visitors from the UK (and South Africa) must now go into quarantine in Switzerland. This might prevent some of the potential further spread of the new variant.
https://twitter.com/C_Althaus/status/1341801850207674369
[warning: (((GISAID))) data lol]
Phylogenetic analysis of SARS-CoV-2 clusters in their international context - cluster S.N501
https://nextstrain.org/groups/neherlab/ncov/S.N501?c=gt-S_501,69&p=grid&r=country
Phylogenetic analysis of SARS-CoV in Europe
https://nextstrain.org/groups/neherlab
UK and South African variant have same N501Y mutations but were "arisen" separately
https://twitter.com/firefoxx66/status/1340359989395861506
Thread with "official" info on how the variants from UK and South Africa have spread
https://twitter.com/firefoxx66/status/1341793323535757312
Genetic epidemiology of variants associated with immune escape from global SARS-CoV-2 genomes
>Out of 14,222 genomes analysed from Australia, 24 immune escape associated variants mapped to 9,895 genomes (70%). Of significant frequency was the S:S477N variant which was present in 9,541 genomes (67%) from Australia. High frequency of this variant was also found in a number of other countries particularly in Europe. S:N439K was also found at high frequencies in genomes from a number of countries in Europe (6).
>S:N501Y, one of the variants in the recently reported emergent SARS-CoV-2 lineage from the United Kingdom, was present in a total of 290 genomes, including genomes from the United Kingdom, Australia, South Africa, USA, Denmark and Brazil (7,8). All 7 genomes from South Africa having S:N501Y also had the S:E484K variant and S:K417N was present in 2 of these genomes (9).
>The ORF3a:G251V variant was also found to be prevalent across global genomes, with the highest frequencies in Hong Kong and South Korea. This variant is also one of the defining variants for the Nextstrain clade A1a (GISAID Clade V) (Figure 1B).
>19 of the 86 genetic variants were found in genomes from India (Supplementary Figure). The S:N440K variant was found to have a frequency of 2.1% in India and a high prevalence in the state of Andhra Pradesh (33.8% of 272 genomes). The variant site was homplasic and the variant was found in genomes belonging to different clades and haplotypes. Time-scale analysis suggested the variant emerged in recent months (Figure 1C). The S:N440K variant was also reported in a case of COVID-19 reinfection from North India (10).
https://www.biorxiv.org/content/10.1101/2020.12.24.424332v1
Single point mutations can potentially enhance infectivity of SARS-CoV-2 revealed by in silico affinity maturation and SPR assay
https://www.biorxiv.org/content/10.1101/2020.12.24.424245v1
SARS-CoV-2 will evolve quickly to evade widely deployed spike RBD-targeting monoclonal antibodies, requiring combinations with at least three antibodies to suppress viral immune evasion
https://archive.vn/X4tL8
>Reinfection with a genetically distinct SARS-CoV-2 strain may occur in an immunocompetent patient shortly after recovery from mild COVID-19. SARS-CoV-2 infection may not confer immunity against a different SARS-CoV-2 strain.
https://archive.vn/V89m4
Details/proof on recombination between SARS-CoV-2 strains
>In samples from Asia, a small haplotype block was identified; whereas, samples from Europe and North America harbored large and different haplotype blocks with nonsynonymous variants. Variant frequency and linkage disequilibrium varied among continents, especially in North America. Recombination between different strains was only observed in North American and European sequences. Additionally, we structurally modeled the two most common mutations D614G and P314L which suggested that these linked mutations may enhance viral entry and stability
>COVID-19 virulence may be more severe in Europe and North America due to coinfection with different SARS-CoV-2 strains leading to genomic recombination which might be challenging for current treatment regimens and vaccine development
https://archive.vn/vBTo3
https://www.medrxiv.org/content/10.1101/2020.11.11.20229765v1.full.pdf
"Natural deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape"
>SARS-2 typically resolves within weeks, before the full maturation of humoral immunity to SARS-CoV-2. During pandemics neither the infected patient nor subsequently infected individuals impart an immunological pressure on the virus. However, during a long-term persistent infection, virus replicates in the presence of endogenous or supplemented (e.g. convalescent sera or therapeutic monoclonal) antibody mediated immunity. Viral evolution in such patients may foreshadow preferred avenues of adaption in immune experienced populations. In individuals, multiple variants with distinct deletions can arise over time, essentially existing as an intra-host quasispecies
>Comparisons between deletions arising independently in persistently infected individuals show striking recurrent and convergent evolution.
https://www.biorxiv.org/content/10.1101/2020.11.19.389916v1
>>>D614G strain with a I472V mutation on it that is also fast growing in the US and Europe. Not only antibody resistant but also more infectious, and there are are now studies underway that might indicate that it's also T-cell resistant
thailandmedical.news/news/covid-19-latest-more-antibody-resistant-sars-cov-2-mutated-strains-emerging-and-increasing-in-circulation
>a loss of an accessory protein orf3b (57 amino acids) in current circulating SARS-CoV-2 strains, contributing around 24% of more than 100,000 complete viral genomes analyzed. The loss of 3b is caused by the presence of an early stop codon which is created by an orf3a Q57H substitution.
>A proteomic study identified STOML2 as its binding partner (10) and it may play a role in mitochondrial homeostasis (11). More importantly, a recent serological study demonstrated a strong antibody response against orf3b protein in a cohort of COVID-19 patients and the anti-orf3b antibodies have been proposed for the use as the serological markers of early and late infection (12). It is noted that a recent paper studying a putative orf3 protein (a 22 amino acids peptide predicted from frame 3 of orf3a (25814-25882; 69bp)) and named it as orf3b (13). Its amino acid sequence is totally different from the orf3b described in this and other studies (4, 10, 12).
>significant host serological differences and immune pressure may exist which leads to the virus escape from such immune pressure of human population by the loss of orf3b protein
https://archive.vn/udRgq
Analysis of SARS-CoV-2 spike glycosylation reveals shedding of a vaccine candidate
>Host-derived glycosylation plays many important roles in viral pathobiology, including mediating viral protein folding and stability, as well as influencing viral tropism and immune evasion.The trimeric spikes protruding from viruses are key targets of the natural immune response. Neutralising antibodies binding to these spikes, especially to S1, prevent cellular uptake of viruses by the host. Consequently, most vaccine design efforts focus on the S protein. The surface of each trimeric spike displays up to 66 N-linked glycans and an undefined number of O-linked glycans
>glycans enable immune evasion by shielding underlying immunogenic protein epitopes from antibody neutralisation, as also observed for other coronaviruses. In other instances, glycans constitute functional epitopes in immune recognition
>Viral vector-based (e.g. ChAdOx1 nCoV-19), as well as nucleic acid-based vaccine strategies (Pfizer BNT162b2 and Moderna mRNA-1273), rely on the supplied antigen-encoding DNA or RNA sequence, once inside a cell, to faithfully produce the spike protein in its fully folded, glycosylated and assembled state, resembling a natural infection and trigger a robust innate immune response, as well as provoking T and B cells
>cellular secretion pathway followed by such vaccine delivered antigens may differ in fundamental ways from antigens in the context of viral infection, where factors other than a single protein coding sequence may play decisive roles in immunogen presentation
>These include the cellular location of viral morphogenesis and overall shape in which an immunogen encounters the host cellular glycosylation machinery during this natural infection.
>The Pfizer BNT162b2 vaccine antigen aims to overcome some of these important differences by following a strategy first employed for MERS, as well as SARS-CoV spike glycoprotein stabilisation for vaccine design, where two proline mutations are introduced in close proximity to the first heptad repeat of each protomer, which stabilises the prefusion conformation.
https://www.biorxiv.org/content/10.1101/2020.11.16.384594v1
The Progression of SARS Coronavirus 2 (SARS-CoV2): Mutation in the Receptor Binding Domain of Spike Gene
>the novel P579L mutation is close to S cleavage site that may influence the infectivity of SARS-CoV2 as reported in previous study
https://immunenetwork.org/DOIx.php?id=10.4110/in.2020.20.e41
Emergence of Novel SARS-CoV-2 Variants in the Netherlands
https://www.medrxiv.org/content/10.1101/2020.11.02.20224352v1
https://www.biorxiv.org/content/10.1101/2020.09.28.317685v1
>SARS-CoV-2 D614G Variant Exhibits Enhanced Replication ex vivo and Earlier Transmission in vivo
>Antibody resistant AND more infectious.
>Overall, the prevalence of mutations correlated with a mild outcome was lower than with severe outcomes, at ~1,500 vs. 6,700 mutations. There were over 5,000 mutations that were not linked to any clinical outcome.
https://archive.vn/IR1UM
SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant
https://www.cell.com/cell-reports/fulltext/S2211-1247(20)31174-8
[]
Recurrent mutations in SARS-CoV-2 genomes isolated from mink point to rapid host-adaptation
https://www.biorxiv.org/content/10.1101/2020.11.16.384743v1
Working paper on SARS-CoV-2 spike mutations arising in Danish mink, their spread to humans and neutralization data.
https://files.ssi.dk/Mink-cluster-5-short-report_AFO2
The mink mutation Y453F (encoded by A22920T) increases affinity of the RBD for human ACE2 (mutation seems to have arisen multiple times in mink in NL since April, & is not commonly found in humans)
https://twitter.com/jbloom_lab/status/1324139464818479105
https://jbloomlab.github.io/SARS-CoV-2-RBD_DMS/
>Baum et al Science paper reports Y453F being an escape mutation from REGN10933, which is one of the two antibodies in the Regeneron cocktail
https://twitter.com/jbloom_lab/status/1324409358944407554
https://archive.is/dx4EK
>Y453F mutation may help the virus infect mink. Mink have a slightly different ACE2 than humans; this mutation may help binding easier. It may not impact infection in humans
https://twitter.com/jpglmrodrigues/status/1324514230389805057
Denmark's measures to prevent and reduce the spread of SARS-2 between humans and mink
https://translate.google.com/translate?sl=da&tl=en&u=https%3A%2F%2Fwww.ssi.dk%2F-%2Fmedia%2Farkiv%2Fdk%2Faktuelt%2Fsygdomsudbrud%2Fcovid19%2Fbesvarelse-virkemidler-til-at-forebygge-smitte-mink-menneske.pdf%3Fla%3Dda
https://archive.vn/3vt1s
>page 8, the document describes 2 variants, defined by mutations A22920T & a 2 amino-acid deletion from 21766-21771. Both are changes in the Spike protein.
>N439K has been reported to confer partial resistance to some antibodies
SSI may have found similar outcomes in their research, if the variant they characterise by the deletions carries N439K, as almost all those we see do
>Very important to highlight here that N439K conferring some level of resistance to an antibody is *not* necessarily the same as influencing the efficacy of a vaccine. The two should *not* be conflated
>It could also be that the deletion itself may have an effect
The SARS-CoV-2 S1 spike protein mutation N501Y alters the protein interactions with both hACE2 and human derived antibody
https://www.biorxiv.org/content/10.1101/2020.12.23.424283v1
The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity
>immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is the most divergent region of S, and provide epidemiological, clinical, and molecular characterization of a prevalent RBM variant, N439K. We demonstrate that N439K S protein has enhanced binding affinity to the hACE2 receptor, and that N439K virus has similar clinical outcomes and in vitro replication fitness as compared to wild-type. We observed that the N439K mutation resulted in immune escape from a panel of neutralizing monoclonal antibodies, including one in clinical trials, as well as from polyclonal sera from a sizeable fraction of persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.
https://www.biorxiv.org/content/10.1101/2020.11.04.355842v1
[bonus]
https://elifesciences.org/articles/61312
http://www.freezepage.com/1604682097HYDDSRVOLW