SHIVER: SARS CoV-2 Historically Identified Variants in Epitope Regions
SHIVER identifies variant forms of the SARS CoV-2 virus with a focus on the NTD and RBD neutralizing antibody epitope regions of the Spike protein, as well as sites related to furin cleavage; the forms are chosen to maximize coverage globally and/or on separate continents[*], depending on which of several strategies is employed.
In the Table of Variants, below, the first column is the pattern at sites where differences occur, relative to initial (Wuhan) sequence, with site numbers read down vertically.
Table of Variants
LPM = Local Pattern Matches = # of seqs in continent that match over epitope region
GPM = Global Pattern Matches = # of seqs in world that match over epitope region
GSM = Global Sequence Matches = # of seqs in world that match over whole Spike protein
1111111222222222333333333344444444444444444444445556666 1111114445555444455556333456777700014444555567778888990025778 4666694672678345823674259668135635870456025605781346081515791 Name LPM GPM GSM GSM/GPM [Mutations] (Lineage) Q----TYHKWEFRALHYGDSGAILGRKLSSSTRDRKNKVGNLLFNASTNVEFFQNYPHQNP 1-Initial 0 0 0 0.0% [] .....I-Q...L.....V......HT.IFPFA.NSNK.PS.R.LK.NK..APSRYH.Y.KH 2-North-America-1 2345 2772 1998 72.1% [T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146Q,F157L,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,L452R,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .MPLFI-....SG..N.....DV.H.T.FPFAKNSNK.HSDWS.K.NKK-KP.RYH.Y.KR 3-Europe-1 892 1315 1002 76.2% [+16MPLF,T19I,R21T,L24-,P25-,P26-,A27S,S50L,H69-,V70-,V127F,G142D,Y144-,F157S,R158G,N211-,L212I,V213G,L216F,H245N,A264D,I332V,G339H,K356T,S371F,S373P,S375F,T376A,R403K,D405N,R408S,K417N,N440K,V445H,G446S,N450D,L452W,L455S,N460K,S477N,T478K,N481K,V483-,E484K,F486P,Q498R,N501Y,Y505H,E554K,A570V,D614G,P621S,H655Y,N679K,P681R,N764K,D796Y,S939F,Q954H,N969K,P1143L] .....I-Q.........V......HT.IFPFA.NSNK.PS..FLK.NK..APSRYH.Y.KH 4-Asia-1 289 2423 901 37.2% [T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,L455F,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-Q.........V......HT.IFPFA.NSNK.PS...LK.NR..APSRYH.Y.KH 5-United-Kingdom-1 72 856 233 27.2% [T19I,L24-,P25-,P26-,A27S,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,F456L,N460K,S477N,T478R,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,A701V,N764K,D796Y,Q954H,N969K] .MPLFI-....SG..N.....DV.H.T.FPFAKNSNK.HSDW..K.NKK-KP.RYH.Y.KR 6-Oceania-1 45 544 346 63.6% [+16MPLF,T19I,R21T,L24-,P25-,P26-,A27S,S50L,H69-,V70-,V127F,G142D,Y144-,F157S,R158G,N211-,L212I,V213G,L216F,H245N,A264D,I332V,G339H,K356T,S371F,S373P,S375F,T376A,R403K,D405N,R408S,K417N,N440K,V445H,G446S,N450D,L452W,N460K,S477N,T478K,N481K,V483-,E484K,F486P,Q498R,N501Y,Y505H,E554K,A570V,D614G,P621S,H655Y,N679K,P681R,N764K,D796Y,S939F,Q954H,N969K,P1143L] .....I-....SG..N.....DV.H.T.FPFAKNSNK.HSDWS.K.NKK-KP.RYH.Y.KR 7-South-America-1 25 89 65 73.0% [T19I,R21T,L24-,P25-,P26-,A27S,S50L,H69-,V70-,V127F,G142D,Y144-,F157S,R158G,N211-,L212I,V213G,L216F,H245N,A264D,I332V,G339H,K356T,S371F,S373P,S375F,T376A,R403K,D405N,R408S,K417N,N440K,V445H,G446S,N450D,L452W,L455S,N460K,S477N,T478K,N481K,V483-,E484K,F486P,Q498R,N501Y,Y505H,E554K,A570V,D614G,P621S,H655Y,N679K,P681R,N764K,D796Y,S939F,Q954H,N969K,P1143L] .......Q..........G.....HT.IFPFA.NSNK.PS....K.NR..APSRYHSY.KH 8-Africa-1 1 1 1 100.0% [L24-,P25-,P26-,A27S,V83A,G142D,H146Q,Q183E,N185D,V213E,D253G,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,N460K,S477N,T478R,E484A,F486P,F490S,Q498R,N501Y,Y505H,P521S,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-Q.........V......HT.IFPFA.NSNK.PS...LK.NK..APSRYH.Y.KH 9-North-America-2 719 1204 700 58.1% [T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-Q.........V......HT.IFPFA.NSNK.PS..FLKVNK..APSRYH.Y.KH 10-Europe-2 329 761 486 63.9% [T19I,L24-,P25-,P26-,A27S,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,L455F,F456L,N460K,A475V,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .MPLFI-....SG..N.....DV.H.T.FPFAKNSNK.HSDWS.K.NKK..P.RYH.Y.KR 11-Asia-2 155 155 77 49.7% [+16MPLF,T19I,R21T,A27S,S50X,H69-,V70-,V127F,G142D,Y144-,F157S,R158G,N211-,L212I,V213G,L216F,H245N,A264D,I332V,G339H,K356T,S371F,S373P,S375F,T376A,R403K,D405N,R408S,K417N,N440K,V445H,G446S,N450D,L452W,L455S,N460K,S477N,T478K,N481K,F486P,Q498R,N501Y,Y505H,E554K,A570V,D614G,P621S,H655Y,N679K,P681R,N764K,D796Y,S939F,Q954H,N969K,P1143L] .....I-Q.........V......HT.IFPFA.NSNK.PS....K.NR..APSRYH.Y.KH 12-United-Kingdom-2 32 311 53 17.0% [T19I,L24-,P25-,P26-,A27S,V83A,G142D,Y144-,H146Q,E180V,Q183E,V213E,G252V,K304N,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,N460K,S477N,T478R,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-...G----....L.....S..FPFA.NSNK..S.R....NK..AP.RYH.Y.KH 13-Oceania-2 34 35 20 57.1% [T19I,P25S,G142D,Y144-,E156G,F157-,R158-,P209L,L212S,D215H,A222V,A243-,L244-,S256L,R346S,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,G446S,L452R,S477N,T478K,E484A,F486P,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N703I,N764K,D796Y,Q954H,N969K] .....I-Q.........V......HT.IFPFA.N.NK.PS...LK.NK..APSRYH.Y.KH 14-South-America-2 6 11 5 45.5% [T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,K417N,N440K,V445P,G446S,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-Q.........V.....SHT.IFPFAKNSNK.PS....K.NR..APSRYH.Y.KH 15-Africa-2 1 19 4 21.1% [T19I,L24-,P25-,P26-,A27S,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,L335S,G339H,R346T,L368I,S371F,S373P,S375F,T376A,R403K,D405N,R408S,K417N,N440K,V445P,G446S,N460K,S477N,T478R,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-K...L.....V......HT.IFPFA.NSNK.PS.R.LK.NK..APSRYH.Y.KH 16-North-America-3 175 183 140 76.5% [T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146K,F157L,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,L452R,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-Q..........G.....HT.IFPFA.NSNK.PS....K.NR..APSRYHSY.KH 17-Europe-3 154 274 100 36.5% [T19I,L24-,P25-,P26-,A27S,V83A,G142D,Y144-,H146Q,Q183E,N185D,V213E,D253G,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,N460K,S477N,T478R,E484A,F486P,F490S,Q498R,N501Y,Y505H,P521S,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] K....I-Q.........V......HT.IFPFA.NSNK.PS..FLK.NK..APSRYH.Y.KH 18-Asia-3 33 161 92 57.1% [Q14K,T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,L455F,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-Q.........V......HT.IFPFA.NSNK.PS..FLK.NR..APSRYH.Y.KH 19-United-Kingdom-3 31 268 180 67.2% [T19I,L24-,P25-,P26-,A27S,V83A,G142D,Y144-,H146Q,E180V,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,L455F,F456L,N460K,S477N,T478R,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-...G----....L.....S..FPFA.NSNK..S.R..H.NK..AP.RYH.Y.KH 20-Oceania-3 19 26 21 80.8% [T19I,P25S,G142D,Y144-,E156G,F157-,R158-,P209L,L212S,D215H,A222V,A243-,L244-,S256L,R346S,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,G446S,L452R,N460H,S477N,T478K,E484A,F486P,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N703I,N764K,D796Y,Q954H,N969K] .....I-Q...L.....V......HT.IFPFA.N.NK.PS.R.LK.NK..APSRYH.Y.KH 21-South-America-3 5 11 10 90.9% [T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146Q,F157L,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,K417N,N440K,V445P,G446S,L452R,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-Q...L.....V......HT.IFPFA.NSNK.PS...LK.NK..APSRYH.Y.KH 22-North-America-4 149 212 147 69.3% [T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146Q,F157L,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I..ER.L........S...HT..FPFA.NSNKT.S.RFLK.NK..AS.RYH.Y.KH 23-Europe-4 63 189 116 61.4% [T19I,L24-,P25-,P26-,A27S,G142D,K147E,W152R,F157L,N185D,I210V,V213G,G257S,G339H,R346T,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,K444T,G446S,L452R,L455F,F456L,N460K,S477N,T478K,E484A,F486S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,L858I,Q954H,N969K] H....I-Q.........V......HT.IFPFA.NSNK.PS..FLK.NK..APSRYH.Y.KH 24-Asia-4 28 46 23 50.0% [Q14H,T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,L455F,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-QN........V......HT.IFPFA.NSNK.PS....K.NR..APSRYHSY.KH 25-United-Kingdom-4 30 143 78 54.5% [T19I,L24-,P25-,P26-,A27S,V83A,G142D,Y144-,H146Q,K147N,E180V,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,N460K,S477N,T478R,E484A,F486P,F490S,Q498R,N501Y,Y505H,P521S,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-Q.........V......HT.IFPFA.NSNK.PS.QFLK.NK..APSRYH.Y.KH 26-Oceania-4 17 18 9 50.0% [T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,L452Q,L455F,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-Q........HV......H..IFPFA.NSNK.PS..FLKVNK..APSRYH.Y.KH 27-South-America-4 3 3 2 66.7% [T19I,L24-,P25-,P26-,A27S,V83A,G142D,Y144-,H146Q,Q183E,V213E,Y248H,G252V,G339H,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,L455F,F456L,N460K,A475V,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681H,N764K,D796Y,Q954H,N969K] K....I-Q.........V......HT.IFPFA.NSNK.PS..FLK.NK..APSRYH.YHKH 28-North-America-5 119 122 82 67.2% [Q14K,T19I,L24-,P25-,P26-,A27S,Q52H,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,L455F,F456L,N460K,S477N,T478K,E484A,F486P,F490S,Q498R,N501Y,Y505H,D614G,H655Y,Q677H,N679K,P681H,N764K,D796Y,Q954H,N969K] .....I-Q.........V......HT.IFPFA.NSNK.PS...LK.NKK.APPRYH.Y.KR 29-Europe-5 57 139 106 76.3% [T19I,L24-,P25-,P26-,A27S,V83A,G142D,Y144-,H146Q,Q183E,V213E,G252V,G339H,R346T,L368I,S371F,S373P,S375F,T376A,D405N,R408S,K417N,N440K,V445P,G446S,F456L,N460K,S477N,T478K,N481K,E484A,F486P,F490P,Q498R,N501Y,Y505H,D614G,H655Y,N679K,P681R,A701V,N764K,D796Y,Q954H,N969K]
In the Table of Variants, above, the first variant in the input alignment is taken as the reference sequence, and is the ancestral Wuhan variant to ensure epitope regions are chosen appropriately. The alignment on the left shows the positions that define unique common forms that are searched using SHIVER. The positions numbers are written vertically. The amino acids in the top row are taken from is the ancestral Wuhan variant. The epitope regions in Spike that are explored for a focused search for the common Spike variants are defined at the end of this document. The epitope and furin cleavage regions in Spike that are featured are defined below.
The basic NTD supersite sites selected are for inclusion are based on:
Sites 14-20, 140-158, and 245-264: McCallum, M. et al. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Cell 184:9 2332-2347.e16 (2021)
Site 13: Impacts signal peptide cleavage and NTDss antibodies. McCallum, M. et al. SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern. Science 373:648-654 (2021)
Sites 242-244: Impacts NTDss antibody potency SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma Wibmer, C. et al. Nature Med. 27(4): 622-625.
Toggling Sites: Site 18 is in the NTDss and toggles frequently between L and F, so we exclude it from the tallies of forms of the regions of interest as it splits the counts on otherwise distinctive forms. An analogous situation is a problem for site 142. Among Delta variants, every common variant within the Delta lineages includes both (the ancestral) G and D at site 142. This is because the ARTIC 3 primers can results in an erroneous call of the ancestral G at position 142. The G142D mutation is the common form, and this error is resolved by using the ARTIC 4 primers. By excluding both sites 18 and 142 from our NTDss definition, we group the forms of Spike that carry either form in our tallies.
Analysis of the ARTIC version 3 and version 4 SARS-CoV-2 primers and their impact on the detection of the G142D amino acid substitution in the spike protein. Davies et al. bioRxiv 10.1101/2021.09.27.461949 (2021)
Sites 330-521: the RBD region includes positions 330-521, based on a synthesis of the literature from early 2020.
Furin related sites: mutations that add positive charge to near the furin cleavage site can enhance Spike cleavage and infectivity. Also, the change at H655Y (Alba2021) has been shown to impact furin cleavage, and we include site 950 as it accompanies P681R in Delta and P681H in Mu, to variants that were particularly fast spreading, though Delta became prevalent. SARS-CoV-2 spike P681R mutation, a hallmark of the Delta variant, enhances viral fusogenicity and pathogenicity. Saito et al. bioRxiv 10.1101/2021.06.17.448820 (2021) SARS-CoV-2 variants of concern have acquired mutations associated with an increased spike cleavage. Alba et al. bioRxiv 10.1101/2021.08.05.455290 (2021)
Table of Coverages
In table below, T-n refers to a batch of the first n variants. Coverage is defined as fraction of sequences in the continent with an exact match (over the region NTDss-18-142+RBD+furin) to one of the first n variants. (Here, 'T' corresponds to the 'Taketurns' strategy.) The coverage table is based on 16509 sequences.
Continent Name Coverage
Global T-1 0.0000 North-America T-1 0.0000 Europe-minus-United-Kingdom T-1 0.0000 Asia T-1 0.0000 United-Kingdom T-1 0.0000 Oceania T-1 0.0000 South-America T-1 0.0000 Africa T-1 0.0000
Global T-8 0.4846 North-America T-8 0.5128 Europe-minus-United-Kingdom T-8 0.4793 Asia T-8 0.3787 United-Kingdom T-8 0.3808 Oceania T-8 0.4572 South-America T-8 0.4286 Africa T-8 0.5000
Global T-15 0.6358 North-America T-15 0.6567 Europe-minus-United-Kingdom T-15 0.6201 Asia T-15 0.6171 United-Kingdom T-15 0.5648 Oceania T-15 0.6070 South-America T-15 0.6494 Africa T-15 1.0000
Global T-22 0.7045 North-America T-22 0.7302 Europe-minus-United-Kingdom T-22 0.6784 Asia T-22 0.6646 United-Kingdom T-22 0.6713 Oceania T-22 0.6820 South-America T-22 0.7143 Africa T-22 1.0000
Global T-29 0.7445 North-America T-29 0.7714 Europe-minus-United-Kingdom T-29 0.7140 Asia T-29 0.7007 United-Kingdom T-29 0.7292 Oceania T-29 0.7248 South-America T-29 0.7532 Africa T-29 1.0000
This run uses the T=taketurns strategy for identifying further variants. Each continent, in turn, chooses the next variant, based on which is the most common variant in that continent that has not already been chosen. The order of the continents is based on number of samples available in those continents.
Sequence sample dates range from 2023-11-06 to 2023-12-01. The number of sequences, broken out by continent is: Total: 16509, North-America: 8594, Europe-minus-United-Kingdom: 5349, Asia: 969, United-Kingdom: 864, Oceania: 654, South-America: 77, Africa: 2. The focus here is specifically on the epitope region: NTDss-18-142+RBD+furin Sites: 13-17,19,20,140,141,143-158,242-264,330-521,655,675,677,679,681,950
[*] Note that the UK is treated as a separate continent because so much of the sequencing has been from the UK.