SHIVER

SARS CoV-2 Historically Identified Variants in Epitope Regions

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.