David D. HoAaron Diamond AIDS Research Center

Columbia University

SARS-CoV-2 Variants of ConcernDavid D. Ho

Aaron Diamond AIDS Research CenterColumbia University Vagelos College of Physicians and Surgeons

Modified from Economist UK

SA NY

BZ

Resistance of B.1.1.7 (UK) and B.1.351 (SA) to select monoclonal antibodies

To

tal=

1273

Legend

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Legend

NTD RBD SD1 SD2 FP HR1 CH CTHR21 14 306 331 528 591 686 816 9

10

985

1035

1068

1163

1211

1273

S1 S2

SAL18F

UK 69-70del 144del N501Y A570D P681H T716I S982A D1118H

D80AD215G

242-244delR246I K417N

E484KN501Y

CD

S2’S1/S2

A701V

Inner side

Outer side

ACE2 binding site

“UP” RBD

Top view of spike

NTD

NTD

NTD

NTDsupersite

Outer side view

E484

2-7 REGN109871-57 C135 S309

N501K417

E484 2-36COVA1-16910-30

2-15 REGN10933C121 LY-CoV555

E484

K417 N501

135°

90°

Inner side viewRBM view

“Down” RBD

2-36

10 -4 10 -3 10 -2 10 -1 100 101 102-20

0

20

40

60

80

100WA1B.1.1.7B.1.351

COVA1-16

10 -4 10 -3 10 -2 10 -1 100 101 102

910-30

10 -4 10 -3 10 -2 10 -1 100 101 102

2-15

10 -4 10 -3 10 -2 10 -1 100 101 102

LY-CoV555

10 -4 10 -3 10 -2 10 -1 100 101 102-20

0

20

40

60

80

100C121

10 -4 10 -3 10 -2 10 -1 100 101 102

REGN10933

10 -4 10 -3 10 -2 10 -1 100 101 102

2-7

10 -4 10 -3 10 -2 10 -1 100 101 102

REGN10987

10 -4 10 -3 10 -2 10 -1 100 101 102-20

0

20

40

60

80

100C135

10 -4 10 -3 10 -2 10 -1 100 101 102

S309

10 -4 10 -3 10 -2 10 -1 100 101 102

1-57

10 -4 10 -3 10 -2 10 -1 100 101 102

% N

eutr

aliz

atio

n

Antibody (g/mL)

5-24

10 -4 10 -3 10 -2 10 -1 100 101 102-20

0

20

40

60

80

100 WA1B.1.1.7B.1.351

4-8

10 -4 10 -3 10 -2 10 -1 100 101 102

4A8

10 -4 10 -3 10 -2 10 -1 100 101 102

2-17

10 -4 10 -3 10 -2 10 -1 100 101 102

4-19

10 -4 10 -3 10 -2 10 -1 100 101 102-20

0

20

40

60

80

1005-7

10 -4 10 -3 10 -2 10 -1 100 101 102

Antibody (g/mL)

% N

eutr

aliz

atio

n

69-70

Y144

R246

242-244

5-244A84-8

NTD supersite

Wang et al, Nature 2021

Red: resistance >3 fold; Green: sensitization >3 fold

Susceptibility of B.1.1.7 and B.1.351 & mutant pseudoviruses to neutralization by RBD and NTD mAbs(fold change in IC50)

Fold Change of IC50 from WT

RBD-directed mAbs NTD-directed mAbs

Inner side RBM Outer side Supersite Others

2-36 COVA1-16 910-30 2-15 LY-CoV555 C121 REGN10933 2-7 REGN10987 C135 S309 1-57 5-24 4-8 4A8 2-17 4-19 5-7

UK

B.1.1.7 3.4 3.4 -10.3 -3.0 -2.8 4.0 1.0 1.5 1.0 3.0 -4.0 -1.5 -330.2 <-1000 <-1000 -42.6 -29.2 -7.5

UKΔ8 1.2 1.3 -14.0 2.2 1.7 2.3 2.5 1.4 2.1 -1.4 -3.1 2.1 <-1000 <-1000 <-1000 -121.2 -20.5 -11.9

69-70del -1.0 1.1 2.7 1.2 1.1 1.7 1.3 -1.2 1.2 1.8 -1.6 1.1 1.1 1.1 1.5 -1.1 -3.6 -4.0

144del 1.5 -1.3 2.3 1.3 1.1 1.7 1.3 1.2 -1.4 1.4 1.4 1.1 <-1000 <-1000 <-1000 -80.7 1.6 -3.7

N501Y -1.2 -1.4 -12.7 1.5 -1.0 1.5 -1.4 -1.0 1.3 1.2 1.2 3.6 -2.9 -6.7 MPI↓ -12.0 -1.4 -3.2

A570D 4.1 1.9 6.7 1.4 1.7 1.7 4.7 -2.3 -1.6 1.1 -1.2 2.2 1.1 -15.1 -2.9 -4.8 -1.9 -2.2

P681H 2.0 1.5 2.5 3.1 2.3 -1.0 1.6 -1.4 -1.9 1.3 -1.2 2.9 -1.5 -2.8 1.1 -4.7 -1.2 1.8

T716I 4.3 3.9 3.9 3.1 3.5 2.0 3.6 -1.1 -1.6 1.2 -1.6 2.9 -3.5 -5.5 MPI↓ -2.6 1.2 -1.0

S982A -3.9 -3.0 -2.4 1.1 -2.0 1.4 -2.3 -2.2 -1.2 1.6 -1.0 -1.5 -1.1 -1.1 -2.9 -4.3 1.2 -1.3

D1118H -1.1 -3.1 1.0 1.2 1.0 1.7 -1.3 -1.4 -1.7 1.2 1.5 1.1 -1.3 -3.1 1.4 -1.1 -1.1 -1.8

SA

B.1.351 -2.1 1.0 -456.6 <-1000 <-1000 <-1000 <-1000 1.1 -3.5 1.0 -2.2 -5.2 <-1000 <-1000 <-1000 -456.4 -595.2 -84.8

SAΔ9 -2.0 1.3 <-1000 <-1000 <-1000 <-1000 -58.8 1.3 1.8 1.2 1.3 3.3 <-1000 <-1000 <-1000 -406.6 <-1000 -18.1

L18F 1.5 1.9 2.8 3.0 1.0 1.8 1.4 -1.4 -1.8 1.1 1.2 -1.6 -2.2 1.3 MPI↓ -107.2 <-1000 -8.9

D80A -1.4 1.2 2.1 2.0 1.5 2.0 1.4 -2.2 -2.2 1.0 2.2 -2.7 2.3 2.0 -1.0 -2.0 <-1000 -9.8

D215G 1.9 1.6 1.5 1.8 1.5 2.1 1.5 -1.8 -2.1 -1.2 1.0 2.2 -1.1 -1.8 -2.3 -6.0 1.1 1.1

242-244del -1.4 1.2 -1.2 1.4 -1.1 1.1 1.0 -1.2 -3.2 1.8 1.2 -1.3 <-1000 <-1000 <-1000 <-1000 <-1000 -20.7

R246I 1.3 1.7 2.2 2.4 1.4 2.1 2.2 1.4 -2.1 1.1 2.3 1.7 <-1000 <-1000 <-1000 -2.8 <-1000 -9.2

K417N 3.2 3.3 <-1000 3.3 8.4 1.2 -13.1 2.1 -1.2 2.9 1.6 7.8 2.9 -1.6 1.7 -1.5 1.2 -1.2

E484K -1.2 -1.0 4.3 <-1000 <-1000 <-1000 -10.5 -3.4 -1.1 2.3 2.5 -1.1 -1.6 -3.2 MPI↓ -2.8 -1.1 -1.4

N501Y -1.2 -1.4 -12.7 1.5 -1.0 1.5 -1.4 -1.0 1.3 1.2 1.2 3.6 -2.9 -6.7 MPI↓ -12.0 -1.4 -3.2

A701V 1.9 1.4 2.1 2.8 2.0 1.6 2.3 -1.8 -2.6 1.5 1.1 2.5 -3.3 -2.0 MPI↓ -3.3 -1.2 -1.3

NTD

69-70

L18

242-244

Y144

N114-26

N267-79

N3141-156

R246

N5246-260

NTD-directed antibodies

RBD

Y53HC

S56HC

E484K

CDRH2

REGN10933

RBD

R50HC

E484K

LY-CoV555

Y101HC

Changes in IC50 of authorized or investigational therapeutic mAbs against B.1.1.7 and B.1.351 as well as UK∆8 and SA∆9 relative to the WT

B.1.1.7 WA1 B.1.351

10 -4

10 -3

10 -2

10 -1

100

101

IC50

(g/

mL)

UKΔ8 D614G SAΔ9

LY-CoV555

REGN10933 + 10987

LY-CoV555 + CB6

S309

Brii-196 + Brii-198COV2-2196 + 2130

Authentic viruses Pseudoviruses

Changes in neutralization IC50 of convalescent plasmaagainst B.1.1.7 and B.1.351 relative to the WT

No protection against re-infection in SA in Novavax placebos

From Lancet 2021

Changes in neutralization activity of vaccinee sera against B.1.1.7 and B.1.351

Novavax protective efficacy

WT 96%B.1.1.7 86%B.1.351 49%

J & J protective efficacy

U.S. 72%Latin Am 66%SA 57%

-8.6X***p < 0.001

-1.8X**p = 0.003

UKΔ8 D614G SAΔ9102

103

104

105

106

-12.4X***p < 0.001

1.6Xp = 0.064

B.1.1.7 WA1 B.1.351102

103

104

105

106

Moderna-10.3X

**p = 0.0021.3X

p = 0.322

B.1.1.7 WA1 B.1.351

Pfizer

Rec

ipro

cal s

erum

IC50

tite

rin

pse

udov

irus

assa

y

-6.5X**p = 0.002

-2.0X**p = 0.004

UKΔ8 D614G SAΔ9

Rec

ipro

cal s

erum

IC50

tite

rin

aut

hent

ic v

irus

assa

y

WT BZ10

10 -4

10 -3

10 -2

10 -1

100

101

IC50

(g/

mL)

REGN10987

REGN10933

LY-CoV555

CB6

WT BZ10

21962130

2-362-15C1212-7

1-57S309

EUA Others

WT BZ10

5-24

4-18

2-17

4-194-8

5-7

-6.5X***p < 0.0001

WT BZ10102

103

104

105

Rec

ipro

cal s

erum

ID50

-2.8X***p = 0.0005

WT BZ10

Moderna-2.2X

**p = 0.0020

WT BZ10

Pfizer

RBD NTD

Monoclonal Antibodies

ConvalescentPlasma

Vaccinee Sera

a

bTotal=1273Legend Legend Legend Legend Legend Legend Legend Legend Legend Legend Legend Legend Legend Legend Legend Legend

NTD RBD SD1 SD2 FP HR1 CH CTHR21 14 306 331 528 591 686 816 9

10

985

1035

1068

1163

1211

1273

S1 S2

SAL18F

UK 69-70del 144del N501Y A570D P681H T716I S982A D1118H

D80AD215G

242-244delR246I K417N

E484KA701VN501Y

CD

782-814680-744

BZ L18FT20NP26S

D138Y R190S K417T

E484K

N501Y H655Y T1027I

Antibody resistance of P.1 (BZ) variant

Wang et alhttps://www.biorxiv.org/content/10.1101/2021.03.01.433466v1

A new SARS-CoV-2 variant in the NY metropolitan area

Hiroshi Mohri Medini AnnavajhalaAnne-Catrin Uhlemann

Past week36%

https://www.medrxiv.org/content/10.1101/2021.02.23.21252259v1

ee s a e

B.1.1.7 (6)

P.2 (2)

B.1.351 (1)

B.1.526 (>70)

ee s a e

SARS-COV-2 variant of concern identified in New York: B.1.526 with E484K mutation

Spike mutations found in B.1.526/E484K and resistance to antibody neutralization

E484K

T95I

D253G

A701V

D614G

NTDRBDS1 (other regions)S2N-linked glycan

mAbs with EUAConvalescent

plasmaVaccinee

sera

B.1.1.7 is becoming dominant in most parts of US but it is out-competed by B.1.526 in NYC

E484K doubling time:~ 12 days

NYC DOH:39% B.1.52612% B.1.1.7

From NY Times