Infection-enhancing anti-SARS-CoV-2

antibodies recognize both the original

Wuhan/D614G strain and Delta variants.
A potential risk for mass vaccination?
Nouara Yahi & Henri Chahinian &
Jacques Fantini
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JID: YJINF
ARTICLE IN PRESS [m5G;August 16, 2021;16:58]
Journal of Infection xxx (xxxx) xxx

Contents lists available at ScienceDirect

Journal of Infection
journal homepage: www.elsevier.com/locate/jinf

Letter to the Editor

Infection-enhancing anti-SARS-CoV-2 antibodies recognize both

the original Wuhan/D614G strain and Delta variants. A
potential risk for mass vaccination?

The aim of the present study was to evaluate the recognition

of SARS-CoV-2 Delta variants by infection enhancing antibodies di-
rected against the NTD. The antibody studied is 1052 (pdb file
#7LAB) which has been isolated from a symptomatic Covid-19 pa-
tient1 . Molecular modeling simulations were performed as previ-
ously described2 . Two currently circulating Delta variants were in-
vestigated, with the following mutational patterns in the NTD :

- G142D/E154K (B.1.617.1)
- T19R/E156G/del157/del158/A222V (B.1.617.2)

Each mutational pattern was introduced in the original

Wuhan/D614G strain, submitted to energy minimization, and then
tested for antibody binding. The energy of interaction (G) of the
reference pdb file #7LAB (Wuhan/D614G strain) in the NTD region Fig. 1. Infection enhancing antibodies recognize the NTD of Delta variants. A.
was estimated to −229 kJ/mol−1 . In the case of Delta variants, the Molecular model of the Delta B.1.617.1 spike trimer as viewed from the host cell
energy of interaction was raised to −272 kJ.mol−1 (B.1.617.1) and surface (chains A, B and C in cyan, yellow and purple, respectively), with the NTD
and RBD of each chain indicated. The 1052 antibody is in green. B. Spike trimer
−246 kJ.mol−1 (B.1.617.2). Thus, these infection enhancing antibod-
with the B subunit bound to a lipid raft (with 6 ganglioside GM1 molecules). C.
ies not only still recognize Delta variants but even display a higher Trimolecular [spike-antibody-raft] complex. D. Focus on the NTD-antibody complex
affinity for those variants than for the original SARS-CoV-2 strain. bound to the lipid raft. E. Secondary structures of the NTD (yellow) and the anti-
The global structure of the trimeric spike of the B.1.617.1 vari- body (green) bound to lipid raft gangliosides. F. The 1052 antibody clamps the NTD
and the edge of the lipid raft.
ant in the cell-facing view is shown in Fig. 1A. As expected, the
facilitating antibody bound to the NTD (in green) is located behind
the contact surface so that it does not interfere with virus-cell at-
tachment. Indeed, a preformed antibody-NTD complex could per-
fectly bind to the host cell membrane. The interaction between the
NTD and a lipid raft is shown in Fig. 1B, and a whole raft-spike-
antibody complex in Fig. 1C. Interestingly, a small part of the anti-
body was found to interact with the lipid raft, as further illustrated
in Figs. 1D-E. More precisely, two distinct loops of the heavy chain
of the antibody encompassing amino acid residues 28–31 and 72–
74, stabilize the complex through a direct interaction with the edge
of the raft (Fig. 1F). Overall, the energy of interaction of the NTD-
raft complex was raised from −399 kJ.mol−1 in absence of the an-
tibody to −457 kJ.mol−1 with the antibody. By clamping the NTD
and the lipid raft, the antibody reinforces the attachment of the Fig. 2. Neutralization vs ADE balance according to SARS-CoV-2 strains.
spike protein to the cell surface and thus facilitates the conforma-
tional change of the RBD which is the next step of the virus infec-
tion process2 . Neutralizing antibodies directed against the NTD have also been
This notion of a dual NTD-raft recognition by an infection en- detected in Covid-19 patients4-5 . The 4A8 antibody is a major rep-
hancing antibody may represent a new type of ADE that could resentant of such antibodies5 . The epitope recognized by this an-
be operative with other viruses. Incidentally, our data provide a tibody on the flat NTD surface is dramatically affected in the NTD
mechanistic explanation of the FcR-independent enhancement of of Delta variants2 , suggesting a significant loss of activity in vacci-
infection induced by anti-NTD antibodies1 . The model we propose, nated people exposed to Delta variants. More generally, it can be
which links for the first time lipid rafts to ADE of SARS-CoV-2, is in reasonably assumed that the balance between neutralizing and fa-
line with previous data showing that intact lipid rafts are required cilitating antibodies may greatly differ according to the virus strain
for ADE of dengue virus infection3 . (Fig. 2).

https://doi.org/10.1016/j.jinf.2021.08.010
0163-4453/© 2021 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
JID: YJINF
ARTICLE IN PRESS
N. Yahi, H. Chahinian and J. Fantini
Current Covid-19 vaccines (either mRNA or viral vectors) are
based on the original Wuhan spike sequence. Inasmuch as neu-
tralizing antibodies overwhelm facilitating antibodies, ADE is not a
concern. However, the emergence of SARS-CoV-2 variants may tip
the scales in favor of infection enhancement. Our structural and
modeling data suggest that it might be indeed the case for Delta
variants.
In conclusion, ADE may occur in people receiving vaccines
based on the original Wuhan strain spike sequence (either mRNA
or viral vectors) and then exposed to a Delta variant. Although
this potential risk has been cleverly anticipated before the mas-
sive use of Covid-19 vaccines6 , the ability of SARS-CoV-2 antibodies
to mediate infection enhancement in vivo has never been formally
demonstrated. However, although the results obtained so far have
been rather reassuring1 , to the best of our knowledge ADE of Delta
variants has not been specifically assessed. Since our data indicate
that Delta variants are especially well recognized by infection en-
hancing antibodies targeting the NTD, the possibility of ADE should
be further investigated as it may represent a potential risk for mass
vaccination during the current Delta variant pandemic. In this re-
spect, second generation vaccines7 with spike protein formulations
lacking structurally-conserved ADE-related epitopes should be con-
sidered.
2
[m5G;August 16, 2021;16:58]
Journal of Infection xxx (xxxx) xxx
References
1. Li D, et al. In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and
neutralizing antibodies. Cell 2021;184:4203–19.
2. Fantini J, Yahi N, Azzaz F, Chahinian H. Structural dynamics of SARS-CoV-2 vari-
ants: a health monitoring strategy for anticipating Covid-19 outbreaks. J Infect
2021;83:197–206.
3. Puerta-Guardo H, Mosso C, Medina F, Liprandi F, Ludert JE, del Angel RM. An-
tibody-dependent enhancement of dengue virus infection in U937 cells requires
cholesterol-rich membrane microdomains. J Gen Virol 2010;91:394–403.
4. Chi X, et al. A neutralizing human antibody binds to the N-terminal domain of
the Spike protein of SARS-CoV-2. Science 2020;369:650–5.
5. Liu L, et al. Potent neutralizing antibodies against multiple epitopes on SARS–
CoV-2 spike. Nature 2020;584:450–6.
6. Iwasaki A, Yang Y. The potential danger of suboptimal antibody responses in
COVID-19. Nat Rev Immunol 2020;20:339–41.
7. Fantini J, Chahinian H, Yahi N. Leveraging coronavirus binding to gangliosides for
innovative vaccine and therapeutic strategies against COVID-19. Biochem Biophys
Res Commun 2021;538:132–6.
Nouara Yahi
Henri Chahinian
Jacques Fantini
INSERM UMR_S 1072, Aix-Marseille Université, 13015 Marseille,
France
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Embolism, capillary,

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of spinal cord,

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causes of hystero-epilepsy,

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state, in general paralysis of the insane,

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Emprosthotonos in tetanus,

551

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Encephalic mass, localization of lesions in,

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799
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Encephalopathy, the, of chronic lead-poisoning,

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1070

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PILEPSY

467

Definition and history,

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493

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495

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495
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494

in malingerers,

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Etiology,

468

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471

Exciting causes,

471
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474

Peripheral origin,

474

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473

Reflex causes,

472

Sexual causes,

473

474

Syphilis, influence on causation,

470
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472

Traumatic causes,

470

471

Morbid anatomy and pathology,

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493

Hughlings-Jackson's cortical theory,

489

490
 Medullary theory of origin,

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Theory of epileptic zones,

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475

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475

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487

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467

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Epilepsy, alcoholic,
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Epileptic attacks in cerebral syphilis,

1010

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955

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149

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1233
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in migraine,

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