An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer
Naveenchandra Suryadevara, … , Ivelin S. Georgiev, James E. Crowe Jr.
Naveenchandra Suryadevara, … , Ivelin S. Georgiev, James E. Crowe Jr.
Published April 26, 2022
Citation Information: J Clin Invest. 2022;132(11):e159062. https://doi.org/10.1172/JCI159062.
View: Text | PDF
Research Article Immunology Virology

An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

Abstract

The protective human antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focuses on the spike (S) protein, which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope (“supersite”) on the N-terminal domain (NTD). Using the single B cell technology called linking B cell receptor to antigen specificity through sequencing (LIBRA-Seq), we isolated a large panel of NTD-reactive and SARS-CoV-2–neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies against the NTD supersite were commonly encoded by the IGHV1-24 gene, forming a genetic cluster representing a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface (TI) and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited the cell-to-cell spread of the virus in culture, and conferred protection in human angiotensin-converting enzyme 2–transgenic (ACE2-transgenic) mice against the SARS-CoV-2 challenge. This study provides insight into antibody targeting of the S protein TI region, suggesting this region may be a site of virus vulnerability.

Authors

Naveenchandra Suryadevara, Andrea R. Shiakolas, Laura A. VanBlargan, Elad Binshtein, Rita E. Chen, James Brett Case, Kevin J. Kramer, Erica C. Armstrong, Luke Myers, Andrew Trivette, Christopher Gainza, Rachel S. Nargi, Christopher N. Selverian, Edgar Davidson, Benjamin J. Doranz, Summer M. Diaz, Laura S. Handal, Robert H. Carnahan, Michael S. Diamond, Ivelin S. Georgiev, James E. Crowe Jr.

×

Figure 6

Escape virus neutralization and protection in K18 hACE2–transgenic mice by the trimer-disrupting antibody COV2-3434.

Options: View larger image (or click on image) Download as PowerPoint
Escape virus neutralization and protection in K18 hACE2–transgenic mice ...
(A) Neutralization of mAb escape viruses selected by the RBD-specific mAbs COV2-2479 (red), COV2-2130 (green), COV2-2094 (magenta), or COV2-2499 (purple) and the NTD-specific mAbs COV2-2676 (blue) or COV2-2489 (cyan) and with VSV-S by COV2-3434 or COV2-2196 (positive control). The mutations selected by those mAbs are listed with the references. In the right column, the RTCA curves show neutralization of those escape viruses; the asterisk indicates a lack of neutralization in wells with only virus and no antibody. (B) Eight-week-old male K18-hACE2–transgenic mice were inoculated via the i.n. route with 104 FFU of SARS-CoV-2 (WA1/2020 D614G). One day prior to virus inoculation, mice were given a single 200 μg (~10 mg/kg) dose of COV2-3434 or COV2-2196 by i.p. injection. Weight change was monitored daily. Data are from 2 independent experiments (n = 10 per group). **P < 0.01 and ****P < 0.0001, by 2-way ANOVA. Error bars represent the SEM. (C) On day 6 after infection, lungs were collected and assessed for infectious viral burden by plaque assay. PFU/g is shown. Bars indicate the mean viral load; the dotted line indicates the limit of detection of the assay. Data are from 2 independent experiments (n = 10 per group). ***P < 0.0001 and ****P < 0.0001, by 1-way ANOVA.