Thread by @veeslerlab

We report an analysis of #SARSCoV2 spike NTD antigenic sites targeted by monoclonal antibodies (mAbs) in #COVID19 patients in collaboration with @DavideCorti6 and Matteo Samuele Pizzuto @Vir_Biotech

Work led by @Dr_MattMcCallum & Anna De Marco

1/10

biorxiv.org/content/10.110…

We found that NTD-specific mAbs account for 6-20% of mAbs cloned from memory B cells in #COVID19 patients and that the most potent of them neutralize #SARSCoV2 as efficiently as ultrapotent RBD-specific mAbs and trigger Fc-mediated effector functions effectively.

2/10

We delineated an antigenic map of the #SARSCoV2 spike NTD using #cryoEM (including a 2.2Å structure) and binding assays revealing the presence of a site of vulnerability recognized by all potently neutralizing mAbs described thus far.

3/10

Analysis of #SARSCoV2 genome sequences available in @GISAID emphasizes the marked variability of the NTD in clinical isolates, especially in the site of vulnerability identified.

4/10

Many of these mutations, including the ones found in the B.1.1.7 and the N501Y.V2 lineages, affect mAb binding suggesting they might have arisen as a result of selective pressure.

5/10

However, we identified a combination of NTD-specific mAbs sensitive to distinct escape mutants although they recognize the same site of vulnerability, which is in line with what @AllieGreaney & @jbloom_lab recently described for RBD-specific mAbs.

6/10

sciencedirect.com/science/articl…

In vitro selection for NTD mAb escape mutants (done in @vsv512 lab) identified many positions found in #SARSCoV2 clinical isolates, further supporting the hypothesis that mAb selective pressure contribute to viral evolution (e.g. in the B.1.1.7 and the N501Y.V2 lineages).

7/10

We also discovered a cool new mechanism of escape mutation involving modification of the signal peptide cleavage site (check out the preprint if you would like to learn more).

8/10

Finally, @neyts_johan team showed that one of our ultrapotent NTD-specific mAb provides prophylactic protection of Syrian hamsters challenged with #SARSCoV2 at doses as low as 1 mg/kg.

9/10

Thank you very much to @aletortorici @coronalexington @SamK_Zepeda @johnbowenbio and many others for their contributions to this work

10/10