PT  - JOURNAL ARTICLE
AU  - Matthew McCallum
AU  - Jessica Bassi
AU  - Anna De Marco
AU  - Alex Chen
AU  - Alexandra C. Walls
AU  - Julia Di Iulio
AU  - M. Alejandra Tortorici
AU  - Mary-Jane Navarro
AU  - Chiara Silacci-Fregni
AU  - Christian Saliba
AU  - Maria Agostini
AU  - Dora Pinto
AU  - Katja Culap
AU  - Siro Bianchi
AU  - Stefano Jaconi
AU  - Elisabetta Cameroni
AU  - John E. Bowen
AU  - Sasha W Tilles
AU  - Matteo Samuele Pizzuto
AU  - Sonja Bernasconi Guastalla
AU  - Giovanni Bona
AU  - Alessandra Franzetti Pellanda
AU  - Christian Garzoni
AU  - Wesley C. Van Voorhis
AU  - Laura E. Rosen
AU  - Gyorgy Snell
AU  - Amalio Telenti
AU  - Herbert W. Virgin
AU  - Luca Piccoli
AU  - Davide Corti
AU  - David Veesler
TI  - SARS-CoV-2 immune evasion by variant B.1.427/B.1.429
AID  - 10.1101/2021.03.31.437925
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.31.437925
4099  - http://biorxiv.org/content/early/2021/04/01/2021.03.31.437925.short
4100  - http://biorxiv.org/content/early/2021/04/01/2021.03.31.437925.full
AB  - SARS-CoV-2 entry is mediated by the spike (S) glycoprotein which contains the receptor-binding domain (RBD) and the N-terminal domain (NTD) as the two main targets of neutralizing antibodies (Abs). A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429) was originally detected in California and is currently spreading throughout the US and 29 additional countries. It is unclear whether antibody responses to SARS-CoV-2 infection or to the prototypic Wuhan-1 isolate-based vaccines will be impacted by the three B.1.427/B.1.429 S mutations: S13I, W152C and L452R. Here, we assessed neutralizing Ab responses following natural infection or mRNA vaccination using pseudoviruses expressing the wildtype or the B.1.427/B.1.429 S protein. Plasma from vaccinated or convalescent individuals exhibited neutralizing titers, which were reduced 3-6 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The RBD L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific monoclonal antibodies (mAbs), including three clinical-stage mAbs. Furthermore, we observed a complete loss of B.1.427/B.1.429 neutralization for a panel of mAbs targeting the N-terminal domain due to a large structural rearrangement of the NTD antigenic supersite involving an S13I-mediated shift of the signal peptide cleavage site. These data warrant closer monitoring of signal peptide variants and their involvement in immune evasion and show that Abs directed to the NTD impose a selection pressure driving SARS-CoV-2 viral evolution through conventional and unconventional escape mechanisms.Competing Interest StatementA.D.M., J.B., A.C., J.d.I., C.S-F., C.S., M.A., D.P., K.C., S.B., S.J., E.C., M.S.P., L.E.R., G.S., A.T., H.W.V., L.P. and D.C. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. D.C. is currently listed as an inventor on multiple patent applications, which disclose the subject matter described in this manuscript. H.W.V. is a founder of PierianDx and Casma Therapeutics. Neither company provided funding for this work or is performing related work. D.V. is a consultant for Vir Biotechnology Inc. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.