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. 2025 Jun 11;33(6):988-1003.e10.
doi: 10.1016/j.chom.2025.04.018. Epub 2025 May 20.

Deep mutational scanning of rabies glycoprotein defines mutational constraint and antibody-escape mutations

Arjun K Aditham  1 , Caelan E Radford  1 , Caleb R Carr  2 , Naveen Jasti  3 , Neil P King  4 , Jesse D Bloom  5
Affiliations

Deep mutational scanning of rabies glycoprotein defines mutational constraint and antibody-escape mutations

Arjun K Aditham et al. Cell Host Microbe. .

Abstract

Rabies virus causes nearly 60,000 human deaths annually. Antibodies that target the rabies glycoprotein (G) are being developed as post-exposure prophylactics, but mutations in G can render such antibodies ineffective. Here, we use pseudovirus deep mutational scanning to measure how all single-amino-acid mutations to G affect cell entry and neutralization by a panel of antibodies. These measurements identify sites critical for G function and define constrained regions that are attractive epitopes for clinical antibodies, including at the apex and base of the protein. We provide complete maps of escape mutations for eight monoclonal antibodies, including some in clinical use or development. Escape mutations for most antibodies are present in some natural rabies strains. Overall, this work provides comprehensive information on the functional and antigenic effects of G mutations that can inform development of stabilized vaccine antigens and antibodies that are resilient to rabies genetic variation.

Keywords: Rabishield; antibody escape; antigenic variation; deep mutational scanning; glycoprotein; pseudovirus; rabies; type III fusion protein.

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Conflict of interest statement

Declaration of interests J.D.B. consults on topics related to viral evolution for Apriori Bio, Invivyd, the Vaccine Company, and Pfizer. J.D.B., A.K.A., and C.E.R. are inventors on Fred Hutch licensed patents related to viral deep mutational scanning. N.P.K. consults on topics related to vaccine design for AstraZeneca, and the King lab has received unrelated sponsored research agreements from Pfizer and GlaxoSmithKline.

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References

    1. Fooks AR, Banyard AC, Horton DL, Johnson N, McElhinney LM, and Jackson AC (2014). Current status of rabies and prospects for elimination. Lancet 384, 1389–1399. 10.1016/S0140-6736(13)62707-5. - DOI - PMC - PubMed
    1. Mollentze N, Biek R, and Streicker DG (2014). The role of viral evolution in rabies host shifts and emergence. Current Opinion in Virology 8, 68–72. 10.1016/j.coviro.2014.07.004. - DOI - PMC - PubMed
    1. Fisher CR, Streicker DG, and Schnell MJ (2018). The spread and evolution of rabies virus: conquering new frontiers. Nat Rev Microbiol 16, 241–255. 10.1038/nrmicro.2018.11. - DOI - PMC - PubMed
    1. Singh R, Singh KP, Cherian S, Saminathan M, Kapoor S, Manjunatha Reddy GB, Panda S, and Dhama K (2017). Rabies – epidemiology, pathogenesis, public health concerns and advances in diagnosis and control: a comprehensive review. Veterinary Quarterly 37, 212–251. 10.1080/01652176.2017.1343516. - DOI - PubMed
    1. Hampson K, Coudeville L, Lembo T, Sambo M, Kieffer A, Attlan M, Barrat J, Blanton JD, Briggs DJ, Cleaveland S, et al. (2015). Estimating the Global Burden of Endemic Canine Rabies. PLoS Negl Trop Dis 9, e0003709. 10.1371/journal.pntd.0003709. - DOI - PMC - PubMed

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