Monoclonal antibodies are increasingly used to prevent and treat viral infections and are pivotal in pandemic response efforts. Antibody-secreting cells (ASCs; plasma cells and plasmablasts) are an excellent source of high-affinity antibodies with therapeutic potential. Current methods to study antigen-specific ASCs either have low throughput, require expensive and labour-intensive screening or are technically demanding and therefore not widely accessible. Here, we present a straightforward technology for the rapid discovery of monoclonal antibodies from ASCs. Our approach combines microfluidic encapsulation of single cells into an antibody capture hydrogel with antigen bait sorting by conventional flow cytometry. With our technology, we screened millions of mouse and human ASCs and obtained anti-SARS-CoV-2 monoclonal antibodies with high affinity (85% of characterised antibodies bound the target). By facilitating access to the underexplored ASC compartment, the approach enables efficient antibody discovery as well as immunological studies into the generation of protective antibodies.This work was supported by the EU Horizon 2020 programme (ERC Advanced Investigator Awards 69566, to F.H. and EU H2020 Marie Skłodowska-Curie Individual Fellowship (MSCA-IF 750772) to T.S.K), the MRC (grant ref. MC_UU_00025/12, to J.E.D.T and TSF ref. MR/T032413/1, to N.J.M, and a scholarship to K.F.), the Medical Research Foundation (MRF-057-0002-RG-THAV-C0798, to J.E.D.T.), the NIHR Cambridge BRC (to J.E.D.T.), NHSBT (grant ref. WPA15-02, to N.J.M), the Wellcome Trust (ISSF ref. 204845/Z/16/Z, to N.J.M), Addenbrooke’s Charitable Trust (grant ref. 900239, to N.J.M), a scholarship from the Cambridge European Trust (to K.F.), a scholarship from St. John’s College Cambridge (to K.F.), a Postdoctoral Research fellowship by Boehringer Ingelheim (to M.I.J.R), an AstraZeneca studentship (to T.N.K), and a Gates Cambridge Scholarship (to G.L.P)
