Broadly reactive human monoclonal antibodies targeting a conserved epitope across multiple pneumococcal surface proteins protect against lethal pneumococcal infection 4668

Description Streptococcus pneumoniae (SPN) poses a global health threat, particularly to young children, the elderly, and immunocompromised individuals. Pneumococcal vaccines targeting the bacterial capsule reduce the risk of severe disease but fail to protect against all SPN serotypes, resulting in increased infections from non-vaccine serotypes. The rise of antibiotic-resistant SPN strains further limits treatment options, necessitating alternative therapeutic approaches. To address these limitations, we isolated human monoclonal antibodies (mAbs) from adults recovered from S. pneumoniae infection, targeting nine conserved SPN surface proteins. Antigen-specific IgG-producing B cells were isolated by flow cytometry and profiled using 10X single-cell RNA sequencing, yielding 157 paired sequences. Five SPN proteins generated high affinity antibodies, with EC50 values ranging from 9 to 82 ng/mL. These mAbs exhibited broad binding to multiple SPN serotypes, and one mAb (AM1) targeting the pneumococcal choline binding protein A (PcpA) showed high binding breadth. AM1 also cross-reacts with the pneumococcal surface protein A (PspA), and binding was mapped to the choline binding region of PspA, which shares ∼50% homology with PcpA. In an SPN challenge model, AM1 conferred complete protection against lethal pneumococcal infection. Ongoing studies are evaluating dose dependency, efficacy in viral-mediated pneumococcal superinfections, and identification of protective epitopes through cryo-EM. Funding Sources R01AI173084 Topic Categories Vaccines and Immunotherapy (VAC)