Our work illuminates previously unidentified differences between two human TSLP variants in modulating vaccine-mediated adaptive immunity by head-to-head comparison, demonstrating that lfTSLP rather than sfTSLP enhances durable antigen-specific systemic and mucosal antibody synthesis after mucosal vaccination with commercial SARS-CoV-2 subunit vaccines, resulting in improved resistance to infection with SARS-CoV-2 wild-type and Delta variants. Here, TSLP is linked to infection.