Abstract Seasonal influenza virus vaccines provide modest protection against endemic viruses but lack effectiveness against pandemic-threat viruses. Therefore, new immunogens and vaccine platforms that induce antibodies against broadly protective epitopes are needed to provide robust protection against seasonal and novel influenza viruses. In a phase 1 clinical trial, the chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved HA stalk domain. However, the landscape of the B cell specificities and subsets induced by this vaccine remain undetermined. Using single cell RNA-sequencing and repertoire sequencing, we identified that formulation of the cHA vaccine differentially induced B cell responses against distinct epitopes. Notably, those participants that received an inactivated vaccine with a squalene-based adjuvant had a greater proportion of B cells targeting two conserved neutralizing epitopes of the stalk domain: the central stalk and anchor epitopes. Moreover, participants that received an inactivated vaccine with adjuvant had distinct transcriptional B cell subsets, including an increase in atypical memory B cells. B cell clonal overlap between acute and memory timepoints was substantial, with several multi-donor clones that targeted distinct broadly protective epitopes. In addition, we identified stalk targeting germline antibodies that could neutralize recent pandemic H1N1 viruses. Altogether, our study reveals that the inactivated cHA vaccine with an oil-in-water adjuvant promotes B cell activation and maturation against broadly protective epitopes. Supported by National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health grant numbers K99AI159136 (JJG), U19AI082724 (PCW), U19AI109946 (PCW), U19AI057266 (PCW), P01AI097092 (PP), R01AI145870-01 (PP), R21AI146529 (LC), and T32AI007244-36 (JH), the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) grant number HHSN272201400005C (PCW), HHSN272201400008C (LC, FK, PP), and the NIAD Centers of Excellence for Influenza Research and Response (CEIRR) grant number 75N93019R00028 (PCW, FK, PP). This work was also partially supported by the NIAID Collaborative Influenza Vaccine Innovation Centers (CIVIC; 75N93019C00051, FK, PP, ABW, PCW).