This study reports the rapid and robust response of influenza-specific IgG-secreting plasma cells (ASCs) after booster vaccination, peaking at approximately day 7 and accounting for up to 6% of peripheral blood B cells. These ASCs were highly specific to influenza and showed a pauciclonal response, with some donors dominated by a few B-cell clones. Despite this, the ASCs accumulated extensive somatic mutations, leading to the production of over 50 high-affinity human monoclonal antibodies (mAbs) that bound to the three influenza vaccine strains. The study also addressed the issue of original antigenic sin (OAS), finding that most influenza-specific mAbs showed the highest affinity for the current vaccine strain, suggesting that OAS does not commonly occur in healthy adults receiving influenza vaccination. The findings highlight the potential for generating therapeutic or diagnostic mAbs rapidly in response to emerging influenza virus strains.This study reports the rapid and robust response of influenza-specific IgG-secreting plasma cells (ASCs) after booster vaccination, peaking at approximately day 7 and accounting for up to 6% of peripheral blood B cells. These ASCs were highly specific to influenza and showed a pauciclonal response, with some donors dominated by a few B-cell clones. Despite this, the ASCs accumulated extensive somatic mutations, leading to the production of over 50 high-affinity human monoclonal antibodies (mAbs) that bound to the three influenza vaccine strains. The study also addressed the issue of original antigenic sin (OAS), finding that most influenza-specific mAbs showed the highest affinity for the current vaccine strain, suggesting that OAS does not commonly occur in healthy adults receiving influenza vaccination. The findings highlight the potential for generating therapeutic or diagnostic mAbs rapidly in response to emerging influenza virus strains.