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The incidence of whooping cough due to Bordetella pertussis (BP) infections has increased recently. It is believed that the shift from whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines may be contributing to this rise. While T cells are key in controlling and preventing disease, nearly all knowledge relates to antigens in aP vaccines. A whole-genome mapping of human BP-specific CD4+ T cell responses was performed in healthy vaccinated adults and revealed unexpected broad reactivity to hundreds of antigens. The overall pattern and magnitude of T cell responses to aP and non-aP vaccine antigens are similar regardless of childhood vaccination, suggesting that asymptomatic infections drive the pattern of T cell reactivity in adults. Lastly, lack of Th1/Th2 polarization to non-aP vaccine antigens suggests these antigens have the potential to counteract aP vaccination Th2 bias. These findings enhance our insights into human T cell responses to BP and identify potential targets for next-generation pertussis vaccines. [Display omitted] • Recent increase in whooping cough may be linked to the shift from wP to aP vaccines • Genome-wide screening revealed broad T cell reactivity to hundreds of antigens • Similar recognition of aP and non-aP antigens regardless of childhood vaccination • Non-aP vaccine antigens could balance aP vaccination Th2 bias da Silva Antunes et al. conducted a genome-wide screening of human Bordetella-pertussis -specific CD4+ T cell responses in healthy vaccinated adults. Targets with similar reactivity patterns were identified regardless of childhood vaccination. Lack of Th1/Th2 polarization to non-aP (acellular pertussis) vaccine antigens could counteract aP vaccination bias, informing next-generation pertussis vaccines. [ABSTRACT FROM AUTHOR]