BACKGROUNDThe live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1.METHODSWe performed multiple assays to dissect the immune responses induced in humans (n = 12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n = 12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, potentially novel immunogenic B. pertussis antigens were identified.RESULTSAll BPZE1 vaccinees showed robust B. pertussis-specific antibody responses with regard to significant increase in 1 or more of the following parameters: IgG, IgA, and memory B cells to B. pertussis antigens. BPZE1-specific T cells showed a Th1 phenotype, and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccines showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared with the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated ROS production in neutrophils and enhanced bactericidal function, which was in line with the finding that antibodies against adenylate cyclase toxin were only elicited by BPZE1.CONCLUSIONThe breadth of the antibodies, the Th1-type cellular response, and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission.TRIAL REGISTRATIONClinicalTrials.gov NCT02453048, NCT00870350.FUNDINGILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-Lung Foundation.