Rethinking the Immune Responses Induced by Commercial Multicomponent Acellular and Whole Cell Pertussis Vaccines and Pertussis Infection in the Baboon Model

Abstract Following the replacement of whole cell pertussis (wP) vaccines with acellular pertussis (aP) vaccines, high-income countries recorded sustained increases in pertussis cases. While aP vaccines protect against severe disease, they fail to prevent colonization and transmission, unlike wP vaccination and natural infection. The mechanisms underlying these differences remain incompletely understood. Trivalent aP vaccines are often characterized as inducing Th2 biased responses due to alum adjuvant. However, most current formulations of aP are combination vaccines containing additional antigens, which may shape the overall immune environment and influence responses to pertussis antigens. To investigate these differences, we profiled immune responses in baboons following aP vaccinations, wP vaccinations and infections using complete blood counts, transcriptomics, and immunological assays. Weighted gene co-expression network analysis revealed fundamental differences in immune polarization. These findings define divergent immune landscapes induced by these three exposures, providing mechanistic insight into their differential protective efficacy and highlighting the importance of vaccine composition in shaping immune responses. Notably, our data suggest that pentavalent aP vaccination may induce distinct innate and cellular immune responses compared to trivalent formulations, with important implications for future vaccine design strategies, and design of clinical trials.