Mucosal inflammation and pre-existing antibodies define protection and disease outcomes in human Bordetella pertussis challenge

Whooping cough, caused by Bordetella pertussis (BP), persists despite widespread vaccination with acellular pertussis (aP) vaccines, which protect against disease but provide incomplete and short-lived immunity against infection and transmission. To define correlates of protection and mechanisms underlying symptom development, we characterized systemic and mucosal immune responses in a North American BP-controlled human infection model (CHIM). Healthy adults, primed in infancy with either whole-cell or aP vaccines, were intranasally challenged with escalating BP doses and classified as symptomatic, asymptomatic, or non-infected. Longitudinal paired blood and nasal samples were analyzed to measure antibody titers, cell subset frequencies, cytokine concentrations, gene expression, and T cell polarization and activation. Non-infected participants exhibited significantly higher pre-challenge serum antigen-specific IgG titers, identifying these antibodies as potential correlates of protection. Only symptomatic individuals developed robust antigen-specific IgG responses post-challenge and displayed pronounced nasal transcriptional inflammation peaking on day 7, characterized by induction of interferon and NF-κB signaling and the presence of HLA-DR⁺ myeloid cells. Systemic responses were modest: plasma cytokine concentrations decreased following challenge regardless of outcome, peripheral blood mononuclear cell transcriptomes remained largely unchanged, and antigen-specific T cell activation and polarization were unaffected. Together, these findings reveal that protection from BP colonization associates with pre-existing serum antibodies, whereas symptom development is driven by localized mucosal inflammation dominated by myeloid cells. The predominance of nasal over systemic immune activation highlights the importance of mucosal immunity in controlling BP and provides critical insights to guide the design of next-generation vaccines aimed at preventing both disease and transmission.