Pre-existing antibodies predict protection while mucosal inflammation correlates with symptomatic Bordetella pertussis infection

Despite decades of widespread vaccination, whooping cough caused by Bordetella pertussis (Bp) continues to circulate globally. To define correlates of protection and mechanisms underlying symptom development, we characterized systemic and mucosal immune responses in a controlled human infection model of Bp (NCT05136599). Healthy vaccinated adults were intranasally challenged with escalating Bp doses and classified as symptomatic, asymptomatic, or non-infected. Longitudinal sampling of blood and nasal mucosa allowed mapping of antibody titers, immune cell subset frequencies, cytokine concentrations, gene expression, and T cell activation and polarization. Non-infected participants exhibited significantly higher pre-challenge serum antigen-specific IgG titers. Post-challenge, only symptomatic participants developed robust antigen-specific IgG responses. Notably, infection-induced IgG responses displayed slower kinetics and a lower overall magnitude compared to the rapid day 7 peak observed following tetanus, diphtheria, and acellular pertussis (Tdap) booster vaccination. Furthermore, symptomatic infection was driven by pronounced nasal inflammation characterized by increased HLA-DR myeloid cells and upregulated mucosal NF-{kappa}B signaling on day 7. Systemic immune responses were comparatively modest post-challenge: plasma cytokine concentrations decreased independently of clinical outcome, peripheral blood mononuclear cell transcriptomes and antigen-specific T cell activation and polarization remained largely unchanged. These findings identify pre-existing serum antibodies as potential correlates of protection from Bp infection and suggest that symptom development is associated with localized mucosal inflammation dominated by a myeloid cell response. 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.