Mucosal and Systemic Antibodies Associated with Clinical Protection in a Pertussis Controlled Human Infection Model
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Background
The engagement of mucosal and systemic immunity in preventing Bordetella pertussis colonization and infection in humans, the impact of prior vaccination on host immunity and protective outcomes, and the dynamics of the host response following exposure remain poorly understood.
Methods
Healthy adults were challenged with increasing colony-forming units (CFUs) doses, 10 6 -10 8 , of B. pertussis D420 intranasally ( NCT05136599 ). Shedding (PCR and culturing) and symptom development were monitored up to 21 days post-challenge. Serum and nasal wash IgA and IgG were measured before challenge (baseline) and up to 6 months post-challenge.
Findings
Antibodies increased post-challenge only in infected individuals, primarily nasal IgA. Participants who remained uninfected had higher baseline levels of filamentous hemagglutinin (FHA)- specific mucosal IgA and IgG, and higher serum IgA against fimbriae 2/3 (FIM). FHA was negatively associated with bacterial load and was a key discriminator between shedders and non-shedders, up to one week post-challenge. By day 14 post-challenge, pertussis toxin (PT) IgG and FIM IgA in both serum and mucosal samples were negatively associated with bacterial colonization. The majority (96·7%) of acellular pertussis (aP) vaccine recipients (n=23, median age 22·0 years) became infected, compared to 69·4% of those who received whole-cell pertussis vaccine (n=36; median age 32·0 years), and their antibody responses remained distinct following infection.
Interpretation
Nasal FHA antibodies emerged as early predictors of protection against pertussis infection, while PT IgG and FIM IgA antibodies may reflect clearance after infection. aP-primed individuals were more susceptible to infection, despite their younger age and more recent vaccination.
Funding
CDC Contract #75D30122C15467 and CDC IPA Agreement #24IPA2417512
Research in Context
Evidence before this study
Immunological correlates of protection against pertussis infection remain elusive. The contributions of mucosal and systemic immunity in preventing infection in humans, the impact of prior vaccination on risk of infection and clinical outcomes, and the recall response following exposure remain incompletely understood. We retrieved PubMed literature in any language since inception through February 1st, 2026, using the terms: (“Pertussis” OR “Whooping Cough”) AND (“IgA” or “immunoglobulin” OR “IgG”) AND (“Coloni*ation” OR “adherence” OR “Clearance” OR “shed*” OR “Challenge”) AND “Human”. A total of 44 publications were identified, two of which report data from controlled human infection model (CHIM) studies. The PERISCOPE CHIM report examined only the serum B. pertussis antibody responses after infection, and the other evaluated the efficacy of the live-attenuated vaccine BPZE1 in preventing B. pertussis colonization. Neither of these studies examined the dynamics of mucosal and systemic antibodies before and after challenge in relation to bacterial colonization and symptomatic illness, nor did they investigate the influence of prior childhood vaccine priming (acellular pertussis [aP] vs. whole-cell pertussis [wP]) on clinical outcomes. The host immune factors that determine susceptibility to pertussis infection remain unknown.
Added Value of this study
We report here that baseline mucosal and systemic antibodies specific to filamentous hemagglutinin (FHA) were associated with clinical protection against pertussis infection among CHIM participants. Two weeks after infection, mucosal and serum pertussis toxin (PT) IgG and Fimbriae 2/3 IgA were negatively correlated with pertussis colonization. Primary vaccine history (whole-cell [wP] or acellular [aP]) imprinted immune profiles that persisted after experimental infection in adulthood and affected clinical outcomes. This study is the first to identify mucosal and systemic temporal markers of pertussis infection and predictors of protective immunity in humans.
Implications of all available evidence
The insights generated by these results on host immunity associated with protection against pertussis, particularly the contribution of mucosal FHA antibodies, can inform vaccine design and guide population assessments of susceptibility to infection.
