Safety, colonization kinetics, transmissibility and immune correlates of protection in healthy UK adults inoculated with <i>Bordetella pertussis</i>: a single-centre, open label, phase 1 controlled human infection study

Background: cyclical epidemics of whooping cough continue to occur despite pertussis vaccination, which fails to suppress colonization and transmission. In this study, we aimed to identify immunological correlates of protection against B. pertussis (Bp) colonization, to guide future pertussis vaccine development.<br/><br/>Methods : in this controlled human infection study at University Hospital Southampton, healthy volunteers aged 18-55 years, recipients of whole-cell vaccine in childhood, were inoculated intranasally with 105 colony forming units (CFU) of wild-type Bp strain B1917. Volunteers were monitored as outpatients for 28 days for safety, colonization and Bp-specific immunological parameters. Healthy bedroom-sharers were enrolled to measure transmission. After three months, volunteers were re-inoculated. Volunteers received azithromycin 14 days after each inoculation. The primary objective was to demonstrate safety; secondary objectives included assessment of immunological biomarkers of protection from colonization (ClinicalTrials.gov NCT03751514, closed to volunteers).<br/><br/>Findings : the per-protocol analysis included fifty volunteers who completed the initial challenge, of whom twenty (40%) became colonized with Bp. Adverse events were mostly mild to moderate, with no significant differences between colonized and non-colonized volunteers. There were no serious adverse events. Non-colonized volunteers (n=30) had significantly higher pre-inoculation serum antibody concentrations against multiple acellular pertussis vaccine antigens, higher nasal and serum IgA antibodies against whole Bp, and higher peripheral T-helper-22 (Th22) responses to pertussis toxin (PT) and filamentous haemagglutinin (FHA). Post-inoculation, only colonized volunteers demonstrated seroconversion, IgA and IgG-binding to Bp, and increases in Bp-specific IgG-secreting memory B cell frequencies. Of the 13 volunteers who became colonized after initial inoculation and who were re-inoculated, only one (8%) became colonized following re-inoculation. Transmission to bedroom-sharers was not detected. <br/><br/>Interpretation: out-patient controlled human infection with B. pertussis is safe. Higher humoral and CD4+ T cell responses with specificity to acellular pertussis vaccine Bp antigens are associated with protection against Bp colonization following experimental challenge.<br/><br/><br/>