Safety, colonisation kinetics, transmissibility, and immune correlates of protection in healthy adults inoculated with Bordetella pertussis in England: a single-centre, open-label, phase 1, controlled human infection study.

内容摘要

Cyclical epidemics of pertussis, also known as whooping cough, continue to occur despite vaccination, because current vaccines fail to suppress colonisation by, and transmission of, the causative agent Bordetella pertussis. We aimed to show the safety of B pertussis controlled human infection delivered in an outpatient setting, as well as identify immunological correlates of protection against B pertussis colonisation, to guide the future development of pertussis vaccines. This open-label, phase 1, controlled human infection study was conducted at University Hospital Southampton, Southampton, UK. Healthy volunteers aged 18-55 years who had received a whole-cell pertussis vaccine in childhood were inoculated intranasally with 105 colony-forming units of wild-type B pertussis strain B1917. Volunteers were monitored as outpatients for 28 days to assess safety, colonisation, and B pertussis-specific immunological parameters. Individuals who shared a bedroom with inoculated volunteers were enrolled to measure transmission to close contacts. After approximately 90 days, volunteers who agreed to participate in a rechallenge phase of the study were re-inoculated with the same dose of B pertussis. Volunteers received azithromycin 14 days after each inoculation. The primary objective was to assess the safety of delivering this controlled human infection model on an outpatient basis; safety endpoints were the occurrence of possible or confirmed pertussis and unsolicited or serious adverse events. Secondary objectives were the assessment of immunological biomarkers of protection from colonisation and the assessment of transmission from volunteers to close contacts. All volunteers who received the inoculum were included in the safety analysis, and all participants who completed follow-up to day 14 were included in the per-protocol population for colonisation and immunological analysis. This trial is registered at ClinicalTrials.gov, NCT03751514, and is ongoing. Between Aug 29, 2019 and March 6, 2023, 77 volunteers were screened and 51 were enrolled and inoculated, of whom 50 completed follow-up to day 14 post-inoculation. 20 (40%) of these 50 volunteers became colonised with B pertussis. One volunteer developed symptoms suggestive of possible pertussis after initial inoculation; this volunteer tested negative for B pertussis throughout the study and all symptoms resolved within 4 days. Adverse events were mostly mild to moderate, with no significant increase in the reporting of any individual symptom by colonised volunteers. All unsolicited adverse events were assessed as either unlikely to be related or unrelated to B pertussis infection, with no increase in the frequency of these events seen in colonised volunteers. There were no serious adverse events and no treatment-related deaths. Compared with those who became colonised with B pertussis, non-colonised volunteers had significantly higher pre-inoculation serum IgG antibody concentrations against several acellular pertussis vaccine antigens (pertussis toxin [p=0·028], pertactin [p=0·037], and filamentous haemagglutinin [p=0·024]); higher nasal (p=0·022) and serum (p=0·044) IgA antibody concentrations against whole B pertussis; higher serum IgA antibody concentrations specific to filamentous haemagglutinin (p=0·024); and higher peripheral T-helper (Th)-22-cell responses to pertussis toxin (p=0·0045) and filamentous haemagglutinin (p=0·029). After inoculation, only colonised volunteers showed seroconversion, IgA and IgG binding to B pertussis, and increases in B pertussis-specific IgG-secreting memory B-cell frequencies by day 28. Th17 responses to pertussis toxin were increased (p=0·039) and Th22 responses to filamentous haemagglutinin were decreased (p=0·014) in non-colonised volunteers. Of the 13 volunteers who became colonised after initial inoculation and were re-inoculated, only one (8%) became colonised after re-inoculation. Transmission from volunteers to 14 enrolled individuals with whom they shared a bedroom was not detected. Our findings suggest that controlled human infection with B pertussis in an outpatient setting is safe. Higher humoral and CD4+ T-cell responses with specificity to acellular pertussis vaccine antigens are associated with protection against colonisation by B pertussis after experimental challenge. This technique could enable the testing of potential novel vaccines or formulations for sustained protection against infection and transmission. EU Horizon 2020 (Innovative Medicines Initiative) and the National Institute for Health and Care Research Southampton Biomedical Research Centre.