A controlled human infection model for symptomatic pertussis in North America using the pertactin-producing clinical isolate D420
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Background
Despite widespread vaccination, pertussis remains a poorly controlled disease globally and results in substantial annual morbidity and mortality, particularly in young children. Controlled human infection models (CHIMs) using the causative agent Bordetella pertussis are promising systems to enable the study of pertussis disease pathogenesis and immunology and to rapidly assess vaccines and therapeutics. While a pertussis CHIM that produces asymptomatic infection has been established in Europe, the development of a CHIM that leads to symptomatic illness would be advantageous for evaluating vaccine efficacy against both infection and disease.
Methods
Healthy participants 18–40 years of age were inoculated intranasally with one of eight doses (ranging from 10 4 to 10 8 colony forming units (CFU)) of the pertactin-producing B. pertussis isolate D420 at the challenge facility within the Canadian Center for Vaccinology (Nova Scotia, Canada). The study occurred in two stages. In stage one, the B. pertussis dose was escalated in cohort groups of five to six participants until reaching an endpoint where 70-90% of participants exhibited mild (non-severe, Grade 1 or 2) symptomatic infection, defined as the Human Infectious Dose 70-90 (HID70-90). In stage two, additional challenges were conducted for doses below, at, and above the identified HID70-90 to characterize the emerging pertussis model. For all challenge doses, participants were closely monitored during an inpatient stay of up to 24 days and post-discharge for laboratory-confirmed infection, pertussis symptoms, safety, and IgG antibody responses to four B. pertussis antigens including pertussis toxin, filamentous hemagglutinin, fimbriae, and pertactin. All participants received a five-day course of azithromycin, where timing of initiation depended on B. pertussis testing and symptoms. The study was conducted between July 4, 2022 and March 19, 2025.
Findings
Seventy-five participants were inoculated with one of the eight B. pertussis D420 challenge doses and completed the inpatient stay. From the stage-one dose escalation, we found that 10 7 CFU of B. pertussis D420 was the lowest dose that achieved the HID70-90, where 9 of 12 participants (75·0%) exhibited mild symptomatic infection. Following stage-two challenges, 16 of 22 total participants at 10 7 CFU (72·7%) developed mild symptomatic infection, thus verifying the HID70-90. The symptomatic infection rate below the HID70-90 at 5×10 6 CFU of D420 was 20·0% and above the HID70-90 at 5×10 7 and 10 8 CFU were 58·3% and 55·6%, respectively. Symptoms with elevated frequency for symptomatic infection (relative to background symptoms in non-infected) included nasal congestion, runny nose, fatigue, malaise, and cough. At the HID70-90, 50% of symptomatic infections included cough. Serological analyses of the four highest (stage-two) challenge doses (5×10 6 , 10 7 , 5×10 7 , 10 8 CFU) revealed that antibody titres increased over time post-challenge. Seroconversion for at least one of the four studied antibodies was nearly twice as common for symptomatic (70·0%) than asymptomatic (35·7%) infection and was absent (0%) for non-infected. All infections were cleared following azithromycin treatment (100%) and there were no study-related serious adverse events.
Interpretation
A safe and reproducible symptomatic pertussis CHIM was achieved, providing a model for research on pertussis disease pathogenesis and immunology and for assessing vaccines and therapeutics. (Clinicaltrials.gov, NCT05136599 ).
Funding
United States (US) Centers for Disease Control and Prevention, US National Institutes of Health
Research in Context
Evidence before this study
Bordetella pertussis , the causative agent of pertussis (whooping cough), remains a global threat despite nearly universal vaccination programs. The burden of pertussis disease is highest for infants but can also lead to complications among some adults, particularly the elderly and immunocompromised. Suboptimal vaccine efficacy and waning immunity post-vaccination have led to resurgences of pertussis in many countries and numerous outbreaks. New strategies are needed to investigate the pathophysiology and immunology of B. pertussis infection and to develop more efficacious vaccines and therapeutics. Controlled human infection models (CHIMs), the intentional exposure of human volunteers to a pathogen under closely monitored conditions, are promising platforms to address knowledge gaps on the disease and to assess the efficacy of novel vaccines. Recently, through a European collaborative effort, an asymptomatic pertussis CHIM was established using the B. pertussis isolate B1917 that showed intranasal bacterial challenge doses of 10 4 to 10⁵ colony-forming units (CFU) produced infection and antibody responses, was safe, and could be eliminated with antibiotics. The development of a symptomatic pertussis CHIM would permit evaluation of vaccine efficacy against both infection and symptomatic disease, and better reflect real-world circumstances.
Added value of this study
This study describes the establishment of a pertussis CHIM that induces mild symptomatic infection using the pertactin-producing isolate D420 at the challenge unit facilities of the Canadian Center for Vaccinology (Nova Scotia, Canada). Infection progression for participants in the study was closely monitored by testing for the pathogen in nasal washes (cultures and polymerase chain reaction (PCRs)), symptom assessments, and assays of pertussis antibodies. Using a dose-escalation design for nasal challenge with D420, we found that a B. pertussis dose of 10 7 CFU led to symptomatic disease in over 70% of participants. Symptoms associated with symptomatic infection included nasal congestion, runny nose, fatigue, malaise, and cough. Additional challenges below, at, and above the HID70-90 (5×10 6 , 10 7 , 5×10 7 , 10 8 CFU) provided insights into infection rates, symptom development, antibody responses, and safety of the CHIM. Overall, all symptoms were low-grade (Grade 1 or 2), infections were cleared with azithromycin, and there were no study-related serious adverse events. We demonstrate that different rates of asymptomatic and symptomatic infection were safely achieved by titrating the challenge dose of B. pertussis .
Implications of all the available evidence
The pertussis CHIM described here provides a platform to evaluate efficacy and safety of novel vaccine candidates and therapeutics against pertussis infection and disease. The CHIM also provides a framework to advance fundamental research in pertussis disease onset and progression, including correlates of infection, symptomology, and immune protection.
