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A controlled human infection model for symptomatic pertussis in North America using the pertactin-producing clinical
May S ElSherif1,2, Kara L Redden1, Joanne M Langley1,3,4
1Canadian Center for Vaccinology (Dalhousie University, IWK Health, Nova Scotia Health), Halifax, NS, Canada.
Insights
This study established a safe and reproducible symptomatic pertussis (whooping cough) controlled human infection model (CHIM) using Bordetella pertussis D420. This model allows for better evaluation of pertussis vaccines and therapeutics against infection and disease.
Area of Science:
- * Infectious Diseases
- * Immunology
- * Microbiology
Background:
- * Pertussis (whooping cough) remains a significant global health concern despite widespread vaccination, causing substantial morbidity and mortality, especially in young children.
- * Controlled human infection models (CHIMs) are crucial for studying pertussis pathogenesis, immunology, and for rapidly assessing vaccines and therapeutics.
- * While an asymptomatic pertussis CHIM exists, a symptomatic model is advantageous for evaluating vaccine efficacy against both infection and disease.
Purpose of the Study:
- * To develop and characterize a safe and reproducible symptomatic pertussis CHIM.
- * To determine the optimal Bordetella pertussis (B. pertussis) D420 challenge dose for inducing symptomatic illness in healthy adults.
- * To assess the safety, symptom profile, and immune responses within this novel CHIM.
Main Methods:
- * Healthy adult participants (18-40 years) were intranasally inoculated with varying doses (10^4 to 10^8 CFU) of B. pertussis D420 in a two-stage study.
- * Stage one involved dose escalation to identify the Human Infectious Dose 70-90 (HID70-90) for mild symptomatic infection.
- * Participants were monitored for infection, symptoms, safety, and antibody responses; all received azithromycin to clear infections.
Main Results:
- * A B. pertussis D420 dose of 10^7 CFU was identified as the lowest dose achieving the HID70-90, with 72.7% of participants developing mild symptomatic infection.
- * Common symptoms included nasal congestion, runny nose, fatigue, malaise, and cough (50% of symptomatic cases).
- * Antibody titers increased post-challenge, with seroconversion nearly twice as common in symptomatic versus asymptomatic infections; all infections were cleared, and no serious adverse events occurred.
Conclusions:
- * A safe and reproducible symptomatic pertussis CHIM was successfully established using B. pertussis D420.
- * This CHIM provides a valuable platform for researching pertussis pathogenesis, immunology, and for evaluating the efficacy and safety of new vaccines and therapeutics.
- * The model allows for the assessment of vaccine efficacy against both infection and symptomatic disease, better reflecting real-world scenarios.
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 104 to 108 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 107 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 107 CFU (72·7%) developed mild symptomatic infection, thus verifying the HID70-90. The symptomatic infection rate below the HID70-90 at 5×106 CFU of D420 was 20·0% and above the HID70-90 at 5×107 and 108 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 (5×106, 107, 5×107, 108 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).
