Establishing a Controlled Human Infection Model of Bordetella Pertussis

Sponsor

Dalhousie University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05136599

Collaborator

National Institute of Allergy and Infectious Diseases (NIAID) (NIH), Centers for Disease Control and Prevention (U.S. Fed), Vanderbilt University Medical Center (Other), Intravacc (Other)

Enrollment

Location

Arms

21.7

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study aims to establish a Controlled Human Infection Model of Bordetella pertussis by determining a reproducible and safe infectious bacterial dose (challenge inoculum) that achieves colonization and mild symptomatic infection in healthy adults.

Condition or Disease	Intervention/Treatment	Phase
Pertussis	Biological: Bordetella pertussis D420	Phase 1

Detailed Description

This is a single-center trial to develop a Bordetella pertussis Controlled Human Infection Model (CHIM) using a two-study approach: the first study is a human infectious dose 70%-90% (HID70-90) identification study, and the second an HID70-90 dose confirmation study to verify and confirm that the infectious endpoint has been reached. The infectious endpoint is positive nasopharyngeal culture(s) and/or polymerase chain reaction(s) (PCR(s)) for B. pertussis with concurrent or subsequent development of mild pertussis disease symptoms such as rhinorrhea and cough within the 16-day inpatient period following challenge.

The trial is an open-label, phase 1, dose escalation, self-contained trial; participants will be allocated to challenge dose groups to receive a single intranasal dose of challenge inoculum. All participants will receive a 5-day course of azithromycin eradication therapy either 24-48 hours after they develop symptoms or at the end of the 16-day postchallenge observation period.

The optimal/target inoculum is one that induces mild symptomatic infection and detection of

pertussis in nasopharyngeal cultures in 70%-90% of participants receiving it, to establish a safe and reproducible pertussis CHIM.

Safety monitoring includes close clinical observation during a 16-21-day inpatient postchallenge period in the Canadian Center for Vaccinology's Challenge Unit, a Data and Safety Monitoring Board, and participant Diary Cards.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

66 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Study 1 is a dose-escalation/de-escalation study in which participants will be allocated consecutively to a challenge dose group (arm) with predetermined dose level based on a decision algorithm. (All potential challenge dose groups are listed below, but not all groups may be required.)Study 1 is a dose-escalation/de-escalation study in which participants will be allocated consecutively to a challenge dose group (arm) with predetermined dose level based on a decision algorithm. (All potential challenge dose groups are listed below, but not all groups may be required.)

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

Open-label, Phase 1, Dose-escalation Clinical Trial to Establish a Controlled Human Infection Model by Determining the Optimal and Safe Bordetella Pertussis Dose That Induces Mild Symptomatic Infection and Colonization in Healthy Adults

Anticipated Study Start Date :

Jan 17, 2022

Anticipated Primary Completion Date :

Nov 11, 2022

Anticipated Study Completion Date :

Nov 10, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Study 1 (Dose-identification study), Dose 1 Challenge dose of 10^3 cfu B. pertussis in 0.2 mL (0.1 mL per naris)	Biological: Bordetella pertussis D420 Intranasal inoculation of Bordetella pertussis D420 in each naris on Day 0 of the study.
Experimental: Study 1 (Dose-identification study), Dose 2 Challenge dose of 5 x 10^3 cfu B. pertussis in 0.2 mL (0.1 mL per naris)	Biological: Bordetella pertussis D420 Intranasal inoculation of Bordetella pertussis D420 in each naris on Day 0 of the study.
Experimental: Study 1 (Dose-identification study), Dose 3 Challenge dose of 10^4 cfu B. pertussis in 0.2 mL (0.1 mL per naris)	Biological: Bordetella pertussis D420 Intranasal inoculation of Bordetella pertussis D420 in each naris on Day 0 of the study.
Experimental: Study 1 (Dose-identification study), Dose 4 Challenge dose of 5 x 10^4 cfu B. pertussis in 0.2 mL (0.1 mL per naris)	Biological: Bordetella pertussis D420 Intranasal inoculation of Bordetella pertussis D420 in each naris on Day 0 of the study.
Experimental: Study 1 (Dose-identification study), Dose 5 Challenge dose of 10^5 cfu B. pertussis in 0.2 mL (0.1 mL per naris)	Biological: Bordetella pertussis D420 Intranasal inoculation of Bordetella pertussis D420 in each naris on Day 0 of the study.
Experimental: Study 1 (Dose-identification study), Dose 6 Challenge dose of 5 x 10^5 cfu B. pertussis in 0.2 mL (0.1 mL per naris)	Biological: Bordetella pertussis D420 Intranasal inoculation of Bordetella pertussis D420 in each naris on Day 0 of the study.
Experimental: Study 1 (Dose-identification study), Dose 7 Challenge dose of 10^6 cfu B. pertussis in 0.2 mL (0.1 mL per naris)	Biological: Bordetella pertussis D420 Intranasal inoculation of Bordetella pertussis D420 in each naris on Day 0 of the study.

Outcome Measures

Primary Outcome Measures

Number of participants with mild symptoms of early pertussis disease postchallenge [Day 0 (challenge day) to Day 16]
Mild, Grade 1, symptoms of pertussis are symptoms that do not interfere with everyday activities. They may include malaise, rhinorrhea, sneezing and/or lacrimation, low-grade fever, or cough.

Secondary Outcome Measures

Number of participants who demonstrate shedding of Bordetella pertussis postchallenge as determined by positive culture and/or PCR test of nasopharyngeal samples [Day 1 to Day 14]
The presence of B. pertussis is detected by positive culture (i.e., presence of any B. pertussis colonies) of nasopharyngeal samples. It is also detected by a positive PCR (polymerase chain reaction) test of nasopharyngeal samples. Both methods are used in this study; a positive result in either culture and/or PCR test demonstrates shedding of B. pertussis.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

To be eligible for the study, each participant must satisfy ALL of the following criteria:

Age 18-40 years, inclusive.
Good general health status, as determined by history and physical examination conducted no longer than 30 days prior to the challenge.
Participants who, in the opinion of the Investigator, can and will comply with the requirements of the protocol (e.g., complete Diary Cards, return for follow-up visits).
Written informed consent obtained from the participant.
If female of child-bearing potential and heterosexually active, has practiced adequate contraception for 28 days prior to challenge and has a negative pregnancy test on the day of B. pertussis challenge and has agreed to continue adequate contraception until 60 days after inoculation. Adequate contraception is defined as a contraceptive method with a failure rate of <1% per year when used consistently and correctly and, when applicable, in accordance with the product label. Examples include the following:

Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable
Intra-uterine device (IUD) with or without hormonal release
Vasectomized partner, provided that this is the participant's sole partner and that he has received a medical assessment of the surgical success
Credible self-reported history of heterosexual abstinence for at least 28 days prior to challenge
Female partner

Exclusion Criteria:

Participants with ANY of the following criteria at the time of screening will be excluded:

Underlying chronic medical condition requiring ongoing follow-up and monitoring by a physician (e.g., diabetes, seizure disorder).
Underlying cardiac and/or pulmonary disease including hypertension, angina, prior myocardial infarction, asthma, emphysema, chronic bronchitis, and pulmonary tuberculosis.
QT prolongation on electrocardiogram (EKG).
Current cigarette smoker or cigarette smoker within the previous 5 years.
Pregnant (known before or established at the time of screening using a urine-based test) or breastfeeding.
Immunocompromised (HIV/AIDS-positive or receiving immunosuppressive therapy involving steroids).
Positive for hepatitis B or C.
Vaccinated against pertussis within previous 5 years and/or >7 cumulative doses from infancy to date of screening.
Reported history of laboratory-confirmed pertussis infection.
Antibody titer to pertussis toxin >10 EU/mL (2x the lower limit of quantification (LLOQ)).
Nasopharyngeal detection of B. pertussis prior to challenge using culture isolation and/or PCR detection, or detection of other respiratory infection.
Living with young children (<1 year of age) or with any household member not current in their pertussis immunization. (Note: Household members whose vaccination is not current will be offered a pertussis-containing vaccine, as recommended and funded by Nova Scotia Department of Health and Wellness.)
Known allergy to macrolides including azithromycin or erythromycin, history of Clostridium difficile within last 2 months.
Taking any antibiotic currently or within the previous 2 weeks.
Currently taking terfenadine, astemizole, theophylline, or cimetidine.
Recent (within 6 months) nasal or sinus surgery, recent use of intranasal steroids (4 weeks), or diagnosis with nasal polyps.
Receipt of any investigational drug within 6 months.
Receipt of any authorized (approved or investigational) vaccines within 2 weeks of study immunization.
Receipt of experimental SARS-CoV-2/COVID-19 vaccine(s) at any time prior to or during the study.
Known current or previous laboratory-confirmed SARS-CoV-1 or SARS-CoV-2 infection, as documented by a positive PCR test from a nasal swab or known positive serology.
Head trauma (e.g., fracture of the cribriform plate) within 1 year of screening.
Any other finding that the Investigator considers will make the participant unsuitable for the study or unable to comply with the study requirements.