A Human Controlled Infection Study to Establish a Safe, Reproducible and Practical Human Bordetella Pertussis Colonisation Model for the Identification of Correlates of Protection Against Colonisation (BPCCS)
试验速览
- 阶段
- 不适用
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Phase A - Inoculum Dose Determination
研究概览
简要总结
This is a prospective controlled human challenge study consisting of two phases; Phase A: Development of a B. pertussis human challenge model; pilot to establish the standard inoculum Phase B: Development of a modified B. pertussis human challenge model
详细描述
This study is part of work package 2 of the Periscope consortium. The Periscope consortium brings together internationally renowned scientists with many years of experience in B. pertussis research, clinical trials, bioinformatics, immunology and public health to promote scientific and technological innovation in pertussis vaccine development and to foster the creation of a laboratory and scientific network that facilitates the testing and helps expedite the development of novel pertussis vaccines in Europe. This study, the development of a human challenge model for B. pertussis, is one of the models that will accelerate the development and registration of novel pertussis vaccines and will provide samples for studies performed within the network.
This is a prospective controlled human challenge study consisting of two phases; Phase A: Development of a B. pertussis human challenge model; pilot to establish the standard inoculum The first aim of phase A is to determine a 'standard inoculum' (SI), which results in safe colonisation of 70% of volunteers. This level of colonisation of 70% has been selected so that baseline immune profiles of individuals who are, or are not colonised following challenge can be assessed and biomarkers of protection from colonisation identified. It is acknowledged that for the future use of the human challenge model for efficacy evaluation of experimental vaccine candidates, it would be optimal if the percentage of subjects successfully colonised were at least 70%. The SI will be identified in a dose escalating or de-escalating experiment commencing at 103 colony forming units B. pertussis administered intranasally. Each group of 5 volunteers will be sequentially inoculated at half log-fold increasing/decreasing doses until the endpoint is reached. The experiment will be continued until the SI yields 10 subjects who are colonised at day 14. Volunteers will be screened to exclude those with evidence of recent B. pertussis infection using anti-pertussis toxin (PT) immunoglobulin G (IgG) ELISA as evidence to allow evaluation of seroconversion. Following the challenge chemical, haematological and clinical parameters will be monitored and nasal swab samples will be cultured at regular intervals to assure safety of the volunteers and to identify the presence of B. pertussis. At day 14 after the challenge, or at the onset of symptoms, whichever occurs soonest, eradication therapy in the form of azithromycin 500 mg once a day for 3 days will be given. Further mucosal and blood samples will be taken over the follow up period of one year.
The second aim of phase A is to identify the 'colonisation period'; the earliest day after inoculation at which colonisation of the nasopharynx (as detected by culture) is observed in 100% of those volunteers who show seroconversion at day 28. This time period will be used to establish the length of participation required from volunteers in future studies. The colonisation period will be deemed biologically relevant if B. pertussis specific mucosal and systemic antibodies are elicited in people who are colonised for the colonisation period. A quantitative PCR assay to detect B. pertussis in nasopharyngeal samples will be evaluated to determine if this can provide more rapid information in addition to culture.
The third aim of phase A is to access environmental shedding of B. pertussis following nasal inoculation of healthy volunteers with B. pertussis. These shedding results will used to determine the length of admission and isolation in phase B. The shedding of B. pertussis by challenged volunteers will be assessed using personal aerosol samplers and environmental sampling. Efficacy of eradication therapy will be assessed.
Phase B: Development of a modified B. pertussis human challenge model In phase B the pilot study data from phase A will be used to design a more practical model, if possible conducted partially in an outpatient setting, which will be conditional on safety and transmission evidence. The final protocol for phase B will be presented as a protocol amendment, because it will be based on the standard inoculum and colonisation period identified in Phase A.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy adults aged 18 to 45 years inclusive on the day of screening
- •Fully conversant in the English language
- •Able to communicate easily by both mobile telephone and text messaging
- •Able and willing (in the investigator's opinion) to comply with all study requirements
- •Written informed consent to participate in the trial
- •Willingness to take a curative antibiotic regimen after inoculation with B. pertussis according to the study protocol
- •Agreement to be admitted to the National Institute for Health Research (NIHR)-Clinical research facility (CRF) Southampton for 17 days for phase A (from inoculation until two days after the eradication therapy is given) and for the duration necessary for phase B, depending on phase A results
- •Able to answer all questions on the informed consent quiz correctly
排除标准
- •Individuals who have inviolable commitments within 3 months of discharge from the inpatient phase of the study to make contact with:
- •unimmunised or partially immunised children and infants aged < 1 year
- •pregnant women >32 weeks who have not received pertussis vaccination at least a week prior to contact
- •Individuals who have household contacts working with
- •unimmunised or partially immunised children and infants aged < 1 year
- •pregnant women >32 weeks who have not received pertussis vaccination at least a week prior to contact
- •Phase A only: Volunteers will be excluded from this study if they have evidence of recent exposure to B. pertussis, as determined by anti-PT IgG ELISA (>20 IU/mL)
- •B. pertussis detected on nasopharyngeal swab taken before the challenge
- •Individuals who have a signs of a current infection at the time of inoculation with B. pertussis
- •Individuals who have participated in other interventional clinical trials in the last 12 weeks
- •Individuals who have a history of receiving B. pertussis vaccination in the last 5 years
- •Individuals who have a history of never being vaccinated against B. pertussis
- •Current smokers defined as having had a cigarette/cigar in the last week.
- •Use of systemic antibiotics within 30 days of or during the challenge
- •Any confirmed or suspected immunosuppressive or immune-deficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (topical steroids are allowed)
- •Use of immunoglobulins or blood products within 3 months prior to enrolment
- •History of allergic disease or reactions likely to be exacerbated by any component of the inoculum
- •Contraindications to the use of azithromycin or macrolides
- •Pregnancy, lactation or intention to become pregnant during the study
- •Any clinically significant abnormal finding on biochemistry, haematology, toxicology or serological blood tests, urinalysis or clinical examination - in the event of abnormal test results, confirmatory repeat tests will be requested
- •Any other significant disease, disorder, or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data, for example recent surgery to the nasopharynx
研究组 & 干预措施
Phase A - SI
Phase A aims to determine a 'standard inoculum' dose (SI), which results in safe colonisation of 70% of volunteers.
The SI will be identified in a dose escalating or de-escalating experiment commencing at 10-3 colony forming units B. pertussis administered intranasally. Each group of volunteers will be inoculated at half log-fold increasing/decreasing doses until the endpoint is reached. The experiment will be continued until the SI yields 10 subjects who are colonised at day 14.
Intervention to be administered: Bordetella Pertussis B1917
干预措施: Bordetella Pertussis B1917 (Biological)
Phase A - SI
Phase A aims to determine a 'standard inoculum' dose (SI), which results in safe colonisation of 70% of volunteers.
The SI will be identified in a dose escalating or de-escalating experiment commencing at 10-3 colony forming units B. pertussis administered intranasally. Each group of volunteers will be inoculated at half log-fold increasing/decreasing doses until the endpoint is reached. The experiment will be continued until the SI yields 10 subjects who are colonised at day 14.
Intervention to be administered: Bordetella Pertussis B1917
干预措施: Azithromycin 500 mg (Drug)
Phase B Inoculum
Phase B, using study data from phase A, will be used to design a more practical model - if possible conducted partially in an outpatient setting, which will be conditional on safety and transmission evidence. The final protocol for phase B will be presented as a protocol amendment, it will be based on the SI and colonisation period identified in Phase A.
The SI determined in phase A will be used for all volunteers and eradication therapy will be given after the colonisation period based on the data of phase A. Approximately 30 individuals will receive the intranasal SI and will be treated with azithromycin for three days at the end of the colonisation period.
Intervention to be administered: Bordetella Pertussis B1917
干预措施: Bordetella Pertussis B1917 (Biological)
Phase B Inoculum
Phase B, using study data from phase A, will be used to design a more practical model - if possible conducted partially in an outpatient setting, which will be conditional on safety and transmission evidence. The final protocol for phase B will be presented as a protocol amendment, it will be based on the SI and colonisation period identified in Phase A.
The SI determined in phase A will be used for all volunteers and eradication therapy will be given after the colonisation period based on the data of phase A. Approximately 30 individuals will receive the intranasal SI and will be treated with azithromycin for three days at the end of the colonisation period.
Intervention to be administered: Bordetella Pertussis B1917
干预措施: Azithromycin 500 mg (Drug)
Phase B Sham
Phase B, using study data from phase A, will be used to design a more practical model - if possible conducted partially in an outpatient setting, which will be conditional on safety and transmission evidence.
Approximately 15 individuals will not receive the Bordetella Pertussis B1917, instead they will be given an intranasal sham of sterile saline and will be treated with azithromycin 500mg for three days at the end of the 'colonisation' period.
干预措施: Azithromycin 500 mg (Drug)
Phase B Sham
Phase B, using study data from phase A, will be used to design a more practical model - if possible conducted partially in an outpatient setting, which will be conditional on safety and transmission evidence.
Approximately 15 individuals will not receive the Bordetella Pertussis B1917, instead they will be given an intranasal sham of sterile saline and will be treated with azithromycin 500mg for three days at the end of the 'colonisation' period.
干预措施: Sterile Saline (Other)
结局指标
主要结局
Phase A - Inoculum Dose Determination
时间窗: Up to volunteer visit Day 14
The inoculum dose required to cause the safe colonisation of 70% of volunteers who are challenged. A starting inoculum of 10\^3 bacteria will be used and incrementally increased until microbiologically proven Bp infection by positive culture of Bp from a nasopharyngeal swab (CFU/mL). Swabs are taken between time points day 0 and day 14 and compare with baseline.
次要结局
- Phase A and B - Bacterial Dynamics after Challenge by PCR(Up to volunteer visit Day 14)
- Phase A - Environmental shedding of Bp(Day 0-16)
- Phase A & B - Immune Response in nasal wash to Challenge(Up to volunteer visit Week 52)
- Phase A & B - Human Immune Response to Challenge in Saliva(Up to volunteer visit Week 52)
- Phase A and B - Immune Responses to exposure to Bordetella pertussis(Up to volunteer visit Week 52)
- Phase A - Accuracy of Inoculum Dosing Evaluation(Up to volunteer visit Day 7)
- Phase A and B - Number of participants with Bp exposure-related adverse events as assessed by study specific adverse event grading system based on CTCAE v4.0(Up to volunteer visit Day 365)
- Phase A & B - Correlation of qPCR results with Culture Results after Challenge(Up to Day 16)
- Phase A - Earliest Timepoint for Colonisation of the Nasopharynx(Up to volunteer visit Day 14)
- Phase A and B - Bacterial Dynamics after Challenge(Up to volunteer visit Day 14)
- Phase A and B - Bacterial Dynamics after Challenge by culture(Up to volunteer visit Day 14)