- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03630250
Challenge of the Nasopharynx With Neisseria Lactamica Expressing the Meningococcal Protein Neisseria Adhesin A (NadA) (NadA-Lac4)
This study is part of a research programme that aims to improve ways of protecting people from serious illnesses such as meningitis and sepsis caused by a bacterium called Neisseria meningitidis (N. meningitidis), using a closely related but harmless bacterium called Neisseria lactamica (N. lactamica). Investigators have previously given nose drops containing N. lactamica to over 350 volunteers - this is known as inoculation. In these studies the investigators have shown that they can cause colonisation of many inoculated volunteers (35-60%) with N. lactamica. Colonisation is when bacteria survive on or in a person without causing any illness or disease. N. lactamica specifically colonises the nose and throat. Investigators have also shown that colonisation with N. lactamica results in an immune (antibody) response.
In this study investigators will be using a genetically modified version of N. lactamica which contains a single gene from N. meningitides. It is anticipated that the presence of this gene will change the number of people who are colonised and how long people remain colonised for, as well as causing them to produce an immune response to N. meningitides.
The purpose of this study are to prove that inoculation with this modified N. lactamica does not cause any symptoms or illness, and to analyse the immune response produced in healthy volunteers.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Early Phase 1
Contacts and Locations
Study Locations
-
-
-
Southampton, United Kingdom
- NIHR Southampton Clinical Research Facility
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
The challenge volunteer must satisfy all the following inclusion criteria to be eligible for the study:
- Healthy adults aged 18 to 45 years inclusive on the day of enrolment
- Fully conversant in the English language
- Able and willing (in the investigator's opinion) to comply with all study requirements
- Provide written informed consent to participate in the trial
- Provide written agreement to abide by infection control guidelines including agreement to abstain from intimate contact with any individual other than one declared and consented bedroom contact during the study period
- Provide written consent to allow the study team to discuss the volunteer's medical history with the General Practitioner
- Written informed contact volunteer consent provided by any bedroom contact
- Agreement to be admitted to Southampton NIHR-CRF for 4.5 days following inoculation
- For females only, willingness to practice continuous effective contraception (see below) during the study and a negative pregnancy test on the day(s) of screening and inoculation
- Able to correctly answer all questions in the pre-consent and infection control questionnaires
- Agreement to take antibiotic eradication therapy according to the study protocol
- TOPS registration completed and no conflict found
Exclusion Criteria:
The challenge volunteer may not enter the study if any of the following criteria apply:
- Current active smokers defined as having smoked a cigarette or cigar in the last four weeks
- N. lactamica or N. meningitidis detected on throat swab or nasal wash taken at screening or at the pre-challenge visit
- Individuals who have a current infection at the time of inoculation
- Individuals who have been involved in other clinical trials involving receipt of an investigational product over the last 12 weeks or if there is planned use of an investigational product during the study period
- Individuals who have previously been involved in clinical trials investigating meningococcal vaccines or experimental challenge with N. lactamica
- Individuals who have received one or more doses of the meningococcus B vaccine Bexsero
- Use of systemic antibiotics within the period 30 days prior to the challenge
- Any confirmed or suspected immunosuppressive or immune-deficient state, including HIV infection; malignancy, 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 ciprofloxacin, specifically a history of epilepsy, prolonged QT interval, hypersensitivity to quinolones or a history of tendon disorders related to quinolone use
- Contraindications to the use of ceftriaxone, specifically hypersensitivity to any cephalosporins
- Any clinically significant abnormal finding on clinical examination or screening investigations. 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
- Occupational, household or intimate contact with immunosuppressed persons, specifically HIV infection with a CD4 count <200 cells/mm3; asplenia; any malignancy, recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (topical steroids are allowed)
- Occupational or household contact with children under 5 years or an older child with a tendency to co-sleep with the volunteer
- Pregnancy, lactation or intention to become pregnant during the study
- Inability of the study team to contact the volunteer's GP to confirm medical history and safety to participate
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Challenge Volunteer - 4BN1
Volunteers will be given a choice of which version of the GM N. lactamica they would like to be given (4BN1 or 4YB2). On Day 0 Challenge volunteers will be asked to lie on their back, 0.5 mL of fluid containing a carefully measured amount of 4BN1 will be dripped slowly into each nostril. The volunteer will be able to breathe through their mouth during the procedure. Volunteers will be asked to remain lying down for 15 minutes. This will be performed only once. Volunteers will then be admitted to the NIHR Southampton CRF for 5 days. Challenge volunteers will then be asked to return for follow up visits on Day 7, 10, 14, 28, 56 90 & 92. A single dose of an antibiotic (Ciprofloxacin) will be administered on day 90 regardless of colonisation with modified N. lactamica 4BN1. |
Genetically modified N. lactamica
|
No Intervention: Contact Volunteer
Contact volunteers are those volunteers whose partner/spouse is a Challenge volunteer.
Investigators will monitor Contact volunteers to collect information about transmission.
A single dose of an antibiotic (Ciprofloxacin) will be administered on Day 90 regardless of colonisation with modified N. lactamica.
|
|
Experimental: Challenge Volunteer - 4YB2
Volunteers will be given a choice of which version of the GM N. lactamica they would like to be given (4BN1 or 4YB2). On Day 0 Challenge volunteers will be asked to lie on their back, 0.5 mL of fluid containing a carefully measured amount of 4YB2 will be dripped slowly into each nostril. The volunteer will be able to breathe through their mouth during the procedure. Volunteers will be asked to remain lying down for 15 minutes. This will be performed only once. Volunteers will then be admitted to the NIHR Southampton CRF for 5 days. Challenge volunteers will then be asked to return for follow up visits on Day 7, 10, 14, 28, 56 90 & 92. A single dose of an antibiotic (Ciprofloxacin) will be administered on day 90 regardless of colonisation with modified N. lactamica 4YB2 |
Genetically modified N. lactamica
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Establish the effect of the nasal inoculation of healthy volunteers with a genetically modified strain of Neisseria lactamica expressing NadA by measuring respiratory rate.
Time Frame: Up to volunteer visit Day 4
|
Volunteers are admitted to the NIHR Southampton CRF and closely observed by trained medical members for any potential effects.
Respiratory rate (breaths per minute) will be measured and compared with baseline measurements.
A consistent increase in respiratory rate could indicate ill health and potential disease.
A study doctor will review each participant twice a day for the duration of the inpatient stay.
|
Up to volunteer visit Day 4
|
Establish the effect of the nasal inoculation of healthy volunteers with a genetically modified strain of Neisseria lactamica expressing NadA by measuring body temperature.
Time Frame: Up to volunteer visit Day 4
|
Volunteers are admitted to the NIHR Southampton CRF and closely observed by trained medical members for any potential effects.
Body temperature (degrees Celsius) will be measured and compared with baseline measurements.
A constant increase in body temperature could indicate ill health and potential disease.
A study doctor will review each participant twice a day for the duration of the inpatient stay.
|
Up to volunteer visit Day 4
|
Establish the effect of the nasal inoculation of healthy volunteers with a genetically modified strain of Neisseria lactamica expressing NadA by measuring heart rate.
Time Frame: Up to volunteer visit Day 4
|
Volunteers are admitted to the NIHR Southampton CRF and closely observed by trained medical members for any potential effects.
Heart rate (beats per minute) will be measured and compared with baseline measurements.
An increase in heart rate could indicate ill health and potential disease.
A study doctor will review each participant twice a day for the duration of the inpatient stay.
|
Up to volunteer visit Day 4
|
Establish the effect of the nasal inoculation of healthy volunteers with a genetically modified strain of Neisseria lactamica expressing NadA by measuring blood pressure.
Time Frame: Up to volunteer visit Day 4
|
Volunteers are admitted to the NIHR Southampton CRF and closely observed by trained medical members for any potential effects.
Blood pressure (mmHg) will be measured and compared with baseline measurements.
An increase in blood pressure could indicate ill health and potential disease.
A study doctor will review each participant twice a day for the duration of the inpatient stay.
|
Up to volunteer visit Day 4
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To measure the NadA specific immunity in healthy volunteers following nasal inoculation with Neisseria lactamica expressing NadA
Time Frame: Up to volunteer visit Day 92
|
Colonisation by Neisseria lactamica has previously shown to elicit a mucosal antibody response.
Saliva samples will be collected from volunteers and antibody levels (µg/mL) specific to NadA pre and post inoculation will be measured to confirm if there is an increase.
Those volunteers successfully colonised are hypothesised to show an increase in antibody production.
|
Up to volunteer visit Day 92
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Robert C Read, University of Southampton
Publications and helpful links
General Publications
- Laver JR, Hughes SE, Read RC. Neisserial Molecular Adaptations to the Nasopharyngeal Niche. Adv Microb Physiol. 2015;66:323-55. doi: 10.1016/bs.ampbs.2015.05.001. Epub 2015 May 30.
- Deasy AM, Guccione E, Dale AP, Andrews N, Evans CM, Bennett JS, Bratcher HB, Maiden MC, Gorringe AR, Read RC. Nasal Inoculation of the Commensal Neisseria lactamica Inhibits Carriage of Neisseria meningitidis by Young Adults: A Controlled Human Infection Study. Clin Infect Dis. 2015 May 15;60(10):1512-20. doi: 10.1093/cid/civ098. Epub 2015 Mar 25.
- Evans CM, Pratt CB, Matheson M, Vaughan TE, Findlow J, Borrow R, Gorringe AR, Read RC. Nasopharyngeal colonization by Neisseria lactamica and induction of protective immunity against Neisseria meningitidis. Clin Infect Dis. 2011 Jan 1;52(1):70-7. doi: 10.1093/cid/ciq065.
- Gbesemete D, Laver JR, de Graaf H, Ibrahim M, Vaughan A, Faust S, Gorringe A, Read RC. Protocol for a controlled human infection with genetically modified Neisseria lactamica expressing the meningococcal vaccine antigen NadA: a potent new technique for experimental medicine. BMJ Open. 2019 May 1;9(4):e026544. doi: 10.1136/bmjopen-2018-026544.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- NadA-Lac4
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Meningitis, Bacterial
-
Rambam Health Care CampusWithdrawnGram Negative Meningitis | Post Traumatic Bacterial MeningitisIsrael
-
Prof. Elizabeth MillerNovartis VaccinesCompletedMeningococcal Meningitis, Serogroup A | Meningococcal Meningitis, Serogroup B | Meningococcal Meningitis, Serogroup C | Meningococcal Meningitis, Serogroup Y | Meningococcal Meningitis, Serogroup WUnited Kingdom
-
Charite University, Berlin, GermanyRecruitingBacterial Meningitis | Implant Infection | Fungal MeningitisGermany
-
Beijing Children's HospitalFirst Affiliated Hospital of Xinjiang Medical University; Xingtai People's... and other collaboratorsUnknownNext Generation Sequencing | Pediatric Bacterial MeningitisChina
-
Kamuzu University of Health SciencesCompletedInfant Bacterial MeningitisMalawi
-
Chiron CorporationUnknownMeningococcal Disease; Meningococcal MeningitisUnited Kingdom
-
Kamuzu University of Health SciencesCompleted
-
Sanofi Pasteur, a Sanofi CompanyCompletedMeningitis | Meningococcal Infections | Meningococcal MeningitisRussian Federation
-
Sanofi Pasteur, a Sanofi CompanyCompletedMeningitis | Meningococcal Infections | Meningococcal MeningitisUnited States, Puerto Rico
Clinical Trials on N. lactamica
-
University of SouthamptonUniversity of Edinburgh; University Hospital Southampton NHS Foundation TrustCompletedMicrobial ColonizationUnited Kingdom
-
University of SouthamptonUniversity Hospital Southampton NHS Foundation TrustCompletedMeningitis, BacterialUnited Kingdom
-
Sheffield Teaching Hospitals NHS Foundation TrustCompleted
-
Center for Vaccine Development - MaliUniversity College, London; University of Oxford; Public Health England; University... and other collaboratorsRecruitingMeningitis, MeningococcalMali
-
University of SouthamptonUniversity Hospital Southampton NHS Foundation TrustUnknownMeningitis, BacterialUnited Kingdom
-
University Hospital Southampton NHS Foundation...University of SouthamptonUnknownMeningitis, MeningococcalUnited Kingdom
-
Hospices Civils de LyonCompletedCardiometabolic RiskFrance
-
Radboud University Medical CenterHavenziekenhuisCompleted
-
University Hospital, Basel, SwitzerlandNot yet recruiting
-
Ain Shams UniversityCompletedRespiratory Distress SyndromeEgypt