Challenge of the Nasopharynx With Neisseria Lactamica Expressing the Meningococcal Protein Neisseria Adhesin A (NadA)

NCT03630250 | Completed Early Phase 1 DMC

• 1 other identifier: NadA-Lac4
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Meningitis, Bacterial; Neisseria Infection

Keywords

meningitis; GMO

Outcome Measures

Primary Outcomes (4)

• Establish the effect of the nasal inoculation of healthy volunteers with a genetically modified strain of Neisseria lactamica expressing NadA by measuring respiratory rate.

  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.

  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.

  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.

  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 Outcomes (1)

• To measure the NadA specific immunity in healthy volunteers following nasal inoculation with Neisseria lactamica expressing NadA

  Up to volunteer visit Day 92

Study Arms (3)

Challenge Volunteer - 4BN1

EXPERIMENTAL

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.

Biological: N. lactamica

Contact Volunteer

NO INTERVENTION

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.

Challenge Volunteer - 4YB2

EXPERIMENTAL

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

Biological: N. lactamica

Interventions

N. lactamica BIOLOGICAL

Genetically modified N. lactamica

Challenge Volunteer - 4BN1; Challenge Volunteer - 4YB2

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Southampton: lead
• University Hospital Southampton NHS Foundation Trust: collaborator

Study Sites (1)

NIHR Southampton Clinical Research Facility

Southampton, United Kingdom

Location

Related Publications (4)

• 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.

  PMID: 26210107 BACKGROUND

• 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.

  PMID: 25814628 BACKGROUND

• 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.

  PMID: 21148522 BACKGROUND

• 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.

  PMID: 31048443 DERIVED

MeSH Terms

Conditions

Meningitis, Bacterial; Meningitis

Condition Hierarchy (Ancestors)

Central Nervous System Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Neuroinflammatory Diseases

Study Officials

• Robert C Read

  University of Southampton

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Cohort

Study Record Dates

• First Submitted: August 3, 2018
• First Posted: August 14, 2018
• Study Start: October 18, 2018
• Primary Completion: September 1, 2019
• Study Completion: September 1, 2019
• Last Updated: February 27, 2020

Record last verified: 2020-02

Locations

GB (1)