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A Study Assessing Colonisation & Immunogenicity After Nasal Inoculation With N. Lactamica and Eradication on Day 4 or 14 (Lac-3)

Primary Purpose

Meningitis, Meningococcal

Status

Unknown status

Phase

Not Applicable

Locations

United Kingdom

Study Type

Interventional

Intervention

Neisseria lactamica

About this trial

This is an interventional prevention trial for Meningitis, Meningococcal focused on measuring Neisseria lactamica, healthy volunteers, nasal inoculation, colonisation

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

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
Written informed consent to participate in the trial
Willingness to take an antibiotic regimen after inoculation according to the study protocol
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

Exclusion Criteria:

Current active smokers
N. lactamica or N. meningitidis detected on throat swab or nasal wash taken before the challenge
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
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; 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
Any clinically significant abnormal finding on clinical examination
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
Pregnancy or lactation

Sites / Locations

Southampton NIHR Clinical Research FacilityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Group 1

Group 2

Arm Description

Nasal drops containing Neisseria lactamica are administered at Day 0 by the study doctor. Eradication therapy with the antibiotic Ciprofloxacin given on Day 4, unless required sooner. Follow up visits occur on Days 5, 14 and 32.

Nasal drops containing Neisseria lactamica are administered at Day 0 by the study doctor. Follow up visits on Day 4 and 7 to check for N. lactamica carriage. Eradication therapy with the antibiotic Ciprofloxacin given on Day 14, unless required sooner. Follow up visits occur on Days 15, 24 and 42.

Outcomes

Primary Outcome Measures

Measure the antibodies, by serological antibody titration, of short term colonisation and longer colonisation

Measure any rise in serological specific antibodies from samples taken at the start of the study (Day 0) and samples taken at antibiotic eradication (Group 1 = Day 4 or Group 2 = Day 14) and last visit samples (Group 1 = Day 32 or Group 2 = Day 42)

Secondary Outcome Measures

Measure the colonisation of Neisseria lactamica

Measure if Neisseria lactamica is able to colonise at or before Day 4 (for group 1) or Day 14 (for group 2) from cultured throat swabs.

Measure the eradication of Neisseria lactamica

Record how successful eradication is up to Day 42, using throat swab samples.

Full Information

NCT ID

NCT03549325

First Posted

October 23, 2017

Last Updated

August 8, 2019

Sponsor

University Hospital Southampton NHS Foundation Trust

Collaborators

University of Southampton

1. Study Identification

Unique Protocol Identification Number

NCT03549325

Brief Title

A Study Assessing Colonisation & Immunogenicity After Nasal Inoculation With N. Lactamica and Eradication on Day 4 or 14

Acronym

Lac-3

Official Title

A Human Controlled Infection Study to Assess Colonisation and Immunogenicity Following Nasal Inoculation With Neisseria Lactamica With Eradication on Day 4 or 14

Study Type

Interventional

2. Study Status

Record Verification Date

August 2019

Overall Recruitment Status

Unknown status

Study Start Date

February 15, 2017 (Actual)

Primary Completion Date

February 2020 (Anticipated)

Study Completion Date

February 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital Southampton NHS Foundation Trust

Collaborators

University of Southampton

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

This study is part of a project that aims to develop a vaccine with N. lactamica that prevents meningitis. The investigators have previously given nose drops containing N. lactamica to over 340 volunteers, and shown that many of the volunteers (35-60%) become colonised without causing any illness or disease. In the future the investigators would like to modify N. lactamica so that it can carry vaccine molecules into the nose of children. To do this the investigators need to know more about the immune response generated against N. lactamica. Previously the investigators have shown that inoculation resulted in an immune (antibody) response in volunteers who were colonised. Taking an antibiotic called ciprofloxacin will treat N.lactamica in the nose and throat of the volunteers. The investigators need to know if the immune response to N. lactamica is the same when colonised volunteers are treated with the antibiotic after 4 days, is the same if the investigators treat volunteers after 14 days of carriage. This information will inform future studies.

Detailed Description

N. lactamica (Nlac) has been shown to be safe to use in human challenge experiments. Even at a very low dose of 10,000 colony forming units (cfu) long lasting colonisation with Nlac is easily induced in 35-65% of volunteers. The investigators have previously showed that increasing the inoculum to 100,000 cfu increased the subsequent carriage of Nlac to 50%. In 80-90% of those volunteers successfully colonised, this is detectable by 1-2 weeks. Data regarding earlier detection of colonisation is currently lacking. Colonisation has a clear effect on the volunteers nasal mucosal microbiome, in that meningococcal acquisition is effectively inhibited in volunteers who carry the organism. Colonisation is immunogenic, with an increase in specific serum IgG by 2 weeks and specific salivary IgA by 4 weeks. No antibiotic eradication therapy has previously been given following experimental inoculation but Ciprofloxacin has been shown to be effective in the eradication of N. meningitidis. To design future planned studies using Nlac nasal inoculation and colonisation in order to prevent invasive N. meningitidis disease, it is necessary to further evaluate the colonisation kinetics and efficacy of the eradication following antibiotic treatment. In previous challenges the investigators inoculated volunteers with Nlac and followed those volunteers for prolonged periods of time (over 6 months). This study will compare the effect of short (4 days) versus longer (14 days) periods of nasal carriage of Nlac in volunteers on immunogenicity, and confirm the efficacy of antibiotic eradication therapy with ciprofloxacin. Healthy adult volunteers will receive a nasal inoculation of Nlac with an antibiotic given on day 4 or 14. This information will be used to inform the design of future research into the colonisation and immunogenicity of related organisms. Before designing future protocols the study investigators need to know whether a short containment of the volunteers will be sufficient for immunogenicity, and how quickly the volunteers can be discharged after antibiotic treatment. A wild-type strain of Nlac (Y92-100) will be used for this study, selected because the investigators have previously used it safely in experimental challenge of over 340 human volunteers. The same strain will be the parent strain for any future GMO work.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Meningitis, Meningococcal

Keywords

Neisseria lactamica, healthy volunteers, nasal inoculation, colonisation

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Model Description

Group 1: Nasal inoculation with Neisseria lactamica with eradication on day 4 - up to 22 volunteers or until 11 colonised on day 4 Group 2: Nasal inoculation with Neisseria lactamica with eradication on day 14 - up to 22 volunteers or until 11 colonised on day 4

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

44 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Group 1

Arm Type

Experimental

Arm Description

Arm Title

Group 2

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

Neisseria lactamica

Intervention Description

Colonisation by bacteria is an immunising event; we proved this in humans by inoculating university students intranasally with the harmless commensal N. lactamica and we observed both specific systemic and mucosal antibody responses by 4 weeks. Experimental challenge with defined bacteria could tease out the Th17-mediated response mechanisms, which include waning of immunity over time, the induction of an incorrectly polarised T cell response, lack of cross-reactivity between strains or active immune evasion mechanisms employed by bacteria to subvert host immune effector mechanisms.

Primary Outcome Measure Information:

Title

Measure the antibodies, by serological antibody titration, of short term colonisation and longer colonisation

Description

Time Frame

Up to 42 Days

Secondary Outcome Measure Information:

Title

Measure the colonisation of Neisseria lactamica

Description

Measure if Neisseria lactamica is able to colonise at or before Day 4 (for group 1) or Day 14 (for group 2) from cultured throat swabs.

Time Frame

Up to 42 Days

Title

Measure the eradication of Neisseria lactamica

Description

Record how successful eradication is up to Day 42, using throat swab samples.

Time Frame

Up to 42 Days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Written informed consent to participate in the trial Willingness to take an antibiotic regimen after inoculation according to the study protocol 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 Exclusion Criteria: Current active smokers N. lactamica or N. meningitidis detected on throat swab or nasal wash taken before the challenge 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 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; 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 Any clinically significant abnormal finding on clinical examination 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 Pregnancy or lactation

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Sara Hughes

Phone

02381204989

CRF@uhs.nhs.uk

First Name & Middle Initial & Last Name or Official Title & Degree

Matthew Harvey

Phone

02381204989

CRF@uhs.nhs.uk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Robert Read

Organizational Affiliation

University of Southampton

Official's Role

Principal Investigator

Facility Information:

Facility Name

Southampton NIHR Clinical Research Facility

City

Southampton

State/Province

Hampshire

ZIP/Postal Code

SO166YD

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Sara Hughes

Phone

02381204989

CRF@uhs.nhs.uk

First Name & Middle Initial & Last Name & Degree

Saul Faust

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

21148522

Citation

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.

Results Reference

result

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A Study Assessing Colonisation & Immunogenicity After Nasal Inoculation With N. Lactamica and Eradication on Day 4 or 14

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