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Defining the Immune Response to Nasopharyngeal Colonisation by the Commensal Neisseria Lactamica (Lac-7)

Primary Purpose

Meningitis, Bacterial

Status

Completed

Phase

Early Phase 1

Locations

United Kingdom

Study Type

Interventional

Intervention

N. lactamica

PBS only

About this trial

This is an interventional prevention trial for Meningitis, Bacterial focused on measuring Healthy volunteer, Human Challenge study

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 study.
For females only, willingness to practice continuous effective contraception (see below) during the study and negative pregnancy test at visit 1 (screening).

Exclusion Criteria:

Active smokers.
N. meningitidis or N. lactamica detected following culture of 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 studies/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 studies/trials investigating meningococcal vaccines or experimental challenge with N. lactamica.
Use of oral or intravenous antibiotics within the period 30 days prior to the challenge.
Any confirmed or suspected immunosuppressive or immunocompromised state, including HIV infection, asplenia, history of recurrent severe infections or use (more than 14 days) of immunosuppressant medication within the past 6 months (topical/inhaled steroids are allowed).
Use of immunoglobulins or blood products within 3 months prior to enrolment.
History of blood donation within the past 12 weeks for male volunteers, or 16 weeks for female volunteers.
Allergy to yeast extract.
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

NIHR Southampton Clinical Research Facility

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

N. Lactamica in PBS

PBS Control

Arm Description

Wild-type Neisseria lactamica (strain Y92-1009, sequence type 3493, clonal complex 613) will be used for this human challenge experiment. This strain is identical to that utilised in our previous challenge experiments (>350 volunteers to date).

PBS only control. Volunteers randomized to this arm will receive a PBS only solution which contains no bacteria.

Outcomes

Primary Outcome Measures

To measure host T-cell and B-cell memory responses and plasma B-cell responses in blood to experimentally-induced nasopharyngeal colonisation with N. lactamica.

Measurements from baseline will compare the host T and B-cell memory response (ug/mL) to samples taken post inoculation.

Secondary Outcome Measures

Determine if N. lactamica-specific CD4+ T-cell memory responses detected in blood cross-react with N. meningitidis.

From PBMC isolation of participants blood, measure if the T-cell response reacts when presented with N. meningitidis (ug/mL)

Full Information

NCT ID

NCT03633474

First Posted

August 13, 2018

Last Updated

October 21, 2019

Sponsor

University of Southampton

Collaborators

University Hospital Southampton NHS Foundation Trust

1. Study Identification

Unique Protocol Identification Number

NCT03633474

Brief Title

Defining the Immune Response to Nasopharyngeal Colonisation by the Commensal Neisseria Lactamica

Acronym

Lac-7

Official Title

Lactamica 7: Defining the Immune Response to Nasopharyngeal Colonisation by the Commensal Neisseria Lactamica

Study Type

Interventional

2. Study Status

Record Verification Date

October 2019

Overall Recruitment Status

Completed

Study Start Date

September 1, 2018 (Actual)

Primary Completion Date

September 1, 2019 (Actual)

Study Completion Date

September 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Southampton

Collaborators

University Hospital Southampton NHS Foundation Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Neisseria meningitidis is a 'bad bacteria' which lives harmlessly in the nose and throat of many young adults (a process called colonisation). However, it can occasionally cause serious disease including meningitis. Vaccines have proven effective in preventing disease associated with a number of strains of this bacterium, however some disease-causing strains are not covered by currently available vaccines. This research is focused on exploring new approaches to preventing colonisation and disease caused by this bacterium. Neisseria lactamica is a 'good bacteria' that colonises the nose and throat of young children. It does not cause disease in healthy people. In a previous study it has been demonstrated that the introduction of Neisseria lactamica into the noses of healthy adult volunteers resulted in a significant decrease in Neisseria meningitidis colonisation. However, it is not yet understood why this effect occurs. One theory is that the immune response the body mounts in response to colonisation with the 'good bacteria' cross-reacts with the 'bad bacteria' and in so doing eradicates the bad bacteria from the nose and throat. This study aims to outline the nature of the immune responses mounted in response to colonisation with the good bacteria, N. lactamica, after introducing it into the noses of healthy adult volunteers. In addition, the study aims to establish how the introduction of the good bacteria changes the other bacterial populations that live in the nose and throat.

Detailed Description

The clinical trial is a controlled, volunteer blinded, N. lactamica human challenge study to enable N. lactamica-specific cellular immune responses to be outlined in detail. In addition, The aim is to determine whether responses directed towards N. lactamica are cross-reactive with N. meningitidis. Following enrolment onto the study, non-meningococcal carriers (as determined by microbiological culture of nasopharyngeal wash and retropharyngeal swab) will be challenged intra-nasally with either 10-5 cfu of N. lactamica wild-type strain Y92-1009 (30,31) suspended in sterile phosphate buffered saline (PBS), as used in previous studies, or PBS alone (control group). Following inoculation on Day 0, biological samples (nasal wash, nasal secretion, throat swabs and blood) will be taken from all volunteers on days +7 (+/-3), +14(+/-3) and +28(+/-5) post-challenge. On the day of inoculation (Day 0) the biological samples listed will be taken except for the nasal wash. N. lactamica-specific B-cell and CD4+ memory T-cell responses will be measured in blood using a selection of in vitro assays and the results compared longitudinally in N. lactamica challenged (colonised or non-colonised) vs. control challenged subjects. The experiments will establish the nature of T-cell and B-cell memory responses and plasma B-cell responses induced in response to N. lactamica colonisation and will determine if these responses are cross-reactive with N. meningitidis. Mucosal immune profiling and microbiome analyses will be performed on nasal secretion and nasal bacterial samples, respectively. Any remaining biological samples (following experiments performed to meet the current study objectives) will be transferred to our registered human tissue bank to enable future studies following additional ethics approval by the relevant bodies.

6. Conditions and Keywords

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

Meningitis, Bacterial

Keywords

Healthy volunteer, Human Challenge study

7. Study Design

Primary Purpose

Prevention

Study Phase

Early Phase 1

Interventional Study Model

Parallel Assignment

Model Description

Volunteers will be blinded to the inoculum type received (i.e. N. lactamica or PBS control) throughout the study duration. Nasal secretion and throat swabs will be taken to enable mucosal immune profiling and microbiome analyses to be performed. Subjects will be screened for nasopharyngeal N. meningitidis carriage -28 to -7 days (visit 1) and non-Neisseria spp. carriers will be challenged with either 105 cfu N. lactamica suspended in PBS or PBS only control (day 0, visit 2). Volunteers identified as carriers of N. meningitidis at visit 1 will be excluded from the study and will not progress to experimental human challenge. Biological samples (nasal secretion, microbiome swab and blood) will be collected from volunteers who progress to the challenge (visit 2, Day 0) and on days +7 (+/-3), +14 (+/-3) and +28 (+/-5) post-challenge. Nasal wash sampling will not be taken at the challenge visit (Day 0) but will be taken on days +7(+/-3), +14 (+/-3) and +28 (+/-5) post-challenge.

Masking

Participant

Masking Description

Non-Neisseria spp. carriers will randomised in a ratio of 2:1 to receive either 10-5 cfu N. lactamica or PBS control using randomisation software, e.g. Sealed envelope (TM) available online.

Allocation

Randomized

Enrollment

31 (Actual)

8. Arms, Groups, and Interventions

Arm Title

N. Lactamica in PBS

Arm Type

Experimental

Arm Description

Arm Title

PBS Control

Arm Type

Placebo Comparator

Arm Description

PBS only control. Volunteers randomized to this arm will receive a PBS only solution which contains no bacteria.

Intervention Type

Biological

Intervention Name(s)

N. lactamica

Intervention Description

Stocks of N. lactamica (strain Y92-1009, sequence type 3493, clonal complex 613) in Frantz medium containing 30% (v/v) glycerol have been previously prepared using the Good Manufacturing Practices pharmaceutical manufacturing facilities at Public Health England (Porton Down, United Kingdom).

Intervention Type

Other

Intervention Name(s)

PBS only

Intervention Description

Sterile PBS only containing no bacteria

Primary Outcome Measure Information:

Title

To measure host T-cell and B-cell memory responses and plasma B-cell responses in blood to experimentally-induced nasopharyngeal colonisation with N. lactamica.

Description

Measurements from baseline will compare the host T and B-cell memory response (ug/mL) to samples taken post inoculation.

Time Frame

Up to Day 33

Secondary Outcome Measure Information:

Title

Determine if N. lactamica-specific CD4+ T-cell memory responses detected in blood cross-react with N. meningitidis.

Description

From PBMC isolation of participants blood, measure if the T-cell response reacts when presented with N. meningitidis (ug/mL)

Time Frame

Up to Day 33

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 study. For females only, willingness to practice continuous effective contraception (see below) during the study and negative pregnancy test at visit 1 (screening). Exclusion Criteria: Active smokers. N. meningitidis or N. lactamica detected following culture of 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 studies/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 studies/trials investigating meningococcal vaccines or experimental challenge with N. lactamica. Use of oral or intravenous antibiotics within the period 30 days prior to the challenge. Any confirmed or suspected immunosuppressive or immunocompromised state, including HIV infection, asplenia, history of recurrent severe infections or use (more than 14 days) of immunosuppressant medication within the past 6 months (topical/inhaled steroids are allowed). Use of immunoglobulins or blood products within 3 months prior to enrolment. History of blood donation within the past 12 weeks for male volunteers, or 16 weeks for female volunteers. Allergy to yeast extract. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Adam P Dale

Organizational Affiliation

University of Southampton

Official's Role

Principal Investigator

Facility Information:

Facility Name

NIHR Southampton Clinical Research Facility

City

Southampton

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Defining the Immune Response to Nasopharyngeal Colonisation by the Commensal Neisseria Lactamica

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