Controlled Human Infection, Streptococcus Pneumonia
Conditions
Keywords
streptococcus pneumoniae, pneumococcus, controlled human infection, serotype 3, SPN3, Adult, Healthy volunteers
Brief summary
The 'Experimental Human Pneumococcal challenge' (EHPC) model is a way of putting drops of bacteria into the nose. Investigators have studied this model of putting bacteria in the nose safely in over 1500 volunteers over the past decade with no serious side effects and now want to test the model using a different strain of the bacteria that is commonly found in the community, SPN3. The aim of this study is to determine how much pneumococcus is needed to achieve nasal colonisation and how long the bacteria live in the nose for before natural immune responses eradicate them. By doing this, Investigators will then be able to test how well future vaccines prevent colonisation with pneumococcus. Investigators want to learn more about how the immune system responds to nasal colonisation with pneumococcus, again to help with development of new vaccines.
Detailed description
In this study, investigators propose to determine the optimal dose and isolate of SPN3 to establish colonisation in the human nasopharynx, as well as improving knowledge of immune responses to SPN3 colonisation. The results from this study will be used to inform development of improved SPN3 vaccines and to inform design of future pneumococcal vaccine RCTs. To increase the relevance of the EHPC model and its use for assessing future vaccines such as V114, investigators are proposing here to set up an EHPC model with carefully selected non-proprietary SPN3 strains. Investigators will conduct a safety and dose-ranging study to determine the optimum SPN3 strain and dose for colonisation acquisition and confirm the dose in a subsequent larger cohort in a reproducibility study and will study mucosal and systemic immune responses to this serotype and their association with protection against colonisation acquisition and clearance.
Interventions
OTHERSerotype 3 Experimental Human Pneumococcal Challenge - Liverpool Isolate (LIV014-S3)
Dose-ranging and reproducibility study of SPN3 inoculation AND targeted booster inoculation at day-14, where prime inoculation fails to lead to experimental colonisation
OTHERSerotype 3 Experimental Human Pneumococcal Challenge - Malawi Isolate (MLW-10V)
Dose-ranging study of SPN3 inoculation AND targeted booster inoculation at day-14, where prime inoculation fails to lead to experimental colonisation
Sponsors
Liverpool School of Tropical Medicine
Merck Sharp & Dohme LLC
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
Liverpool University Hospitals NHS Foundation Trust
University of Oxford
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
• Healthy young adults aged 18-50 years (inclusive). This age range minimises the risk of invasive pneumococcal infection and allows comparison with previously published experimental work done by our group. * Fluent spoken English - to ensure a comprehensive understanding of the research project and their proposed involvement, enabling valid consent to be given. * Access to their own mobile telephone - to ensure safety and timely communication. * Capacity to give informed consent.
Exclusion criteria
* o Currently involved in another study unless observational or non-interventional, excluding the EHPC bronchoscopy study (at the discretion of the study team). This is to ensure no harm comes to the participants through over-sampling. * Participant in any previous EHPC trial in past year * Participant in previous EHPC trial inoculated with SPN3 in the last 3 years * Participant in EHPC Pneumo 2 trial * Vaccination: Previous pneumococcal vaccination PPV23 or PCV13 (routine in babies born in the UK since 2005) or PCV10. This can be self-reported or confirmed from GP questionnaire (GPQ) if deemed necessary at clinician discretion. * Allergy: to penicillin/amoxicillin * Health history (self-reported or confirmed by GPQ or medical summary if felt to be necessary at clinician discretion): * Chronic ill health including immunosuppressive history, diabetes, asthma (on regular medication), recurrent otitis media or other respiratory disease. * Medication that may affect the immune system e.g., steroids, inflammation altering or disease-modifying anti-rheumatoid drugs. * Long term use of antibiotics for chronic infection. * Major pneumococcal illness requiring hospitalisation in the last 10 years. * Other conditions considered by the clinical team as a concern for participant safety or integrity of the study * Significant mental health problems (uncontrolled condition or requiring previous admission to a psychiatric unit) that would impair ability to participate • Direct caring role or close contact with individuals at higher risk of infection during the inoculation period if personal protective equipment (PPE) not worn: * Children under 5 years age * Adults with chronic ill health or immunosuppression * Hospital patients • Smoker: * Current or ex-smoker (daily cigarettes, daily e-cigarettes/vaping and daily smoking of recreational drugs) in the last 6 months. Participants who smoke \<5 cigarettes per week may be included. * Previous significant smoking history (\>20 cigarettes per day for 20 years or equivalent \[\>20 pack years\]). • Biologically female participants of child-bearing potential (WOCBP) who are: * Currently pregnant/lactating * Intending on becoming pregnant during the study * Not deemed to have effective birth control • History of or current drug or alcohol abuse: * Men should not drink \>3 units/day regularly * Women should not drink \>2 units/day regularly * Overseas travel planned in follow up period of study visits * Natural SPN 3 colonisation in baseline nasal wash - if a participant is colonised with non-SPN3 pneumococcus, they can be included as part of exploratory analyses, but would not be included in the primary analysis * STOP criteria - participants who meet STOP criteria at time of screening (Table 3) 6.3 Temporary
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Determine the Optimal SPN3 Dose and Isolate to Establish Colonisation of the Nasopharynx in Healthy Adults | From inoculation (day 0) to the final visit for each participant (28 days post-inoculation) | The proportion of participants with experimental SPN3 colonisation of the nasopharynx, determined by SPN3 presence in classical microbiological culture in at least one nasal wash (NW) sample, at any time point following one or two inoculations (combined and individually). This will be assessed for each isolate and dose separately. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Determine the Duration of Experimental SPN3 Colonisation of the Nasopharynx. | From inoculation (day 0) to the final visit for each participant (28 days post-inoculation) | The duration of experimental SPN3 colonisation of nasopharynx determined by the last NW sample following one or two inoculations in which SPN3 is detected by classical microbiological culture, assessed for each isolate and dose separately. Note - number of participants analyzed in this outcome measure is different (and lower) than overall number of participants in participant flow section, because duration of colonisation can only apply to participants who developed experimental colonisation from at least one timepoint post-inoculation. |
| To Determine the Density of Experimental SPN3 Colonisation of the Nasopharynx. | From inoculation (day 0) to the final visit for each participant (28 days post-inoculation) | The bacterial density of experimental SPN3 colonisation of the nasopharynx in NW, at each and any time point following one or two inoculations (combined and individually), determined by classical microbiological culture, assessed for each isolate and dose separately. The number of participants analysed includes only the participants who developed SPN3 colonisation in each arm/group, rather than the total number of participants inoculated. |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORAndrea Collins, MBChB, PhD
Senior Clinical Lecturer
Participant flow
Pre-assignment details
4 participants excluded from intervention due to natural carriage of pneumococcus at screening. 1 participant discontinued after intervention due to antibiotics given for separate illness, before primary outcome data could be collected. Per protocol enrolment n=91; mITT analysis n=86.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 22 Years |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 65 Participants |
| Sex: Female, Male Female | 57 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 10 | 0 / 10 | 0 / 7 | 0 / 10 | 0 / 40 |
| other Total, other adverse events | 1 / 9 | 9 / 10 | 5 / 10 | 5 / 7 | 5 / 10 | 28 / 40 |
| serious Total, serious adverse events | 0 / 9 | 0 / 10 | 0 / 10 | 0 / 7 | 0 / 10 | 0 / 40 |
Outcome results
None listed