Streptococcus pneumoniae nasopharyngeal experimental carriage study of attenuated strains to assess whether reducing the ability of this bacteria to cause illness can assist in improving immunity

INTERVENTION: A single blind randomised controlled trial design allows an unbiased methods for comparison of four groups comparing S. pneumoniae i) attenuated strain I, ii) attenuated strain, II iii) wild type bacteria (control), and v) saline (control). The laboratory team are blinded for Stage II at the time of assessing carriage as the detection of the wild type S. pneumoniae in nasal washes is the primary outcome. As such there is no need to blind the participant or clinical team. Justification of control: this provides a comparison of symptoms for example that may be influenced by seasonal changes over the period of the study. Clinical visits will take place in the dedicated research facility: Accelerator Research Clinic in the Liverpool School of Tropical Medicine. This is an adaptive trial design with an interim analysis. In the event that one strain does not show either carriage or immune response then the TSC will determine whether to replace this rather than continue with a strain that is unlikely to be effective as a potential vaccine. The strain is attenuated with the intention of making it safer by removing genes associated with illness. Pre‐clinical data in mice suggests this strain will stimulate an immune response and this research will evaluate whether this translates to humans. Procedures to reduce bias: the trial will be single blind achieved by blinding the laboratory staff who assess the primary outcome in stage II. Participants are randomised to one of four arms including two control arms. Recruitment: The target is to complete 108 participants, up to 150 may be screened to achieve this as we anticipate 1: 10 will already have pneumococcus in their nose 'natural carriers' (it is commonly found in the nose of healthy adults and more common in children). Also, a higher drop out rate than in previous studies is anticipated due to the 6‐month interval between stage I and II. Group size calculations using two‐tailed T tests and 80% power CONDITION: Specialty: Respiratory Disorders, Primary sub‐specialty: Pulmonary fibrosis / interstitial lung disease; Health Category: Infection, Inflammatory and immune system; Disease/Condition: Other bacterial diseases, Certain disorders involving the immune mechanism ; Respiratory ; Pneumonia due to Streptococcus pneumoniae PRIMARY OUTCOME: The efficacy of nasal administration of attenuated Strepotococcus pneumoniae strains to induce mucosal immunity thereby prevent future colonisation with wild type Streptococcus pneumoniae using the Experimental Human Pneumococcal Challenge Model; Timepoint(s): Participants are challenged with the wild type 6B at six months post inoculation. SECONDARY OUTCOME: 1. Antibodies and cellular adaptive immune responses local and systemic to S. pneumoniae pre and post colonisation; 2. The presence, density and duration of pneumococcus measured using classical microbiological and qPCR techniques on nasal wash collected following inoculation on day, 2, 6, 16, 22, 27 or 36 and after challenge on day 2, 6 or 14; 3. Sequencing and in vitro testing of bacteria recovered to ensure genome and phenotypic stability ; 4. Presence of S. pneumoniae in nasal wash following cultures when carriage positive at each study visit 2, 6, 16, 22, 27 or 36 and after challenge on day 2, 6 or 14; 5. Presence of S. pneumoniae on hand swabs or culture plate following standard microbiology cultures when carriage positive at selected visits subject to carriage status INCLUSION CRITERIA: 1. Healthy volunteers 2. Age 18 – 50 years 3. Capacity to give informed consent 4. Ability to speak fluent English