The primary objective of this study is to reduce respiratory tract infections and wheezing in moderate-late preterms in the first years of life by bacterial lysate administration. Next to determine the correlation of biological markers with respiratory symptoms, immune protection and treatment effect.

This is a randomised placebo-controlled trial including 500 otherwise healthy moderate-late preterm infants. Participants will receive bacterial lysate (OM-85/Broncho-Vaxom, 3,5mg) or placebo powder for ten days each month, from 6-10 weeks after birth until 12 months after birth. At 12 months, parents of participants are asked to join in Protea-2. If they do, participants in the treatment arm of year 1 are randomised again over placebo and OM-85 and treated until the age of 24 months. Clinical data will be continuously collected by e-Health and 3 (possibly digital) study visits; with optional biological sampling and lung function at baseline, 6 and 12 months. And in case of participation in Protea-2 also at 24 months.

Main study parameters are doctor diagnosed lower RTI and wheezing episodes in the first year of life. Biological sampling will allow investigation of immune maturation, as well as microbiome development in the respiratory tract and gut. Also, biomarkers for risk-group selection and/or treatment success will be examined.

Inclusion Criteria:

• Gestational age at delivery between 30+0 and 35+6 weeks
• Postnatal age at least 6 weeks at randomization & postmenstrual age at least 37 weeks
• Written informed consent by both parents or formal caregivers

Exclusion Criteria:

• Underlying other severe respiratory disease such as broncho-pulmonary dysplasia (unexpected in this group); hemodynamic significant cardiac disease; immunodefi-ciency; severe failure to thrive; birth asphyxia with predicted poor neurological out-come; syndrome or serious congenital disorder.
• Lower RTI before randomization
• Dysmaturity and/or weight < 2.5 kg at age of randomization.
• Maternal TNF-alpha inhibitors or other immunosuppression during pregnancy and/or breastfeeding
• Parents unable to speak and read Dutch/English language
• Known allergic hypersensitivity to the active ingredients/substance or to any of the excipients.

Researchdata will be shared in data repositories according to the FAIR principle. Clinical data about respiratory health will be shared in the DANS repository. Inlcuding metadata which will ensure reusability. Sequencing data will be shared online in the ENA repository which will provide an unique global identifier. All used bioinformatics pipelines for data analysis will be made accessible on a GitHub account. Immunological data will be shared in NCBI Gene Expression omnibus and ImmPort. Used analysis pipelines for the transcriptomics data will also be tracked and can be shared using a Github account.

All data shared will be pneudonymized.

Data will come available after publication of the data in articles by initating researchers.

Data will be available under restricted access. A request for data sharing will include at least the reason for request (for what will the receiver use the data?) and agreements about authorship.

Study subjects, all study investigators including the principal investigator and treating physicians will be blinded for the allocation during the complete study period. A sealed envelope with the treatment allocation per code is present at the pharmacy to be used only when 1) crucial for a medical emergency, 2) the participant will continue with Protea-2 and the database concerning year 1 is locked for this specific participant, and 3) at trial completion after the last patient last visit.