PROTEA study: a protocol for a randomised controlled trial evaluating the efficacy, immune effects and cost-effectiveness of oral bacterial lysate therapy to protect moderate-late preterm infants from respiratory tract infections and wheezing.

Infants, children and adults born moderate-late preterm (after 30-36 weeks of pregnancy) are at increased risk of respiratory infections, wheezing and lower lung function leading to increased medication use and hospitalisation. Risk factors frequently present in this population are, at least in part, associated with (lack of) exposure to microbes and subsequent perturbations in microbiome and immune system development. This manuscript presents the protocol of the double-blinded randomised placebo-controlled PROTEA trial, which will demonstrate whether treatment with immunomodulatory bacterial lysates (OM-85) can reduce lower respiratory tract infections and wheeze in the first year of life. The follow-up PROTEA-2 trial will identify possible carry-over effects of OM-85 treatment and investigate the clinical effect of continued treatment in the second year of life. Infants included are otherwise healthy infants born after 30-36 weeks of gestation, excluding those small for gestational age (<3rd percentile). They are recruited shortly after birth in 22 medical centres in the Netherlands. Participants will take OM-85 or placebo starting from 6-10 weeks of life till age 1 year (PROTEA study) or 2 years (PROTEA-2 study) and are closely monitored regarding respiratory health through e-applications. Biological samples, lung function measurements and detailed information on covariates will be collected at ages 2, 6, 12 and 24 months. Biological samples will aid in estimating the impact of bacterial lysate administration on immune cell composition, activation and maturation, vaccination responses, and microbiome diversity and maturation. Participant recruitment started in March 2022.