"Respiratory infections are the most frequent cause of childhood morbidity and mortality worldwide. For many respiratory pathogens no vaccine is available, for others classical immunisations remain insufficiently effective. This project concerns the development of novel, nasal vaccines against two major respiratory pathogens, B. pertussis and Respiratory Syncytial Virus (RSV). No vaccine is yet available against RSV, and, although efficacious vaccines against pertussis are widely used, roughly 40 million cases and 200,000-400,000 pertussis-linked deaths are recorded annually, mostly in infants (<6 months) not yet sufficiently protected by the current vaccines. This proposal will yield proof of principle and provide prototypes of multivalent nasal vaccines based on attenuated B. pertussis. The concept is based on the fact that early in life, infants can mount strong anti-B. pertussis T cell responses upon natural infection in contrast to vaccination. Live attenuated B. pertussis BPZE1 has already been constructed and shown to be much more protective in infant mice after a single nasal dose than two doses of current pertussis vaccines. Immunity induced by BPZE1 will be studied in detail, and its genetic and biological stability and safety in various mouse models will be characterised. GMP lots of BPZE1 will be produced and tested for safety in a phase 1 trial in adults as a prerequisite to future trials in the target population. In parallel, human immune responses, in particular memory responses to infection and vaccination will be analysed, which will serve as a basis for immunogenic evaluations of BPZE1. Finally, we will develop BPZE1 as a vector for the presentation of heterologous RSV antigens to the respiratory mucosa. This will be tested in mouse models. A successful outcome of this project should lead to further clinical trials with BPZE1 and to the development of multivalent nasal vaccines able to protect against several respiratory pathogens simultaneously."