Pilot 22 – Investigating Mechanisms of Vaccine Response Deficiency in Cystic Fibrosis

P.I.: Jim Kublin, MD, MPH
Principal Staff Scientist, Vaccine and Infectious Disease Division, Fred Hutch

In this project, we will determine whether the cystic fibrosis transmembrane conductance regulator (CFTR) protein plays a role in vaccine response. This is a question of high significance for the treatment and management of infection in cystic fibrosis (CF) patients, which our work and others have shown display sub-optimal responses to common childhood vaccines. The community of microorganisms residing in the gastrointestinal tract of CF infants (termed the microbiome) is dramatically altered compared to infants not experiencing CF. The microbiome is an important determinant of our immune development, however whether the CF-associated microbiome contributes to immune-dysregulation is unknown. In this project, we will determine whether the microbiome plays a role in mediating the immune alterations observed in a CF mouse model by studying these mice in completely bacteria-free conditions. In addition, we will isolate specific species of bacteria that we have found to be associated with high or low vaccine response in CF infants and determine how they modulate a vaccine response by introducing them into a mouse model. Identifying how specific gastrointestinal bacteria contribute to vaccine response deficiency and wider immune dysfunction in CF has the potential to offer novel therapeutic options to benefit patients. Our proposal integrates clinical and preclinical approaches to interrogate the mechanisms underlying vaccine response deficiency and the role of the microbiome in CF by utilizing and developing novel innovative approaches. These are objectives of high relevance and significance to patients with CF.