Grant: Project Grant

Haemophilus influenzae is responsible for a substantial proportion of respiratory infections in humans, including ear infections, sinus infections and pneumonia, as well as invasive infections such as meningitis. This bacterium lives in the human upper respiratory tract, not in other animals or in the environment. While most bacteria cannot live in human tissues because there is no free iron, which is essential for life, H. influenzae binds and removes iron from the iron transport protein in human blood, transferrin (Tf). Because this is an essential process, and because the Tf binding proteins (Tbps) must be accessible at the bacterial surface, these receptor proteins are ideal targets for vaccination to produce antibodies that protect against infection. In contrast to other H. influenzae vaccine targets, the Tbps are shared by both groups of pathogenic H. influenzae for which vaccines are needed. This means that a single Tbp-based vaccine could protect against both the respiratory tract and invasive infections. Moreover, we have recently demonstrated that Tbp-based vaccines prevent bacterial colonization of respiratory tissues, so that they provide 'sterilizing' immunity that should ultimately allow elimination of the bacteria rather than just protecting against clinical disease caused by infection. The purpose of this project is to apply our established approaches to understand the structure, function and sequence diversity of H. influenzae Tbps and then use protein engineering to create vaccine antigens that are capable of preventing colonization by all known strains of H. influenzae. Then, our novel, integrated vaccine design and evaluation pipeline approach, which includes the use of a 'humanized' mouse model for colonization, will be used to confirm how well the engineered antigens work and refine the composition of engineered antigens to produce a safe, effective and broadly protective vaccine.