Covalent locking of the influenza virus hemagglutinin prefusion structure: an innovative concept to create broadly protective influenza vaccines

Seasonal influenza causes each year a huge medical and economic burden. Though used since years to protect people at risk, the current influenza vaccines have important shortcomings such as modest efficacy, strain specificity and the need for yearly injection. There is an unmet need for broad (‘universal’) influenza vaccines that would solve these problems. One priority antigen is the prefusion stem domain of the viral hemagglutinin (HA). This structure carries conserved epitopes that induce broadly protective antibodies against all influenza A virus subtypes. However, due to immunodominance of the HA head domain and high instability of prefusion HA, the current vaccines induce very low titers of broad anti-stem antibodies. A logical approach is therefore to create HA vaccines with stabilized stem domains. In this project, we explore an innovative ‘Flu vaccine with Locked Stem’ (FLoS) concept that is based on covalent locking of prefusion HA. This technology combines the use of small molecule ‘stem stabilizers’ to lock a defined stem region, with key mutations to stabilize additional parts of prefusion HA. In the first part, we will develop the methodology to produce FLoS vaccines with locked and mutant HA proteins. Next, their potential to induce broadly protective heterosubtypic immunity will be assessed in influenza virus mouse models. Hence, we will provide proof-of-concept for a conceptually unique and easily accessible technology to create superior influenza vaccines.