Duo Xu

The Xu Lab is broadly interested in understanding the protein-protein interactions at the host-pathogen interface. We take a protein engineering approach, in combination with biochemistry, structural biology and immunology, to identify new classes of antibodies and design principles to manipulate immunogenicity. The long-term goal is to identify new targets and design principles for designing vaccines and therapeutics, especially against important infectious diseases with unmet human needs.

Research Highlights

Immunofocusing via antigen reorientation – towards a universal flu vaccine

A major challenge in vaccine development is the ability to focus the immune response toward evolutionarily conserved antigenic regions to confer broad protection. In the case of influenza, current seasonal vaccines primarily elicit immunity to the variable head region of the viral glycoprotein, hemagglutinin (HA), even though this region (HA-head) exhibits high plasticity and evolves continuously. By contrast, the stem region of HA (HA-stem) contains conserved epitopes and represents a prime target for universal flu-vaccine design. Here we introduce an approach to controlling antigen orientation by modulating antigen-binding to alum adjuvants. We use this approach to reorient HA in an “upside down” configuration, which we envision increases HA-stem exposure, therefore also improving its immunogenicity compared to HA-head. In immunization studies, the reoriented HA on alum induced a stem-directed antibody response that cross-reacted with both group 1 and 2 influenza A subtypes. Electron microscopy polyclonal epitope mapping (EMPEM) provided direct visual evidence that reoriented HA elicited stem-directed cross-reactive antibodies. Our results demonstrate the possibility and benefits of antigen reorientation, which represents a generalizable immunofocusing approach readily applicable for designing epitope-focused vaccine candidates.

Immunofocusing via hyperglycosylation – towards a universal Ebola vaccine

Ebola virus causes hemorrhagic fever in humans and poses a significant threat to global public health. Current viral vaccines require cold-chain storage and are distributed in limited ring vaccination settings. In addition, they are only indicated for protection against Zaire ebolavirus (EBOV), one of three Ebola virus species that have caused previous outbreaks. Ebola virus glycoprotein (GP) mediates viral infection and serves as the primary target of neutralizing antibodies. Here we harness hyperglycosylation as an immunofocusing approach to design universal Ebola virus vaccine candidates based on GP displayed on ferritin nanoparticles (Fer). Compared with wild-type GP-Fer, immunization with hyperglycosylated GP-Fer elicited potently neutralizing antisera against EBOV, and more importantly, consistent cross-neutralizing activity against the other two ebolavirus species (Bundibugyo and Sudan virus). Our work shows that immunofocusing antibody responses toward conserved and neutralizing epitopes of GP represents a promising strategy to establish cross-protective immunity against existing and emerging ebolavirus species.