(443b) Protein Nanoclusters and Nanocages As Broadly Protecting Influenza Vaccines

Peptide and protein subunit vaccines are desirable because they increase control over the immune response and safety of vaccines by reducing the risk of off-target responses to molecules other than the target antigen. A particularly important use of subunit vaccines is as “universal” vaccines against pathogens with high diversity and mutation rates, such as flu. A universal flu vaccine could protect against both seasonal and pandemic strains, even those that do not yet exist. To achieve this, conserved components of protein antigens must be used, instead of the highly variable antigens presented by the virus that are most immunogenic. However, the immunogenicity of many subunit antigens is low, particularly those that are widely conserved. We have developed protein nanoclusters as a subunit vaccine delivery system made completely of desolvated, crosslinked protein or peptide antigen. Nanoclusters exhibit improved antigen delivery and presentation. By incorporating different combinations and spatial organizations of influenza protein antigens into nanoclusters, we have created vaccines capable of broadly protecting mice against challenge by divergent influenza A viruses. Most recently, we have developed self-assembled protein nanocages (SAPN) that overcome the limitations of nanoclusters in terms of controlling antigen orientation and preserving antigen structure. Their structure is reminiscent of virus like particles, yet the structural building blocks do not induce an immune response, only the antigens do. In this talk, I will present the progression of our nanocluster and SAPN vaccines towards the goal of a universal influenza vaccine and the impact of antigen placement and structure on the breadth of the immune response.