Engineering of Norovirus-like Particles for Vaccine Applications

Vaccination is an old but increasingly important tool for controlling infectious diseases that spread at an ever-increasing pace in the globalized world. One of the most interesting modern vaccine technologies are virus-like particle vaccines, where the composition of the product can be precisely tailored and rationally modified. Virus-like particles are noninfectious, but physically resemble the related native virus, and can thus be used as safe, stable vaccines. More recently, virus-like particles have been decorated with parts of antigens related to other diseases, so in the resulting vaccine the virus-like particle acts as an immune activator that can direct the immune response against the target. The target does not need to be immunogenic by itself, so vaccination can be used to target select, small parts of antigens or even self- antigens. The norovirus-like particle is well-studied and known to be particularly stable and easy to handle, but its use as a vaccine carrier molecule has not been comprehensively studied. During this thesis, we developed various versions of modified norovirus-like particles that we decorated with antigens of different kinds using split-protein conjugation. The experiments yielded the SpyTag-norovirus-like particle vaccine platform that can be covalently decorated to a high density with SpyCatcher-fused antigens by simple mixing in solution. We used the platform to generate novel vaccine candidates against influenza virus and against proprotein convertase self-proteins. The most promising vaccine candidates could be developed into universal influenza vaccines that inhibit several strains of influenza for a longer time span. We also showed in mice that the norovirus-like particle platform can be used to elicit an immune response against their own proteins, facilitating new treatments for diseases such as hypercholesterolemia and cancer.