Abstract
Proprotein convertase (PCSK) enzymes serve a wide range of regulatory roles in mammals, for example in metabolism and immunity, and altered activity of PCSKs is associated with disorders, such as cardiovascular disease and cancer. Inhibition of PCSK9 activity with therapeutic antibodies or small interfering RNAs is used in the clinic to lower blood cholesterol, and RNA interference -based silencing of FURIN (PCSK3) is being evaluated in clinical trials as a cancer treatment. Inhibiting these proteins through vaccine-induced autoantibodies could be a patient-friendly way to reduce the frequency of intervention and the overall price of treatment. Here, we show that a self-directed immune response against PCSK9 and furin can be generated in mice by presenting fragments of the proteins on norovirus-like particles (noro-VLPs). We genetically fused three PCSK peptides and the P domain of furin to the SpyCatcher linker protein and covalently conjugated them on noro-VLPs via SpyCatcher/SpyTag linkage. Both PCSK9 peptides and the furin P domain generated antigen specific IgGs even without conventional adjuvants. Importantly, vaccinating against furin did not cause adverse events or immune-mediated inflammatory disease. This study adds further support for the feasibility of VLP-based anti-PCSK9 vaccines and shows that the same principles can be applied to make novel vaccine candidates against other endogenous proteins such as furin. We also demonstrate that the noro-VLP can be used as a vaccine platform for presenting self-antigens.