Harnessing the innate immune system for improved VLP-based immunotherapy

Vaccination is deemed as the most successful intervention in public health1. As the overall life span of the human population increases and exposure to pathogens strongly decreased due to efficient vaccine programs, the accepted risks associated with prophylactic measures, such as attenuated vaccines, is substantially reduced and efforts need to be focused on the development of safer and better tolerated vaccines. Recombinant, non-replicating vaccines may therefore represent an attractive alternative. Virus-like particles (VLPs) have emerged as a promising alternative due to their excellent safety profile and remarkable immunogenicity. Recently, the successful concept of educating the immune system to fight infectious diseases has been expanded not only to prevent but also to treat existing chronic and autoimmune diseases. VLPs are increasingly being explored as a platform for vaccines, delivery of drugs and adjuvants, and as a tool to investigate the immune system in the context of infectious and non-infectious diseases. Here, applications of VLPs as prophylactic and therapeutic vaccines are explored. The immune response raised in response to immunisation is investigated and the findings directly translated and applied to the development of vaccines against tumours and Influenza. First, the impact on the immune response of the size of vaccine components and mode of presentation of heterologous antigens is evaluated in the context of humoral and cellular responses in a HPV tumour model. Second, the initial events in the immune response mediated by dendritic cells that lead to protective T cell responses induced by VLP-based T cell vaccines is investigated. Thirdly, the ability of VLPs to modulate humoral responses is explored and we show that appropriate TLR7 engagement is crucial for the induction of protective antibody responses against influenza. Finally, this thesis provides insights into the immune response following immunisation with VLP-based vaccines and considerations for vaccine development.