Development and characterization of a human papillomavirus-based nanoparticle carrier for heterologous vaccine antigens.

The display of a repetitive array of antigens on the surface of nanoparticles has been shown to effectively trigger the activation of cognate B cells and to increase humoral immune responses. Building on extensive knowledge from the development and clinical use of virus-like particle (VLP) vaccines against Human Papilloma Viruses (HPV), we developed an HPV-based nanoparticle carrier presenting Human Immunodeficiency Virus Type 1 (HIV-1) envelope glycoprotein (Env) as a heterologous vaccine antigen on the surface. After purification of the L1 capsid protein of HPV-16 from a bacterial expression system and assembly of L1 proteins into VLPs (L1-VLPs), we conjugated HIV-1 Env trimers with the C-terminus to the surface of the nanoparticles (L1-Env) using copper-free click reactions via Dibenzocyclooctyne (DBCO)-terminated linker molecules. These L1-Env nanoparticles activated Env-specific B cells more efficiently than non-conjugated Env in a B cell receptor-dependent manner. In general, immunization of mice with L1-Env nanoparticles resulted in Env- and L1-specific antibody responses without the need for an adjuvant. L1-Env nanoparticles induced significantly higher Env-specific antibody responses in comparison to a control group that received a mixture of Env trimers and uncoupled L1-VLPs. Concurrently, we observed decreased L1-specific antibody responses in comparison to mice that were immunized with uncoupled L1-VLPs suggesting partial shielding of L1 epitopes by conjugated Env trimers. In summary, HPV-based nanoparticles provide an attractive novel approach for combinatorial vaccines against sexually transmitted pathogens.