Protein nanovaccine confers robust immunity against Toxoplasma

El Bissati, Kamal; Zhou, Ying; Paulillo, Sara Maria; Raman, Senthil Kumar; Karch, Christopher P.; Roberts, Craig W.; Lanar, David E.; Reed, Steve; Fox, Chris; Carter, Darrick; Alexander, Jeff; Sette, Alessandro; Sidney, John; Lorenzi, Hernan; Begeman, Ian J.; Burkhard, Peter; McLeod, Rima

We designed and produced a self-assembling protein nanoparticle. This self-assembling protein nanoparticle contains five CD8(+) HLA-A03-11 supertypes-restricted epitopes from antigens expressed during Toxoplasma gondii’s lifecycle, the universal CD4(+) T cell epitope PADRE, and flagellin as a scaffold and TLR5 agonist. These CD8(+) T cell epitopes were separated by N/KAAA spacers and optimized for proteasomal cleavage. Self-assembling protein nanoparticle adjuvanted with TLR4 ligand-emulsion GLA-SE were evaluated for their efficacy in inducing IFN-γ responses and protection of HLA-A*1101 transgenic mice against T. gondii. Immunization, using self-assembling protein nanoparticle-GLA-SE, activated CD8(+) T cells to produce IFN-γ. Self-assembling protein nanoparticle-GLA-SE also protected HLA-A*1101 transgenic mice against subsequent challenge with Type II parasites. Hence, combining CD8(+) T cell-eliciting peptides and PADRE into a multi-epitope protein that forms a nanoparticle, administered with GLA-SE, leads to efficient presentation by major histocompatibility complex Class I and II molecules. Furthermore, these results suggest that activation of TLR4 and TLR5 could be useful for development of vaccines that elicit T cells to prevent toxoplasmosis in humans.