Protein nanovaccine confers robust immunity against Toxoplasma

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

doi:10.1038/s41541-017-0024-6

Abstract

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.

Highlights

HLA-A*1101-transgenic mice were immunized intramuscularly with CD8+ T cell-eliciting SAPNs combined with GLA-SE
CD8+-T cell-eliciting SAPN-GLA-SE vs. EmptySAPN-GLA-SE were compared in HLA-A*1101 transgenic mice as described
The association of CD8+ T cell- and CD4+ T cellrestricted peptides contributes to IFN-γ production in HLA-A*1101 transgenic mice

Summary

Introduction

It can cause severe brain and eye damage in the fetus, in newborn infants, and in immunecompromised individuals.[1] anti-parasitic medicines such as sulfadiazine and pyrimethamine are available, some patients experience side effects including toxicity and hypersensitivity. One approach for toxoplasmosis vaccine development is an epitope-based vaccine designed to enhance host immunity. Protection is achieved through stimulation of CD4+ helper T lymphocytes and CD8+ IFN-γ producing T lymphocyte responses. These CD8+ T cells recognize octamer/nonamer peptides presented on HLA supermotif molecules on infected cells. As the discovery of such protective peptide epitopes accumulates, mechanisms are needed to effectively present these epitopes to the immune system of the host

Methods

Results

Conclusion