Immunogenicity of HLA-restricted peptide vaccine candidates delivered by self-assembling protein nanoparticle (SAPN) technology

Abstract

Malaria infection remains a significant threat worldwide, with the development of a vaccine that induces long-term sterile immunity proving difficult due to the complexity of the parasite, Plasmodium. The identification of conserved and human leukocyte antigen (HLA)-promiscuous, protection-associated epitopes within target antigens offer promise of developing effective vaccines. We previously identified immunodominant T cell regions within selected P. falciparum (Pf) antigens using samples from semi-immune individuals in Southern Ghana. The aim was to design, produce and assess immunogenicity of Pf-antigen-specific vaccines containing conserved and promiscuous HLA class I-restricted epitopes using the self-assembling protein nanoparticle (SAPN) delivery platform. We produced five SAPN vaccines based on epitopes identified in our earlier studies from Pf antigens (PfCSP, PfAMA1 and PfTRAP) and presented by HLA supertypes HLA A*02 and HLA A*03. The vaccines were used to immunize transgenic HLA A*02 and A*03 mice at 3, 7 and 10 μg doses, and the levels of cellular responses and antibodies to sporozoites assessed by IFN-γ/IL2 FluoroSpot and immunofluorescence antibody assays (IFA), respectively. Transgenic mice vaccinated with the CSP A*02 SAPN vaccine elicited increased IFN-γ T-cell responses against the inserted epitopes, NANPNANPNV and AILSVSSFLF and significantly higher antibody responses against Pf sporozoites assessed by IFA (median titer = 10,240 in vaccinated group vs 10 in adjuvant group, p value = 0.0003).The AMA1 SAPN vaccine containing the A*02 epitope YMGNPWTEYM elicited a median IFN-γ sfc/m of 259 in the 10 μg dose group while the adjuvant only response was 47 sfc/m (p value = 0.03). The AMA1 A*03 epitope NSTCRFFVCK elicited a median IFN-γ sfc/m of 180 and 217 in the 10 and 3 μg doses respectively, while the adjuvant only response was 0 sfc/m for both doses (p value = 0.0079). Our approach demonstrates feasibility of developing a novel potentially efficacious epitope-based vaccine and affirms the potential of the SAPN technology as an effective delivery platform.