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In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf) sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs). Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg-specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer >1x106) and provided 80–100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc-Pv-78), which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P.falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine.
Copyright: © 2015 Whitacre et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Is Part Of
VCU Biochemistry and Molecular Biology Publications
Development and characterization of hybrid PB/PF parasites carrying the PF C-Terminus (PB/PF-CSP-CT).
S1_Table.pdf (43 kB)
Kinetics of IgG Ab titers through primary immunization (1°) with WHc(C61S)-Mal-78-3T, at the boost (2°) and at 3 months post-challenge.
S2_Fig.tif (804 kB)
CS Epitope Sequences.
S2_Table.pdf (41 kB)
Immunogenicity of WHc-Pv-78 VLPs.
S3_Fig.tif (712 kB)
Only anti-CS repeat antibodies protect against a sporozoite challenge.
S4_Fig.tif (675 kB)
Comparison of WHc-CS VLPs containing malaria-specific T cell epitopes.
S5_Fig.tif (420 kB)
Conservation of T cell epitopes on P. falciparum and P. berghei CS.