P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections

• Published in: PloS one 2015-05, Vol.10 (5), p.e0124856-e0124856
• Main Authors: Whitacre, David C, Espinosa, Diego A, Peters, Cory J, Jones, Joyce E, Tucker, Amy E, Peterson, Darrell L, Zavala, Fidel P, Milich, David R
• Format: Article
• Language: English
• Subjects: Alum; Aluminum sulfate; Animals; Antibodies; Antibodies, Protozoan - immunology; Antigenic determinants; Antigens; Blood; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; Circumsporozoite protein; Core protein; Dilution; Epitopes; Epitopes, B-Lymphocyte - chemistry; Epitopes, B-Lymphocyte - immunology; Epitopes, T-Lymphocyte - chemistry; Epitopes, T-Lymphocyte - immunology; Erythrocytes; Health aspects; Hepatitis; Hepatitis B Virus, Woodchuck - immunology; Immunity; Immunization; Immunology; Infections; Lead; Life Cycle Stages; Liver; Lymphocytes; Lymphocytes B; Lymphocytes T; Malaria; Malaria vaccines; Malaria, Falciparum - immunology; Malaria, Falciparum - parasitology; Malaria, Falciparum - prevention & control; Malaria, Vivax - immunology; Malaria, Vivax - parasitology; Malaria, Vivax - prevention & control; Mice, Inbred C57BL; Parasites; Photovoltaic cells; Plasmodium berghei; Plasmodium falciparum; Plasmodium falciparum - immunology; Plasmodium vivax; Plasmodium vivax - immunology; Proteins; Protozoan Proteins - immunology; Public health; Rabbits; Repetitive Sequences, Amino Acid; Reproducibility of Results; Solar cells; Sporozoites; T cells; Vaccines; Vector-borne diseases; Virion - immunology; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0124856

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 >1x10(6)) 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.