P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections.
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.
Vaccine Research Institute of San Diego, San Diego, California, United States of America; VLP Biotech, Inc., San Diego, California, United States of America.
David C
DC
Whitacre
Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
Diego A
DA
Espinosa
Vaccine Research Institute of San Diego, San Diego, California, United States of America; VLP Biotech, Inc., San Diego, California, United States of America.
Cory J
CJ
Peters
Vaccine Research Institute of San Diego, San Diego, California, United States of America; VLP Biotech, Inc., San Diego, California, United States of America.
Joyce E
JE
Jones
VLP Biotech, Inc., San Diego, California, United States of America.
Amy E
AE
Tucker
Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Darrell L
DL
Peterson
Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
Fidel P
FP
Zavala
Vaccine Research Institute of San Diego, San Diego, California, United States of America; VLP Biotech, Inc., San Diego, California, United States of America.
David R
DR
Milich
D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D017919:Hepatitis B Virus, Woodchuck / Q000276:immunology; D007109:Immunity; D007114:Immunization; D008018:Life Cycle Stages; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D016780:Malaria, Vivax / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000276:immunology*; D010966:Plasmodium vivax / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology; D011817:Rabbits; D020449:Repetitive Sequences, Amino Acid; D015203:Reproducibility of Results; D014771:Virion / Q000276:immunology*
D000913:Antibodies, Protozoan; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan