title: Enhanced protection against malaria by a chimeric merozoite surface protein vaccine.
abstract: The 42-kDa processed fragment of Plasmodium falciparum merozoite surface protein 1 (MSP-1(42)) is a prime candidate for a blood-stage malaria vaccine. Merozoite surface protein 8 contains two C-terminal epidermal growth factor (EGF)-like domains that may function similarly to those of MSP-1(42). Immunization with either MSP-1 or MSP-8 induces protection that is mediated primarily by antibodies against conformation-dependent epitopes. In a series of comparative immunogenicity and efficacy studies using the Plasmodium yoelii rodent model, we tested the ability of recombinant P. yoelii MSP-8 (rPyMSP-8) to complement rPyMSP-1-based vaccines. Unlike MSP-1, PyMSP-8-dependent protection required immunization with the full-length protein and was not induced with recombinant antigens that contained only the C-terminal EGF-like domains. Unlike PyMSP-8, the immunogenicity of the PyMSP-1 EGF-like domains was low when present as part of the rPyMSP-1(42) antigen. Immunization with a mixture of rPyMSP-1(42) and rPyMSP-8 further inhibited the antibody response to protective epitopes of rPyMSP-1(42) and did not improve vaccine efficacy. To improve PyMSP-1 immunogenicity, we produced a chimeric antigen containing the EGF-like domains of PyMSP-1 fused to the N terminus of PyMSP-8. Immunization with the chimeric rPyMSP-1/8 antigen induced high and comparable antibody responses against the EGF-like domains of both PyMSP-1 and PyMSP-8. This enhanced MSP-1-specific antibody response and the concurrent targeting of MSP-1 and MSP-8 resulted in improved, nearly complete protection against lethal P. yoelii 17XL malaria. Unexpectedly, immunization with rPyMSP-1/8 failed to protect against challenge infection with reticulocyte-restricted P. yoelii 17X parasites. Overall, these data establish an effective strategy to improve the efficacy of P. falciparum MSP-based vaccines.
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Shi
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Lynch
authors.forename: Margarita
authors.initials: M
authors.lastname: Romero
authors.forename: James M
authors.initials: JM
authors.lastname: Burns
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000235:genetics; D000818:Animals; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D020066:Merozoite Surface Protein 1 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D052940:Merozoites / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010967:Plasmodium yoelii / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D008565:Membrane Proteins; D020066:Merozoite Surface Protein 1; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D022223:Vaccines, Subunit; C431669:merozoite surface protein 8, Plasmodium