title: Antibodies to a full-length VAR2CSA immunogen are broadly strain-transcendent but do not cross-inhibit different placental-type parasite isolates.
abstract: The high molecular weight, multidomain VAR2CSA protein mediating adhesion of Plasmodium falciparum-infected erythrocytes in the placenta is the leading candidate for a pregnancy malaria vaccine. However, it has been difficult so far to generate strong and consistent adhesion blocking antibody responses against most single-domain VAR2CSA immunogens. Recent advances in expression of the full-length recombinant protein showed it binds with much greater specificity and affinity to chondroitin sulphate A (CSA) than individual VAR2CSA domains. This raises the possibility that a specific CSA binding pocket(s) is formed in the full length antigen and could be an important target for vaccine development. In this study, we compared the immunogenicity of a full-length VAR2CSA recombinant protein containing all six Duffy binding-like (DBL) domains to that of a three-domain construct (DBL4-6) in mice and rabbits. Animals immunized with either immunogen acquired antibodies reacting with several VAR2CSA individual domains by ELISA, but antibody responses against the highly conserved DBL4 domain were weaker in animals immunized with full-length DBL1-6 recombinant protein compared to DBL4-6 recombinant protein. Both immunogens induced cross-reactive antibodies to several heterologous CSA-binding parasite lines expressing different VAR2CSA orthologues. However, antibodies that inhibited adhesion of parasites to CSA were only elicited in rabbits immunized with full-length immunogen and inhibition was restricted to the homologous CSA-binding parasite. These findings demonstrate that partial and full-length VAR2CSA immunogens induce cross-reactive antibodies, but inhibitory antibody responses to full-length immunogen were highly allele-specific and variable between animal species.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, United States of America.
authors.forename: Marion
authors.initials: M
authors.lastname: Avril
authors.forename: Marianne J
authors.initials: MJ
authors.lastname: Hathaway
authors.forename: Anand
authors.initials: A
authors.lastname: Srivastava
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dechavanne
authors.forename: Mirja
authors.initials: M
authors.lastname: Hommel
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Smith
authors.forename: Benoît
authors.initials: B
authors.lastname: Gamain
mesh_terms: D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D000918:Antibody Specificity / Q000276:immunology / Q000502:physiology; D000953:Antigens, Protozoan / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D002478:Cells, Cultured; D003429:Cross Reactions / Q000276:immunology; D005260:Female; D006801:Humans; D007114:Immunization; D017780:Malaria Vaccines / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D016778:Malaria, Falciparum / Q000469:parasitology / Q000473:pathology / Q000517:prevention & control / Q000635:transmission; D051379:Mice; D008807:Mice, Inbred BALB C; D010920:Placenta / Q000276:immunology / Q000469:parasitology*; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000469:parasitology* / Q000473:pathology / Q000628:therapy; D020033:Protein Isoforms / Q000276:immunology; D011817:Rabbits; D013045:Species Specificity
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D020033:Protein Isoforms; C512601:VAR2CSA protein, Plasmodium falciparum