Enhanced protective immunity against malaria by vaccination with a recombinant adenovirus encoding the circumsporozoite protein of Plasmodium lacking the GPI-anchoring motif.
A major malaria vaccine candidate, the circumsporozoite (CS) protein of Plasmodium, is a pre-erythrocytic stage antigen that is attached to the surface of the sporozoites through a glycosylphosphatidylinositol (GPI) anchor. However, here we show that the motif that signals for glycosylphosphatidylinositol anchor addition interferes with the immunogenicity of this protein and reduces protection in mice upon immunization with a recombinant adenovirus. The presence of the glycosylphosphatidylinositol-anchoring motif sequentially affected total circumsporozoite protein production, cellular distribution, antigen processing and secretion, leading to less effective antigen presentation. Consistently, vaccination with an adenovirus recombinant carrying the anchoring motif-disrupted circumsporozoite gene, resulted in significant increase of the number of interferon-gamma (IFN-gamma) producing T cells and specific IgG2a isotype antibodies, ensuing more effective vaccination. Given that the anchoring motif is highly conserved among different species of Plasmodium, anti-malaria subunit vaccines encoded by recombinant vectors that aim at the induction of strong cellular immunity could maximize immunogenicity by removing anchoring motifs.
Laboratory of Immunopathology, Centro de Pesquisas René Rachou, FIOCRUZ, Av Augusto de Lima 1715, Belo Horizonte 30190-002, MG, Brazil. oscar@cpqrr.fiocruz.br
Oscar
O
Bruna-Romero
Carolina D
CD
Rocha
Moriya
M
Tsuji
Ricardo T
RT
Gazzinelli
D000256:Adenoviridae / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D017124:Conserved Sequence; D004279:DNA, Viral / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005455:Fluorescent Antibody Technique; D017261:Glycosylphosphatidylinositols / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D008288:Malaria / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010967:Plasmodium yoelii / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013347:Subcellular Fractions / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D014614:Vaccines, Synthetic / Q000627:therapeutic use
D004279:DNA, Viral; D017261:Glycosylphosphatidylinositols; D007074:Immunoglobulin G; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma