Induction of specific T-cell responses, opsonizing antibodies, and protection against Plasmodium chabaudi adami infection in mice vaccinated with genomic expression libraries expressed in targeted and secretory DNA vectors.
It has been proposed that a multivalent malaria vaccine is necessary to mimic the naturally acquired resistance to this disease observed in humans. A major experimental challenge is to identify the optimal components to be used in such a multivalent vaccine. Expression library immunization (ELI) is a method for screening genomes of a pathogen to identify novel combinations of vaccine sequences. Here we describe immune responses associated with, and the protective efficacy of, genomic Plasmodium chabaudi adami DS expression libraries constructed in VR1020 (secretory), monocyte chemotactic protein-3 (chemoattractant), and cytotoxic T lymphocyte antigen 4 (lymph node-targeting) DNA vaccine vectors. With splenocytes from vaccinated mice, specific T-cell responses, as well as gamma interferon and interleukin-4 production, were observed after stimulation with P. chabaudi adami-infected erythrocytes, demonstrating the specificity of genomic library vaccination for two of the three libraries constructed. Sera obtained from mice vaccinated with genomic libraries promoted the opsonization of P. chabaudi adami-infected erythrocytes by murine macrophages in vitro, further demonstrating the induction of malaria-specific immune responses following ELI. Over three vaccine trials using biolistic delivery of the three libraries, protection after lethal challenge with P. chabaudi adami DS ranged from 33 to 50%. These results show that protective epitopes or antigens are expressed within the libraries and that ELI induces responses specific to P. chabaudi adami malaria. This study further demonstrates that ELI is a suitable approach for screening the malaria genome to identify the components of multivalent vaccines.
Rainczuk
A
A
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
Scorza
T
T
Smooker
P M
PM
Spithill
T W
TW
D000069594:Abatacept; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics; D000953:Antigens, Protozoan / Q000235:genetics; D001483:Base Sequence; D060908:CTLA-4 Antigen; D054410:Chemokine CCL7; D016207:Cytokines; D016054:DNA, Protozoan / Q000235:genetics; D005260:Female; D015723:Gene Library; D005822:Genetic Vectors; D018503:Genome, Protozoan; D006801:Humans; D007111:Immunity, Cellular; D018796:Immunoconjugates; D066298:In Vitro Techniques; D008264:Macrophages / Q000276:immunology; D008288:Malaria / Q000276:immunology* / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics; D009895:Opsonin Proteins / Q000096:biosynthesis*; D010587:Phagocytosis; D016788:Plasmodium chabaudi / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D013601:T-Lymphocytes / Q000276:immunology*; D019444:Vaccines, DNA / Q000235:genetics / Q000494:pharmacology
D000913:Antibodies, Protozoan; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000953:Antigens, Protozoan; C515450:CCL7 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; C556707:Ctla4 protein, mouse; D016207:Cytokines; D016054:DNA, Protozoan; D018796:Immunoconjugates; D017780:Malaria Vaccines; D018945:Monocyte Chemoattractant Proteins; D009895:Opsonin Proteins; D019444:Vaccines, DNA; D000069594:Abatacept