title: A Novel Virus-Like Particle Based Vaccine Platform Displaying the Placental Malaria Antigen VAR2CSA.
abstract: Placental malaria caused by Plasmodium falciparum is a major cause of mortality and severe morbidity. Clinical testing of a soluble protein-based vaccine containing the parasite ligand, VAR2CSA, has been initiated. VAR2CSA binds to the human receptor chondroitin sulphate A (CSA) and is responsible for sequestration of Plasmodium falciparum infected erythrocytes in the placenta. It is imperative that a vaccine against malaria in pregnancy, if administered to women before they become pregnant, can induce a strong and long lasting immune response. While most soluble protein-based vaccines have failed during clinical testing, virus-like particle (VLP) based vaccines (e.g., the licensed human papillomavirus vaccines) have demonstrated high efficacy, suggesting that the spatial assembly of the vaccine antigen is a critical parameter for inducing an optimal long-lasting protective immune response. We have developed a VLP vaccine display platform by identifying regions of the HPV16 L1 coat protein where a biotin acceptor site (AviTagTM) can be inserted without compromising VLP-assembly. Subsequent biotinylation of Avi-L1 VLPs allow us to anchor monovalent streptavidin (mSA)-fused proteins to the biotin, thereby obtaining a dense and repetitive VLP-display of the vaccine antigen. The mSA-VAR2CSA antigen was delivered on the Avi-L1 VLP platform and tested in C57BL/6 mice in comparison to two soluble protein-based vaccines consisting of naked VAR2CSA and mSA-VAR2CSA. The mSA-VAR2CSA Avi-L1 VLP and soluble mSA-VAR2CSA vaccines induced higher antibody titers than the soluble naked VAR2CSA vaccine after three immunizations. The VAR2CSA Avi-L1 VLP vaccine induced statistically significantly higher endpoint titres compared to the soluble mSA-VAR2CSA vaccine, after 1st and 2nd immunization; however, this difference was not statistically significant after 3rd immunization. Importantly, the VLP-VAR2CSA induced antibodies were functional in inhibiting the binding of parasites to CSA. This study demonstrates that the described Avi-L1 VLP-platform may serve as a versatile system for facilitating optimal VLP-display of large and complex vaccine antigens.
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Susan
authors.initials: S
authors.lastname: Thrane
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Janitzek
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Mette Ø
authors.initials: MØ
authors.lastname: Agerbæk
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Sisse B
authors.initials: SB
authors.lastname: Ditlev
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Resende
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Nielsen
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
authors.affiliation: Centre for Medical Parasitology at the Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Sander
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology*; D019921:Biotinylation; D015153:Blotting, Western; D036022:Capsid Proteins / Q000737:chemistry / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000378:metabolism; D010271:Parasites / Q000276:immunology; D010920:Placenta / Q000469:parasitology*; D011247:Pregnancy; D015203:Reproducibility of Results; D014461:Ultracentrifugation; D014611:Vaccination; D014771:Virion / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D036022:Capsid Proteins; D017780:Malaria Vaccines; D009856:Oncogene Proteins, Viral; C512601:VAR2CSA protein, Plasmodium falciparum; C063317:L1 protein, Human papillomavirus type 16