title: Novel adenovirus encoded virus-like particles displaying the placental malaria associated VAR2CSA antigen.
abstract: The malaria parasite Plasmodium falciparum presents antigens on the infected erythrocyte surface that bind human receptors expressed on the vascular endothelium. The VAR2CSA mediated binding to a distinct chondroitin sulphate A (CSA) is a crucial step in the pathophysiology of placental malaria and the CSA binding region of VAR2CSA has been identified as a promising vaccine target against placental malaria. Here we designed adenovirus encoded virus-like particles (VLP) by co-encoding Simian Immunodeficiency Virus (SIV) gag and VAR2CSA. The VAR2CSA antigen was fused to the transmembrane (TM) and cytoplasmic tail (CT) domains of either the envelope protein of mouse mammary tumour virus (MMTV) or the hemagglutinin (HA) of influenza A. For a non-VLP incorporation control, a third design was made where VAR2CSA was expressed without TM-CT domains. In the primary immunogenicity study in Balb/c mice, VAR2CSA fused to HA TM-CT was significantly superior in inducing ID1-ID2a specific antibodies after the first immunization. A sequential study was performed to include a comparison to the soluble VAR2CSA protein vaccine, which has entered a phase I clinical trial (NCT02647489). The results revealed the induction of higher antibody responses and increased inhibition of parasite binding to CSA using either VAR2CSA HA TM-CT or VAR2CSA MMTV TM-CT as priming vaccines for protein double-boost immunizations, compared to protein prime-double boost regimen. Analysis of pooled serum samples on peptide arrays revealed a unique targeting of several epitopes in mice that had been primed with VAR2CSA HA TM-CT. Consequently, modification of VLP anchors is an important point of optimization in virus-encoded retroviral VLP-based vaccines, and adenovirus VLPs boosted by recombinant proteins offer hope of increasing the levels of protective VAR2CSA specific antibodies.
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and at Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Denmark. Electronic address: anmaca.andersson@gmail.com.
authors.forename: Anne-Marie C
authors.initials: AC
authors.lastname: Andersson
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and at Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Denmark. Electronic address: mafaldaresende@gmail.com.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Resende
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and at Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Denmark. Electronic address: salanti@sund.ku.dk.
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and at Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Denmark. Electronic address: mortenn@sund.ku.dk.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Nielsen
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and at Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Denmark. Electronic address: pholst@sund.ku.dk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Holst
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis*; D000953:Antigens, Protozoan / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000276:immunology; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D005260:Female; D015683:Gene Products, gag / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors / Q000737:chemistry / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D007114:Immunization; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D016778:Malaria, Falciparum / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008807:Mice, Inbred BALB C; D010920:Placenta / Q000737:chemistry / Q000276:immunology / Q000469:parasitology; D010963:Plasmodium falciparum / Q000737:chemistry / Q000187:drug effects / Q000276:immunology*; D011247:Pregnancy; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015302:Simian Immunodeficiency Virus; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D015683:Gene Products, gag; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D017780:Malaria Vaccines; D011993:Recombinant Fusion Proteins; C512601:VAR2CSA protein, Plasmodium falciparum; D058425:Vaccines, Virus-Like Particle; C483468:hemagglutinin, human influenza A virus; D002809:Chondroitin Sulfates
keywords: Adenoviral vectors; Placental malaria; Prime-boost regimens; VAR2CSA; Virus-like particles