A Novel Virus-Like Particle Based Vaccine Platform Displaying the Placental Malaria Antigen VAR2CSA

• Published in: PloS one 2015-11, Vol.10 (11), p.e0143071-e0143071
• Main Authors: Thrane, Susan, Janitzek, Christoph M, Agerbæk, Mette Ø, Ditlev, Sisse B, Resende, Mafalda, Nielsen, Morten A, Theander, Thor G, Salanti, Ali, Sander, Adam F
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies; Antibodies, Protozoan - immunology; Antigens; Antigens, Protozoan - immunology; Assembly; Binding sites; Biotin; Biotinylation; Blotting, Western; Capsid Proteins - chemistry; Capsid Proteins - metabolism; Coat protein; Drug delivery systems; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Female; Health aspects; Human papillomavirus; Immune response; Immune system; Immunization; Immunoglobulins; Immunology; Infectious diseases; Internet; Malaria; Malaria Vaccines - immunology; Malaria, Falciparum - blood; Malaria, Falciparum - immunology; Mice, Inbred C57BL; Molecular Sequence Data; Morbidity; Oncogene Proteins, Viral - chemistry; Oncogene Proteins, Viral - metabolism; Papillomavirus infections; Parasites; Parasites - immunology; Parasitology; Pathogens; Placenta; Placenta - parasitology; Plasmodium falciparum; Pregnancy; Proteins; Reproducibility of Results; Statistical analysis; Streptavidin; Ultracentrifugation; Vaccination; Vaccines; Vector-borne diseases; Virion - immunology; Viruses; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0143071

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.