Journal Article

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

Ali Salanti, Susan Thrane, Adam F. Sander, Sisse B. Ditlev, Thor G. Theander, Christoph M. Janitzek, Morten Nielsen, Mafalda Resende, Mette Ø. Agerbæk

2015

Overview

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.

• Publisher: Public Library of Science (PLoS),Public Library of Science
• Subject: Amino Acid Sequence / Animals / Antibodies / Antibodies, Protozoan / Antibodies, Protozoan - immunology / Antigens / Antigens, Protozoan / Antigens, Protozoan - immunology / Assembly / Binding sites / Biotin / Biotinylation / Blotting, Western / Capsid Proteins / 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 / Malaria Vaccines - immunology / Malaria, Falciparum / Malaria, Falciparum - blood / Malaria, Falciparum - immunology / Medicine / Mice, Inbred C57BL / Molecular Sequence Data / Morbidity / Oncogene Proteins, Viral / Oncogene Proteins, Viral - chemistry / Oncogene Proteins, Viral - metabolism / Papillomavirus infections / Parasites / Parasites - immunology / Parasitology / Pathogens / Placenta / Placenta - parasitology / Plasmodium falciparum / Pregnancy / Proteins / Q / R / Reproducibility of Results / Research Article / Science / Statistical analysis / Streptavidin / Ultracentrifugation / Vaccination / Vaccines / Vector-borne diseases / Virion / Virion - immunology / Viruses / Womens health