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

PLoS One. 2015 Nov 23;10(11):e0143071. doi: 10.1371/journal.pone.0143071. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Protozoan / immunology
  • Antigens, Protozoan / immunology*
  • Biotinylation
  • Blotting, Western
  • Capsid Proteins / chemistry
  • Capsid Proteins / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Malaria Vaccines / immunology*
  • Malaria, Falciparum / blood
  • Malaria, Falciparum / immunology
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Oncogene Proteins, Viral / chemistry
  • Oncogene Proteins, Viral / metabolism
  • Parasites / immunology
  • Placenta / parasitology*
  • Pregnancy
  • Reproducibility of Results
  • Ultracentrifugation
  • Vaccination
  • Virion / immunology*

Substances

  • Antibodies, Protozoan
  • Antigens, Protozoan
  • Capsid Proteins
  • Malaria Vaccines
  • Oncogene Proteins, Viral
  • VAR2CSA protein, Plasmodium falciparum
  • L1 protein, Human papillomavirus type 16

Grants and funding

The project was funded through a grant from Bill and Melinda Gates Foundation Grant ID APP178218 [http://www.gatesfoundation.org]. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.