Abstract
An effective vaccine against the Plasmodium parasite is likely to require the induction of robust antibody and T cell responses. Chimeric virus-like particles are an effective vaccine platform for induction of antibody responses, but their capacity to induce robust cellular responses and cell-mediated protection against pathogen challenge has not been established. To evaluate this, we produced chimeric constructs using the murine polyomavirus structural protein with surface-exposed CD8+ or CD4+ T cell or B cell repeat epitopes derived from the Plasmodium yoelii circumsporozoite protein, and assessed immunogenicity and protective capacity in a murine model. Robust CD8+ T cell responses were induced by immunization with the chimeric CD8+ T cell epitope virus-like particles, however CD4+ T cell responses were very low. The B cell chimeric construct induced robust antibody responses but there was no apparent synergy when T cell and B cell constructs were administered as a pool. A heterologous prime/boost regimen using plasmid DNA priming followed by a VLP boost was more effective than homologous VLP immunization for cellular immunity and protection. These data show that chimeric murine polyomavirus virus-like particles are a good platform for induction of CD8+ T cell responses as well as antibody responses.
Highlights
Annual malaria related mortality rates have decreased by approximately 25% since 2010, improvements in morbidity and mortality have stabilized in recent years (World Malaria Report, 2017) and rebounds have been reported in some countries (Alonso et al, 2011)
This sub-unit virus-like particle (VLP) based vaccine targets the P. falciparum circumsporozoite protein (Pf CSP) by combining a protein which includes multiple Pf CSP B cell repeats and T cell epitopes fused with recombinant hepatitis B surface antigen (RTS), and recombinant wild-type hepatitis B surface antigen (S) (Gordon et al, 1995)
IFN-γ responses detected by ELISpot showed that homologous immunization with the CD8 VLP induced significant IFN-γ spot forming cells (SFCs) when stimulated with pooled peptide or PyCSP transfected A20 cells (p < 0.001) (Figures 3A, 4A)
Summary
Annual malaria related mortality rates have decreased by approximately 25% since 2010, improvements in morbidity and mortality have stabilized in recent years (World Malaria Report, 2017) and rebounds have been reported in some countries (Alonso et al, 2011). GlaxoSmithKline achieved a significant milestone with MosquirixTM ( known as RTS,S) by receiving a positive scientific opinion from the European Medicines Agency as the first malaria vaccine for the immunization of children aged 6 weeks to 17 months This sub-unit virus-like particle (VLP) based vaccine targets the P. falciparum circumsporozoite protein (Pf CSP) by combining a protein which includes multiple Pf CSP B cell repeats and T cell epitopes fused with recombinant hepatitis B surface antigen (RTS), and recombinant wild-type hepatitis B surface antigen (S) (Gordon et al, 1995). These data emphasize the urgent need to identify new vaccine targets and vaccine delivery platforms that enhance immunogenicity and provide durable protection
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