Abstract
Despite extensive research, the development of an effective malaria vaccine remains elusive. The induction of robust and sustained T cell and antibody response by vaccination is an urgent unmet need. Chimeric virus-like particles (VLPs) are a promising vaccine platform. VLPs are composed of multiple subunit capsomeres which can be rapidly produced in a cost-effective manner, but the ability of capsomeres to induce antigen-specific cellular immune responses has not been thoroughly investigated. Accordingly, we have compared chimeric VLPs and their sub-unit capsomeres for capacity to induce CD8+ and CD4+ T cell and antibody responses. We produced chimeric murine polyomavirus VLPs and capsomeres each incorporating defined CD8+ T cell, CD4+ T cell or B cell repeat epitopes derived from Plasmodium yoelii CSP. VLPs and capsomeres were evaluated using both homologous or heterologous DNA prime/boost immunization regimens for T cell and antibody immunogenicity. Chimeric VLP and capsomere vaccine platforms induced robust CD8+ T cell responses at similar levels which was enhanced by a heterologous DNA prime. The capsomere platform was, however, more efficient at inducing CD4+ T cell responses and less efficient at inducing antigen-specific antibody responses. Our data suggest that capsomeres, which have significant manufacturing advantages over VLPs, should be considered for diseases where a T cell response is the desired outcome.
Highlights
The annual mortality rate of malaria is currently estimated at 405,000 people of whom 67% are children under 5 years of age [1]
The virus-like particles (VLPs) forming proteins were assembled in vitro and analyzed by AF4-MALS analysis, which showed the mean radius of the chimeric VLPs [wild-type, 21.00 ± 1.27 nm; CD8 VLPs, 20.51 ± 0.67 nm; CD4 VLPs, 21.07 ± 0.61 nm; B cell VLPs, 20.85 ± 0.67 nm] with minimal amounts of aggregation [18]
We constructed chimeric VLPs and capsomeres incorporating a CD8+ T cell epitope, CD4+ T cell epitope, or B cell epitope derived from PyCSP in order to evaluate and compare the ability of capsomeres and VLP vaccine platforms to induce epitope-specific cellular and antibody responses
Summary
The annual mortality rate of malaria is currently estimated at 405,000 people of whom 67% are children under 5 years of age [1]. The identification and development of vaccine delivery platforms which induce long-lasting robust cellular and antibody immune responses is a global health priority. A specific goal is a vaccine against the pre-erythrocytic (sporozoite/liver) stage of Plasmodium sporozoites which would prevent both the clinical symptoms which develop during the blood stage, and the transmission of the diseases which occurs during the sexual stage. Early clinical studies showed some protective efficacy in the first year after vaccination, it is established that RTS,S induced protection is low and wanes quickly [5, 6]. Significant research efforts have been directed at either improving the vaccine platform, or incorporating additional antigens to broaden the protective immune response. Ease and cost of manufacturing is an important consideration
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