Plasmodium falciparum malaria is a major cause of global morbidity and mortality, and the development of an efficacious vaccine would greatly aid control and elimination efforts. RTS,S is the leading malaria vaccine candidate, but has demonstrated only moderate protective efficacy in clinical trials. RTS,S is a virus-like particle (VLP) that uses human hepatitis B virus as a scaffold to display the malaria antigen, circumsporozoite protein (CSP). Particle formation requires fourfold excess scaffolding antigen compared to the target CSP antigen, which may limit vaccine immunogenicity and efficacy.
Here, we describe a novel VLP that uses the small surface antigen (dS) of duck hepatitis B virus to display the CSP antigen. The CSP-dS fusion protein successfully formed particles without the need for excess scaffold antigen, and therefore CSP represented a larger portion of the vaccine construct compared to conventional VLP-based vaccines, such as RTS,S. CSP-dS VLPs formed large particles up to 70 nm in size that correctly displayed CSP on the surface.
The novel CSP-dS VLP formulated with an alum adjuvant was highly immunogenic in mice and induced antibodies to multiple regions of the CSP, even when administered at a lower vaccine dose. We recently established that functional antibody responses were associated with protective efficacy in human clinical trials of the RTS,S malaria vaccine. These included antibody-mediated fixation and activation of the complement system, and antibody interactions with Fcγ-receptors to promote opsonic phagocytosis. Importantly, our novel CSP-dS VLPs also induced functional antibodies in mice that fixed complement and interacted with Fcγ-receptors.
The platform we describe to produce VLPs without the need for excess scaffolding antigen is highly novel and warrants further evaluation in pre-clinical efficacy studies and as a platform to produce other candidate malaria antigens as VLP-based vaccines.