Wines, B. D. | bioRxiv Science

bioRxiv2020

Novel virus-like particle vaccine encoding the circumsporozoite protein of Plasmodium falciparum is immunogenic and induces functional antibody responses

RTS,S is the leading malaria vaccine in development, but has demonstrated only moderate protective efficacy in clinical trials. RTS,S is a virus-like particle (VLP) that uses the human hepatitis B virus as scaffold to display the malaria sporozoite antigen, circumsporozoite protein (CSP). Particle formation requires fourfold excess scaffold antigen, and as a result, CSP represents only a small portion of the final vaccine construct. Alternative VLP or nanoparticle platforms that reduce the amount of scaffold antigen and increase the amount of the target CSP antigen present in particles may enhance vaccine immunogenicity and efficacy. Here, we describe the production and characterization of a novel VLP that uses the small surface antigen (dS) of duck hepatitis B virus to display CSP. The CSP-dS fusion protein successfully formed VLPs without the need for excess scaffold antigen, and thus CSP represented a larger portion of the vaccine construct. Importantly, this is the first report of a dS-based vaccine that formed particles without excess scaffold protein. CSP-dS formed large particles approximately 31-74 nm in size and were confirmed to display CSP on the surface. The CSP-dS VLP was highly immunogenic in mice and induced antibodies to multiple regions of CSP, even when administered at a lower vaccine dosage. Vaccine-induced antibodies demonstrated functional activity, including the ability to interact with complement and Fc{gamma}-receptors, both previously identified as important in malaria immunity. Our novel platform to produce VLPs without excess scaffold protein has wide implications for the future development of innovative vaccines for malaria and other infectious diseases.

immunology↗

bioRxiv2019

Multi-functional antibodies are induced by the RTS,S malaria vaccine and associated with protection in a phase I/IIa trial

BackgroundRTS,S is the leading malaria vaccine candidate, but only confers partial efficacy against malaria in children. RTS,S is based on the major Plasmodium falciparum sporozoite surface antigen, circumsporozoite protein (CSP). The induction of anti-CSP antibodies is important for protection, however, it is unclear how protective antibodies function. MethodsWe quantified the induction of functional anti-CSP antibody responses in healthy malaria-naive adults (N=45) vaccinated with RTS,S/AS01. This included the ability to mediate effector functions via the fragment crystallizable (Fc) region, such as interacting with human complement proteins and Fc{gamma}-receptors (Fc{gamma}Rs) that are expressed on immune cells, which promote various immunological functions. ResultsOur major findings were i) RTS,S-induced antibodies mediate Fc-dependent effector functions, ii) functional antibodies were generally highest after the second vaccine dose; iii) functional antibodies targeted multiple regions of CSP, iv) participants with higher levels of functional antibodies had a reduced probability of developing parasitemia following homologous challenge (p<0.05); v) non-protected subjects had higher levels of anti-CSP IgM. ConclusionsOur data suggests a role for Fc-dependent antibody effector functions in RTS,S-induced immunity. Enhancing the induction of these functional activities may be a strategy to improve the protective efficacy of RTS,S or other malaria vaccines.

immunology↗