Abstract
The most advanced malaria vaccine, RTS,S, includes the central repeat and C-terminal domains of the Plasmodium falciparum circumsporozoite protein (PfCSP). We have recently isolated human antibodies that target the junctional region between the N-terminal and repeat domains that are not included in RTS,S. Due to the fact that these antibodies protect against malaria challenge in mice, their epitopes could be effective vaccine targets. Here, we developed immunogens displaying PfCSP junctional epitopes by genetic fusion to either the N-terminus or B domain loop of the E2 protein from chikungunya (CHIK) alphavirus and produced CHIK virus-like particles (CHIK-VLPs). The structural integrity of these junctional-epitope–CHIK-VLP immunogens was confirmed by negative-stain electron microscopy. Immunization of these CHIK-VLP immunogens reduced parasite liver load by up to 95% in a mouse model of malaria infection and elicited better protection than when displayed on keyhole limpet hemocyanin, a commonly used immunogenic carrier. Protection correlated with PfCSP serum titer. Of note, different junctional sequences elicited qualitatively different reactivities to overlapping PfCSP peptides. Overall, these results show that the junctional epitopes of PfCSP can induce protective responses when displayed on CHIK-VLP immunogens and provide a basis for the development of a next generation malaria vaccine to expand the breadth of anti-PfCSP immunity.
Highlights
Malaria is a global health burden that afflicts over 200 million people each year, causing an estimated 405,000 deaths in 2018 [1]
Subsequent to the development of R21, we described a new neutralizing epitope on Plasmodium falciparum circumsporozoite protein (PfCSP), termed the junctional epitope, which is targeted by the highly potent human monoclonal antibody CIS43, derived from a subject vaccinated with the PfSPZ vaccine [31]
Linear PfCSP repeat epitope maps were created by plotting reciprocal IC50 values from peptide competition of monoclonal antibody (mAb) binding to recombinant PfCSP, as determined in [34], on the Y-axis and the overlapping peptide number (Table S1) on the X-axis
Summary
Malaria is a global health burden that afflicts over 200 million people each year, causing an estimated 405,000 deaths in 2018 [1]. In terms of using the vaccine regimen to alter the quality of the antibody response, delaying and fractioning the last dose of RTS,S has been shown to improve serum avidity and protection [29,30] Another potential approach toward improving the potency of RTS,S is to display a more dense array of the immunogen on hepatitis B surface antigen particles, which is termed R21. Other groups have subsequently cloned mAbs that react with the PfCSP junction following vaccination of Tanzanian volunteers [32] and from immunized Kymab mice [33] Because this new epitope is located at the junction of the N-terminal and repeat domains, it is not present in RTS,S or R21. The CHIK-VLP platform was used to evaluate immunogenicity and protection elicited by PfCSP junctional epitope-based immunogen designs
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