Protective immunity against malaria by a nanoparticle CIS43-based junctional vaccine alone or in combination with R21

Repetitive display of the major repeats of the Plasmodium falciparum circumsporozoite protein (PfCSP) is the basis for two WHO-recommended vaccines: RTS,S/AS01 and R21/Matrix-M. Recently, however, the CIS43 monoclonal antibody that preferentially targets the junctional region of PfCSP has been shown to be highly protective in humans, highlighting its junctional epitope as a key vaccine target. Here, we develop a vaccine based on tandem repeats of the junctional epitope displayed on a self-assembling nanoparticle and compare this CIS43-based junctional vaccine alone or in combination with the benchmark R21 vaccine, using both B cell analysis and monoclonal antibody isolation to define targeting of the immune response. Comparable reduction in liver burden was observed following vaccination with the best junctional vaccine and R21 at a dose of 1 μg. At a dose of 0.25 μg, a modest reduction of malaria liver burden with the junctional vaccine was observed compared to R21. Further, combining the junctional and R21 vaccines did not yield substantial improvement, although a modest trend was observed. While the R21 vaccine elicited antibodies primarily against the major repeats, the junctional vaccine elicited antibodies against both junctional and major repeat regions. In vivo B cell analysis and isolation of monoclonal antibodies confirmed differences in vaccine-induced antibody specificities. Altogether, these data suggest the nanoparticle-formatted tandem-repeated CIS43-junctional vaccine to be a promising approach to broaden immunity against malaria, either as a standalone intervention or in combination with R21.