Search

Antibodies can prevent malaria by neutralizing the infectious Plasmodium falciparum sporozoites (SPZ) before they establish an infection in the liver. Circumsporozoite protein (CSP), the most abundant surface protein of SPZ is the leading candidate for passive (and subunit) immunization approaches against malaria. Comprehensive assessment of the parasite-inhibitory capacity of anti-CSP monoclonal antibodies (mAbs) is an important step in advancing CSP-based immunization strategies. In this study, we employed a quantitative imaging-based motility assay to quantify the effect of anti-CSP mAbs on SPZ motility, both in vitro and in human skin. Our assay provided a quantitative measure of mAb parasite-inhibitory capacity through measurement of the half-maximal motility inhibitory concentration (IC50M) value for anti-CSP mAbs (IC50M 2A10: 24 nM, IC50M 3SP2: 71 nM). We found a sevenfold discrepancy between the IC50M and the binding saturation concentration measured by ELISA, possibly related to the observed shedding of CSP-mAb complexes during SPZ movement. In a subset of SPZ (5%), in vitro motility was unaffected by the presence of 2A10 while 3SP2 was able to completely block movement. In our ex vivo skin explant model, SPZ proved less susceptible to anti-CSP mAbs compared to SPZ in an in vitro environment. By quantitatively assessing motility, we created a valuable tool that can be used for comprehensive assessment of anti-CSP mAb potency. Insight that will help deepen our understanding of anti-CSP mAb potency and guide selection of the most promising anti-CSP mAbs for downstream clinical development. [ABSTRACT FROM AUTHOR]

The malaria vaccination landscape has seen significant advancements with the recent endorsement of RTS,S/AS01 and R21/Matrix-M vaccines, which target the pre-erythrocytic stages of Plasmodium falciparum (Pf) infection. However, several challenges remain to be addressed, including the incomplete protection afforded by these vaccines, their dependence on a single Pf antigen, and the fact that they were not designed to protect against P. vivax (Pv) malaria. Injectable formulations of whole-sporozoite (WSpz) malaria vaccines offer a promising alternative to existing subunit vaccines, with recent developments including genetically engineered parasites and optimized administration regimens. Clinical evaluations demonstrate varying efficacy, influenced by factors, such as immune status, prior exposure to malaria, and age. Despite significant progress, a few hurdles persist in vaccine production, deployment, and efficacy in malaria-endemic regions, particularly in children. Concurrently, transgenic parasites expressing Pv antigens emerge as potential solutions for PvWSpz vaccine development. Ongoing clinical studies and advancements in vaccine technology, including the recently described PfSPZ-LARC2 candidate, signify a hopeful future for WSpz malaria vaccines, which hold great promise in the global fight against malaria. This Review discusses challenges in developing malaria vaccines and promising recent developments in whole-sporozoite vaccines using genetically engineered parasites with a perspective on future directions of these vaccines for the prevention of malaria. [ABSTRACT FROM AUTHOR]

Radiation-attenuated sporozoite (RAS) vaccines can completely prevent blood stage Plasmodium infection by inducing liver-resident memory CD8+ T cells to target parasites in the liver. Such T cells can be induced by 'Prime-and-trap' vaccination, which here combines DNA priming against the P. yoelii circumsporozoite protein (CSP) with a subsequent intravenous (IV) dose of liver-homing RAS to "trap" the activated and expanding T cells in the liver. Prime-and-trap confers durable protection in mice, and efforts are underway to translate this vaccine strategy to the clinic. However, it is unclear whether the RAS trapping dose must be strictly administered by the IV route. Here we show that intradermal (ID) RAS administration can be as effective as IV administration if RAS are co-administrated with the glycolipid adjuvant 7DW8-5 in an ultra-low inoculation volume. In mice, the co-administration of RAS and 7DW8-5 in ultra-low ID volumes (2.5 µL) was completely protective and dose sparing compared to standard volumes (10–50 µL) and induced protective levels of CSP-specific CD8+ T cells in the liver. Our finding that adjuvants and ultra-low volumes are required for ID RAS efficacy may explain why prior reports about higher volumes of unadjuvanted ID RAS proved less effective than IV RAS. The ID route may offer significant translational advantages over the IV route and could improve sporozoite vaccine development. [ABSTRACT FROM AUTHOR]