Sero-epidemiological and functional evaluation of IgG specific for a cysteine protease inhibitor of Plasmodium falciparum, falstatin.

Recently approved malaria pre-erythrocytic vaccines are important public health tools for the reduction of malaria morbidity and mortality. However, these vaccines have shown reduced protection in some of the most vulnerable age groups, require multiple dosing, and have the potential for parasite escape. These limitations have motivated the development of vaccines targeting multiple stages of the parasite life cycle. To ensure a robust pipeline, pre-clinical evaluation of additional malaria vaccine candidate antigens remains a key priority. The P. falciparum cysteine protease inhibitor falstatin can limit the cysteine protease activity of falcipains, controlling proteolysis at the site of merozoite entry on erythrocytes, thereby facilitating parasite invasion. Antibodies against falstatin have been shown to reduce the ability of merozoites to invade erythrocytes, raising the possibility that naturally acquired antibody responses could confer a similar advantage to the host. Here, IgG responses to full-length falstatin (falstatinFL) and two smaller, conserved regions (falstatin35-68 and falstatin289-335) were determined at the pre-malaria season baseline in a prospective cohort study conducted in Kalifabougou, Mali. The presence of anti-falstatin IgG was not associated with reduced risk of clinical malaria overall. However, baseline falstatin seropositivity predicted a non-statistically significant reduction in risk of febrile malaria within the first 30 days after incident parasitemia (log-rank statistic 3.2, P = 0.072). Using in vitro growth inhibitory assays, neither affinity-purified anti-falstatin289-335 IgG nor affinity-purified anti-falstatinFL IgG consistently inhibited P. falciparum blood-stage parasites. Larger cohort studies would be needed to confirm whether pre-existing anti-falstatin antibodies can delay the progression of malaria symptoms after blood-stage infection.