Identifying the targets of protective immunity to severe falciparum malaria

Of the ~100 malaria vaccine candidates currently under investigation, more than 60% are based on only four parasite antigens and the most advanced vaccine, RTS,S, generates only modest protection 1, 2. In previous studies, a highly innovative whole proteome differential screening strategy was developed which identifies the subset of parasite antigens that are recognized by antibodies expressed by resistant individuals but not susceptible individuals. Using this strategy, Schizont Egress Antigen-1 (PfSEA-1), a 244-kDa parasite antigen was discovered that is the target of antibodies which arrest parasites at the schizont stage and are associated with significant protection from severe malarial disease in a cohort of n=785 two yr old children. This is the first demonstration that antibodies that specifically block egress can protect against severe malaria in humans. In parallel studies, PfGARP was also identified, a previously unrecognized vaccine candidate which localized to the exofacial surface of the RBC membrane in trophozoite infected RBC. Antibodies to the highly invariant carboxyl terminal of PfGARP (PfGARP-A, aa 411-673) inhibit parasite growth in vitro by 99% compared to controls (P < 0.001) by killing trophozoite stage parasites. Numerous mechanistic assays demonstrated that the binding of anti-PfGARP to the surface of the infected RBC induces parasite programed cell death as evidenced by pyknotic nuclear morphology, caspase activation, mitochondrial depolarization, DNA fragmentation, and release of intracellular calcium. In addition, vaccination of non-human primates with PfGARP formulated as a lipid encapsulated mRNA results in significant protection from P. falciparum challenge compared to controls. These preliminary results were based on differential screening using sera from resistant and susceptible individuals with the definition of resistance based solely on parasitemia. Previous work has demonstrated that children develop resistance to severe malaria after only one or two episodes, and this protection is distinct from responses that simply control parasitemia.

NIH Project details

Product Development
Vaccines (Immune Correlates)

Sep 2023 — Aug 2024

$500,144

Kenya
United States