Friday, May 16, 2025
5/16/2025
Identifying the targets of protective immunity to severe falciparum malaria - Abstract The goal of this R01 resubmission is to discover the targets of naturally acquired protection against severe Plasmodium falciparum malaria and to develop them as novel blood-stage vaccine candidates to complement existing liver-stage vaccines. 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 4, 5.The malaria vaccine pipeline is focused on a remarkably limited repertoire of candidates 6. New candidates are urgently needed, but strategies to identify them are limited. Previously, we developed a highly innovative whole proteome differential screening (WPDS) strategy which identifies the subset of parasite antigens that are recognized by antibodies expressed by resistant individuals but not susceptible individuals. Using this strategy, we discovered Schizont Egress Antigen-1 (PfSEA-1), a 244-kDa parasite antigen that is the target of antibodies which arrest parasites at the schizont stage and are associated with significant protection from severe malaria (SM) in a cohort of n=785 two yr old children. This was the first demonstration that antibodies that block egress can protect against SM in humans 2. Recently, we used WPDS to identify Glutamic Acid Rich Protein (PfGARP), a previously unrecognized vaccine candidate which localized to the exofacial surface of the RBC membrane in trophozoite and early schizont infected RBCs, but not to other parasite stages or uninfected RBC. Polyclonal antibodies to the highly invariant carboxyl terminal of PfGARP (PfGARP-A, aa 411-673) inhibit parasite growth in vitro (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 and vaccination of non-human primates with PfGARP formulated as a lipid encapsulated mRNA results in significant protection from P. falciparum challenge compared to controls 1. 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 SM after only one or two episodes, and this protection can be distinguished from responses that simply control parasitemia 7-11. In the current proposal, we will capitalize on this observation to identify parasite antigens that are targets of antibody responses which develop during the convalescent phase of an episode of SM and protect against future episodes of SM. We will: 1) conduct a case-control study at our field site in a holoendemic region of western Kenya to identify infants and children with severe malaria and matched controls. 2) perform WPDS using sera from this case- control study, and 3) down select candidates for follow-on vaccine studies using a Systems Serology approach including functional antibody, growth inhibition, and human immunoepidemiologic studies.
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