Poster Presentation 15th Lorne Infection and Immunity 2025

Targets of Fc-dependent functional antibody responses in immunity to severe Plasmodium falciparum malaria in children (#352)

Grace Wright 1 2 , D. Herbert Opi 1 2 3 , Liriye Kurtovic 1 3 , Kaitlin Pekin 1 4 , Rhea Longley 5 6 , Sandra Chishimba 1 2 , Moses Laman 7 , Laurens Manning 8 , Ivo Mueller 5 , Stephen J. Rogerson 2 , James G. Beeson 1 2 3
  1. Burnet Institute, Melbourne, Australia
  2. Department of Medicine, University of Melbourne, Melbourne, Australia
  3. Central Clinical School and Department of Microbiology, Monash University, Melbourne, Australia
  4. School of Biological Sciences, University of Adelaide, Adelaide, Australia
  5. Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
  6. Department of Medical Biology, University of Melbourne, Melbourne, Australia
  7. Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea
  8. Department of Infectious Diseases, University of Western Australia, Perth, Australia

Plasmodium falciparum malaria is a major cause of morbidity and mortality worldwide with young children being particularly susceptible to severe malaria. Vaccines are a key intervention. However, the vaccines that are currently licensed have suboptimal efficacy, particularly against severe malaria, and do not target the blood stage of infection associated with clinical symptoms and severe disease. A limited understanding of the targets and mechanisms of action of immunity against severe malaria is hindering the development of vaccines with greater efficacy. Antibodies are important in immunity and may mediate protection through different mechanisms, including Fc-dependent functional antibody responses. While Fc-dependent functional antibody responses are important in protective immunity against uncomplicated malaria, their role, along with the specific antigenic targets, in severe malaria remains unknown. In this study, we aimed to identify blood stage parasite antigens targeted by Fc-dependent functional antibodies and evaluate their association with protection against severe malaria in children from Papua New Guinea (severe; n=201 and uncomplicated; n=163). Using a high throughput bead-based multiplex assay, we evaluated the functional activity of antibodies to interact with Fcγ receptors I, IIa, and IIIa/b, as well as IgG and IgM, for 33 Plasmodium falciparum antigens. We found an increase in Fcγ receptor binding antibody responses to several antigens was associated with a substantially reduced risk of severe malaria, including antibody responses to current vaccine candidate antigens as well as less-studied antigens. Furthermore, an increase in antibody responses to a breadth of both antigens and Fcγ receptors was associated with a greater reduction in the risk of severe malaria compared to individual responses. Overall, we identified specific antigens that were targeted by Fc-dependent functional antibody responses and associated with protection against severe malaria. These findings will inform the development of highly efficacious vaccines to reduce the global burden of severe and life-threatening malaria.