Oral Presentation Lorne Infection and Immunity 2023

Identification of targets of protective antibody responses against Plasmodium vivax malaria using a multifunctional antibody profiling approach (#33)

D. Herbert Opi 1 2 3 , Rhea Longley 4 , Linda Reiling 1 , Kael Schoffer 4 , Yanie Tayipto 4 , Ali Haghiri 5 , Kaitlin Pekin 1 , Jessica Brewster 4 , Damien Drew 1 , Gaqian Feng 1 , Bruce Wines 1 , Danielle Stanisic 6 , Matthias Harbers 7 , Takafumi Tsuboi 8 , Mark Hogarth 1 , Benson Kiniboro 9 , Leanne Robinson 1 , Julie Simpson 5 , Ivo Mueller 4 , James Beeson 1 2 10 11
  1. Burnet Institute of Medical Research and Public Health, Melbourne, VIC, Australia
  2. Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
  3. Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia
  4. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  5. Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia
  6. Institute for Glycomics, Griffith University, Southport, Queensland, Australia
  7. RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Japan
  8. Division of Malaria Research, Proteo-Science Center, Ehime University, Matsuyama, Japan
  9. Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea
  10. Department of Infectious Diseases, Monash University, Melbourne, Victoria, Australia
  11. Department of Microbiology, Monash University, Clayton, Victoria, Australia

A need for highly effective vaccines against malaria has been made more urgent following stalled progress in reducing the global burden of malaria since 2015 and increases in malaria burden from COVID-19 pandemic-related disruptions. While advances in Plasmodium falciparum malaria vaccine development have seen the recent approval of the RTS,S vaccine, very limited progress has been made towards development of a vaccine against P. vivax. No vaccines for P. vivax have completed testing for efficacy in malaria-endemic settings and limited candidates are in the discovery pipeline. P. vivax is the most widespread Plasmodium species and a major cause of malaria outside Africa, with over 3 billion people at risk of infection with P. vivax malaria. A major challenge to developing a P. vivax vaccine is a limited knowledge of the targets of protective immune responses. Antibodies play the major role in acquired immunity to malaria and are likely to act through three major mechanisms: direct inhibition of host cell invasion, recruitment and activation of complement, and interactions with Fcγ-receptors to promote phagocytosis or killing by immune cells. However, knowledge of functional antibody mechanisms in P. vivax immunity is very limited. To address this, we developed novel high throughput multiplex assays to identify the targets of functional antibodies against P. vivax that interact with complement and Fcγ-receptors. In a longitudinal cohort study of 1–3-year-old children from PNG, we measured antibody magnitude (IgG, IgG subclasses and IgM) and antibody functions (complement fixation, FcγR binding, opsonic phagocytosis and avidity) to 30 P. vivax antigens. Using these approaches, we identified known and novel antibody targets and specific functions associated with protection against clinical P. vivax malaria. Using statistical modelling approaches we identify important combinations of antigen-specific antibodies, both magnitude and function, that may provide maximal protection against P. vivax malaria. Our findings identify promising antigens for prioritisation in P. vivax vaccine development, and a knowledge of target-specific functional immune responses that are most important for protective P. vivax immunity.