Project Details

Validating Immune Correlates of Protection in Children to Advance Malaria Vaccines

Liriye (Lydia) Kurtovic, PhD

Summary

BACKGROUND: Malaria is one of the greatest contributors to childhood mortality, and the development of a highly efficacious vaccine is urgently needed. RTS,S is the only malaria vaccine to undergo phase III clinical testing and was recently recommended for use in African children living in regions with high to moderate malaria transmission. While the use of RTS,S is an important milestone, protective efficacy is only 30-50% and rapidly wanes after vaccination. GAP: Vaccine development is challenging as we poorly understand the immune mechanisms that confer protection against malaria. Antibodies play a crucial role, but antibody titer does not predict clinical outcome and is not a strong correlate of protection. Our research identified novel antibody mechanisms that target the malaria-causing parasite, and initial findings suggest these responses are associated with protection. HYPOTHESIS: Specific functional antibody responses induced by the RTS,S malaria vaccine will positively correlate with protection against clinical malaria in children. METHODS: We will quantify functional antibody responses in RTS,S vaccine trials and validate their association with clinical protection and evaluate the longevity of these responses. Specifically, we will measure the functional ability of antibodies to interact with serum complement and Fcγ receptors that are expressed on immune cells. This will be performed using serum collected from phase IIb and III trials performed in African children (>16,000 samples). RESULTS: We found significant associations between specific antibody response types and clinical protection against malaria in children vaccinated with the RTS,S malaria vaccine. IMPACT: Validated correlates of protection will transform vaccine development, and aid the prioritization of new vaccines or inform improvements to the current RTS,S vaccine. Our approaches could be rapidly adapted into other laboratories to advance malaria vaccines and predict clinical outcomes prior to conducting efficacy studies. Website Link: https://www.burnet.edu.au/people/463_liriye_kurtovic

Publications:

Kurtovic L, Feng G, Hysa A, Haghiri A, O'Flaherty K, Wines BD, Santano R, D'Andrea L, Drummer HE, Hogarth PM, Sacarlal J, Fowkes FJI, Simpson JA, Dobaño C, Beeson JG. Antibody mechanisms of protection against malaria in RTS,S-vaccinated children: a post-hoc serological analysis of phase 2 trial. Lancet Microbe. 2024 Aug 7:100898. doi: 10.1016/S2666-5247(24)00130-7. Epub ahead of print. PMID: 39127054.