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Background: Overcoming antigenic diversity is a key challenge in the development of effective P. falciparum malaria vaccines. Strategies that promote the generation of antibodies targeting conserved epitopes of vaccine antigens may provide protection against diverse parasites strains. Understanding differences between vaccine-induced and naturally-acquired immunity is important to achieving this goal. Methods: We analysed antibodies generated in a phase 1 human vaccine trial, MSP2-C1, which included two allelic forms MSP2, an abundant vaccine antigen on the merozoites surface. Vaccine-induced responses were assessed for functional activity against multiple parasite strains, and cross-reactivity of antibodies was determined using competition ELISA and epitope mapping approaches. Results: Vaccination induced cytophilic antibody responses with strain-transcending opsonic phagocytosis and complement-fixing function. In contrast to antibodies acquired via natural infection, vaccine-induced antibodies were directed towards conserved epitopes at the C-terminus of MSP2, whereas naturally-acquired antibodies mainly targeted polymorphic epitopes. Functional activity of C-terminal targeted antibodies was confirmed using monoclonal antibodies that promoted opsonic phagocytosis against multiple parasite strains. Conclusion: Vaccination generated markedly different responses to polymorphic antigens than naturally-acquired immunity and targeted conserved functional epitopes. Induction of antibodies targeting conserved regions of malaria antigens provides a promising vaccine strategy to overcome antigenic diversity for developing effective malaria vaccines.
This work was supported by the National Health and Medical Research Council of Australia (NHMRC, Program grant, and Senior research fellowship to JG Beeson and I Mueller, Project Grant, Early Career Fellowship and Career Development Award to MJ Boyle), the Australian Research Council (Future fellowship to JG Beeson), and the Wellcome Trust (F. Osier). The Burnet Institute is supported by the NHMRC for Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support. The MSP2-C1 clinical trial was funded by the PATH Malaria Vaccine Initiative.