Malaria continues to be a major cause of mortality and morbidity globally and there is a strong need for a highly effective vaccine. The World Health Organization and Malaria Vaccine Funders Group set a strategic goal of achieving malaria vaccines with >75% efficacy by 2030. However, achieving vaccines with sustained high levels of efficacy has been an enduring challenge in malaria vaccine development (1). A fundamental challenge is how can we successfully identify and prioritize targets of protective immunity as vaccine candidates if we do not have a good understanding of the mechanisms and targets of human immunity and if we lack suitable correlates-of-immunity assays to identify and evaluate vaccine candidates? We aimed to address these fundamental questions in our recent study, published in Nature Communications.
Naturally-acquired immunity to malaria develops after repeated infections, and the observation that immunity can develop has long-provided a strong rationale that effective vaccines against malaria are achievable. It is during blood-stage of infection that clinical malaria and severe disease occurs, and a key target of vaccine development is the merozoite form of P. falciparum, which invades human red blood cells and replicates inside them. However, new insights into the targets of immunity to malaria are urgently needed to advance more effective strategies in vaccine development.
We recently established that acquired and vaccine-induced human antibodies to merozoites can fix and activate complement to inhibit parasite replication (2). In our new paper, we provide evidence supporting a critical role for antibody-complement interactions in immunity to malaria in clinical studies of children, and we identify key targets of these antibodies in clinical studies in malaria-endemic populations using new approaches we developed.
First, we demonstrated that complement-fixing activity of antibodies is much more strongly predictive of immunity in a longitudinal cohort study than antibody activity quantified in the current standard reference assay, known as the growth inhibition assay (GIA). To date the GIA has only shown inconsistent and generally weak associations with protective immunity, so our finding suggests new assays for evaluating vaccine candidates may be more informative. We demonstrate that complement-fixing antibodies acquired by children can effectively inhibit P. falciparum replication in vitro, and that human cytophilic antibodies promote complement fixation and activation of the classical complement pathway targeting multiple different merozoite antigens.
Our findings provided the rationale for detailed studies to identify major targets of these functional antibodies in the acquisition of immunity. Therefore, to achieve this, we developed and optimized robust and efficient assays that enabled the quantification of functional antibodies to the multitude of antigens expressed by P. falciparum merozoites. We applied our approaches in a longitudinal cohort of 206 children residing in a malaria-endemic area and we identified several antigen-specific responses that were very strongly associated with protective immunity, suggesting these antigens as promising leads for vaccine development.
We used statistical modelling approaches to evaluate all possible antigen combinations (over 60,000 combinations) for their associations with protective immunity. This analysis revealed that that an optimal combination of just 3 antigens was sufficient as a strong correlate of protection and is likely to be sufficient for achieving high protective efficacy by vaccines. This has important implications for vaccine strategies, and suggests that larger combinations of antigens may offer limited benefit.
Profiling antigen-specific functional antibodies in human studies enables identification of promising leads for vaccine development and the development of assays as correlates of immunity in population studies and clinical trials. Exploiting vaccine targets and strategies that induce strong complement-fixing antibodies may lead to vaccines with greater efficacy in protecting against malaria.
Figure: Targets of malaria vaccine development across the life-cycle of malaria. (from Beeson JG et al, Science Translational Medicine 2019, copyright The Authors)
1. Beeson, J.G., et al. Challenges and strategies for developing efficacious and long-lasting malaria vaccines. Science translational medicine 11(2019).
2. Boyle, M., et al. Human antibodies fix complement to inhibit Plasmodium falciparum invasion of erythrocytes and are associated with protection against clinical malaria. Immunity 42, 580-590 (2015).