The endemic dilemma: why whole sporozoite malaria vaccine efficacy falls in the field

Whole sporozoite vaccines (WSVs) are the most effective malaria vaccines developed to date. However, their durable efficacy declines sharply when moving from homologous CHMI studies to field trials in endemic regions. We argue this reduced efficacy reflects the complex context of vaccine deployment rather than a single cause. The antigen mismatch hypothesis postulates that limited genetic diversity in current vaccines fails to capture the diversity of field parasites, reducing immune recognition. The host-context hypothesis describes how genetics, infection history, microbiome, and nutrition influence vaccine outcomes. We propose that the future of malaria vaccines will depend on integrating parasite genomics, systems immunology, and the development of animal models which more accurately depict the context of individuals living in malaria endemic regions.