Malaria vaccines: facing unknowns

Much of the gain in malaria control, in terms of regional achievements in restricting geographical spread and reducing malaria cases and deaths, can be attributed to large-scale deployment of antimalarial drugs, insecticide-treated bed nets, and early diagnostics. However, despite impressive progress, control efforts have stalled because of logistics, unsustainable delivery, or short-term effectiveness of existing interventions or a combination of these reasons. A highly efficacious malaria vaccine as an additional tool would go a long way, but success in the development of this important intervention remains elusive. Moreover, most of the vaccine candidate antigens that were investigated in early-stage clinical trials, selected partly because of their immunogenicity and abundance during natural malaria infection, were polymorphic or structurally complex or both. Likewise, we have a limited understanding of immune mechanisms that confer protection. We reflect on some considerable technological and scientific progress that has been achieved and the lessons learned.