Recent data suggest that approaches to developing a subunit blood-stage malaria vaccine may be misdirected. While antigenic polymorphism is recognized as a challenge, efforts to counter this have primarily involved enhancing the quantity and quality of antibody with potent adjuvants, identifying conserved target proteins, or combining multiple antigens to broaden the immune response. However, paradoxically, evidence has emerged that narrowing, rather than broadening, the immune response may be required to obtain an immune response protective against multiple Plasmodium strains. Non-immunodominant, conserved epitopes are crucial. The evidence comes from studying the immune response to red cell surface-expressed antigens but should also be applicable to merozoite surface antigens. Strategies to define the targets of these highly focused immune responses are provided.
