Malaria's deadly secret: a skin stage.

The role skin plays in malaria infection has long been overlooked. Recent analysis, however, suggests skin-infecting sporozoites initiate rapid suppression of immunity, establishing early tolerance to subsequent lifecycle stages. This explains susceptibility to reinfection by mosquito bite, independent of blood stage-induced immunosuppression or semi-immunity. Vaccine trials corroborate skin-initiated immunosubversion due to skin-infecting forms, tightly correlating bite pre-exposure, live parasites in the skin and endemic vaccine failure. Rapidly advancing skin immunobiology and recently described parasite development in host skin further substantiate the proposed model, consolidating a new concept in parasite biology, exemplified by malaria: natural infection has a defined, potently immunosubversive skin stage, crucially affecting vaccine function and vitally relevant to eradication.

Why functional pre-erythrocytic and bloodstage malaria vaccines fail: a meta-analysis of fully protective immunizations and novel immunological model.

BACKGROUND: Clinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants. METHODOLOGY/PRINCIPAL FINDINGS: We identify and evaluate 1916 immunization studies between 1965-February 2010, and exclude partially or nonprotective results to find 177 completely protective immunization experiments. Detailed reexamination reveals an unexpectedly mundane basis for selective vaccine failure: live malaria parasites in the skin inhibit vaccine function. We next show published molecular and cellular data support a testable, novel model where parasite-host interactions in the skin induce malaria-specific regulatory T cells, and subvert early antigen-specific immunity to parasite-specific immunotolerance. This ensures infection and tolerance to reinfection. Exposure to Plasmodium-infected mosquito bites therefore systematically triggers immunosuppression of endemic vaccine-elicited responses. The extensive vaccine trial data solidly substantiate this model experimentally. CONCLUSIONS/SIGNIFICANCE: We conclude skinstage-initiated immunosuppression, unassociated with bloodstage parasites, systematically blocks vaccine function in the field. Our model exposes novel molecular and procedural strategies to significantly and quickly increase protective efficacy in both pipeline and currently ineffective malaria vaccines, and forces fundamental reassessment of central precepts determining vaccine development. This has major implications for accelerated local eliminations of malaria, and significantly increases potential for eradication.