Abstract
BackgroundClinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants.Methodology/Principal FindingsWe 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/SignificanceWe 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.
Highlights
The malaria vaccine paradoxes A solitary subunit vaccine marginally [1,2,3,4,5,6] protects children in endemic areas [7,8] against malaria, and only partially protects infants [9,10,11], to malaria-naıve adults [12,13]
Immunity to earlier skinstage parasites does not develop, and endemic populations remain tolerant to continual reinfection [32,33,34] remaining at risk for severe malaria should immunocompetence weaken
Potentially protective [17,35,36,37,38] T cell responses elicited by diverse attenuated-parasite [20,39,40,41,42,43,44,45,46,47,48,49,50,51] and subunit [52,53, 54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69] malaria vaccines, and laboratory infections [35,42,51,70,71,72,73,74,75,76,77] provide sterile immunity [38,47,78,79,80] to infection, yet are ineffective in endemic populations [14,15,81,82,83,84] and are effectively blocked by the parasite [85]
Summary
The malaria vaccine paradoxes A solitary subunit vaccine marginally [1,2,3,4,5,6] protects children in endemic areas [7,8] against malaria, and only partially protects infants [9,10,11], to malaria-naıve adults [12,13]. Protection is blocked only in endemic areas, implying a conditional difference between laboratory and field infections which systematically triggers an immunological block to vaccine function in the field. This rationale pinpoints an activatable immune mechanism which blocks existing T cell responses. Obvious candidates are the normal immune mechanisms suppressing autoimmunity and allergy, or self- and nonself-tolerance. These mechanisms centre largely around suppressive function of regulatory T cell subsets (Tregs) [86,87]. Protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants
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