title: Why functional pre-erythrocytic and bloodstage malaria vaccines fail: a meta-analysis of fully protective immunizations and novel immunological model.
abstract: BACKGROUND
  Clinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants.
  
  
  RESULTS
  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
  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.
authors.affiliation: Deutsches Krebsforschungszentrum, Heidelberg, Germany. lys@malariaresearchfoundation.com
authors.forename: D Lys
authors.initials: DL
authors.lastname: Guilbride
authors.forename: Pawel
authors.initials: P
authors.lastname: Gawlinski
authors.forename: Patrick D L
authors.initials: PD
authors.lastname: Guilbride
mesh_terms: D000818:Animals; D002738:Chloroquine / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology*; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007114:Immunization; D056747:Immunomodulation / Q000187:drug effects; D008018:Life Cycle Stages / Q000187:drug effects / Q000276:immunology*; D008288:Malaria / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000276:immunology*; D018448:Models, Immunological; D010961:Plasmodium / Q000187:drug effects / Q000254:growth & development*; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000469:parasitology; D013997:Time Factors
chemical_list: D017780:Malaria Vaccines; D002738:Chloroquine