title: Addition of histamine to subcutaneously injected Plasmodium berghei sporozoites increases the parasite liver load and could facilitate whole-parasite vaccination.
abstract: BACKGROUND
  Whole-parasite immunization remains the benchmark in malaria vaccine development. A major bottleneck in the translation of whole-parasite immunization towards routine vaccination is the mode of administration, since high degrees of protection are currently only achieved by intravenous, and not by intradermal or subcutaneous injection of viable parasites. It is known that only a small proportion of subcutaneously administered parasites reach the subsequent liver stage and low parasite liver load was shown to be associated with low protective efficacy. The objective of this analysis was to evaluate whether the liver load following subcutaneous parasite injection could be augmented by co-administration of pro-inflammatory or anti-coagulatory drugs.
  
  
  METHODS
  In the C57BL/6 Plasmodium berghei ANKA model, the clinical outcome (time to patent blood stage infection and survival) and relative parasite liver load was assessed in mice infected by subcutaneous or intramuscular sporozoite (SPZ) administration in the presence or absence of histamine and heparin supplementation in comparison to intravenously administered SPZ. In addition, a vaccination experiment was carried out to assess the protective efficacy of an improved, histamine-supplemented subcutaneous immunization regimen.
  
  
  RESULTS
  The parasite liver load following subcutaneous SPZ administration can be significantly increased by co-administration of histamine and heparin. A dose-dependent relation between parasite liver load and histamine dosage was observed. However, despite a relatively high parasite liver load, the protective efficacy of histamine-supplemented subcutaneous immunization remains inferior as compared to intravenous SPZ administration.
  
  
  CONCLUSIONS
  Histamine supplementation might facilitate the future development of a non-intravenous whole-parasite vaccine. Further investigations are needed to reveal the effect of histamine supplementation and subcutaneous SPZ administration on the acquisition of protective immunity.
authors: Centre for Childhood and Adolescent Medicine (General Paediatrics), University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany. Johannes.Pfeil@med.uni-heidelberg.de.|Centre for Infectious Diseases, Parasitology Unit, University Hospital, Heidelberg, Germany. Johannes.Pfeil@med.uni-heidelberg.de.|German Centre for Infectious Diseases (DZIF), Heidelberg, Germany. Johannes.Pfeil@med.uni-heidelberg.de.
authors: Johannes
authors: J
authors: Pfeil
authors: Centre for Infectious Diseases, Parasitology Unit, University Hospital, Heidelberg, Germany. jan_frederik_heine@yahoo.de.
authors: Jan F
authors: JF
authors: Heine
authors: Centre for Infectious Diseases, Parasitology Unit, University Hospital, Heidelberg, Germany. ann-kristin.mueller@uni-heidelberg.de.|German Centre for Infectious Diseases (DZIF), Heidelberg, Germany. ann-kristin.mueller@uni-heidelberg.de.
authors: Ann-Kristin
authors: AK
authors: Mueller
mesh_terms: D000818:Animals; D006632:Histamine / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000469:parasitology*; D008288:Malaria / Q000276:immunology / Q000401:mortality / Q000469:parasitology / Q000517:prevention & control; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D008810:Mice, Inbred C57BL; D059208:Parasite Load; D010962:Plasmodium berghei / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology*
chemical_list: D017780:Malaria Vaccines; D006632:Histamine
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