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Addition of histamine to subcutaneously injected Plasmodium berghei sporozoites increases the parasite liver load and could facilitate whole-parasite vaccination.

Pfeil J, Heine JF, Mueller AK - Malar. J. (2015)

Bottom Line: The parasite liver load following subcutaneous SPZ administration can be significantly increased by co-administration of histamine and heparin.However, despite a relatively high parasite liver load, the protective efficacy of histamine-supplemented subcutaneous immunization remains inferior as compared to intravenous SPZ administration.Further investigations are needed to reveal the effect of histamine supplementation and subcutaneous SPZ administration on the acquisition of protective immunity.

View Article: PubMed Central - PubMed

Affiliation: Centre for Childhood and Adolescent Medicine (General Paediatrics), University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany. Johannes.Pfeil@med.uni-heidelberg.de.

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.

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Related in: MedlinePlus

Survival time of malaria-infected animals. Animals were infected by a single injection of 104 SPZ, administered either in PBS (n = 10), or in PBS supplemented with 5 IU of heparin and 1 μg (1 μg sc, n = 10) or 3 μg (3 μg sc, n = 10) of histamine.
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Fig2: Survival time of malaria-infected animals. Animals were infected by a single injection of 104 SPZ, administered either in PBS (n = 10), or in PBS supplemented with 5 IU of heparin and 1 μg (1 μg sc, n = 10) or 3 μg (3 μg sc, n = 10) of histamine.

Mentions: The addition of histamine and heparin decreased the time period to first microscopic detection of parasites in the blood smear (prepatency), and this effect seemed to be dependent on the total dosage of histamine supplementation. Mean prepatency was 6.9 (95% CI 5.1-8.7), 6.5 (4.6-8.4) and 5.5 (4.9-6.1) days in the sc, 1 μg sc and 3 μg sc groups, respectively. In comparison to the sc group, prepatency was significantly shortened in mice that received SPZ together with 3 μg histamine (P <0.05), but not in those that received 1 μg histamine (P = 0.25). In all groups, the mean prepatency was longer than expected after iv infection (usually three to four days), which was confirmed by a small group of four control animals infected with 104 SPZ iv (Figure 1). In addition, the survival time within these groups of SPZ-infected animals was observed. The mean survival time post-infection decreased from 10.8 (95% CI 9.9-11.7) to 10 (8.5-11.5) and 8.8 (8.3-9.3) days in the sc, 1 μg sc and 3 μg sc groups, respectively. The survival time was significantly shortened in animals receiving SPZ supplemented with 3 μg histamine versus sc controls (P <0.001), but not in the 1 μg sc versus sc group (P = 0.22, Figure 2).Figure 1


Addition of histamine to subcutaneously injected Plasmodium berghei sporozoites increases the parasite liver load and could facilitate whole-parasite vaccination.

Pfeil J, Heine JF, Mueller AK - Malar. J. (2015)

Survival time of malaria-infected animals. Animals were infected by a single injection of 104 SPZ, administered either in PBS (n = 10), or in PBS supplemented with 5 IU of heparin and 1 μg (1 μg sc, n = 10) or 3 μg (3 μg sc, n = 10) of histamine.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4318155&req=5

Fig2: Survival time of malaria-infected animals. Animals were infected by a single injection of 104 SPZ, administered either in PBS (n = 10), or in PBS supplemented with 5 IU of heparin and 1 μg (1 μg sc, n = 10) or 3 μg (3 μg sc, n = 10) of histamine.
Mentions: The addition of histamine and heparin decreased the time period to first microscopic detection of parasites in the blood smear (prepatency), and this effect seemed to be dependent on the total dosage of histamine supplementation. Mean prepatency was 6.9 (95% CI 5.1-8.7), 6.5 (4.6-8.4) and 5.5 (4.9-6.1) days in the sc, 1 μg sc and 3 μg sc groups, respectively. In comparison to the sc group, prepatency was significantly shortened in mice that received SPZ together with 3 μg histamine (P <0.05), but not in those that received 1 μg histamine (P = 0.25). In all groups, the mean prepatency was longer than expected after iv infection (usually three to four days), which was confirmed by a small group of four control animals infected with 104 SPZ iv (Figure 1). In addition, the survival time within these groups of SPZ-infected animals was observed. The mean survival time post-infection decreased from 10.8 (95% CI 9.9-11.7) to 10 (8.5-11.5) and 8.8 (8.3-9.3) days in the sc, 1 μg sc and 3 μg sc groups, respectively. The survival time was significantly shortened in animals receiving SPZ supplemented with 3 μg histamine versus sc controls (P <0.001), but not in the 1 μg sc versus sc group (P = 0.22, Figure 2).Figure 1

Bottom Line: The parasite liver load following subcutaneous SPZ administration can be significantly increased by co-administration of histamine and heparin.However, despite a relatively high parasite liver load, the protective efficacy of histamine-supplemented subcutaneous immunization remains inferior as compared to intravenous SPZ administration.Further investigations are needed to reveal the effect of histamine supplementation and subcutaneous SPZ administration on the acquisition of protective immunity.

View Article: PubMed Central - PubMed

Affiliation: Centre for Childhood and Adolescent Medicine (General Paediatrics), University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany. Johannes.Pfeil@med.uni-heidelberg.de.

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.

Show MeSH
Related in: MedlinePlus