A review of malaria vaccine clinical projects based on the WHO rainbow table

Development and Phase 3 testing of the most advanced malaria vaccine, RTS,S/AS01, indicates that malaria vaccine R&D is moving into a new phase. Field trials of several research malaria vaccines have also confirmed that it is possible to impact the host-parasite relationship through vaccine-induced immune responses to multiple antigenic targets using different platforms. Other approaches have been appropriately tested but turned out to be disappointing after clinical evaluation. As the malaria community considers the potential role of a first-generation malaria vaccine in malaria control efforts, it is an apposite time to carefully document terminated and ongoing malaria vaccine research projects so that lessons learned can be applied to increase the chances of success for second-generation malaria vaccines over the next 10 years. The most comprehensive resource of malaria vaccine projects is a spreadsheet compiled by WHO thanks to the input from funding agencies, sponsors and investigators worldwide. This spreadsheet, available from WHO's website, is known as "the rainbow table". By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of malaria vaccine projects to be published in the last several years is provided below.     

Bioguided Fractionation and Isolation of an Antiplasmodial Saponin from the Roots of Nauclea xanthoxylon (A.Chev.) Aubrév. (Rubiaceae)

The root extract of Nauclea xanthoxylon (A.Chev.) Aubrév. displayed significant 50 % inhibition concentration (IC₅₀s) of 0.57 and 1.26 μg/mL against chloroquine resistant and sensitive Plasmodium falciparum (Pf) Dd2 and 3D7 strains, respectively. Bio-guided fractionation led to an ethyl acetate fraction with IC₅₀s of 2.68 and 1.85 μg/mL and subsequently, to the new quinovic acid saponin named xanthoxyloside ( 1 ) with IC₅₀s of 0.33 and 1.30 μM, respectively against the tested strains. Further compounds obtained from ethyl acetate and hexane fractions were the known clethric acid ( 2 ), ursolic acid ( 3 ), quafrinoic acid ( 4 ), quinovic acid ( 5 ), quinovic acid 3-O-β-D-fucopyranoside ( 6 ), oleanolic acid ( 7 ), oleanolic acid 3-acetate ( 8 ), friedelin ( 9 ), β-sitosterol ( 10a ), stigmasterol ( 10b ) and stigmasterol 3-O-β-D-glucopyranoside ( 11 ). Their structures were characterised with the aid of comprehensive spectroscopic methods (1 and 2D NMR, Mass). Bio-assays were performed using nucleic acid gel stain (SYBR green I)-based fluorescence assay with chloroquine as reference. Extracts and compounds exhibited good selectivity indices (SIs) of >10. Significant antiplasmodial activities measured for the crude extract, the ethyl acetate fraction and xanthoxyloside ( 1 ) from that fraction can justify the use of the root of N. xanthoxylon in ethnomedicine to treat malaria.     

Effects of isoflurane, halothane, and enflurane on myocardial flow and energy stores in the perfused rat heart

The effect of three volatile anesthetics (halothane, enflurane, and isoflurane) on coronary flow and metabolic state of isolated rat hearts was studied. These anesthetics are coronary dilators and their effects are dose dependent. At 2 MAC (minimum alveolar concentration), isoflurane, enflurane, and halothane increase coronary flow by 114 +/- 5.9, 93 +/- 6.1, and 77 +/- 6.4%, respectively (p less than 0.001). At these concentrations, they also have a modest but significant metabolic effect causing a 30% reduction in myocardial ATP and phosphocreatine levels, with no significant modification in ADP and AMP concentrations. Energy charge and lactate/pyruvate ratio were also unaffected by these anesthetics. The vascular and metabolic effects were reversible within 2 and 30 min, respectively. Perfusion of the hearts with a Krebs-Henseleit solution without Pi did not interfere with the vascular and the metabolic effect of the anesthetics; however, in this case, ATP and phosphocreatine concentration did not return to control levels after their discontinuation despite full recovery of the vascular effect. These data suggest that the volatile anesthetics have direct coronary vascular and myocardial metabolic effects and that these effects occur independently.     

Effects of starvation on valine and alanine transport across the intestinal mucosal border in sea bass,Dicentrarchus labrax

Summary kinetics of intestinal transport of l-alanine and l-valine (substrates of the A-system and the L-system, respectively, in mammals) across the brush-border membrane in sea bass, Dicentrarchus labrax, were studied on intact mucosa using a short-term uptake technique. When fish were starved for 4–8 weeks, total influx (mucosa-to-cell) of valine fell owing to disappearance or modification of the diffusion component. The maximum influx rate of saturable component increased but its affinity (reflected by the Michaelis constant) decreased. Alanine transport by Na⁺-dependent and diffusion pathways was unchanged after starvation Fasting also induced an almost 20% decrease in the length of intestinal microvilli.Abbreviations K _d diffusional constant - K _m Michaelis constant - V _max maximum influx rate     

Effects of selected pharmaceutical products on phagocytic activity in Elliptio complanata mussels

Municipal wastewaters are recognized as a major source of pharmaceutical and personal care products to the aquatic environment, thereby exposing biota to unknown chronic effects. This study sought to examine the immunotoxic effects of pharmaceutical and urban waste products on the freshwater mussel Elliptio complanata. Hemolymph samples were collected and treated in vitro with increasing concentrations of various drugs (bezafibrate, carbamazepine, fluoxetine, gemfibrozil, morphine, naproxen, novobiocin, oxytetracycline, sulfamethazole, sulfapyridine and trimethoprim) and urban waste related chemicals (coprostanol, caffeine, cotinine) for 24 h at 15 degrees C. In a parallel experiment, mussels were caged and placed in two final aeration lagoons for the treatment of domestic wastewaters. At the end of the exposure period, hemolymphs were tested for phagocytic activity, intracellular esterase activity, cell adherence and lipid peroxidation (LPO). The products that most increased phagocytosis were bezafibrate, gemfibrozil and trimethoprim, while novobiocin and morphine reduced its activity. Intracellular esterase activity was reduced most strongly with sulfamethazole, novobiocin, gemfibrozil, bezafibrate and carbamazepine. Cell adherence was decreased by oxytetracycline, novobiocin and naproxen, and increased by gemfibrozil, bezafibrate and sulfapyridine. Exposure to these products also modulated LPO in hemocytes. Coprostanol and naproxen were more potent to reduce LPO while novobiocin and sulfapyridine were the most potent to induce LPO. The potential to induce LPO was positively correlated with the number of functional groups on the molecule (i.e., its nucleophilicity). Mussels exposed to domestic wastewater treatment plant aeration lagoons had decreased intracellular esterase and phagocytic activity as well, suggesting immunosuppression. PPCPs (pharmaceuticals and personal care products) that are recognized to disrupt cytokine signalling network by the nitric oxide pathway and cell permeability were generally the most potent ones. The data suggest that PPCPs have the potential to cause adverse effects on the immune system of bivalves.