Center for Clinical Vaccinology and Tropical Medicine

Oxford, United Kingdom

Center for Clinical Vaccinology and Tropical Medicine

Oxford, United Kingdom
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Boudhar A.,National University of Singapore | Ng X.W.,National University of Singapore | Loh C.Y.,National University of Singapore | Chia W.N.,National University of Singapore | And 5 more authors.
European Journal of Medicinal Chemistry | Year: 2016

Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies. © 2016 Published by Elsevier Masson SAS.

Ogwang C.,Kenya Medical Research Institute | Kimani D.,Kenya Medical Research Institute | Edwards N.J.,Center for Clinical Vaccinology and Tropical Medicine | Edwards N.J.,Jenner Institute | And 60 more authors.
Science Translational Medicine | Year: 2015

Protective immunity to the liver stage of the malaria parasite can be conferred by vaccine-induced T cells, but no subunit vaccination approach based on cellular immunity has shown efficacy in field studies. We randomly allocated 121 healthy adult male volunteers in Kilifi, Kenya, to vaccination with the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the malaria peptide sequence ME-TRAP (the multiple epitope string and thrombospondin-related adhesion protein), or to vaccination with rabies vaccine as a control. We gave antimalarials to clear parasitemia and conducted PCR (polymerase chain reaction) analysis on blood samples three times a week to identify infection with the malaria parasite Plasmodium falciparum. On Cox regression, vaccination reduced the risk of infection by 67% [95% confidence interval (CI), 33 to 83%; P = 0.002] during 8 weeks of monitoring. T cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio,0.24; 95% CI, 0.08 to 0.75; P = 0.016).

Boudhar A.,National University of Singapore | Ng X.W.,National University of Singapore | Loh C.Y.,National University of Singapore | Chia W.N.,National University of Singapore | And 5 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2016

Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Ch'ng J.-H.,National University of Singapore | Renia L.,Agency for Science, Technology and Research Singapore | Nosten F.,Shoklo Malaria Research Unit | Nosten F.,Center for Clinical Vaccinology and Tropical Medicine | Tan K.S.W.,National University of Singapore
Trends in Parasitology | Year: 2012

Although resistance to chloroquine (CQ) has relegated it from modern chemotherapeutic strategies to treat . Plasmodium falciparum malaria, new evidence suggests that higher doses of the drug may exert a different killing mechanism and offers this drug a new lease of life. Whereas the established antimalarial mechanisms of CQ are usually associated with nanomolar levels of the drug, micromolar levels of CQ trigger a distinct cell death pathway involving the permeabilization of the digestive vacuole of the parasite and a release of hydrolytic enzymes. In this paper, we propose that this pathway is a promising antimalarial strategy and suggest that revising the CQ treatment regimen may elevate blood drug levels to trigger this pathway without increasing the incidence of adverse reactions. © 2012 Elsevier Ltd.

Ch'Ng J.-H.,National University of Singapore | Mok S.,Nanyang Technological University | Bozdech Z.,Nanyang Technological University | Lear M.J.,Tohoku University | And 5 more authors.
Scientific Reports | Year: 2013

Due to the widespread prevalence of resistant parasites, chloroquine (CQ) was removed from front-line antimalarial chemotherapy in the 1990s despite its initial promise of disease eradication. Since then, resistance-conferring mutations have been identified in transporters such as the PfCRT, that allow for the efflux of CQ from its primary site of action, the parasite digestive vacuole. Chemosensitizing/chemoreversing compounds interfere with the function of these transporters thereby sensitizing parasites to CQ once again. However, compounds identified thus far have disappointing in vivo efficacy and screening for alternative candidates is required to revive this strategy. In this study, we propose a simple and direct means to rapidly screen for such compounds using a fluorescent-tagged CQ molecule. When this screen was applied to a small library, seven novel chemosensitizers (octoclothepin, methiothepin, metergoline, loperamide, chlorprothixene, L-703,606 and mibefradil) were quickly elucidated, including two which showed greater potency than the classical chemosensitizers verapamil and desipramine.

PubMed | QIMR Berghofer Medical Research Institute, Center for Clinical Vaccinology and Tropical Medicine, Imperial College London, Walter Reed Army Institute of Research and 8 more.
Type: Journal Article | Journal: The Journal of infectious diseases | Year: 2016

Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point.Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data.FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine- or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR.FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates.NCT02044198.

Imwong M.,Mahidol University | Russell B.,Agency for Science, Technology and Research Singapore | Suwanarusk R.,Agency for Science, Technology and Research Singapore | Nzila A.,Kenya Medical Research Institute | And 11 more authors.
Journal of Infectious Diseases | Year: 2011

Resistance of vivax malaria to treatment with antifolates, such as pyrimethamine (Pyr), is spreading as mutations in the dihydrofolatereductase (dhfr) genes are selected and disseminated. We tested the antitumor drug methotrexate (MTX), a potent competitive inhibitor of dhfr, against 11 Plasmodium vivax isolates ex vivo, 10 of which had multiple dhfr mutations associated with Pyr resistance. Despite high-grade resistance to Pyr (median 50% inhibitory concentration [IC50], 13,345 nM), these parasites were all highly susceptible to MTX (median IC50, 2.6 nM). Given its potency against Pyr-resistant P. vivax, the antimalarial potential of MTX deserves further investigation. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

Kosaisavee V.,Mahidol University | Lek-Uthai U.,Mahidol University | Suwanarusk R.,Agency for Science, Technology and Research Singapore | Gruner A.C.,Agency for Science, Technology and Research Singapore | And 6 more authors.
PLoS ONE | Year: 2012

Background: Plasmodium vivax merozoites specifically invade reticulocytes. Until recently, two reticulocyte-binding proteins (Pvrbp1 and Pvrbp2) expressed at the apical pole of the P. vivax merozoite were considered to be involved in reticulocyte recognition. The genome sequence recently obtained for the Salvador I (Sal-I) strain of P. vivax revealed additional genes in this family, and in particular Pvrbp2a, Pvrbp2b (Pvrbp2 has been renamed as Pvrbp2c) and two pseudogenes Pvrbp2d and Pvrbp3. It had been previously found that Pvrbp2c is substantially more polymorphic than Pvrbp1. The primary goal of this study was to ascertain the level of polymorphism of these new genes. Methodology/Principal Findings: The sequence of the Pvrbp2a, Pvrbp2b, Pvrbp2d and Pvrbp3 genes were obtained by amplification/cloning using DNA purified from four isolates collected from patients that acquired the infection in the four cardinal regions of Thailand (west, north, south and east). An additional seven isolates from western Thailand were analyzed for gene copy number variation. There were significant polymorphisms exhibited by these genes (compared to the reference Sal-I strain) with the ratio of mutations leading to a non-synonymous or synonymous amino acid change close to 3:1 for Pvrbp2a and Pvrbp2b. Although the degree of polymorphism exhibited by these two genes was higher than that of Pvrbp1, it did not reach the exceptional diversity noted for Pvrbp2c. It was interesting to note that variations in the copy number of Pvrbp2a and Pvrbp2b occurred in some isolates. Conclusions/Significance: The evolution of different members of the Pvrbp2 family and their relatively high degree of polymorphism suggests that the proteins encoded by these genes are important for parasite survival and are under immune selection. Our data also shows that there are highly conserved regions in rbp2a and rbp2b, which might provide suitable targets for future vaccine development against the blood stage of P. vivax. © 2012 Kosaisavee et al.

Burgoine K.L.,Shoklo Malaria Research Unit | Burgoine K.L.,University of Oxford | Bancone G.,Shoklo Malaria Research Unit | Bancone G.,Mahidol University | And 3 more authors.
Malaria Journal | Year: 2010

Background: Primaquine is currently the only medication used for radical cure of Plasmodium vivax infection. Unfortunately, its use is not without risk. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency have an increased susceptibility to haemolysis when given primaquine. This potentially fatal clinical syndrome can be avoided if patients are tested for G6PD deficiency and adequately informed before being treated. Case presentation. A 35-year old male presented to our clinic on the Thai-Burmese border with a history and clinical examination consistent with intravascular haemolysis. The patient had been prescribed primaquine and chloroquine four days earlier for a P. vivax infection. The medication instructions had not been given in a language understood by the patient and he had not been tested for G6PD deficiency. The patient was not only G6PD deficient but misunderstood the instructions and took all his primaquine tablets together. With appropriate treatment the patient recovered and was discharged home a week later. Conclusions. Whilst primaquine remains the drug of choice to eradicate hypnozoites and control P. vivax transmission, the risks associated with its use must be minimized during its deployment. In areas where P. vivax exists, patients should be tested for G6PD deficiency and adequately informed before administration of primaquine. © 2010 Burgoine et al; licensee BioMed Central Ltd.

Russell B.,Agency for Science, Technology and Research Singapore | Suwanarusk R.,Agency for Science, Technology and Research Singapore | Borlon C.,Institute of Tropical Medicine | Costa F.T.M.,University of Campinas | And 18 more authors.
Blood | Year: 2011

Currently, there are no reliable RBC invasion assays to guide the discovery of vaccines against Plasmodium vivax, the most prevalent malaria parasite in Asia and South America. Here we describe a protocol for an ex vivo P vivax invasion assay that can be easily deployed in laboratories located in endemic countries. The assay is based on mixing enriched cord blood reticulocytes with matured, trypsin-treated P vivax schizonts concentrated from clinical isolates. The reliability of this assay was demonstrated using a large panel of P vivax isolates freshly collected from patients in Thailand. © 2011 by The American Society of Hematology.

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