Kampala, Uganda
Kampala, Uganda

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Grant
Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: PEOPLE-2007-3-1-IAPP | Award Amount: 1.87M | Year: 2008

People living in malaria endemic areas develop, with time, a form of immunity to infection and clinical disease mediated by antibodies directed against P. falciparum antigens. Currently there are no assays or clinical parameters that predict whether an exposed person is protected against malaria. This represents a major obstacle for vaccine development. Here research institutions and industrial partners, combining cutting edge expertise in protein microarrays, immunoassay development, immunology, protein expression and epidemiology join their efforts with the objective of translating the genome sequence information of Plasmodium falciparum into a tool to unravel correlates of protection against human malaria. Recombinant P. falciparum proteins, encompassing the repertoire of secreted and surface antigens, will be printed onto microarrays to develop an immunoassay capable of unraveling antibodies directed against a vast number of parasite molecules. This assay will be utilized to compare the antigen-antibody recognition profiles of protected and non-protected persons in malaria-exposed communities, thus facilitating the identification of the antigens that either alone or in combination function as targets of protective immunity. The underlying project structure in terms of research activities, task distribution and management has been planned with the priority of facilitating the interactions of human resources, between academic institutions and industry. Exchange of staff and networking activities will bridge the scientific and cultural differences existing between the academic and industrial partners. Exchange of scientific knowledge and technical skill will unleash the full potential of the collective expertise of the participating laboratories towards the objectives of the proposal and will be instrumental in building collaborative links that will extend beyond the duration of the project.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-CSA-Infra | Phase: INFRA-2008-1.1.1 | Award Amount: 10.78M | Year: 2009

Mosquitoes transmit a variety of infectious diseases that cause a tremendous burden to public health. Due to climate changes and to the increase in international trade and tourism the threats posed by mosquitoes are increasingly affecting large parts of Europe, causing understandable concerns among the populations of many Member States. Control methods, mainly based on insecticide usage, are struggling to cope with the challenges posed by the biology and ecology of mosquito vectors. INFRAVEC aims at bridging the gap between the recent advances in transgenic technology and its implementation as a novel powerful approach for vector control. To this aim, a large European Infrastructure will be established, in which the coordination of efforts, expertise and facilities provided by the individual research groups and institutions will bolster and considerably expand the overall research capabilities of the research community. INFRAVEC will operate, through a number of Networking, Joint Research, Transnational and Service activities, towards the objective of considerably strengthening research capability in Europe by sharing knowledge, resources and technology. INFRAVEC will mainly focus on Anopheles gambiae, the major vector of malaria, and Aedes albopictus, a viral disease vector that is rapidly spreading through Europe. Four Infrastructure facilities will be integrated in the project: 1) the Genetically Modified mosquito laboratory of Imperial College London; 2) the Mosquito Mass-rearing facility at the Centro Agricoltura ed Ambiente (with the support of the International Atomic Energy Agency); 3) the Bioinformatics facility at EMBLEBI, UK; and 4) the Mosquito Confined Release facility at ISRIM. INFRAVEC will provide a formidable research capability to external users and facilitate the performance of five research projects aimed at utilizing basic knowledge of mosquito genetics and biology in an unprecedented effort to develop novel opportunities for mosquito control.


Amato R.,Wellcome Trust Sanger Institute | Amato R.,Oxford Genetics | Miotto O.,Wellcome Trust Sanger Institute | Miotto O.,Oxford Genetics | And 118 more authors.
eLife | Year: 2016

The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions. © 2016, eLife Sciences Publications Ltd. All rights reserved.


Palacpac N.M.Q.,Osaka University | Ntege E.,Med Biotech Laboratories | Yeka A.,Med Biotech Laboratories | Yeka A.,Makerere University | And 22 more authors.
PLoS ONE | Year: 2013

Background:Up to now a malaria vaccine remains elusive. The Plasmodium falciparum serine repeat antigen-5 formulated with aluminum hydroxyl gel (BK-SE36) is a blood-stage malaria vaccine candidate that has undergone phase 1a trial in malaria-naive Japanese adults. We have now assessed the safety and immunogenicity of BK-SE36 in a malaria endemic area in Northern Uganda.Methods:We performed a two-stage, randomized, single-blinded, placebo-controlled phase 1b trial (Current Controlled trials ISRCTN71619711). A computer-generated sequence randomized healthy subjects for 2 subcutaneous injections at 21-day intervals in Stage1 (21-40 year-olds) to 1-mL BK-SE36 (BKSE1.0) (n = 36) or saline (n = 20) and in Stage2 (6-20 year-olds) to BKSE1.0 (n = 33), 0.5-mL BK-SE36 (BKSE0.5) (n = 33), or saline (n = 18). Subjects and laboratory personnel were blinded. Safety and antibody responses 21-days post-second vaccination (Day42) were assessed. Post-trial, to compare the risk of malaria episodes 130-365 days post-second vaccination, Stage2 subjects were age-matched to 50 control individuals.Results:Nearly all subjects who received BK-SE36 had induration (Stage1, n = 33, 92%; Stage2, n = 63, 96%) as a local adverse event. No serious adverse event related to BK-SE36 was reported. Pre-existing anti-SE36 antibody titers negatively correlated with vaccination-induced antibody response. At Day42, change in antibody titers was significant for seronegative adults (1.95-fold higher than baseline [95% CI, 1.56-2.43], p = 0.004) and 6-10 year-olds (5.71-fold [95% CI, 2.38-13.72], p = 0.002) vaccinated with BKSE1.0. Immunogenicity response to BKSE0.5 was low and not significant (1.55-fold [95% CI, 1.24-1.94], p = 0.75). In the ancillary analysis, cumulative incidence of first malaria episodes with ≥5000 parasites/μL was 7 cases/33 subjects in BKSE1.0 and 10 cases/33 subjects in BKSE0.5 vs. 29 cases/66 subjects in the control group. Risk ratio for BKSE1.0 was 0.48 (95% CI, 0.24-0.98; p = 0.04).Conclusion:BK-SE36 is safe and immunogenic. The promising potential of BK-SE36, observed in the follow-up study, warrants a double-blind phase 1/2b trial in children under 5 years.Trial Registration:Controlled-Trials.com ISRCTN71619711. © 2013 Palacpac et al.


PubMed | Tokyo Women's Medical University, Juntendo University, St Marys Hospital Lacor, Gulu University and 4 more.
Type: Journal Article | Journal: Malaria journal | Year: 2017

Individual drug treatment may select resistant parasites in the human body, a process termed in vivo selection. Some single nucleotide polymorphisms in Plasmodium falciparum chloroquine-resistance transporter (pfcrt) and multidrug resistance gene 1 (pfmdr1) genes have been reportedly selected after artemether-lumefantrine treatment. However, there is a paucity of data regarding in vivo selection of P. falciparum Kelch propeller domain (pfkelch13) polymorphisms, responsible for artemisinin-resistance in Asia, and six putative background mutations for artemisinin resistance; D193Y in ferredoxin, T484I in multiple resistance protein 2, V127M in apicoplast ribosomal protein S10, I356T in pfcrt, V1157L in protein phosphatase and C1484F in phosphoinositide-binding protein.Artemether-lumefantrine efficacy study with a follow-up period of 28days was conducted in northern Uganda in 2014. The above-mentioned genotypes were comparatively analysed before drug administration and on days; 3, 7, and 28days after treatment.In 61 individuals with successful follow-up, artemether-lumefantrine treatment regimen was very effective with PCR adjusted efficacy of 95.2%. Among 146 isolates obtained before treatment, wild-type alleles were observed in 98.6% of isolates in pfkelch13 and in all isolates in the six putative background genes except I356T in pfcrt, which had 2.4% of isolates as mixed infections. In vivo selection study revealed that all isolates detected in the follow-up period harboured wild type alleles in pfkelch13 and the six background genes.Mutations in pfkelch13 and the six background genes may not play an important role in the in vivo selection after artemether-lumefantrine treatment in Uganda. Different mechanisms might rather be associated with the existence of parasites after treatment.


Ribacke U.,Karolinska Institutet | Ribacke U.,Harvard University | Moll K.,Karolinska Institutet | Albrecht L.,Karolinska Institutet | And 10 more authors.
PLoS ONE | Year: 2013

To be able to robustly propagate P. falciparum at optimal conditions in vitro is of fundamental importance for genotypic and phenotypic studies of both established and fresh clinical isolates. Cryo-preserved P. falciparum isolates from Ugandan children with severe or uncomplicated malaria were investigated for parasite phenotypes under different in vitro growth conditions or studied directly from the peripheral blood. The parasite cultures showed a minimal loss of parasite-mass and preserved percentage of multiple infected pRBCs to that in peripheral blood, maintained adhesive phenotypes and good outgrowth and multiplication rates when grown in suspension and supplemented with gas. In contrast, abnormal and greatly fluctuating levels of multiple infections were observed during static growth conditions and outgrowth and multiplication rates were inferior. Serum, as compared to Albumax, was found necessary for optimal presentation of PfEMP1 at the pRBC surface and/or for binding of serum proteins (immunoglobulins). Optimal in vitro growth conditions of P. falciparum therefore include orbital shaking (50 rev/min), human serum (10%) and a fixed gas composition (5% O2, 5% CO2, 90% N2). We subsequently established 100% of 76 frozen patient isolates and found rosetting with schizont pRBCs in every isolate (>26% schizont rosetting rate). Rosetting during schizogony was often followed by invasion of the bound RBC as seen by regular and time-lapse microscopy as well as transmission electron microscopy. The peripheral parasitemia, the level of rosetting and the rate of multiplication correlated positively to one another for individual isolates. Rosetting was also more frequent with trophozoite and schizont pRBCs of children with severe versus uncomplicated malaria (p<0.002; p<0.004). The associations suggest that rosetting enhances the ability of the parasite to multiply within the human host. © 2013 Ribacke et al.


Olobo-Okao J.,Makerere University | Olobo-Okao J.,Med Biotech Laboratories | Sagaki P.,Amudat Hospital
Pan African Medical Journal | Year: 2014

Visceral leishmaniasis (VL) or kala azar is a fatal and neglected disease caused by protozoan parasites. It occurs worldwide including north-eastern Uganda. This review gives a historical account of and reviews available literature on VL in Uganda to raise more awareness about the disease. Information was collected from: MEDLINE searches; records of Ministry of Health (Uganda), Amudat hospital records; records of NGOs and multilateral institutions; dissertations and personal communication. Results show that VL in Uganda was first reported in the 1950's, followed by almost four decades of neglect. Earlier records from the ministry of health and Amudat hospital on VL are also incomplete. From early 2000, reports mainly on the disease management and risk factors, started to appear in the literature. Management of VL has mainly been by NGOs and multilateral institutions including MSF Swiss. Currently DNDi is funding its management and clinical trials in Amudat hospital through LEAP. New cases of VL were reported recently from Moroto and Kotido districts and more patients continue to be received from these areas. In conclusion, management of VL is well established in Amudat hospital. However its sustainability and wider coverage remains a challenge. First-line drugs have now been registered in the country. Visceral leishmaniasis is apparently more widespread in north-eastern Uganda than originally thought. Research and surveillance on leishmaniasis is still weak. Strengthening the capacity of local institutions to; conduct surveillance and research, combined with effective management should mitigate VL in Uganda. © Joseph Olobo-Okao et al.


Palacpac N.M.Q.,Osaka University | Ntege E.,Med Biotech Laboratories | Ntege E.,Ehime University | Balikagala B.,Med Biotech Laboratories | And 13 more authors.
International Journal of Environmental Research and Public Health | Year: 2014

Reference intervals for common hematological and clinical chemistry parameters constitute an important basis for health care. Moreover, with increasing priority in drug and vaccine development for infectious diseases in Africa, the first priority is the safety evaluation and tolerability of the candidate interventions in healthy populations. To accurately assess health status and address adverse events, clinical reference intervals in the target population are necessary. We report on hematological and biochemical indices from healthy volunteers who participated in a clinical trial in Lira, northern Uganda. Median and nonparametric 95% percentiles on five hematology and 15 biochemistry analytes are shown. Although most hematological analytes conformed to reported reference intervals and trends in Africa, literature review from different African countries highlight the need for a region-specific children reference interval that can be appropriate for the population.


Yagi M.,Osaka University | Bang G.,Institute Pasteur Paris | Tougan T.,Osaka University | Palacpac N.M.Q.,Osaka University | And 9 more authors.
PLoS ONE | Year: 2014

The malaria vaccine candidate antigen, SE36, is based on the N-terminal 47 kDa domain of Plasmodium falciparum serine repeat antigen 5 (SERA5). In epidemiological studies, we have previously shown the inhibitory effects of SE36 specific antibodies on in vitro parasite growth and the negative correlation between antibody level and malaria symptoms. A phase 1 b trial of the BK-SE36 vaccine in Uganda elicited 72% protective efficacy against symptomatic malaria in children aged 6- 20 years during the follow-up period 130-365 days post-second vaccination. Here, we performed epitope mapping with synthetic peptides covering the whole sequence of SE36 to identify and map dominant epitopes in Ugandan adult serum presumed to have clinical immunity to P. falciparum malaria. High titer sera from the Ugandan adults predominantly reacted with peptides corresponding to two successive N-terminal regions of SERA5 containing octamer repeats and serine rich sequences, regions of SERA5 that were previously reported to have limited polymorphism. Affinity purified antibodies specifically recognizing the octamer repeats and serine rich sequences exhibited a high antibody-dependent cellular inhibition (ADCI) activity that inhibited parasite growth. Furthermore, protein structure predictions and structural analysis of SE36 using spectroscopic methods indicated that N-terminal regions possessing inhibitory epitopes are intrinsically unstructured. Collectively, these results suggest that strict tertiary structure of SE36 epitopes is not required to elicit protective antibodies in naturally immune Ugandan adults. © 2014 Yagi et al.

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