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      Synergistic malaria vaccine combinations identified by systematic antigen screening

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Malaria still kills hundreds of thousands of children each year. Malaria vaccine development is complicated by high levels of parasite genetic diversity, which makes single target vaccines vulnerable to the development of variant-specific immunity. To overcome this hurdle, we systematically screened a panel of 29 blood-stage antigens from the most deadly human malaria parasite, Plasmodium falciparum. We identified several targets that were able to inhibit erythrocyte invasion in two genetically diverse strains. Testing these targets in combination identified several pairs that blocked invasion more effectively in combination than in isolation. Video microscopy and studies of natural immune responses to malaria in patients suggest that targeting multiple steps in invasion is more likely to produce a synergistic vaccine response.


          A highly effective vaccine would be a valuable weapon in the drive toward malaria elimination. No such vaccine currently exists, and only a handful of the hundreds of potential candidates in the parasite genome have been evaluated. In this study, we systematically evaluated 29 antigens likely to be involved in erythrocyte invasion, an essential developmental stage during which the malaria parasite is vulnerable to antibody-mediated inhibition. Testing antigens alone and in combination identified several strain-transcending targets that had synergistic combinatorial effects in vitro, while studies in an endemic population revealed that combinations of the same antigens were associated with protection from febrile malaria. Video microscopy established that the most effective combinations targeted multiple discrete stages of invasion, suggesting a mechanistic explanation for synergy. Overall, this study both identifies specific antigen combinations for high-priority clinical testing and establishes a generalizable approach that is more likely to produce effective vaccines.

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          Most cited references37

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          The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015

          Since the year 2000, a concerted campaign against malaria has led to unprecedented levels of intervention coverage across sub-Saharan Africa. Understanding the effect of this control effort is vital to inform future control planning. However, the effect of malaria interventions across the varied epidemiological settings of Africa remains poorly understood owing to the absence of reliable surveillance data and the simplistic approaches underlying current disease estimates. Here we link a large database of malaria field surveys with detailed reconstructions of changing intervention coverage to directly evaluate trends from 2000 to 2015 and quantify the attributable effect of malaria disease control efforts. We found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015. We estimate that interventions have averted 663 (542–753 credible interval) million clinical cases since 2000. Insecticide-treated nets, the most widespread intervention, were by far the largest contributor (68% of cases averted). Although still below target levels, current malaria interventions have substantially reduced malaria disease incidence across the continent. Increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance, should form a cornerstone of post-2015 control strategies.
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            Spread of artemisinin resistance in Plasmodium falciparum malaria.

            Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).
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              Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial.

              The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose.

                Author and article information

                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                7 November 2017
                23 October 2017
                23 October 2017
                : 114
                : 45
                : 12045-12050
                [1] aMalaria Programme, Wellcome Trust Sanger Institute , Cambridge CB10 1SA, United Kingdom;
                [2] bCell Surface Signalling Laboratory, Wellcome Trust Sanger Institute , Cambridge CB10 1SA, United Kingdom;
                [3] cCavendish Laboratory, University of Cambridge , Cambridge CB3 0HE, United Kingdom;
                [4] dDivision of Infectious Diseases, Department of Medicine, Indiana University School of Medicine , Indianapolis, IN 46202;
                [5] eMalaria Research and Training Centre, Department of Epidemiology of Parasitic Diseases, International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako , Bamako, Mali;
                [6] fLaboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Rockville, MD 20852
                Author notes
                4To whom correspondence should be addressed. Email: julian.rayner@ 123456sanger.ac.uk .

                Edited by Rino Rappuoli, GlaxoSmithKline Vaccines, Siena, Italy, and approved September 25, 2017 (received for review February 24, 2017)

                Author contributions: L.Y.B., G.T.P., P. Cicuta, T.M.T., G.J.W., and J.C.R. designed research; L.Y.B., G.T.P., Y.-C.L., M.D.M., N.C., A.K., P. Cawkill, C.C., N.M.-S., and T.M.T. performed research; T.S., O.K.D., B.T., P.D.C., and P. Cicuta contributed new reagents/analytic tools; L.Y.B., G.T.P., Y.-C.L., M.D.M., N.C., A.K., P. Cawkill, T.S., C.C., T.M.T., G.J.W., and J.C.R. analyzed data; and L.Y.B., G.T.P., P.D.C., P. Cicuta, T.M.T., G.J.W., and J.C.R. wrote the paper.

                1L.Y.B. and G.T.P. contributed equally to this work.

                2Present address: Chemical Biology Laboratory, Ferrier Research Institute, Victoria University of Wellington, Wellington 6140, New Zealand.

                3Present address: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.

                Author information
                Copyright © 2017 the Author(s). Published by PNAS.

                This is an open access article distributed under the PNAS license.

                Page count
                Pages: 6
                Funded by: Wellcome Trust
                Award ID: 090851
                Funded by: Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) 100006492
                Award ID: KL2TR000163
                Biological Sciences

                malaria,vaccine,plasmodium falciparum,antigen combinations,erythrocyte invasion


                Malaria vaccine development collection topic 5) Identifying and developing the new generation of malaria vaccines - Making use of reverse vaccinology and serology information:

                See https://www.scienceopen.com/collection/malariavaccine

                This study makes use of reverse vaccinology to generate and systematically evaluate 29 antigens likely to be involved in erythrocyte invasion as potential vaccine candidates. Antibodies to this library were tested in vitro alone and in combinations, and several strain-transcending targets with synergistic combinatorial effects were identified.

                2018-10-08 20:31 UTC

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