130 research outputs found
BMTS US 2019 Moorthy_WHO.pptx
No full textDr Moorthy of WHO presentation at BMTS US 2019 on the WHO's position on clinical trial transparency, outlining adverse consequences of not disclosing results, and developments in WHO's International Clinical Trial Registry Platform
Malaria vaccine research and development: the role of the WHO MALVAC committee.
No full textThe WHO Malaria Vaccine Advisory Committee (MALVAC) provides advice to WHO on strategic priorities, activities and technical issues related to global efforts to develop vaccines against malaria. MALVAC convened a series of meetings to obtain expert, impartial consensus views on the priorities and best practice for vaccine-related research and development strategies. The technical areas covered during these consultations included: guidance on clinical trial design for candidate sporozoite and asexual blood stage vaccines; measures of efficacy of malaria vaccines in Phase IIb and Phase III trials; standardization of immunoassays; the challenges of developing assays and designing trials for interventions against malaria transmission; modelling impact of anti-malarial interventions; whole organism malaria vaccines, and Plasmodium vivax vaccine-related research and evaluation. These informed discussions and opinions are summarized here to provide guidance on harmonization of strategies to help ensure high standards of practice and comparability between centres and the outcome of vaccine trials
Evaluation of approaches to identify the targets of cellular immunity on a proteome-wide scale
No full textBackground: Vaccine development against malaria and other complex diseases remains a challenge for the scientific community. The recent elucidation of the genome, proteome and transcriptome of many of these complex pathogens provides the basis for rational vaccine design by identifying, on a proteome-wide scale, novel target antigens that are recognized by T cells and antibodies from exposed individuals. However, there is currently no algorithm to effectively identify important target antigens from genome sequence data; this is especially challenging for T cell targets. Furthermore, for some of these pathogens, such as Plasmodium, protein expression using conventional platforms has been problematic but cell-free in vitro transcription translation (IVTT) strategies have recently proved successful. Herein, we report a novel approach for proteome-wide scale identification of the antigenic targets of T cell responses using IVTT products. Principal Findings: We conducted a series of in vitro and in vivo experiments using IVTT proteins either unpurified, absorbed to carboxylated polybeads, or affinity purified through nickel resin or magnetic beads. In vitro studies in humans using CMV, EBV, and Influenza A virus proteins showed antigen-specific cytokine production in ELIspot and Cytometric Bead Array assays with cells stimulated with purified or unpurified IVTT antigens. In vitro and in vivo studies in mice immunized with the Plasmodium yoelii circumsporozoite DNA vaccine with or without IVTT protein boost showed antigen-specific cytokine production using purified IVTT antigens only. Overall, the nickel resin method of IVTT antigen purification proved optimal in both human and murine systems. Conclusions: This work provides proof of concept for the potential of high-throughput approaches to identify T cell targets of complex parasitic, viral or bacterial pathogens from genomic sequence data, for rational vaccine development against emerging and re-emerging diseases that pose a threat to public health
Perspective: Adhesion Mediated Signal Transduction in Bacterial Pathogens
No full textDuring the infection process, pathogenic bacteria undergo large-scale transcriptional changes to promote virulence and increase intrahost survival. While much of this reprogramming occurs in response to changes in chemical environment, such as nutrient availability and pH, there is increasing evidence that adhesion to host-tissue can also trigger signal transduction pathways resulting in differential gene expression. Determining the molecular mechanisms of adhesion-mediated signaling requires disentangling the contributions of chemical and mechanical stimuli. Here we highlight recent work demonstrating that surface attachment drives a transcriptional response in bacterial pathogens, including uropathogenic Escherichia coli (E. coli), and discuss the complexity of experimental design when dissecting the specific role of adhesion-mediated signaling during infection.Peer reviewe
Analysis of DNA and recombinant viral vaccines against P. falciparum in malaria-naïve and malaria-exposed humans
No full textEThOS - Electronic Theses Online ServiceGBUnited Kingdo
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Analysis of DNA and recombinant viral vaccines against <i>P. falciparum</i> in malaria-naïve and malaria-exposed humans
No full textThe hypotheses under test were as follows. Firstly that sequential immunisation of humans with two candidate vaccines recombinant for the same malarial DNA sequence would be safe, would produce higher frequencies of antigen-specific T cells in peripheral blood and greater efficacy than repeated immunisation with one vaccine. Secondly that recombinant viral malaria immunization would be more immunogenic in malaria-exposed than malaria-naive individuals. The third hypothesis was contingent on the conduct of a field efficacy trial; liver-stage specific T cells induced by the regimen with greatest immunogenicity would provide protection against natural infection. Three delivery systems were evaluated - a circular plasmid DNA molecule (DNA), modified vaccinia virus Ankara (MVA) and fowlpox strain 9 (FP9); each recombinant for the multiple epitope - thrombospondin related anonymous (or adhesion) protein (ME-TRAP) P. falciparum DNA sequence. DNA ME-TRAP and MVA ME-TRAP were safe but poorly immunogenic when given alone in both UK and Gambian adults. Two doses of 1mg DNA ME-TRAP administered intramuscularly followed by one dose of 3 x 107 plaque forming units (pfu) MVA ME-TRAP administered intradermally induced higher effector T cell frequencies as measured by ex vivo γ-interferon ELISPOT (enzyme-linked immunospot) assay than three doses of either alone. A second MVA ME-TRAP immunisation did not increase immunogenicity above that after a single immunisation. At these doses the DNA/MVA regimen was more immunogenic in malaria-experienced Gambian adults than in malaria-naive British adults. Increasing the dose of DNA to 2mg and MVA to 1.5 x 108 pfu increased immunogenicity further. Two doses of FP9 ME-TRAP showed a trend towards to being less immunogenic than two doses of DNA ME-TRAP prior to a single MVA immunisation. The heterologous DNA/MVA regimen afforded protection manifested by delay in time to parasitaemia in a clinical challenge model in the UK. Therefore a randomised double-blind controlled trial was conducted in men aged 15 45 in The Gambia. This trial confirmed safety and high immunogenicity but there was 10.3% (95%CI -22% to +34%) efficacy for the time to infection primary endpoint. Potential reasons for failure of the intervention include an unfavourable CD4+/CD8+ T cell ratio, inadequate TRAP expression in infected hepatocytes, inadequate cross-reactivity and the duration or magnitude of the peak T cell immunogenicity
Clinical trials to estimate the efficacy of preventive interventions against malaria in paediatric populations: a methodological review.
No full textBACKGROUND: Recent years have seen publication of a considerable number of clinical trials of preventive interventions against clinical malaria in children. There has been variability in the specification of end-points, case definitions, analysis methods and reporting and the relative lack of standardization complicates the ability to make comparative evaluations between trials. METHODS: To prepare for a WHO consultation on design issues in malaria vaccine trials, controlled trials of preventive interventions against malaria in children in endemic countries were identified in which clinical malaria, or death, had been one of the main end-points. Trials were included that evaluated the impact of vaccines, insecticide-treated bed nets (ITN), intermittent presumptive or preventive therapy in infants (IPTi) or, in one instance, vitamin A supplementation. Methods that had been used in these trials were summarized and compared in order to identify issues that were directly relevant to the design of malaria vaccine trials. RESULTS: 29 controlled trials of preventive malaria interventions were identified, of which eight were vaccine trials. Vaccine trials that were designed to detect an effect on clinical malaria all reported the incidence rate of first episodes of clinical malaria as their primary endpoint. Only one trial of a preventive intervention (of ITN) was identified that was designed to detect an effect on severe malaria. A group of larger trials were designed to detect an effect of impregnated bed nets or curtains on all-cause mortality as the primary end-point. Key methodological and reporting differences between trials are noted in the text. Two issues have been identified that are of some concern. Firstly, the choice of primary endpoint is not stated in the reports of a number of the trials and, secondly, the relationship between pre-specified analysis plans and trial reports is rarely made clear. CONCLUSION: This article reports an investigation into the ways in which trial design and reporting could be improved and standardized to enable comparative evaluation of the relative merits of malaria control measures, and specifically with respect to the design of malaria vaccine trials. The need for standardization of clinical trial design, conduct, analysis and reporting has been also affirmed as a priority area by the Malaria Vaccine Technology Roadmap
Immunological mechanisms underlying protection mediated by RTS,S: a review of the available data
No full textAbstract The RTS,S/AS candidate malaria vaccine has demonstrated efficacy against a variety of endpoints in Phase IIa and Phase IIb trials over more than a decade. A multi-country phase III trial of RTS,S/AS01 is now underway with submission as early as 2012, if vaccine safety and efficacy are confirmed. The immunologic basis for how the vaccine protects against both infection and disease remains uncertain. It is, therefore, timely to review the information currently available about the vaccine with regard to how it impacts the human-Plasmodium falciparum host-pathogen relationship. In this article, what is known about mechanisms involved in partial protection against malaria induced by RTS,S is reviewed.</p
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