Immunological outcomes of new tuberculosis vaccine trials: WHO panel recommendations.
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ABSTRACT:
SUBMITTER: Hanekom WA
PROVIDER: S-EPMC2443198 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease.
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Project description:About half of survivors with stroke experience severe and significant long-term disability. The purpose of this article is to review the state of the science and to make recommendations for measuring patient-centric outcomes in interventions for motor improvement in the chronic stroke phase.A 9-member expert panel reviewed evidence to identify measures of upper and lower extremity function used to date as outcomes in trials with patients who experienced a stroke ?6 months before assessment. Outcome measures were screened using StrokEDGE consensus panel recommendations, and evaluated for availability of a published minimal clinically important difference. Measures meeting these criteria were further evaluated with regard to their level of measurement, psychometric properties, and ability of minimal clinically important difference to capture gains associated with improved function and clinical relevance to patients, to arrive at recommendations. A systematic literature review yielded 115 clinical trials of upper and lower extremity function in chronic stroke that used a total of 34 outcome measures. Seven of these had published minimal clinically important differences and were recommended or highly recommended by StrokEDGE. Those are the Fugl-Meyer Upper Extremity and Lower Extremity scales, Wolf Motor Function Test, Action Research Arm Test, Ten-Meter and Six-Minute Walk Tests, and the Stroke Impact Scale. All had evidence for their psychometric performance, although the strength of evidence for validity varied, especially in populations with chronic stroke Fugl-Meyer Upper and Lower Extremity scales showing the strongest evidence for validity.The panel recommends that the Fugl-Meyer Upper and Lower Extremity scales be used as primary outcomes in intervention trials targeting motor function in populations with chronic stroke. The other 6 measures are recommended as secondary outcomes.
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Project description:Backgroundone of the World Health Organization Millennium Development Goal is to reduce tuberculosis incidence by 2015. However, more of 8.5 million tuberculosis cases have been reported in 2011, with an increase of multidrug-resistant strains. Therefore, the World Health Organization target cannot be reach without the help of a vaccine able to limit the spread of tuberculosis. Nowadays, bacille Calmette-Guérin is the only vaccine available against tuberculosis. It prevents against meningeal and disseminated tuberculosis in children, but its effectiveness against pulmonary form in adolescents and adults is argued.Methoda systematic review was performed by searches of Pubmed, references of the relevant articles and Aeras and ClinicalTrial.gov websites.Results100 articles were included in this review. Three viral vectored booster vaccines, five protein adjuvant booster vaccines, two priming vaccines and two therapeutic vaccines have been analyzed.ConclusionsSeveral vaccines are in the pipeline, but further studies on basic research, clinical trial and mass vaccination campaigns are needed to achieve the TB eradication target by 2050.
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Project description:IntroductionTuberculosis (TB) is the leading infectious killer globally and new TB vaccines will be crucial to ending the epidemic. Since the introduction in 1921 of the only currently licensed TB vaccine, BCG, very few novel vaccine candidates or strategies have advanced into clinical efficacy trials. Areas covered: Recently, however, two TB vaccine efficacy trials with novel designs have reported positive results and are now driving new momentum in the field. They are the first Prevention of Infection trial, evaluating the H4:IC31 candidate or BCG revaccination in high-risk adolescents and a Prevention of Disease trial evaluating the M72/AS01E candidate in M.tuberculosis-infected, healthy adults. These trials are briefly reviewed, and lessons learned are proposed to help inform the design of future efficacy trials. The references cited were chosen by the author based on PubMed searches to provide context for the opinions expressed in this Perspective article. Expert opinion: The opportunities created by these two trials for gaining critically important knowledge are game-changing for TB vaccine development. Their results clearly establish feasibility in the relatively near term of developing novel, effective vaccines that could be crucial to ending the TB epidemic.
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Project description:Neurofibromatosis type 1 (NF1) is associated with neurocognitive deficits that can impact everyday functioning of children, adolescents, and adults with this disease. However, there is little agreement regarding measures to use as cognitive endpoints in clinical trials. This article describes the work of the Neurocognitive Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration. The goal of this committee is to identify standardized and specific cognitive assessment tools for use in NF clinical trials. The committee first identified cognitive domains relevant to NF1 and prioritized attention as the first domain of focus given prior and current trends in NF1 cognitive clinical trials. Performance measures and behavioral rating questionnaires of attention were reviewed by the group using established criteria to assess patient characteristics, psychometric properties, and feasibility. The highest rated tests underwent side-by-side comparison. The Digit Span subtest from the Wechsler scales was given the highest ratings of the performance measures due to its good psychometrics, feasibility, utility across a wide age range, and extensive use in previous research. The Conners scales achieved the highest ratings of the behavioral questionnaires for similar reasons. Future articles will focus on other cognitive domains, with the ultimate goal of achieving agreement for cognitive endpoints that can be used across NF clinical trials.
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Project description:The current standard therapy for patients with diabetic macular oedema (DME)--focal/grid laser photocoagulation--usually does not improve impaired vision, and many patients lose vision despite laser therapy. Recent approval of ranibizumab by the European Medicines Agency to treat visual impairment due to DME fulfils the previously unmet medical need for a treatment that can improve visual acuity (VA) in these patients. We reviewed 1- and 2-year clinical trial findings for ranibizumab used as treatment for DME to formulate evidence-based treatment recommendations in the context of this new therapy. DME with or without visual impairment should be considered for treatment when it fulfils the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria for clinically significant oedema. For DME with centre involvement and associated vision loss due to DME, monthly ranibizumab monotherapy with treatment interruption and re-initiation based on VA stability is recommended. Laser therapy based on ETDRS guidelines is recommended for other forms of clinically significant DME without centre involvement or when no vision loss has occurred, despite centre involvement. Because these recommendations are based on randomised controlled trials of 1-2 years duration, guidance may need updating as long-term ranibizumab data become available and as additional therapeutic agents are assessed in clinical trials.
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Project description:During a recent Food and Drug Administration workshop on clinical trials to evaluate new TB drugs, questions were raised regarding the use of bacteriologic endpoints such as treatment failure and relapse as measures of improvement in health status and long term outcome after treatment. FDA scientists asked how patients' clinical signs and symptoms changed during therapy, noting that while such information is usually collected during clinical trials, it is not often reported. We analyzed data from an international phase 3 TB treatment trial that included systematic assessments of symptoms. The percentage of subjects with self-reported symptoms at baseline ranged from 30% for dyspnea to 81% for cough, with 51% reporting fever. During therapy, fever, sweats, and dyspnea decreased most rapidly, with near resolution by the end of therapy. Chest pain and cough resolved more slowly; 13% of subjects reported cough at six months. Symptom resolution during treatment did not differ between those who relapsed and those who did not. Among those with microbiological relapse, symptoms returned with significant increases in the proportion with fever, cough, and chest pain. At the time of relapse, cough was the most frequent symptom, occurring in 75% of subjects who relapsed but only 12% of those who did not. Our data support the continued use of bacteriologic endpoints based on sputum culture as surrogate measures of the relief of symptoms, improvement in health status and favorable long term treatment outcome in TB drug trials.
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Project description:Pediatric tuberculosis contributes significantly to the burden of TB disease worldwide. In order to achieve the goal of eliminating TB by 2050, an effective TB vaccine is urgently needed to prevent TB transmission in children. BCG vaccination can protect children from the severe types of TB such as TB meningitis and miliary TB, while its efficacy against pediatric pulmonary TB ranged from no protection to very high protection. In recent decades, multiple new vaccine candidates have been developed, and shown encouraging safety and immunogenicity in the preclinical experiments. However, the limited data on protective efficacy in infants evaluated by clinical trials has been disappointing, an example being MVA85A. To date, no vaccine has been shown to be clinically safer and more effective than the presently licensed BCG vaccine. Hence, before a new vaccine is developed with more promising efficacy, we must reconsider how to better use the current BCG vaccine to maximize its effectiveness in children.
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Project description:ObjectivesTo provide recommendations for the selection of comparators for randomized controlled trials of health-related behavioral interventions.Study design and settingThe National Institutes of Health Office of Behavioral and Social Science Research convened an expert panel to critically review the literature on control or comparison groups for behavioral trials and to develop strategies for improving comparator choices and for resolving controversies and disagreements about comparators.ResultsThe panel developed a Pragmatic Model for Comparator Selection in Health-Related Behavioral Trials. The model indicates that the optimal comparator is the one that best serves the primary purpose of the trial but that the optimal comparator's limitations and barriers to its use must also be taken into account.ConclusionWe developed best practice recommendations for the selection of comparators for health-related behavioral trials. Use of the Pragmatic Model for Comparator Selection in Health-Related Behavioral Trials can improve the comparator selection process and help resolve disagreements about comparator choices.
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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted primarily through respiratory droplets/aerosols and it causes COVID-19. The virus infects epithelial cells by using the spike protein on its surface to bind to angiotensin-converting enzyme 2 receptor on the cells. Thus, candidate vaccines targeting the spike protein are currently being developed to prevent against infections. Approximately 44 SARS-CoV-2 candidate vaccines are in clinical trials (phase I-III) and an additional 164 candidates are in preclinical stages. The efficacy data from phase I/II trials of lead candidate vaccines look very promising with virus-neutralizing geometric mean antibody titers in the range of 16.6-3906. Most recently, two SARS-CoV-2 candidate vaccines, BNT162b2 and mRNA-1273, have been granted the first emergency use authorization (EUA) in the U.S.; BNT162b2 has also been granted an EUA in the United Kingdom, Canada, and in the European Union. This review assesses whether SARS-CoV-2 candidate vaccines (with approved EUA or in phase III trials) meet the criteria for an ideal SARS-CoV-2 vaccine. The review concludes with expectations from phase III trials and recommendations for phase IV studies (post-vaccine approval).
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