Development of standard clinical endpoints for use in dengue interventional trials: introduction and methodology

Background: As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification. Methods: The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research. Results: Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1–10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets. Conclusion: The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue

Intérêt de la biologie moléculaire dans le diagnostic des infections vlrales du système nerveux central

International audienceThe use of PCR and hybridization for the detection of viral nucleic acids in cerebrospinal fluid (CSF) currently represents the most reliable method for the meningoencephalitis diagnosis due to herpes viruses, enteroviruses, JC polyomavirus and HIV-1 primary infection. The molecular tools are less suitable for the postinfectious encephalitis associated with a systemic viral infection such as neurologic complications of measles, rubella, influenza and varicella, The speed and high sensitivity allow earlier diagnosis and specific treatment. The monitoring of the antiviral therapy is assessed by the development of quantitative amplification assays in CSF or by a negative PCR result. The pattern mutations conferring resistance and the genetic variability of viruses (HIV-1, Dengue virus) could be determined from different locations in the genome. Theses methods performed over the past several years as research tools have now a large scale application with the commercialization of some tests. But before becoming the first line diagnostic test, PCR of CSF could be conducted with control quality and evaluated protocols for avoiding false positive and negative results.a détection de génomes viraux par amplification génique (PCR) et hybridation à partir du liquide céphalorachidien est un outil performant pour le diagnostic des méningoencéphalites virales primitives dues aux virus du groupe herpès, aux entérovirus, au polyomavirus JC ou observées lors de primo-infection à VIH-1. Au cours des maladies virales éruptives ou respiratoires, ces techniques sont moins adaptées car l'atteinte cérébrale est secondaire à la virémie. La biologie moléculaire est applicable au suivi thérapeutique des infections par la mesure de la charge virale dans le liquide céphalorachidien ou par la négativation de la PCR. Elle permet la caractérisation de mutants résistants par le séquençage d'une région du génome et présente un intérêt épidémiologique dans létude de la variabilité génétique de souches virales (VIH-1, virus de la Dengue). La diffusion de ces méthodes, initialement de la compétence de laboratoires spécialisés, a été favorisée par la mise au point de trousses commercialisées. Mais du fait de l'extrême sensibilité de ces outils, l'instauration de modes opératoires standardisés et de contrôles de qualité sont des garanties indispensables

Evaluation of lockdown effect on SARS-CoV-2 dynamics through viral genome quantification in waste water, Greater Paris, France, 5 March to 23 April 2020

International audienceIntroduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease (COVID-19). People infected with SARS-CoV-2 may exhibit no or mild non-specific symptoms; thus, they may contribute to silent circulation of the virus among humans. Since SARS-CoV-2 RNA can be detected in stool samples, monitoring SARS-CoV-2 RNA in waste water (WW) has been proposed as a complementary tool to investigate virus circulation in human populations. Aim: To test if the quantification of SARS-CoV-2 genomes in WW correlates with the number of symptomatic or non-symptomatic carriers. Method: We performed a time-course quantitative analysis of SARS-CoV-2 by RT-qPCR in raw WW samples collected from several major WW treatment plants in Greater Paris. The study period was 5 March to 23 April 2020, including the lockdown period in France (from 17 March). Results: We showed that the increase of genome units in raw WW accurately followed the increase of human COVID-19 cases observed at the regional level. Of note, the viral genome could be detected before the epidemic grew massively (around 8 March). Equally importantly, a marked decrease in the quantities of genome units was observed concomitantly with the reduction in the number of new COVID-19 cases, 29 days following the lockdown. Conclusion: This work suggests that a quantitative monitoring of SARS-CoV-2 genomes in WW could generate important additional information for improved monitoring of SARS-CoV-2 circulation at local or regional levels and emphasises the role of WW-based epidemiology

A critical assessment of vector control for dengue prevention.

Recently, the Vaccines to Vaccinate (v2V) initiative was reconfigured into the Partnership for Dengue Control (PDC), a multi-sponsored and independent initiative. This redirection is consistent with the growing consensus among the dengue-prevention community that no single intervention will be sufficient to control dengue disease. The PDC's expectation is that when an effective dengue virus (DENV) vaccine is commercially available, the public health community will continue to rely on vector control because the two strategies complement and enhance one another. Although the concept of integrated intervention for dengue prevention is gaining increasingly broader acceptance, to date, no consensus has been reached regarding the details of how and what combination of approaches can be most effectively implemented to manage disease. To fill that gap, the PDC proposed a three step process: (1) a critical assessment of current vector control tools and those under development, (2) outlining a research agenda for determining, in a definitive way, what existing tools work best, and (3) determining how to combine the best vector control options, which have systematically been defined in this process, with DENV vaccines. To address the first step, the PDC convened a meeting of international experts during November 2013 in Washington, DC, to critically assess existing vector control interventions and tools under development. This report summarizes those deliberations

A critical assessment of vector control for Dengue prevention

Recently, the Vaccines to Vaccinate (v2V) initiative was reconfigured into the Partnership for Dengue Control (PDC), a multi-sponsored and independent initiative. This redirection is consistent with the growing consensus among the dengue-prevention community that no single intervention will be sufficient to control dengue disease. The PDC's expectation is that when an effective dengue virus (DENV) vaccine is commercially available, the public health community will continue to rely on vector control because the two strategies complement and enhance one another. Although the concept of integrated intervention for dengue prevention is gaining increasingly broader acceptance, to date, no consensus has been reached regarding the details of how and what combination of approaches can be most effectively implemented to manage disease. To fill that gap, the PDC proposed a three step process: (1) a critical assessment of current vector control tools and those under development, (2) outlining a research agenda for determining, in a definitive way, what existing tools work best, and (3) determining how to combine the best vector control options, which have systematically been defined in this process, with DENV vaccines. To address the first step, the PDC convened a meeting of international experts during November 2013 in Washington, DC, to critically assess existing vector control interventions and tools under development. This report summarizes those deliberations

Workshop on vaccine pressure and Neisseria meningitidis, Annecy, France, 9-11 March 2005

A 3-day workshop, "Vaccine pressure and Neisseria meningitidis", was held in Annecy, France, 9-11 March 2005, to summarize the current state of knowledge regarding N. meningitidis capsule switching and vaccine pressure from capsular polysaccharide-based N. meningitidis vaccines, including conjugates. Main discussion topics were the host-bacteria relationship and N. meningitidis population, worldwide experience of meningococcal vaccination, and using existing experience to shape the future of meningococcal vaccination strategies. The workshop concluded that there is no current evidence to suggest that serogroup C conjugate vaccine pressure has resulted in meningococcal serogroup switching or replacement

Transmission of Bordetella pertussis to young infants

International audienceBACKGROUND:Pertussis vaccination has reduced the number of notified cases in industrialized countries from peak years by more than 95%. The effect of recently recommended adult and adolescent vaccination strategies on infant pertussis depends, in part, on the proportion of infants infected by adults and adolescents. This proportion, however, remains unclear, because studies have not been able to determine the source case for 47%-60% of infant cases.METHODS:A prospective international multicenter study was conducted of laboratory confirmed infant pertussis cases (aged <or=6 months) and their household and nonhousehold contacts. Comprehensive diagnostic evaluation (including PCR and serology) was performed on all participants independent of symptoms. Source cases were identified and described by relationship to the infant, age and household status.RESULTS:The study population comprised 95 index cases and 404 contacts. The source of pertussis was identified for 48% of infants in the primary analysis and up to 78% in sensitivity analyses. In the primary analysis, parents accounted for 55% of source cases, followed by siblings (16%), aunts/uncles (10%), friends/cousins (10%), grandparents (6%) and part-time caretakers (2%). The distribution of source cases was robust to sensitivity analyses.CONCLUSIONS:This study provides solid evidence that among infants for whom a source case was identified, household members were responsible for 76%-83% of transmission of Bordetella pertussis to this high-risk group. Vaccination of adolescents and adults in close contact with young infants may thus eliminate a substantial proportion of infant pertussis if high coverage rates can be achieved

Existing and developing control methods.

<p>Existing methods (upper green region) and methods under development (lower yellow region) are enumerated and separated by those that affect larval mosquito stages (left) and those that affect adult mosquito stages (right). Methods that target a particular sub-stage within a mosquito’s life cycle are oriented vertically with those sub-stages.</p

Development of standard clinical endpoints for use in dengue interventional trials: introduction and methodology

BACKGROUND: As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification. METHODS: The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research. RESULTS: Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1-10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets. CONCLUSION: The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue.status: publishe