Specimen sharing for epidemic preparedness:Building a virtual biorepository system from local governance to global partnerships

We present a framework for a federated, virtual biorepository system (VBS) with locally collected and managed specimens, as a 'global public good' model based on principles of equitable access and benefit sharing. The VBS is intended to facilitate timely access to biological specimens and associated data for outbreak-prone infectious diseases to accelerate the development and evaluation of diagnostics, assess vaccine efficacy, and to support surveillance and research needs. The VBS is aimed to be aligned with the WHO BioHub and other specimen sharing efforts as a force multiplier to meet the needs of strengthening global tools for countering epidemics. The purpose of our initial research is to lay the basis of the collaboration, management and principles of equitable sharing focused on low- and middle-income country partners. Here we report on surveys and interviews undertaken with biorepository-interested parties to better understand needs and barriers for specimen access and share examples from the ZIKAlliance partnership on the governance and operations of locally organized biorepositories.</p

Diagnostic performance of anti-Zika virus IgM, IgAM and IgG ELISAs during co-circulation of Zika, dengue, and chikungunya viruses in Brazil and Venezuela

BACKGROUND: Serological diagnosis of Zika virus (ZIKV) infection is challenging because of the antibody cross-reactivity among flaviviruses. At the same time, the role of Nucleic Acid Testing (NAT) is limited by the low proportion of symptomatic infections and the low average viral load. Here, we compared the diagnostic performance of commercially available IgM, IgAM, and IgG ELISAs in sequential samples during the ZIKV and chikungunya (CHIKV) epidemics and co-circulation of dengue virus (DENV) in Brazil and Venezuela. METHODOLOGY/PRINCIPAL FINDINGS: Acute (day of illness 1-5) and follow-up (day of illness ≥ 6) blood samples were collected from nine hundred and seven symptomatic patients enrolled in a prospective multicenter study of symptomatic patients recruited between June 2012 and August 2016. Acute samples were tested by RT-PCR for ZIKV, DENV, and CHIKV. Acute and follow-up samples were tested for IgM, IgAM, and IgG antibodies to ZIKV using commercially available ELISAs. Among follow-up samples with a RT-PCR confirmed ZIKV infection, anti-ZIKV IgAM sensitivity was 93.5% (43/48), while IgM and IgG exhibited sensitivities of 30.3% (10/35) and 72% (18/25), respectively. An additional 24% (26/109) of ZIKV infections were detected via IgAM seroconversion in ZIKV/DENV/CHIKV RT-PCR negative patients. The specificity of anti-ZIKV IgM was estimated at 93% and that of IgAM at 85%. CONCLUSIONS/SIGNIFICANCE: Our findings exemplify the challenges of the assessment of test performance for ZIKV serological tests in the real-world setting, during co-circulation of DENV, ZIKV, and CHIKV. However, we can also demonstrate that the IgAM immunoassay exhibits superior sensitivity to detect ZIKV RT-PCR confirmed infections compared to IgG and IgM immunoassays. The IgAM assay also proves to be promising for detection of anti-ZIKV seroconversions in sequential samples, both in ZIKV PCR-positive as well as PCR-negative patients, making this a candidate assay for serological monitoring of pregnant women in future ZIKV outbreaks

Clinical evaluation of dengue and identification of risk factors for severe disease: protocol for a multicentre study in 8 countries

Background: The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging. This study aims to improve diagnosis and clinical management through approaches designed a) to differentiate between dengue and other common febrile illness within 72 h of fever onset, and b) among patients with dengue to identify markers that are predictive of the likelihood of evolving to a more severe disease course. Method/Design: This is a prospective multi-centre observational study aiming to enrol 7–8000 participants aged ≥ 5 years presenting with a febrile illness consistent with dengue to outpatient health facilities in 8 countries across Asia and Latin America. Patients presenting within 72 h of fever onset who do not exhibit signs of severe disease are eligible for the study. A broad range of clinical and laboratory parameters are assessed daily for up to 6 days during the acute illness, and also at a follow up visit 1 week later. Discussion: Data from this large cohort of patients, enrolled early with undifferentiated fever, will be used to develop a practical diagnostic algorithm and a robust clinical case definition for dengue. Additionally, among patients with confirmed dengue we aim to identify simple clinical and laboratory parameters associated with progression to a more severe disease course. We will also investigate early virological and serological correlates of severe disease, and examine genetic associations in this large heterogeneous cohort. In addition the results will be used to assess the new World Health Organization classification scheme for dengue in practice, and to update the guidelines for “Integrated Management of Childhood Illness” used in dengue-endemic countries. Trial registration: NCT01550016. Registration Date: March 7, 201

Study protocol for the multicentre cohorts of Zika virus infection in pregnant women, infants, and acute clinical cases in Latin America and the Caribbean: The ZIKAlliance consortium

Background: The European Commission (EC) Horizon 2020 (H2020)-funded ZIKAlliance Consortium designed a multicentre study including pregnant women (PW), children (CH) and natural history (NH) cohorts. Clinical sites were selected over a wide geographic range within Latin America and the Caribbean, taking into account the dynamic course of the ZIKV epidemic. Methods: Recruitment to the PW cohort will take place in antenatal care clinics. PW will be enrolled regardless of symptoms and followed over the course of pregnancy, approximately every 4 weeks. PW will be revisited at delivery (or after miscarriage/abortion) to assess birth outcomes, including microcephaly and other congenital abnormalities according to the evolving definition of congenital Zika syndrome (CZS). After birth, children will be followed for 2 years in the CH cohort. Follow-up visits are scheduled at ages 1-3, 4-6, 12, and 24 months to assess neurocognitive and developmental milestones. In addition, a NH cohort for the characterization of symptomatic rash/fever illness was designed, including follow-up to capture persisting health problems. Blood, urine, and other biological materials will be collected, and tested for ZIKV and other relevant arboviral diseases (dengue, chikungunya, yellow fever) using RT-PCR or serological methods. A virtual, decentralized biobank will be created. Reciprocal clinical monitoring has been established between partner sites. Substudies of ZIKV seroprevalence, transmissio

Zika virus infection in pregnancy: a protocol for the joint analysis of the prospective cohort studies of the ZIKAlliance, ZikaPLAN and ZIKAction consortia

INTRODUCTION: Zika virus (ZIKV) infection in pregnancy has been associated with microcephaly and severe neurological damage to the fetus. Our aim is to document the risks of adverse pregnancy and birth outcomes and the prevalence of laboratory markers of congenital infection in deliveries to women experiencing ZIKV infection during pregnancy, using data from European Commission-funded prospective cohort studies in 20 centres in 11 countries across Latin America and the Caribbean. METHODS AND ANALYSIS: We will carry out a centre-by-centre analysis of the risks of adverse pregnancy and birth outcomes, comparing women with confirmed and suspected ZIKV infection in pregnancy to those with no evidence of infection in pregnancy. We will document the proportion of deliveries in which laboratory markers of congenital infection were present. Finally, we will investigate the associations of trimester of maternal infection in pregnancy, presence or absence of maternal symptoms of acute ZIKV infection and previous flavivirus infections with adverse outcomes and with markers of congenital infection. Centre-specific estimates will be pooled using a two-stage approach. ETHICS AND DISSEMINATION: Ethical approval was obtained at each centre. Findings will be presented at international conferences and published in peer-reviewed open access journals and discussed with local public health officials and representatives of the national Ministries of Health, Pan American Health Organization and WHO involved with ZIKV prevention and control activities

Understanding the relation between Zika virus infection during pregnancy and adverse fetal, infant and child outcomes: a protocol for a systematic review and individual participant data meta-analysis of longitudinal studies of pregnant women and their infants and children

IntroductionZika virus (ZIKV) infection during pregnancy is a known cause of microcephaly and other congenital and developmental anomalies. In the absence of a ZIKV vaccine or prophylactics, principal investigators (PIs) and international leaders in ZIKV research have formed the ZIKV Individual Participant Data (IPD) Consortium to identify, collect and synthesise IPD from longitudinal studies of pregnant women that measure ZIKV infection during pregnancy and fetal, infant or child outcomes.Methods and analysisWe will identify eligible studies through the ZIKV IPD Consortium membership and a systematic review and invite study PIs to participate in the IPD meta-analysis (IPD-MA). We will use the combined dataset to estimate the relative and absolute risk of congenital Zika syndrome (CZS), including microcephaly and late symptomatic congenital infections; identify and explore sources of heterogeneity in those estimates and develop and validate a risk prediction model to identify the pregnancies at the highest risk of CZS or adverse developmental outcomes. The variable accuracy of diagnostic assays and differences in exposure and outcome definitions means that included studies will have a higher level of systematic variability, a component of measurement error, than an IPD-MA of studies of an established pathogen. We will use expert testimony, existing internal and external diagnostic accuracy validation studies and laboratory external quality assessments to inform the distribution of measurement error in our models. We will apply both Bayesian and frequentist methods to directly account for these and other sources of uncertainty.Ethics and disseminationThe IPD-MA was deemed exempt from ethical review. We will convene a group of patient advocates to evaluate the ethical implications and utility of the risk stratification tool. Findings from these analyses will be shared via national and international conferences and through publication in open access, peer-reviewed journals.Trial registration numberPROSPERO International prospective register of systematic reviews (CRD42017068915).</jats:sec

Incidencia de anticuerpos antifosfolípidos en mujeres embarazadas sanas y en mujeres con abortos espontáneos, atendidas en la consulta de ginecología y obstetricia de la Ciudad Hospitalaria Dr. Enrique Tejera. Valencia. Carabobo. 2006

Los anticuerpos antifosfolípidos son una familia heterogénea de inmunoglobulinas que se unen a los fosfolípidos cargados negativamente presentes en las membranas celulares. Los anticuerpos anticardiolipinas y los anticoagulantes lúpicos son los principales representantes de esta familia de autoanticuerpos, que están siendo relacionados con complicaciones obstétricas, principalmente abortos espontáneos a repetición. Se determinó la incidencia de estos autoanticuerpos en mujeres con embarazos normales y en mujeres con más de 2 abortos a repetición; para ello se realizaron determinaciones séricas de los isotipos M y G de las inmunoglobulinas para anticuerpos anticardiolipinas (ACA) y para anti beta2glicoproteina I (antiß2GPI) utilizando la metodología ELISA. Los resultados obtenidos muestran 11,1% de las mujeres con embarazos normales dieron resultados positivos para la IgM ACA, mientras que en las mujeres con abortos espontáneos a repetición el porcentaje de positividad fue de 23%. En cuanto al isotipo IgG ACA se obtuvo 15% de positividad en las mujeres con embarazos normales contra 57% de positividad en las mujeres con abortos (p<0,01). Cuando se evaluó el isotipo IgM de la antiß2GPI la positividad observada fue de 1% en las mujeres con embarazos normales contra 43% de positividad en mujeres con abortos (p<0,01). En cuanto a los porcentajes de positividad para el isotipo IgG de la antiß2GPI fue de 20% para las mujeres con embarazos normales y de 9% en las mujeres con abortos. Se concluye que IgG ACA e IgM antiß2GPI pueden estar asociadas a interrupción espontánea del embarazo

ANTICUERPOS ANTIFOSFOLÍPIDOS EN EMBARAZO NORMAL A TÉRMINO Y ABORTO ESPONTÁNEO RECURRENTE

Los anticuerpos antifosfol&iacute;pidos son una familia heterog&eacute;nea de inmunoglobulinas que se unen a los fosfol&iacute;pidos,cargados negativamente, presentes en las membranas celulares. Los anticuerpos anticardiolipinas y losanticoagulantes l&uacute;picos, principales representantes de esta familia de autoanticuerpos, est&aacute;n siendo relacionadoscon complicaciones obst&eacute;tricas, principalmente abortos a repetici&oacute;n. Se determin&oacute; la significaci&oacute;n cl&iacute;nico biol&oacute;gicade estos autoanticuerpos en una muestra conformada por 45 mujeres con embarazo normal y 35 con m&aacute;s de 2 abortosa repetici&oacute;n, para ello se determinaron en sangre perif&eacute;rica IgM e IgG anticardiolipinas (ACA) y anti&beta;2glicoproteinacon el m&eacute;todo de ELISA. Los resultados muestran que 11,1% de las mujeres con embarazo normal fueron positivaspara IgM ACA, mientras que en las pacientes con aborto a repetici&oacute;n el porcentaje de positividad fue de 23%. Encuanto a la IgG ACA se obtuvo 15% de positividad en las mujeres con embarazo normal vs 57% en las pacientescon aborto a repetici&oacute;n (p&lt;0,001). En el caso de la IgM anti &beta;2 glicoprote&iacute;na se encontr&oacute; una positividad de 1% enlas mujeres con embarazo normal vs 43% en las pacientes con aborto a repetici&oacute;n (p&lt;0,001), la positividad de laIgG anti anti &beta;2 glicoprote&iacute;na fue de 20% en las mujeres con embarazo normal y de 9% en pacientes con aborto arepetici&oacute;n. Se concluye que IgG ACA e IgM anti &beta;2 glicoprote&iacute;na se encontraron asociadas a problemas obst&eacute;tricos