Molecular and Epidemiological Investigation of Fluconazole-resistant Candida parapsilosis-Georgia, United States, 2021.

Background: Reports of fluconazole-resistant Candida parapsilosis bloodstream infections are increasing. We describe a cluster of fluconazole-resistant C parapsilosis bloodstream infections identified in 2021 on routine surveillance by the Georgia Emerging Infections Program in conjunction with the Centers for Disease Control and Prevention. Methods: Whole-genome sequencing was used to analyze C parapsilosis bloodstream infections isolates. Epidemiological data were obtained from medical records. A social network analysis was conducted using Georgia Hospital Discharge Data. Results: Twenty fluconazole-resistant isolates were identified in 2021, representing the largest proportion (34%) of fluconazole-resistant C parapsilosis bloodstream infections identified in Georgia since surveillance began in 2008. All resistant isolates were closely genetically related and contained the Y132F mutation in the ERG11 gene. Patients with fluconazole-resistant isolates were more likely to have resided at long-term acute care hospitals compared with patients with susceptible isolates (P = .01). There was a trend toward increased mechanical ventilation and prior azole use in patients with fluconazole-resistant isolates. Social network analysis revealed that patients with fluconazole-resistant isolates interfaced with a distinct set of healthcare facilities centered around 2 long-term acute care hospitals compared with patients with susceptible isolates. Conclusions: Whole-genome sequencing results showing that fluconazole-resistant C parapsilosis isolates from Georgia surveillance demonstrated low genetic diversity compared with susceptible isolates and their association with a facility network centered around 2 long-term acute care hospitals suggests clonal spread of fluconazole-resistant C parapsilosis. Further studies are needed to better understand the sudden emergence and transmission of fluconazole-resistant C parapsilosis.

Prevention in Hepatology.

The prevention of liver disease has improved significantly in the last few decades, to the point that it can now be considered a true success story. The wide variety of interventions, including comprehensive vaccination strategies, novel medications, lifestyle changes, and even preventive surgeries, have reduced the morbidity and mortality of chronic liver diseases. However, the prevalence of chronic liver diseases is increasing worldwide. Currently, fatty liver disease alone is estimated to be present in as much as 30% of the adult population. Furthermore, there is a trend towards increasing incidences of chronic hepatitis B, and a global lack of success in efforts to eliminate chronic hepatitis C. Thus, improving and efficiently rolling out existing and successful prevention strategies for chronic liver diseases will play an essential role in healthcare throughout the upcoming decades. In this review, we summarize the current options and concepts for preventing chronic liver diseases, highlight their limitations, and provide an outlook on probable future developments to improve awareness, integrated care, and the analysis of big data.

Cohorte descriptiva de pacientes adultos con hipertensión portal en una institución de tercer nivel en Colombia / Descriptive cohort of adult patients with portal hypertension at a tertiary care institution in Colombia

Introducción. La hipertensión portal (HTP) se define como una elevación anormal de la presión venosa en el sistema portal que lleva al desarrollo de vías colaterales para desviar el flujo sanguíneo de la zona. Dentro de su etiología están las relacionadas con la cirrosis hepática y otras causas denominadas no cirróticas. El objetivo de este estudio fue evaluar los principales hallazgos demográficos, clínicos y paraclínicos en un grupo de pacientes con HTP, y determinar el uso de ayudas invasivas y no invasivas, y su disponibilidad para el diagnóstico y seguimiento de los pacientes en los centros que no cuentan con laboratorio de hemodinamia hepática, reflejando la dinámica de múltiples escenarios en Colombia. Metodología. Se realizó un estudio descriptivo de corte transversal, retrospectivo, en pacientes atendidos en una institución de tercer nivel del sur de Colombia, entre enero del año 2015 y diciembre del año 2020. Resultados. Se obtuvo una muestra de 61 pacientes en donde la mayoría de casos correspondían a hombres en la séptima década de la vida, procedentes del área urbana. La principal causa de consulta fue el sangrado digestivo (39,3 %), asociado a la presencia de telangiectasias (arañas vasculares) en el 37,2 %, seguido de circulación colateral (31,3 %) e ictericia (19,7 %). En la ecografía abdominal (realizada en el 57,4 % de los pacientes) predominaron la cirrosis (68 %) y la presencia de esplenomegalia (14,2 %), y en lospacientes con Doppler portal (realizado en el 16,4 %) se encontró hígado cirrótico (80 %) y dilatación portal (40 %). Con respecto a los hallazgos en la esofagogastroduodenoscopia predominó la presencia de várices esofágicas y gastritis crónica. Conclusión. El principal motivo de consulta fue el sangrado digestivo, en tanto que la cirrosis fue el antecedente y el hallazgo imagenológico más frecuente, seguido de las várices esofágicas. Se encontró que el uso de paraclínicos, ecografía abdominal, ecografía con Doppler portal y esofagogastroduodenoscopia fueron los más utilizados en el contexto clínico de los pacientes con el diagnóstico de HTP.

Introduction. Portal hypertension (PHT) is defined as an abnormal elevation of venous pressure in the portal system that leads to the development of collateral pathways to divert blood flow from the area. Within its etiology are those related to liver cirrhosis and other so-called non cirrhotic causes. The aim of this study was to evaluate the main demographic, clinical and paraclinical findings in a group of patients with PHT, and to determine the use of invasive and non-invasive aids, and their availability for the diagnosis and follow-up of patients in centers that do not have a hepatic hemodynamics laboratory, reflecting the dynamics of multiple scenarios in Colombia. Methodology. A descriptive, retrospective, cross-sectional, retrospective study was conducted in patients attended in a third level institution in Southern Colombia, between January 2015 and December 2020. Results. A sample of 61 patients was obtained where the majority of cases corresponded to men in the seventh decade of life, from the urban area. The main cause of consultation was digestive bleeding (39.3%), associated with the presence of telangiectasias (spider veins) in 37.2%, followed by collateral circulation (31.3%) and jaundice (19.7%). In abdominal ultrasound (performed in 57.4% of the patients), cirrhosis (68%) and the presence of splenomegaly (14.2%) predominated, and in patients with portal Doppler (performed in 16.4%), cirrhotic liver (80%) and portal dilatation (40%) were found. With respect to the findings in the esophagogastroduodenoscopy, esophageal varices and chronic gastritis were predominant. Conclusion. The main reason for consultation was gastrointestinal bleeding, while cirrhosis was the most frequent history and imaging finding, followed by esophageal varices. It was found that the use of paraclinics, abdominal ultrasound, ultrasound with portal Doppler and esophagogastroduodenoscopy were the most used in the clinical context of patients diagnosed with PHT.

Educational Strategy for Breastfeeding Maintenance During the COVID-19 Post-Pandemic Period in Popayán / Estrategia educativa para el mantenimiento de la lactancia materna en pospandemia de la covid-19 en Popayán / Estratégia educacional para a manutenção do aleitamento materno na pós-pandemia da covid-19 em Popayán, Colômbia

Introduction: The scientific literature indicates that the COVID-19 pandemic has exerted an important impact on delivery care and breastfeeding, such as abandoning practices like skin-to-skin contact and early breastfeeding initiation, which offer major benefits for maternal-child health. Objective: To know the experiences undergone by mothers of hospitalized breastfeeding infants regarding educational strategies for breastfeeding maintenance during the COVID-19 post-pandemic period. Materials and methods: A qualitative study with a phenomenological approach. The population was comprised of 39 mothers of newborns hospitalized in the neonatal unit of the Susana López de Valencia hospital, Popayán (Cauca). Semi-structured interviews and a discussion group consisting of randomly selected mothers who did not know each other were employed as techniques to obtain the information. The semi-structured interviews eased an in-depth search for information until reaching data saturation. Results: Five categories emerged from the analysis: 1) The mothers' knowledge about breastfeeding; 2) Barriers identified by the mothers in the educational process; 3) Nurses' willingness to provide support, listen and help; 4) The best strategy concerning breastfeeding education; and 5) The pandemic as a factor that increases fear and apprehension during hospitalization of a child. Conclusions: Knowing the experiences undergone by mothers of hospitalized children regarding breastfeeding allows us to get closer to proposing an educational strategy that includes their needs, previous knowledge, facilitating elements and barriers, to maintain breastfeeding during hospitalization.

Introducción: la literatura científica indica que la pandemia por la covid-19 ha tenido un impacto importante en la atención al parto y la lactancia, por ejemplo, el abandono de prácticas como el contacto piel a piel y el inicio temprano de la lactancia materna, que ofrecen grandes beneficios para la salud materno-infantil. Objetivo: conocer las experiencias de las madres de lactantes hospitalizados respecto a las estrategias educativas en torno al mantenimiento de la lactancia materna durante la post pandemia por covid-19. Materiales y métodos: estudio cualitativo, con enfoque fenomenológico. La población se constituyó por 39 madres de recién nacidos hospitalizados en la unidad neonatal del hospital Susana López de Valencia, Popayán (Cauca). Como técnicas de acceso a la información, se emplearon una entrevista semiestructurada y un grupo de discusión conformado por madres que no se conocían entre sí y que fueron elegidas al azar. La entrevista semiestructurada facilitó la búsqueda de información a profundidad hasta que se saturaron los datos. Resultados: emergieron cinco categorías de análisis: 1) los conocimientos de las madres acerca de la lactancia materna; 2) las barreras que identifican las madres en el proceso educativo; 3) la disposición de las enfermeras como apoyo, escucha y ayuda; 4) la mejor estrategia en torno a la educación en lactancia materna; y 5) la pandemia como factor que aumenta el temor y miedo durante la hospitalización de un hijo. Conclusiones: el conocimiento de las experiencias de las madres de niños hospitalizados en torno a la lactancia permite aproximarnos a la propuesta de una estrategia educativa que incluya sus necesidades, conocimientos previos, elementos facilitadores y barreras, con el fin de mantener la lactancia materna durante la hospitalización.

Introdução: a literatura científica indica que a pandemia da covid-19 teve um impacto importante na assistência ao parto e à amamentação, por exemplo, o abandono de práticas como o contato pele a pele e o início precoce do aleitamento materno, que oferecem grandes benefícios para a saúde materno-infantil. Objetivo: conhecer as experiências das mães de bebês hospitalizados quanto às estratégias educacionais para a manutenção do aleitamento materno durante a pós-pandemia da covid-19. Materiais e método: estudo qualitativo, com abordagem fenomenológica. A população foi composta de 39 mães de recém-nascidos hospitalizados na unidade neonatal do Hospital Susana López de Valencia, Popayán (Cauca, Colômbia). Uma entrevista semiestruturada e um grupo de discussão formado por mães que não se conheciam e que foram escolhidas aleatoriamente foram usados como técnicas para acessar as informações. A entrevista semiestruturada facilitou a busca de informações aprofundadas até a saturação dos dados. Resultados: surgiram cinco categorias de análise: 1) o conhecimento das mães sobre amamentação; 2) as barreiras identificadas pelas mães no processo educacional; 3) a disposição dos enfermeiros para apoiar, ouvir e ajudar; 4) a melhor estratégia em torno da educação sobre amamentação; e 5) a pandemia como fator que aumenta o medo e a apreensão durante a hospitalização de uma criança. Conclusões: o conhecimento das experiências das mães de crianças hospitalizadas quanto ao aleitamento materno nos permite propor uma estratégia educacional que inclua suas necessidades, conhecimento prévio, facilitadores e barreiras, a fim de manter o aleitamento materno durante a hospitalização.

Quantifying the value of viral genomics when inferring who infected whom in the 2014-16 Ebola virus outbreak in Guinea.

Transmission trees can be established through detailed contact histories, statistical or phylogenetic inference, or a combination of methods. Each approach has its limitations, and the extent to which they succeed in revealing a 'true' transmission history remains unclear. In this study, we compared the transmission trees obtained through contact tracing investigations and various inference methods to identify the contribution and value of each approach. We studied eighty-six sequenced cases reported in Guinea between March and November 2015. Contact tracing investigations classified these cases into eight independent transmission chains. We inferred the transmission history from the genetic sequences of the cases (phylogenetic approach), their onset date (epidemiological approach), and a combination of both (combined approach). The inferred transmission trees were then compared to those from the contact tracing investigations. Inference methods using individual data sources (i.e. the phylogenetic analysis and the epidemiological approach) were insufficiently informative to accurately reconstruct the transmission trees and the direction of transmission. The combined approach was able to identify a reduced pool of infectors for each case and highlight likely connections among chains classified as independent by the contact tracing investigations. Overall, the transmissions identified by the contact tracing investigations agreed with the evolutionary history of the viral genomes, even though some cases appeared to be misclassified. Therefore, collecting genetic sequences during outbreak is key to supplement the information contained in contact tracing investigations. Although none of the methods we used could identify one unique infector per case, the combined approach highlighted the added value of mixing epidemiological and genetic information to reconstruct who infected whom.

Hemangioma hepático gigante: presentación de caso clínico / Giant hepatic hemangioma: case report

Los hemangiomas hepáticos se consideran las lesiones benignas hepáticas más comunes. Se de-nominan hemangiomas gigantes cuando su diámetro supera los 5 cm. La etiología es poco clara y su mayor prevalencia se ubica en mujeres de mediana edad. A continuación, se presenta el caso de una paciente de 73 años con dispepsia tipo distrés postprandial. La paciente acudió a consulta donde se documentó una masa heterogénea en segmentos hepáticos VI y VII con componente exofítico, realce periférico y llenado centrípeto en fases tardías. Recibió manejo sintomático con buena respuesta clínica y continúa en seguimiento. La presentación de este caso clínico obedece a que el hemangioma hepático es diagnosticado, por lo general, de forma incidental por imágenes abdominales realizadas desde un enfoque distinto en el paciente, y por las numerosas consultas al servicio de salud por síntomas diferentes a los directamente relacionados con el hemangioma hepá-tico. Adicionalmente, puede generar complicaciones asociadas al efecto de masa, y su prevalencia dentro de las lesiones hepáticas benignas es considerable

Hepatic hemangiomas are the most common benign tumors of the liver. They are called giant he-mangiomas when their diameter exceeds 5 cm. The pathophysiology is unclear, and middle-aged women have the highest prevalence. The case of a 73-year-old woman with dyspepsia postprandial distress syndrome is presented. The patient had a heterogeneous mass in the liver segments VI and VII with an exophytic component, peripheral enhancement, and centripetal filling in late phases. The patient received symptomatic treatment with adequate clinical response and continues in observa-tion. The presentation of this clinical report is due to the fact that hepatic hemangioma is generally diagnosed incidentally by abdominal imaging performed from a different approach, and to the numerous visits to the health service due to symptoms other than those directly related to hepatic hemangioma. Additionally, it can involve mass-related complications, and the prevalence within benign liver lesions is substantial.

An introduction to the Marburg virus vaccine consortium, MARVAC.

The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine "MARVAC" consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines.

A platform trial design for preventive vaccines against Marburg virus and other emerging infectious disease threats.

BACKGROUND: The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines. METHODS: A core protocol approach will be used, allowing multiple vaccine candidates to be tested against controls. The primary objective of the trial will be to evaluate the effect of each vaccine on the rate of virologically confirmed Marburg virus disease, although Marburg infection assessed via seroconversion could be the primary objective in some cases. The overall trial design will be a mixture of individually and cluster-randomized designs, with individual randomization done whenever possible. Clusters will consist of either contacts and contacts of contacts of index cases, that is, ring vaccination, or other transmission units. RESULTS: The primary efficacy endpoint will be analysed as a time-to-event outcome. A vaccine will be considered successful if its estimated efficacy is greater than 50% and has sufficient precision to rule out that true efficacy is less than 30%. This will require approximately 150 total endpoints, that is, cases of confirmed Marburg virus disease, per vaccine/comparator combination. Interim analyses will be conducted after 50 and after 100 events. Statistical analysis of the trial will be blended across the different types of designs. Under the assumption of a 6-month attack rate of 1% of the participants in the placebo arm for both the individually and cluster-randomized populations, the most likely sample size is about 20,000 participants per arm. CONCLUSION: This event-driven design takes into the account the potentially sporadic spread of Marburg virus. The proposed trial design may be applicable for other pathogens against which effective vaccines are not yet available.

Advances and gaps in SARS-CoV-2 infection models.

The global response to Coronavirus Disease 2019 (COVID-19) is now facing new challenges such as vaccine inequity and the emergence of SARS-CoV-2 variants of concern (VOCs). Preclinical models of disease, in particular animal models, are essential to investigate VOC pathogenesis, vaccine correlates of protection and postexposure therapies. Here, we provide an update from the World Health Organization (WHO) COVID-19 modeling expert group (WHO-COM) assembled by WHO, regarding advances in preclinical models. In particular, we discuss how animal model research is playing a key role to evaluate VOC virulence, transmission and immune escape, and how animal models are being refined to recapitulate COVID-19 demographic variables such as comorbidities and age.

Electronic Data Management for Vaccine Trials in Low Resource Settings: Upgrades, Scalability, and Impact of ODK.

Background: ODK provides software and standards that are popular solutions for off-grid electronic data collection and has substantial code overlap and interoperability with a number of related software products including CommCare, Enketo, Ona, SurveyCTO, and KoBoToolbox. These tools provide open-source options for off-grid use in public health data collection, management, analysis, and reporting. During the 2018-2020 Ebola epidemic in the North Kivu and Ituri regions of Democratic Republic of Congo, we used these tools to support the DRC Ministère de la Santé RDC and World Health Organization in their efforts to administer an experimental vaccine (VSV-Zebov-GP) as part of their strategy to control the transmission of infection. Method: New functions were developed to facilitate the use of ODK, Enketo and R in large scale data collection, aggregation, monitoring, and near-real-time analysis during clinical research in health emergencies. We present enhancements to ODK that include a built-in audit-trail, a framework and companion app for biometric registration of ISO/IEC 19794-2 fingerprint templates, enhanced performance features, better scalability for studies featuring millions of data form submissions, increased options for parallelization of research projects, and pipelines for automated management and analysis of data. We also developed novel encryption protocols for enhanced web-form security in Enketo. Results: Against the backdrop of a complex and challenging epidemic response, our enhanced platform of open tools was used to collect and manage data from more than 280,000 eligible study participants who received VSV-Zebov-GP under informed consent. These data were used to determine whether the VSV-Zebov-GP was safe and effective and to guide daily field operations. Conclusions: We present open-source developments that make electronic data management during clinical research and health emergencies more viable and robust. These developments will also enhance and expand the functionality of a diverse range of data collection platforms that are based on the ODK software and standards.

SARS-CoV-2 Variants and Vaccines.

Viral variants of concern may emerge with dangerous resistance to the immunity generated by the current vaccines to prevent coronavirus disease 2019 (Covid-19). Moreover, if some variants of concern have increased transmissibility or virulence, the importance of efficient public health measures and vaccination programs will increase. The global response must be both timely and science based.

COVID-19 vaccine trials: The potential for "hybrid" analyses.

BACKGROUND: Although several COVID-19 vaccines have been found to be effective in rigorous evaluation and have emerging availability in parts of the world, their supply will be inadequate to meet international needs for a considerable period of time. There also will be continued interest in vaccines that are more effective or have improved scalability to facilitate mass vaccination campaigns. Ongoing clinical testing of new vaccines also will be needed as variant strains continue to emerge that may elude some aspects of immunity induced by current vaccines. Randomized clinical trials meaningfully enhance the efficiency and reliability of such clinical testing. In clinical settings with limited or no access to known effective vaccines, placebo-controlled randomized trials of new vaccines remain a preferred approach to maximize the reliability, efficiency and interpretability of results. When emerging availability of licensed vaccines makes it no longer possible to use a placebo control, randomized active comparator non-inferiority trials may enable reliable insights. METHODS: In this article, "hybrid" methods are proposed to address settings where, during the conduct of a placebo-controlled trial, a judgment is made to replace the placebo arm by a licensed COVID-19 vaccine due to emerging availability of effective vaccines in regions participating in that trial. These hybrid methods are based on proposed statistics that aggregate evidence to formally test as well as to estimate the efficacy of the experimental vaccine, by combining placebo-controlled data during the first period of trial conduct with active-controlled data during the second period. RESULTS: Application of the proposed methods is illustrated in two important scenarios where the active control vaccine would become available in regions engaging in the experimental vaccine's placebo-controlled trial: in the first, the active comparator's vaccine efficacy would have been established to be 50%-70% for the 4- to 6-month duration of follow-up of its placebo-controlled trial; in the second, the active comparator's vaccine efficacy would have been established to be 90%-95% during that duration. These two scenarios approximate what has been seen with adenovirus vaccines or mRNA vaccines, respectively, assuming the early estimates of vaccine efficacy for those vaccines would hold over longer-term follow-up. CONCLUSION: The proposed hybrid methods could readily play an important role in the near future in the design, conduct and analysis of randomized clinical trials performed to address the need for multiple additional vaccines reliably established to be safe and have worthwhile efficacy in reducing the risk of symptomatic disease from SARS-CoV-2 infections.

COVID-19 vaccine trials: The use of active controls and non-inferiority studies.

BACKGROUND: Recently emerging results from a few placebo-controlled randomized trials of COVID-19 vaccines revealed estimates of 62%-95% relative reductions in risk of virologically confirmed symptomatic COVID-19 disease, over approximately 2-month average follow-up period. Additional safe and effective COVID-19 vaccines are needed in a timely manner to adequately address the pandemic on an international scale. Such safe and effective vaccines would be especially appealing for international deployment if they also have favorable stability, supply, and potential for implementation in mass vaccination campaigns. Randomized trials provide particularly reliable insights about vaccine efficacy and safety. While enhanced efficiency and interpretability can be obtained from placebo-controlled trials, in settings where their conduct is no longer possible, randomized non-inferiority trials may enable obtaining reliable evaluations of experimental vaccines through direct comparison with active comparator vaccines established to have worthwhile efficacy. METHODS: The usual objective of non-inferiority trials is to reliably assess whether the efficacy of an experimental vaccine is not unacceptably worse than that of an active control vaccine previously established to be effective, likely in a placebo-controlled trial. This is formally achieved by ruling out a non-inferiority margin identified to be the minimum threshold for what would constitute an unacceptable loss of efficacy. This article not only investigates non-inferiority margins, denoted by δ, that address the usual objective of determining whether the experimental vaccine is "at least similarly effective to" the active comparator vaccine in the non-inferiority trial, but also develops non-inferiority margins, denoted by δo, intended to address the worldwide need for multiple safe and effective vaccines by satisfying the less stringent requirement that the experimental vaccine be "at least similarly effective to" an active comparator vaccine having efficacy that satisfies the widely accepted World Health Organization-Food and Drug Administration criteria for "worthwhile" vaccine efficacy. RESULTS: Using the margin δ enables non-inferiority trials to reliably evaluate experimental vaccines that truly are similarly effective to an active comparator vaccine having any level of "worthwhile" efficacy. When active comparator vaccines have efficacy in the range of 50%-70%, non-inferiority trials designed to use the margin δo have appealing properties, especially for experimental vaccines having true efficacy of approximately 60%. CONCLUSION: Non-inferiority trials using the proposed margins may enable reliable randomized evaluations of efficacy and safety of experimental COVID-19 vaccines. Such trials often require approximately two- to three-fold the person-years follow-up than a placebo-controlled trial. This could be achieved, without substantive increases in sample size, by increasing the average duration of follow-up from 2 months to approximately 4-6 months, assuming efficacy of the active comparator vaccine has been reliably evaluated over that longer duration.

Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-monitored Challenge Model of Coronavirus Disease 2019 (COVID-19) in Healthy Volunteers.

WHO convened an Advisory Group (AG) to consider the feasibility, potential value, and limitations of establishing a closely-monitored challenge model of experimental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) in healthy adult volunteers. The AG included experts in design, establishment, and performance of challenges. This report summarizes issues that render a COVID-19 model daunting to establish (the potential of SARS-CoV-2 to cause severe/fatal illness, its high transmissibility, and lack of a "rescue treatment" to prevent progression from mild/moderate to severe clinical illness) and it proffers prudent strategies for stepwise model development, challenge virus selection, guidelines for manufacturing challenge doses, and ways to contain SARS-CoV-2 and prevent transmission to household/community contacts. A COVID-19 model could demonstrate protection against virus shedding and/or illness induced by prior SARS-CoV-2 challenge or vaccination. A limitation of the model is that vaccine efficacy in experimentally challenged healthy young adults cannot per se be extrapolated to predict efficacy in elderly/high-risk adults.

Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.

BACKGROUND: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study.

BACKGROUND: The 2013-16 Ebola virus disease epidemic in west Africa caused international alarm due to its rapid and extensive spread resulting in a significant death toll and social unrest within the affected region. The large number of cases provided an opportunity to study the long-term kinetics of Zaire ebolavirus-specific immune response of survivors in addition to known contacts of those infected with the virus. METHODS: In this observational cohort study, we worked with leaders of Ebola virus disease survivor associations in two regions of Guinea, Guéckédou and Coyah, to recruit survivors of Ebola virus disease, contacts from households of individuals known to have had Ebola virus disease, and individuals who were not knowingly associated with infected individuals or had not had Ebola virus disease symptoms to serve as negative controls. We did Zaire ebolavirus glycoprotein-specific T cell analysis on peripheral blood mononuclear cells (PBMCs) on location in Guinea and transported plasma and PBMCs back to Europe for antibody quantification by ELISA, functional neutralising antibody analysis using live Zaire ebolavirus, and T cell phenotype studies. We report on the longitudinal cellular and humoral response among Ebola virus disease survivors and highlight potentially paucisymptomatic infection. FINDINGS: We recruited 117 survivors of Ebola virus disease, 66 contacts, and 23 negative controls. The mean neutralising antibody titre among the Ebola virus disease survivors 3-14 months after infection was 1/174 (95% CI 1/136-1/223). Individual results varied greatly from 1/10 to more than 1/1000 but were on average ten times greater than that induced after 1 month by single dose Ebola virus vaccines. Following reactivation with glycoprotein peptide, the mean T cell responses among 116 Ebola virus disease survivors as measured by ELISpot was 305 spot-forming units (95% CI 257-353). The dominant CD8+ polyfunctional T cell phenotype, as measured among 53 Ebola virus disease survivors, was interferon γ+, tumour necrosis factor+, interleukin-2-, and the mean response was 0·046% of total CD8+ T cells (95% CI 0·021-0·071). Additionally, both neutralising antibody and T cell responses were detected in six (9%) of 66 Ebola virus disease contacts. We also noted that four (3%) of 117 individuals with Ebola virus disease infections did not have circulating Ebola virus-specific antibodies 3 months after infection. INTERPRETATION: The continuous high titre of neutralising antibodies and increased T cell response might support the concept of long-term protective immunity in survivors. The existence of antibody and T cell responses in contacts of individuals with Ebola virus disease adds further evidence to the existence of sub-clinical Ebola virus infection. FUNDING: US Food & Drug Administration, Horizon 2020 EU EVIDENT, Wellcome, UK Department for International Development. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.