Contextual determinants of mass drug administration performance: Modelling fourteen years of lymphatic filariasis treatments in West Africa.

BACKGROUND: Effective mass drug administration (MDA) is the cornerstone in the elimination of lymphatic filariasis (LF) and a critical component in combatting all neglected tropical diseases for which preventative chemotherapy is recommended (PC-NTDs). Despite its importance, MDA coverage, however defined, is rarely investigated systematically across time and geography. Most commonly, investigations into coverage react to unsatisfactory outcomes and tend to focus on a single year and health district. Such investigations omit more macro-level influences including sociological, environmental, and programmatic factors. The USAID NTD database contains measures of performance from thousands of district-level LF MDA campaigns across 14 years and 10 West African countries. Specifically, performance was measured as an MDA's epidemiological coverage, calculated as persons treated divided by persons at risk. This analysis aims to explain MDA coverage across time and geography in West Africa using sociological, environmental, and programmatic factors. METHODOLOGY: The analysis links epidemiological coverage data from 3,880 LF MDAs with contextual, non-NTD data via location (each MDA was specific to a health district) and time (MDA month, year). Contextual data included rainfall, temperature, violence or social unrest, COVID-19, the 2014 Ebola outbreak, road access/isolation, population density, observance of Ramadan, and the number of previously completed MDAs. PRINCIPAL FINDINGS: We fit a hierarchical linear regression model with coverage as the dependent variable and performed sensitivity analyses to confirm the selection of the explanatory factors. Above average rainfall, COVID-19, Ebola, violence and social unrest were all significantly associated with lower coverage. Years of prior experience in a district and above average temperature were significantly associated with higher coverage. CONCLUSIONS/SIGNIFICANCE: These generalized and context-focused findings supplement current literature on coverage dynamics and MDA performance. Findings may be used to quantify typically anecdotal considerations in MDA planning. The model and methodology are offered as a tool for further investigation.

Effects of therapies for Ebola virus disease: a systematic review and network meta-analysis.

BACKGROUND: Specific treatments targeting Ebola virus are crucial in managing Ebola virus disease. To support the development of clinical practice guidelines on medications for Ebola virus disease, we aimed to evaluate the efficacy and safety of therapies for patients with Ebola virus disease. METHODS: In this systematic review and network meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Scopus, Global Health, African Index Medicus, World Health Organization Global Index Medicus, the Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, Epistemonikos, bioRxiv, medRxiv, and SSRN without language restrictions for randomised controlled trials (RCTs) published between database inception and Jan 1, 2022, comparing at least one therapeutic agent for Ebola virus disease against standard care or another therapeutic agent for Ebola virus disease. Two reviewers assessed study eligibility and extracted summary data independently using a standardised form. Our outcomes of interest were mortality, adverse maternal outcomes, risk of onward transmission, duration of admission to a health-care facility, functional status after Ebola virus disease, serious adverse events from medication, adverse perinatal outcomes, time to symptom resolution, and time to viral clearance. We did frequentist network meta-analyses to estimate the effect of all interventions and applied the Grading of Recommendations Assessment, Development and Evaluation approach to rate the certainty of the evidence. We registered the protocol with PROSPERO, CRD42022296539. FINDINGS: We identified 7840 records through database searches, of which two RCTs with a total of 753 patients proved eligible. Only data on mortality, the duration of admission, serious adverse events, and time to viral clearance were available for meta-analysis. Compared with standard care, REGN-EB3 (relative risk [RR] 0·40, 95% CI 0·18 to 0·89; moderate certainty) and mAb114 (0·42, 0·19 to 0·93; moderate certainty) probably reduce mortality. Whether ZMapp (0·60, 0·28 to 1·26; very low certainty) and remdesivir (0·64, 0·29 to 1·39; very low certainty) reduce mortality compared with standard care is uncertain. With high certainty, REGN-EB3 reduces mortality compared with ZMapp (0·67, 0·52 to 0·88) and remdesivir (0·63, 0·49 to 0·82). With high certainty, mAb114 also reduces mortality compared with ZMapp (0·71, 0·55 to 0·91) and remdesivir (0·66, 0·52 to 0·84). Compared with standard care, REGN-EB3, mAb114, ZMapp, and remdesivir might have little or no effect on the time to viral clearance (mean difference ranged from -0·25 days to -1·14 days; low certainty). ZMapp might reduce the duration of admission compared with standard care (mean difference -2·02 days, 95% CI -4·05 to 0·01; low certainty). Findings for all comparisons suggested that there might be little or no difference in the prevalence of serious adverse events, but certainty was low or very low in all comparisons but one. INTERPRETATION: REGN-EB3 and mAb114 separately reduce mortality compared with ZMapp, remdesivir, or standard care in patients with Ebola virus disease. These findings suggest that health-care workers should prioritise the use of REGN-EB3 and mAb114 for patients with Ebola virus disease during future outbreaks. FUNDING: WHO.

Instruction of molecular structure similarity and scaffolds of drugs under investigation in ebola virus treatment by atom-pair and graph network: A combination of favipiravir and molnupiravir.

The virus that causes Ebola is fatal. Although many researchers have attempted to contain this deadly infection, the fatality rate remains high. The atom-pair fingerprint technique was used to compare drugs suggested for the treatment of Ebola or those that are currently being tested in clinical settings. Subsequently, using scaffold network graph (SNG) methods, the molecular and structural scaffolds of the drugs chosen based on these similar results were created, and the drug structures were examined. Public databases (PubChem and DrugBank) and literature regarding Ebola treatment were used in the analysis. Graphical representations of the molecular architecture and core structures of the drugs with the highest similarity to Food and Drug Administration (FDA)-approved drugs were produced using the SNG method. The combination of molnupiravir, the first licensed oral medication candidate for COVID-19, and favipiravir, employed in other viral outbreaks, should be further researched for treating Ebola, as observed in our study. We also believe that chemists will benefit from understanding the core structure(s) of medication molecules effective against the Ebola virus, their inhibitors, and the chemical structure similarities of existing pharmaceuticals utilized to build alternative drugs or drug combinations.

Molecular Docking and In-Silico Analysis of Natural Biomolecules against Dengue, Ebola, Zika, SARS-CoV-2 Variants of Concern and Monkeypox Virus.

The emergence and rapid evolution of human pathogenic viruses, combined with the difficulties in developing effective vaccines, underline the need to develop innovative broad-spectrum antiviral therapeutic agents. The present study aims to determine the in silico antiviral potential of six bacterial antimicrobial peptides (AMPs), two phytochemicals (silvestrol, andrographolide), and two bacterial secondary metabolites (lyngbyabellin A, hapalindole H) against dengue virus, Zika virus, Ebola virus, the major variants of SARS-CoV-2 and monkeypox virus. The comparison of docking scores obtained with natural biomolecules was performed with specific neutralizing antibodies (positive controls for ClusPro) and antiviral drugs (negative controls for Autodock Vina). Glycocin F was the only natural biomolecule tested to show high binding energies to all viral surface proteins and the corresponding viral cell receptors. Lactococcin G and plantaricin ASM1 also achieved high docking scores with all viral surface proteins and most corresponding cell surface receptors. Silvestrol, andrographolide, hapalindole H, and lyngbyabellin A showed variable docking scores depending on the viral surface proteins and cell receptors tested. Three glycocin F mutants with amino acid modifications showed an increase in their docking energy to the spike proteins of SARS-CoV-2 B.1.617.2 Indian variant, and of the SARS-CoV-2 P.1 Japan/Brazil variant, and the dengue DENV envelope protein. All mutant AMPs indicated a frequent occurrence of valine and proline amino acid rotamers. AMPs and glycocin F in particular are the most promising biomolecules for the development of broad-spectrum antiviral treatments targeting the attachment and entry of viruses into their target cell.

Pyronaridine Protects against SARS-CoV-2 Infection in Mouse.

There are currently relatively few small-molecule antiviral drugs that are either approved or emergency-approved for use against severe acute respiratory coronavirus 2 (SARS-CoV-2). One of these is remdesivir, which was originally repurposed from its use against Ebola. We evaluated three molecules we had previously identified computationally with antiviral activity against Ebola and Marburg and identified pyronaridine, which inhibited the SARS-CoV-2 replication in A549-ACE2 cells. The in vivo efficacy of pyronaridine has now been assessed in a K18-hACE transgenic mouse model of COVID-19. Pyronaridine treatment demonstrated a statistically significant reduction of viral load in the lungs of SARS-CoV-2-infected mice, reducing lung pathology, which was also associated with significant reduction in the levels of pro-inflammatory cytokines/chemokine and cell infiltration. Pyronaridine inhibited the viral PLpro activity in vitro (IC50 of 1.8 µM) without any effect on Mpro, indicating a possible molecular mechanism involved in its ability to inhibit SARS-CoV-2 replication. We have also generated several pyronaridine analogs to assist in understanding the structure activity relationship for PLpro inhibition. Our results indicate that pyronaridine is a potential therapeutic candidate for COVID-19.

Unique Mode of Antiviral Action of a Marine Alkaloid against Ebola Virus and SARS-CoV-2.

Lamellarin α 20-sulfate is a cell-impenetrable marine alkaloid that can suppress infection that is mediated by the envelope glycoprotein of human immunodeficiency virus type 1. We explored the antiviral action and mechanisms of this alkaloid against emerging enveloped RNA viruses that use endocytosis for infection. The alkaloid inhibited the infection of retroviral vectors that had been pseudotyped with the envelope glycoprotein of Ebola virus and SARS-CoV-2. The antiviral effects of lamellarin were independent of the retrovirus Gag-Pol proteins. Interestingly, although heparin and dextran sulfate suppressed the cell attachment of vector particles, lamellarin did not. In silico structural analyses of the trimeric glycoprotein of the Ebola virus disclosed that the principal lamellarin-binding site is confined to a previously unappreciated cavity near the NPC1-binding site and fusion loop, whereas those for heparin and dextran sulfate were dispersed across the attachment and fusion subunits of the glycoproteins. Notably, lamellarin binding to this cavity was augmented under conditions where the pH was 5.0. These results suggest that the final action of the alkaloid against Ebola virus is specific to events following endocytosis, possibly during conformational glycoprotein changes in the acidic environment of endosomes. Our findings highlight the unique biological and physicochemical features of lamellarin α 20-sulfate and should lead to the further use of broadly reactive antivirals to explore the structural mechanisms of virus replication.

Protein Folding Interdiction Strategy for Therapeutic Drug Development in Viral Diseases: Ebola VP40 and Influenza A M1.

In a recent paper, we proposed the folding interdiction target region (FITR) strategy for therapeutic drug design in SARS-CoV-2. This paper expands the application of the FITR strategy by proposing therapeutic drug design approaches against Ebola virus disease and influenza A. We predict target regions for folding interdicting drugs on correspondingly relevant structural proteins of both pathogenic viruses: VP40 of Ebola, and matrix protein M1 of influenza A. Identification of the protein targets employs the sequential collapse model (SCM) for protein folding. It is explained that the model predicts natural peptide candidates in each case from which to start the search for therapeutic drugs. The paper also discusses how these predictions could be tested, as well as some challenges likely to be found when designing effective therapeutic drugs from the proposed peptide candidates. The FITR strategy opens a potential new avenue for the design of therapeutic drugs that promises to be effective against infectious diseases.

[Remdesivir for COVID-19].

Remdesivir is a direct-acting antiviral agent that inhibits viral RNA synthesis developed by Gilead Sciences, Inc. in the United States. It has been shown to have antiviral activity against single-stranded RNA viruses, including coronaviruses, in cell culture systems and animal models, and has been developed as a therapeutic agent for Ebola virus infection since 2015. however, to date, it has not been approved in any country. A novel coronavirus infection (COVID-19) was identified in Wuhan, Hubei Province, China in Dec, 2019, and is a respiratory disease characterized by fever, cough, and dyspnea. In severe cases, it may cause serious pneumonia, multi-organ failure and death. Gilead Sciences, Inc. U.S. embarked on the development of COVID-19 as a therapeutic drug, using remdesivir, which has shown in vitro and in vivo antiviral activities against MERS-CoV and SARS-CoV, which are single-stranded RNA coronaviruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). The in vitro antiviral activity of remdesivir against SARS-CoV-2, which causes COVID-19, was confirmed and clinical studies were initiated in February 2020. Based on the results of clinical studies conducted by the National Institute of Allergy and Infectious Diseases (NIAID) and Gilead Sciences, Inc. and experience of administration from a compassionate use, an exceptional approval system based on the "Pharmaceuticals and Medical Devices Act" was also approved in Japan as of May 7, 2020 for the indication of "infections caused by SARS-CoV-2." In this article, the background of the development and clinical results of remdesivir are described.

Luminore CopperTouch Surface Coating Effectively Inactivates SARS-CoV-2, Ebola Virus, and Marburg Virus In Vitro.

We investigated the ability of Luminore CopperTouch copper and copper-nickel surfaces to inactivate filoviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The copper and copper-nickel surfaces inactivated 99.9% of Ebola and Marburg viruses after 30 min, and the copper surfaces inactivated 99% of SARS-CoV-2 in 2 h. These data reveal that Ebola virus, Marburg virus, and SARS-CoV-2 are inactivated by exposure to copper ions, validating Luminore CopperTouch as an efficacious tool for infection control.

Accessing unproven interventions in the COVID-19 pandemic: discussion on the ethics of 'compassionate therapies' in times of catastrophic pandemics.

Since the onset of the SARS-CoV-2 pandemic, an array of off-label interventions has been used to treat patients, either provided as compassionate care or tested in clinical trials. There is a challenge in determining the justification for conducting randomised controlled trials over providing compassionate use in an emergency setting. A rapid and more accurate evaluation tool is needed to assess the effect of these treatments. Given the similarity to the Ebola Virus Disease (EVD) pandemic in Africa in 2014, we suggest using a tool designed by the WHO committee in the aftermath of the EVD pandemic: Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI). Considering the uncertainty around SARS-CoV-2, we propose using an improved MEURI including the Plan-Do-Study-Act tool. This combined tool may facilitate dynamic monitoring, analysing, re-evaluating and re-authorising emergency use of unproven treatments and repeat it in cycles. It will enable adjustment and application of outcomes to clinical practice according to changing circumstances and increase the production of valuable data to promote the best standard of care and high-quality research-even during a pandemic.

Remdesivir is efficacious in rhesus monkeys exposed to aerosolized Ebola virus.

Efficacious therapeutics for Ebola virus disease are in great demand. Ebola virus infections mediated by mucosal exposure, and aerosolization in particular, present a novel challenge due to nontypical massive early infection of respiratory lymphoid tissues. We performed a randomized and blinded study to compare outcomes from vehicle-treated and remdesivir-treated rhesus monkeys in a lethal model of infection resulting from aerosolized Ebola virus exposure. Remdesivir treatment initiated 4 days after exposure was associated with a significant survival benefit, significant reduction in serum viral titer, and improvements in clinical pathology biomarker levels and lung histology compared to vehicle treatment. These observations indicate that remdesivir may have value in countering aerosol-induced Ebola virus disease.

Review: Insights on Current FDA-Approved Monoclonal Antibodies Against Ebola Virus Infection.

The unprecedented 2013-2016 West Africa Ebola outbreak accelerated several medical countermeasures (MCMs) against Ebola virus disease (EVD). Several investigational products (IPs) were used throughout the outbreak but were not conclusive for efficacy results. Only the Randomized Controlled Trial (RCT) on ZMapp was promising but inconclusive. More recently, during the second-largest Ebola outbreak in North Kivu and Ituri provinces, Democratic Republic of the Congo (DRC), four IPs, including one small molecule (Remdesivir), two monoclonal antibody (mAb) cocktails (ZMapp and REGN-EB3) and a single mAb (mAb114), were evaluated in an RCT, the Pamoja Tulinde Maisha (PALM) study. Two products (REGN-EB3 and mAb114) demonstrated efficacy as compared to the control arm, ZMapp. There were remarkably few side effects recorded in the trial. The FDA approved both medications in this scientifically sound study, marking a watershed moment in the field of EVD therapy. These products can be produced relatively inexpensively and can be stockpiled. The administration of mAbs in EVD patients appears to be safe and effective, while several critical knowledge gaps remain; the impact of early administration of Ebola-specific mAbs on developing a robust immune response for future Ebola virus exposure is unknown. The viral mutation escape, leading to resistance, presents a potential limitation for single mAb therapy; further improvements need to be explored. Understanding the contribution of Fc-mediated antibody functions such as antibody-dependent cellular cytotoxicity (ADCC) of those approved mAbs is still critical. The potential merit of combination therapy and post-exposure prophylaxis (PEP) need to be demonstrated. Furthermore, the PALM trial has accounted for 30% of mortality despite the administration of specific treatments. The putative role of EBOV soluble Glycoprotein (sGP) as a decoy to the immune system, the virus persistence, and relapses might be investigated for treatment failure. The development of pan-filovirus or pan-species mAbs remains essential for protection. The interaction between FDA-approved mAbs and vaccines remains unclear and needs to be investigated. In this review, we summarize the efficacy and safety results of the PALM study and review current research questions for the further development of mAbs in pre-exposure or emergency post-exposure use.

Why Remdesivir Failed: Preclinical Assumptions Overestimate the Clinical Efficacy of Remdesivir for COVID-19 and Ebola.

Remdesivir is a nucleoside monophosphoramidate prodrug that has been FDA approved for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of remdesivir for COVID-19 remains contentious, as several trials have not found statistically significant differences in either time to clinical improvement or mortality between remdesivir-treated and control groups. Similarly, the inability of remdesivir to provide a clinically significant benefit above other investigational agents in patients with Ebola contrasts with strong, curative preclinical data generated in rhesus macaque models. For both COVID-19 and Ebola, significant discordance between the robust preclinical data and remdesivir's lackluster clinical performance have left many puzzled. Here, we critically evaluate the assumptions of the models underlying remdesivir's promising preclinical data and show that such assumptions overpredict efficacy and minimize toxicity of remdesivir in humans. Had the limitations of in vitro drug efficacy testing and species differences in drug metabolism been considered, the underwhelming clinical performance of remdesivir for both COVID-19 and Ebola would have been fully anticipated.

COVID-19, Ebola virus disease, and Nipah virus infection reclassification as novel acute immune dysrhythmia syndrome (n-AIDS): potential crucial role for immunomodulators.

In this manuscript, COVID-19, Ebola virus disease, Nipah virus infection, SARS, and MERS are suggested to be considered for a novel immunological reclassification as acute onset immune dysrhythmia syndrome (n-AIDS) due to altered monocytic, Th1/Th2, as well as cytokines and chemokines balances. n-AIDs is postulated to be the cause of the acute respiratory distress and multi-inflammatory syndromes which are described with fatal COVID-19, and immunomodulators are suggested to effectively manage the mentioned diseases as well as for other disorders caused by Th1/Th2 imbalance. Meanwhile, para COVID syndrome is suggested to describe various immune-related complications, whether before or after recovery, and to embrace a potential of a latent infection, that might be discovered later, as occurred with Ebola virus disease. Finally, our hypothesis has evolved out of our real-life practice that uses immunomodulatory drugs to manage COVID-19 safely and effectively.

Toward a Coronavirus Knowledge Graph.

This study builds a coronavirus knowledge graph (KG) by merging two information sources. The first source is Analytical Graph (AG), which integrates more than 20 different public datasets related to drug discovery. The second source is CORD-19, a collection of published scientific articles related to COVID-19. We combined both chemo genomic entities in AG with entities extracted from CORD-19 to expand knowledge in the COVID-19 domain. Before populating KG with those entities, we perform entity disambiguation on CORD-19 collections using Wikidata. Our newly built KG contains at least 21,700 genes, 2500 diseases, 94,000 phenotypes, and other biological entities (e.g., compound, species, and cell lines). We define 27 relationship types and use them to label each edge in our KG. This research presents two cases to evaluate the KG's usability: analyzing a subgraph (ego-centered network) from the angiotensin-converting enzyme (ACE) and revealing paths between biological entities (hydroxychloroquine and IL-6 receptor; chloroquine and STAT1). The ego-centered network captured information related to COVID-19. We also found significant COVID-19-related information in top-ranked paths with a depth of three based on our path evaluation.

DrugComb update: a more comprehensive drug sensitivity data repository and analysis portal.

Combinatorial therapies that target multiple pathways have shown great promises for treating complex diseases. DrugComb (https://drugcomb.org/) is a web-based portal for the deposition and analysis of drug combination screening datasets. Since its first release, DrugComb has received continuous updates on the coverage of data resources, as well as on the functionality of the web server to improve the analysis, visualization and interpretation of drug combination screens. Here, we report significant updates of DrugComb, including: (i) manual curation and harmonization of more comprehensive drug combination and monotherapy screening data, not only for cancers but also for other diseases such as malaria and COVID-19; (ii) enhanced algorithms for assessing the sensitivity and synergy of drug combinations; (iii) network modelling tools to visualize the mechanisms of action of drugs or drug combinations for a given cancer sample and (iv) state-of-the-art machine learning models to predict drug combination sensitivity and synergy. These improvements have been provided with more user-friendly graphical interface and faster database infrastructure, which make DrugComb the most comprehensive web-based resources for the study of drug sensitivities for multiple diseases.

Broad-Spectrum Antiviral Strategies and Nucleoside Analogues.

The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents significant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine development, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action.

Remdesivir: From Ebola to COVID-19.

Human coronaviruses (HCoV) were discovered in the 1960s and were originally thought to cause only mild upper respiratory tract diseases in immunocompetent hosts. This view changed since the beginning of this century, with the 2002 SARS (severe acute respiratory syndrome) epidemic and the 2012 MERS (Middle East respiratory syndrome) outbreak, two zoonotic infections that resulted in mortality rates of approximately 10% and 35%, respectively. Despite the importance of these pathogens, no approved antiviral drugs for the treatment of human coronavirus infections became available. However, remdesivir, a nucleotide analogue prodrug originally developed for the treatment of Ebola virus, was found to inhibit the replication of a wide range of human and animal coronaviruses in vitro and in preclinical studies. It is therefore not surprising that when the highly pathogenic SARS-CoV-2 coronavirus emerged in late 2019 in China, causing global health concern due to the virus strong human-to-human transmission ability, remdesivir was one of the first clinical candidates that received attention. After in vitro studies had shown its antiviral activity against SARS-CoV-2, and a first patient was successfully treated with the drug in the USA, a number of trials on remdesivir were initiated. Several had encouraging results, particularly the ACTT-1 double blind, randomized, and placebo controlled trial that has shown shortening of the time to recovery in hospitalized patients treated with remdesivir. The results of other trials were instead negative. Here, we provide an overview of remdesivir discovery, molecular mechanism of action, and initial and current clinical studies on its efficacy.