"Just in Time": The Role of Cryo-Electron Microscopy in Combating Recent Pandemics.

Single-particle cryogenic electron microscopy (cryo-EM), whose full power was not realized until the advent of powerful detectors in 2012, has a unique position as a method of structure determination as it is capable of providing information about not only the structure but also the dynamical features of biomolecules. This information is of special importance in understanding virus-host interaction and explains the crucial role of cryo-EM in the efforts to find vaccinations and cures for pandemics the world has experienced in the past decade.

On the effectiveness of communication strategies as non-pharmaceutical interventions to tackle epidemics.

When pharmaceutical interventions are unavailable to deal with an epidemic outbreak, adequate management of communication strategies can be key to reduce the contagion risks. On the one hand, accessibility to trustworthy and timely information, whilst on the other, the adoption of preventive behaviors may be both crucial. However, despite the abundance of communication strategies, their effectiveness has been scarcely evaluated or merely circumscribed to the scrutiny of public affairs. To study the influence of communication strategies on the spreading dynamics of an infectious disease, we implemented a susceptible-exposed-infected-removed-dead (SEIRD) epidemiological model, using an agent-based approach. Agents in our systems can obtain information modulating their behavior from two sources: (i) through the local interaction with other neighboring agents and, (ii) from a central entity delivering information with a certain periodicity. In doing so, we highlight how global information delivered from a central entity can reduce the impact of an infectious disease and how informing even a small fraction of the population has a remarkable impact, when compared to not informing the population at all. Moreover, having a scheme of delivering daily messages makes a stark difference on the reduction of cases, compared to the other evaluated strategies, denoting that daily delivery of information produces the largest decrease in the number of cases. Furthermore, when the information spreading relies only on local interactions between agents, and no central entity takes actions along the dynamics, then the epidemic spreading is virtually independent of the initial amount of informed agents. On top of that, we found that local communication plays an important role in an intermediate regime where information coming from a central entity is scarce. As a whole, our results highlight the importance of proper communication strategies, both accurate and daily, to tackle epidemic outbreaks.

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.

Application of pseudotyped virus particles to monitor Ebola virus and SARS-CoV-2 viral entry in human cell lines.

Experimental work on highly pathogenic viruses such as Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus-2 requires high-level biosafety facilities. Here, we provide a detailed step-by-step protocol which details the production and application of replication-incompetent murine leukemia virus-based pseudotyped particles to monitor and quantify the viral entry efficiency in human cell lines under biosafety level-2 conditions. We describe the use of viral particles encoding luciferase gene and the quantification of transduction efficiency by measuring luciferase activity. For complete details on the use and execution of this protocol, please refer to Imre et al. (2021).

Remdesivir against COVID-19 and Other Viral Diseases.

Patients and physicians worldwide are facing tremendous health care hazards that are caused by the ongoing severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) pandemic. Remdesivir (GS-5734) is the first approved treatment for severe coronavirus disease 2019 (COVID-19). It is a novel nucleoside analog with a broad antiviral activity spectrum among RNA viruses, including ebolavirus (EBOV) and the respiratory pathogens Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2. First described in 2016, the drug was derived from an antiviral library of small molecules intended to target emerging pathogenic RNA viruses. In vivo, remdesivir showed therapeutic and prophylactic effects in animal models of EBOV, MERS-CoV, SARS-CoV, and SARS-CoV-2 infection. However, the substance failed in a clinical trial on ebolavirus disease (EVD), where it was inferior to investigational monoclonal antibodies in an interim analysis. As there was no placebo control in this study, no conclusions on its efficacy in EVD can be made. In contrast, data from a placebo-controlled trial show beneficial effects for patients with COVID-19. Remdesivir reduces the time to recovery of hospitalized patients who require supplemental oxygen and may have a positive impact on mortality outcomes while having a favorable safety profile. Although this is an important milestone in the fight against COVID-19, approval of this drug will not be sufficient to solve the public health issues caused by the ongoing pandemic. Further scientific efforts are needed to evaluate the full potential of nucleoside analogs as treatment or prophylaxis of viral respiratory infections and to develop effective antivirals that are orally bioavailable.

Persistence of Bacteriophage Phi 6 on Porous and Nonporous Surfaces and the Potential for Its Use as an Ebola Virus or Coronavirus Surrogate.

The infection of health care workers during the 2013 to 2016 Ebola outbreak raised concerns about fomite transmission. In the wake of the coronavirus disease 2019 (COVID-19) pandemic, investigations are ongoing to determine the role of fomites in coronavirus transmission as well. The bacteriophage phi 6 has a phospholipid envelope and is commonly used in environmental studies as a surrogate for human enveloped viruses. The persistence of phi 6 was evaluated as a surrogate for Ebola virus (EBOV) and coronaviruses on porous and nonporous hospital surfaces. Phi 6 was suspended in a body fluid simulant and inoculated onto 1-cm2 coupons of steel, plastic, and two fabric curtain types. The coupons were placed at two controlled absolute humidity (AH) levels: a low AH of 3.0 g/m3 and a high AH of 14.4 g/m3 Phi 6 declined at a lower rate on all materials under low-AH conditions, with a decay rate of 0.06-log10 PFU/day to 0.11-log10 PFU/day, than under the higher AH conditions, with a decay rate of 0.65-log10 PFU/h to 1.42-log10 PFU/day. There was a significant difference in decay rates between porous and nonporous surfaces at both low AH (P < 0.0001) and high AH (P < 0.0001). Under these laboratory-simulated conditions, phi 6 was found to be a conservative surrogate for EBOV under low-AH conditions in that it persisted longer than Ebola virus in similar AH conditions. Additionally, some coronaviruses persist longer than phi 6 under similar conditions; therefore, phi 6 may not be a suitable surrogate for coronaviruses.IMPORTANCE Understanding the persistence of enveloped viruses helps inform infection control practices and procedures in health care facilities and community settings. These data convey to public health investigators that enveloped viruses can persist and remain infective on surfaces, thus demonstrating a potential risk for transmission. Under these laboratory-simulated Western indoor hospital conditions, we assessed the suitability of phi 6 as a surrogate for environmental persistence research related to enveloped viruses, including EBOV and coronaviruses.

MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses.

Recent outbreaks of Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have exposed our limited therapeutic options for such diseases and our poor understanding of the cellular mechanisms that block viral infections. Using a transposon-mediated gene-activation screen in human cells, we identify that the major histocompatibility complex (MHC) class II transactivator (CIITA) has antiviral activity against EBOV. CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein. We further show that CD74 p41 can block the endosomal entry pathway of coronaviruses, including SARS-CoV-2. These data therefore implicate CIITA and CD74 in host defense against a range of viruses, and they identify an additional function of these proteins beyond their canonical roles in antigen presentation.

Sheltering at Our Common Home.

The current COVID-19 pandemic has reactivated ancient metaphors (especially military ones) but also initiated a new vocabulary: social distancing, lockdown, self-isolation, and sheltering in place. Terminology is not ethically neutral but reflects prevailing value systems. I will argue that there are two metaphorical vocabularies at work: an authoritarian one and a liberal one. Missing is an ecological vocabulary. It has been known for a long time that emerging infectious diseases are associated with the destruction of functioning ecosystems and biodiversity. Ebola and avian influenza viruses have been significant warnings. Obviously, this pandemic will not be the last one. As the planet is our common home, the major metaphor to explore is sheltering at this home.

Remdesivir: A beacon of hope from Ebola virus disease to COVID-19.

Since the emergence of coronavirus disease 2019 (Covid-19), many studies have been performed to characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and find the optimum way to combat this virus. After suggestions and assessments of several therapeutic options, remdesivir (GS-5734), a direct-acting antiviral drug previously tested against Ebola virus disease, was found to be moderately effective and probably safe for inhibiting SARS-CoV-2 replication. Finally, on 1 May 2020, remdesivir (GS-5734) was granted emergency use authorization as an investigational drug for the treatment of Covid-19 by the Food and Drug Administration. However, without a doubt, there are challenging days ahead. Here, we provide a review of the latest findings (based on preprints, post-prints, and news releases in scientific websites) related to remdesivir efficacy and safety for the treatment of Covid-19, along with covering remdesivir history from bench-to-bedside, as well as an overview of its mechanism of action. In addition, active clinical trials, as well as challenging issues related to the future of remdesivir in Covid-19, are covered. Up to the date of writing this review (19 May 2020), there is one finished randomized clinical trial and two completed non-randomized studies, in addition to some ongoing studies, including three observational studies, two expanded access studies, and seven active clinical trials registered on the clinicaltrials.gov and isrctn.com websites. Based on these studies, it seems that remdesivir could be an effective and probably safe treatment option for Covid-19. However, more randomized controlled studies are required.

Working Hard or Hardly Working? Regulatory Bottlenecks in Developing a COVID-19 Vaccine.

Vaccine solutions rarely reach the public until after an outbreak abates; an Ebola vaccine was approved 5 years after peak outbreak and SARS, MERS, and Zika vaccines are still in clinical development. Despite massive leaps forward in rapid science, other regulatory bottlenecks are hamstringing the global effort for pandemic vaccines.