4'-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses.

Influenza outbreaks are associated with substantial morbidity, mortality and economic burden. Next generation antivirals are needed to treat seasonal infections and prepare against zoonotic spillover of avian influenza viruses with pandemic potential. Having previously identified oral efficacy of the nucleoside analog 4'-Fluorouridine (4'-FlU, EIDD-2749) against SARS-CoV-2 and respiratory syncytial virus (RSV), we explored activity of the compound against seasonal and highly pathogenic influenza (HPAI) viruses in cell culture, human airway epithelium (HAE) models, and/or two animal models, ferrets and mice, that assess IAV transmission and lethal viral pneumonia, respectively. 4'-FlU inhibited a panel of relevant influenza A and B viruses with nanomolar to sub-micromolar potency in HAE cells. In vitro polymerase assays revealed immediate chain termination of IAV polymerase after 4'-FlU incorporation, in contrast to delayed chain termination of SARS-CoV-2 and RSV polymerase. Once-daily oral treatment of ferrets with 2 mg/kg 4'-FlU initiated 12 hours after infection rapidly stopped virus shedding and prevented transmission to untreated sentinels. Treatment of mice infected with a lethal inoculum of pandemic A/CA/07/2009 (H1N1)pdm09 (pdmCa09) with 4'-FlU alleviated pneumonia. Three doses mediated complete survival when treatment was initiated up to 60 hours after infection, indicating a broad time window for effective intervention. Therapeutic oral 4'-FlU ensured survival of animals infected with HPAI A/VN/12/2003 (H5N1) and of immunocompromised mice infected with pdmCa09. Recoverees were protected against homologous reinfection. This study defines the mechanistic foundation for high sensitivity of influenza viruses to 4'-FlU and supports 4'-FlU as developmental candidate for the treatment of seasonal and pandemic influenza.

Going virtual during the COVID-19 pandemic: adaptation of a mixed-methods dietary behavior study within a community-based participatory research study of African-American adults at risk for cardiovascular disease.

BACKGROUND: Identifying mechanisms to maintain CBPR studies during an infectious disease pandemic is vital. The current paper describes the changes in methods and processes conducted within a CBPR mixed-methods study to a virtual setting during the novel coronavirus (COVID-19) pandemic. METHOD: The DC Community Organizing for Optimal Culinary Knowledge study with Heart (DC COOKS with Heart) was designed to assess the feasibility of a dietary behavior intervention among African-American adults that are at risk for cardiovascular disease (CVD). The study is under the umbrella of an ongoing CBPR study and community advisory board that facilitates community involvement in study design and promotes ongoing engagement with community members and leaders. The study population for D.C. COOKS with Heart consists of adult African-American individuals who live in two low-resource neighborhoods in Washington, D.C., which were impacted disproportionately by COVID. Eligible study participants who previously participated in the DC CHOC community-based studies were contacted to participate in Phase 1. The quantitative part of the mixed-methods included survey data collection. RESULTS: Due to the pandemic, the mode of data collection for surveys changed from self-administered face-to-face to internet-based. All virtual study procedures were conducted between March and April, 2021. Anticipated benefits of the virtual setting included participant safety during the pandemic, ease of logistics for participants. Anticipated challenges included administration of electronic devices to participants, research team training, and potential threats to established trust related to the privacy and confidentiality of participants. CONCLUSION: The transition to a virtual setting for study procedures in a mixed-methods study was conducted successfully in terms of recruitment, retention of participants, and training of research team members. The virtual transition required established and ongoing engagement through the community advisory board and CBPR practices, institutional support through virtual research policies, collaborations with information technology-based teams, and equipment administration for the study. TRIALS REGISTRATION: NCT04305431 . Registered on March 12, 2020.

For want of a champion: why the EU won’t be ready for the next public health crisis

This article argues that the EU response to the COVID-19 crisis follows a pattern much like its response to earlier public health threats. Though each time the EU commits to being prepared for the next cross-border threat to health, as the immediate crisis recedes, so does the momentum to build the necessary administrative capacity, leaving the EU unprepared to take a leadership role when the next public health crisis emerges. The literature on administrative capacity, identifies authority, autonomy, and resources as three crucial dimensions of administrative capacity. An examination of the efforts to build administrative capacity after several recent public health crises (SARS, Avian Flu, MERS and COVID-19) shows that the EU has made only modest progress in granting such capacity to its supranational agency, The European Center for Disease Prevention and Control (ECDC). Despite the claims that COVID-19 was a new level of public health threat that demanded supranational action, the EU response again seems to fall back into a familiar pattern of making minor adjustments. [ FROM AUTHOR]

Gut microbiota-derived metabolites confer protection against SARS-CoV-2 infection.

The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.

SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model.

SARS-CoV-2 variants of concern (VOC) have triggered infection waves. Oral antivirals such as molnupiravir promise to improve disease management, but efficacy against VOC delta was questioned and potency against omicron is unknown. This study evaluates molnupiravir against VOC in human airway epithelium organoids, ferrets, and a lethal Roborovski dwarf hamster model of severe COVID-19-like lung injury. VOC were equally inhibited by molnupiravir in cells and organoids. Treatment reduced shedding in ferrets and prevented transmission. Pathogenicity in dwarf hamsters was VOC-dependent and highest for delta, gamma, and omicron. All molnupiravir-treated dwarf hamsters survived, showing reduction in lung virus load from one (delta) to four (gamma) orders of magnitude. Treatment effect size varied in individual dwarf hamsters infected with omicron and was significant in males, but not females. The dwarf hamster model recapitulates mixed efficacy of molnupiravir in human trials and alerts that benefit must be reassessed in vivo as VOC evolve.

4'-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication.

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and older adults. We describe 4'-fluorouridine (4'-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with high selectivity index in cells and human airway epithelia organoids. Polymerase inhibition within in vitro RNA-dependent RNA polymerase assays established for RSV and SARS-CoV-2 revealed transcriptional stalling after incorporation. Once-daily oral treatment was highly efficacious at 5 milligrams per kilogram (mg/kg) in RSV-infected mice or 20 mg/kg in ferrets infected with different SARS-CoV-2 variants of concern, initiated 24 or 12 hours after infection, respectively. These properties define 4'-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2, and related RNA virus infections.

Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets.

Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.

Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets.

The coronavirus disease 2019 (COVID-19) pandemic is having a catastrophic impact on human health1. Widespread community transmission has triggered stringent distancing measures with severe socio-economic consequences. Gaining control of the pandemic will depend on the interruption of transmission chains until vaccine-induced or naturally acquired protective herd immunity arises. However, approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control. We previously reported the development of an orally efficacious ribonucleoside analogue inhibitor of influenza viruses, MK-4482/EIDD-2801 (refs. 4,5), that was repurposed for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently in phase II/III clinical trials (NCT04405570 and NCT04405739). Here, we explored the efficacy of therapeutically administered MK-4482/EIDD-2801 to mitigate SARS-CoV-2 infection and block transmission in the ferret model, given that ferrets and related members of the weasel genus transmit the virus efficiently with minimal clinical signs6-9, which resembles the spread in the human young-adult population. We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Therapeutic treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.

The impact of high-resolution structural data on stemming the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has had a catastrophic impact on human health and the world economy. The response of the scientific community was unparalleled, and a combined global effort has resulted in the creation of vaccines in a shorter time frame than previously unimaginable. Reflecting this concerted effort, the structural analysis of the etiological agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has progressed with an unprecedented pace. Since the onset of the pandemic, over 1000 high-resolution structures of a broad range of SARS-CoV-2 proteins have been solved and made publicly available. These structures have aided in the identification of numerous potential druggable targets and have contributed to the design of different vaccine candidates. This opinion article will discuss the impact of high-resolution structures in understanding SARS-CoV-2 biology and explore their role in the development of vaccines and antivirals.

Therapeutic MK-4482/EIDD-2801 Blocks SARS-CoV-2 Transmission in Ferrets.

The COVID-19 pandemic is having a catastrophic impact on human health. Widespread community transmission has triggered stringent distancing measures with severe socioeconomic consequences. Gaining control of the pandemic will depend on interruption of transmission chains until protective herd immunity arises. Ferrets and related members of the weasel genus transmit SARS-CoV-2 efficiently with minimal clinical signs, resembling spread in the young-adult population. We previously reported an orally efficacious nucleoside analog inhibitor of influenza viruses, EIDD-2801 (or MK-4482), that was repurposed against SARS-CoV-2 and is in phase II/III clinical trials. Employing the ferret model, we demonstrate in this study high SARS-CoV-2 burden in nasal tissues and secretions that coincides with efficient direct-contact transmission. Therapeutic treatment of infected animals with twice-daily MK-4482/EIDD-2801 significantly reduced upper respiratory tract SARS-CoV-2 load and completely suppressed spread to untreated contact animals. This study identifies oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.