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  ABSTRACT Mpox, caused by monkeypox virus (MPXV) infection, has emerged as a significant global health threat . The World Health Organization (WHO) has twice declared a Public Health Emergency of International Concern for mpox: first for the 2022–2023 global outbreak and subsequently for concurrent outbreaks in Africa. Beyond MPXV, other members of the Orthopoxvirus genus also pose growing risks of zoonotic spillover , with the potential to jump from animal reservoirs to humans . Clinically, mpox is distinguished from other Orthopoxvirus infections by its propensity to cause severe systemic manifestations alongside localized skin lesions , disproportionately affecting vulnerable groups such as children, pregnant women, and immunocompromised individuals . Although vaccines are available, effective therapeutics are equally essential in combating the mpox crisis. Current antiviral agents , including tecovirimat and brincidofovir , have demonstrated uncertain or disappointing efficacy...

Abstract Effective and reliable treatments for SARS-CoV-2 infections are a key part of global COVID-19 management . Based on vitro studies, niclosamide has been considered as a potential drug candidate for SARS-CoV-2, but its clinical development has been limited due to poor solubility and bioavailability. Here we report results from a randomized, double-blind, placebo-controlled clinical trial involving 300 patients (Clinical Trial Registration Number: KCT0007307) that assessed the efficacy and safety of the niclosamide nanohybrid CP-COV03 at two different doses. Oral CP-COV03 was well tolerated, with no serious adverse events reported in any treatment group. The primary endpoints demonstrated that CP-COV03 significantly alleviated all 12 FDA-recommended COVID-19 symptoms , with symptom improvement sustained for more than 48 h. Additionally, CP-COV03 reduced SARS-CoV-2 viral load by 56.7% within 16 h of the initial dose compared to baseline. Secondary endpoints, including time to sust...

Abstract Influenza A virus (IAV) poses a significant global health risk, with highly pathogenic strains like H5N1 (CFR ~52%) causing severe disease compared to less lethal but more transmissible strains like H1N1 (CFR 0.01-0.03%). Although IAV primarily infects lung epithelial cells , causing cell death and tissue damage , the molecular basis of strain-specific pathogenesis remains poorly understood. Here we show that in cell culture , H5N1 induced more rapid and extensive cell death than H1N1. Since Interferon (IFN) signaling is key to innate immunity, we examined its role in virus-induced cell death using STAT1-knockout A549 cells and JAK/STAT pathway inhibitors like Baricitinib . Both approaches reduced cell death across various IAV strains, including H1N1, H5N1, H7N9 , and H3N2 . However, inhibition increased viral titers , raising concerns about its clinical use in isolation. To overcome this, we tested a combination of Oseltamivir (antiviral) and Baricitinib (anti-inflammatory). ...

Highlights •  Mol shows greater antiviral effects against IAV and IBV in cell cultures. •  Mol and Ose together showed a synergistic effect against IAV. •  In mice, Mol alone or with Ose reduced lung injury and viral load. Abstract Oseltamivir, a neuraminidase inhibitor, is widely used in the clinic for treating influenza virus infections . However, suboptimal efficacy and risk of drug resistance development remain major challenges. Molnupiravir , a ribonucleoside analog, was originally developed to treat influenza, but was repurposed and first approved for treating COVID-19 in 2021. Considering their complementary mode-of-actions, this study aimed to investigate the combinatorial activities of oseltamivir and molnupiravir against influenza virus infections . In cell culture models, we found that β-d-N4-hydroxycytidine (NHC), the active form of molnupiravir, exerted more potent antiviral activities against influenza A and B viruses , when compared to oseltamivir treatment...

Abstract Various SARS-CoV-2 remdesivir resistance-associated substitutions (RAS) have been reported, but a comprehensive comparison of their resistance levels is lacking . We identified novel RAS and performed head-to-head comparisons with known RAS in Vero E6 cells. A remdesivir escape polyclonal virus exhibited a 3.6-fold increase in remdesivir EC50 and mutations throughout the genome, including substitutions in nsp12 (E796D) and nsp14 (A255S). However, in reverse-genetics infectious assays, viruses harboring both these substitutions exhibited only a slight decrease in remdesivir susceptibility (1.3-fold increase in EC50). The nsp12-E796D substitution did not impair viral fitness (Vero E6 cells or Syrian hamsters) and was reported in a remdesivir-treated COVID-19 patient . In replication assays, a subgenomic replicon containing nsp12-E796D+nsp14-A255S led to a 16.1-fold increase in replication under remdesivir treatment . A comparison with known RAS showed that S759A, located in the ...

Abstract In March 2024, clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses were first detected in U.S. dairy cattle . Similar viruses have since caused 70 zoonotic human infections . To assess changes to zoonotic potential , we characterized A( H5N1 ) clade 2.3.4.4b viruses isolated from cows’ milk and birds . Bovine-derived viruses are lethal in mice and ferrets and transmit to direct but not airborne contact ferrets. All viruses replicate in human bronchial epithelial cells despite preferentially binding avian virus-like receptors. The bovine-derived viruses remain susceptible to FDA-approved antivirals , and they are inhibited by sera from ferrets vaccinated with WHO-recommended candidate vaccine viruses (CVV) or human sera from clade 2.3.4.4c vaccinees. While 2.3.4.4b viruses induce severe disease in mammalian models , they retain many avian virus-like characteristics. Combined, we conclude that the risk of contemporary bovine-derived viruses to humans not in contact ...

{Excerpt} Highly pathogenic avian influenza (HPAI) A(H5Nx) clade 2.3.4.4b viruses have been circulating in North America since late 2021. Since their initial incursion, they have been associated with unprecedented mortality in wild birds, domestic poultry, and marine mammals throughout the Americas, and are now seen across all global regions except Oceania. Furthermore, transmission among dairy cattle and poultry in the United States has led to growing numbers of human cases, and there was a severe human case in Canada with no known infected animal exposure (1,2). (...) Source: Journal of the Association of Medical Microbiology and Infectious Disease Canada,  https://utppublishing.com/doi/10.3138/jammi-2025-0307 ____

Summary Background Nirmatrelvir–ritonavir is approved for adults with mild-to-moderate COVID-19 who are at risk of severe disease . There are little clinical data to guide the duration of therapy in patients who are immunocompromised. We aimed to compare the approved 5-day regimen of nirmatrelvir–ritonavir with 10-day and 15-day regimens. Methods This placebo-controlled, randomised, double-blind, phase 2 trial enrolled non-hospitalised, immunocompromised individuals aged 12 years or older with symptomatic COVID-19 from 73 sites across nine countries. Participants were randomly assigned (1:1:1) to receive 300 mg nirmatrelvir and 100 mg ritonavir orally twice per day for 5, 10, or 15 days. Randomisation was stratified according to whether participants were considered immunocompromised due to use of corticosteroids or tumour necrosis factor blockers. Investigators, participants, and caregivers were masked to the assigned study group. The primary endpoint was proportion of randomly assigne...

Summary Background Obeldesivir is an oral nucleoside analogue prodrug antiviral that inhibits SARS-CoV-2 replication . We aimed to assess the efficacy, safety, and tolerability of obeldesivir for the treatment of COVID-19 in non-hospitalised individuals at low risk of progression to severe disease. Methods OAKTREE was a phase 3, randomised, double-blind, placebo-controlled trial in 107 centres (including research centres, primary care centres, and hospitals) in Japan and the USA . Low-risk, non-hospitalised adults and adolescents with mild-to-moderate COVID-19 were enrolled within 3 days of symptom onset. Eligible participants were randomly assigned 1:1 using permuted block randomisation (block size of four), stratified by historical completion of a primary COVID-19 vaccination series, to receive either oral obeldesivir 350 mg or matched placebo twice daily for 5 days. The primary efficacy endpoint was time to COVID-19 symptom alleviation by day 29, which was assessed in all randomly a...

Abstract The current study aimed to investigate the genetic characterization and evolution of low pathogenic avian influenza virus H9N2 in Egypt . Ten H9N2 viruses were recently isolated from samples collected between 2019 and 2023. Phylogenetic analysis of the haemagglutinin (HA) gene segment of the H9N2 isolates showed a relatedness with G1 H9 4.2 lineage and clustered within genotype III of the Egyptian strains identified earlier in 2018. The majority of H9N2 strains had seven and eight glycosylation sites in HA and neuraminidase (NA) respectively . All strains carried H191 and L234 residues in their hemagglutinin which are markers facilitating avian-to-human cross species barrier transmission . No stalk deletions were detected in NA gene. In addition, genetic analysis of the NA and M encoding proteins revealed the absence of substitutions associated with resistance to oseltamivir and amantadine . The NA showed S372A and R403W substitutions which were previously detected in H3N2 and...

Highlights •  In a landscape of a very narrow arsenal of influenza antivirals, resistance mutations are a significant threat. •  Resistance mutations were present in 0.5-5% in A and B influenza viruses during the last 15 years. •  However, S247N resistance mutation in the NA gene sharply increased during 2023-2024 season. •  While this mutation does not confer strong resistance by itself, their fixation could increase the risk of resistance in the future if other resistance mutations appears or get fixed together with it. Abstract The therapeutic arsenal against influenza is extremely limited and resistance often arises due to the emergence of mutations , especially in the neuraminidase (NA) gene. This study aimed to evaluate the evolution of NA mutations over 15 years in Spain . To do so, we used the GISAID database from which we downloaded a total of 11,125 influenza A(H1N1)pdm09, A(H3N2), B/Victoria and B/Yamagata NA virus sequences , and analyzed the resistance m...

Highlights •  Antiviral susceptibility to NA inhibitors and PA inhibitor baloxavir was determined for seasonal and zoonotic influenza viruses circulating globally during 2020–2023. •  Low global frequencies (0.1-0.2%) of seasonal influenza viruses with reduced or highly reduced inhibition by NAI inhibitors were observed as in previous years. •  Low global frequencies of seasonal influenza viruses (∼ 0.1%) with reduced susceptibility to baloxavir were observed, with the rate in Japan elevated (3.3%) in 2022–2023, as has been seen previously. •  For zoonotic viruses, 2.7% contained genetic markers associated with reduced or highly reduced inhibition to NA inhibitors and none contained markers associated with reduced susceptibility for baloxavir. •  For the treatment of influenza , NA inhibitors and baloxavir remain suitable. ABSTRACT Antiviral susceptibility of influenza viruses is monitored by the World Health Organization Global Influenza Surveillance and Respon...

Abstract Since the first detection of highly pathogenic avian influenza (HPAI) H5N1 (clade 2.3.4.4b) in U.S. dairy cattle in early 2024, the virus has spread rapidly, posing a major public health concern as the number of human cases continues to rise. Although human-to-human transmission has not been confirmed, experimental data suggest that the bovine H5N1 virus can transmit via respiratory droplets in ferrets , highlighting its pandemic potential . With no vaccines currently available, antiviral drugs remain the only treatment option. Here, we investigate the efficacy of the polymerase inhibitor baloxavir marboxil (BXM) against this virus in mice. We find that early treatment post-infection is effective, but delayed treatment significantly reduces BXM efficacy and increases the risk of BXM resistance, underscoring the importance of timely BXM administration for effective treatment. Source: Nature Communications,  https://www.nature.com/articles/s41467-025-60791-5 ____

Key Points -- Question:   In adults with influenza requiring admission to hospital, is oseltamivir treatment within the first 2 days of admission, when compared with supportive care without oseltamivir, associated with a decreased risk of death in hospital? -- Findings:  In this cohort study of 11 073 patients hospitalized with influenza, oseltamivir treatment was associated with an adjusted risk reduction of 1.8% for in-hospital mortality when compared with supportive care. -- Meaning:  The findings of this study support current guidelines that recommend oseltamivir treatment for patients admitted to hospital with influenza; clinical trials should be conducted to generate better quality evidence. Abstract Importance    Current guidelines recommend oseltamivir treatment for all patients hospitalized with influenza, but this guidance is based on suboptimal evidence. Objective    To evaluate outcomes associated with oseltamivir treatment when compared wi...

Summary Background Onradivir (ZSP1273) is a potent inhibitor of the PB2 subunit of influenza A virus (IAV) polymerase . Our previous, phase 2 clinical trial showed that a 600 mg regimen of onradivir initiated within 48 h of symptom onset can expedite the recovery of adult patients from acute, uncomplicated influenza. Here, we aimed to evaluate the safety and therapeutic efficacy of onradivir in a larger group with acute, uncomplicated influenza. Methods This randomised, double-blind, multicentre, placebo-controlled and oseltamivir-controlled, phase 3 trial was conducted at 68 clinical sites in China . Eligible participants were adults (aged 18–64 years) with an influenza-like illness who screened positive by rapid IAV antigen testing at the first clinical visit, and had a fever (axillary temperature ≥38·0°C) with at least one moderate systemic and one moderate respiratory symptom within 48 h of symptom onset. Patients were randomly assigned into three treatment groups, stratified by in...

Abstract Avian influenza viruses (AIVs) pose a growing global health threat , particularly in low- and middle-income countries (LMICs), where limited surveillance capacity and under-resourced healthcare systems hinder timely detection and response. Migratory birds play a significant role in the transboundary spread of AIVs, yet data from key regions along migratory flyways remain sparse. To address these surveillance gaps, we conducted a study between December 2021 and February 2023 using fresh bird guano collected across 10 countries in the Global South . Here, we show that remote, uninhabited regions in previously unsampled areas harbor a high diversity of AIV strains , with H5N1 emerging as the most prevalent . Some of these H5N1 samples also carry mutations that may make them less responsive to the antiviral drug oseltamivir . Our findings documented the presence of AIVs in several underrepresented regions and highlighted critical transmission hotspots where viral evolution may be ...

ABSTRACT Background and Objectives This randomised controlled trial evaluated whether higher doses of oseltamivir would improve virological and clinical outcomes in severe influenza patients requiring invasive mechanical ventilation. Methods Forty intubated adult patients with severe influenza A or B from four intensive care units in Hong Kong were enrolled and randomised to receive either a double dose (300 mg/day) or a triple dose (450 mg/day) of oseltamivir for 10 days. Baseline data were collected, and outcomes were assessed daily using SOFA and Murray scores. Viral RNA was quantified from nasopharyngeal and tracheal aspirates. The primary outcome was the viral clearance rate after 5 days of treatment; secondary outcomes included 28-day and hospital mortality rates, changes in viral load, and serial SOFA and Murray scores. Results Viral clearance rates after 5 days of treatment were low and similar between the double (3/20, 15%) and triple-dose groups (2/20, 10%). No significant di...

Abstract The COVID-19 pandemic has had a significant impact and continues to alarm the entire world due to the rapid emergence of new variants , even after mass vaccinations . There is still an urgent need for new antivirals or strategies to combat the SARS-CoV-2 infections; however, we have success stories with nirmatrelvir . Drug repurposing and drug discovery may lead to a successful SARS-CoV-2 antiviral; however, rapid drug use may cause unexpected mutations and antiviral drug resistance. Conversely, novel variants of the SARS-CoV-2 can diminish the neutralizing efficacy of vaccines, thereby enhancing viral fitness and increasing the likelihood of drug resistance emergence. Additionally, the disposal of antivirals in wastewater also contributes to drug resistance. Overall, the present review summarizes the strategies and mechanisms involved in the development of drug resistance in SARS-CoV-2. Understanding the mechanism of antiviral resistance is crucial to mitigate the significant...

Abstract Background Every year, more than one billion people around the world are infected with influenza , an acute infection of the respiratory tract. Influenza spreads from person to person through air, contaminated hands or objects. Antiviral and immunomodulatory drugs are available for treatment of patients and prophylaxis of exposed persons. Reverse transcription polymerase chain reaction (RT-PCR), nucleic acid amplification tests (NAATs) and rapid tests are available for the diagnosis of influenza.  Objective   The aim of this World Health Organization (WHO) guideline is to provide recommendations for the diagnosis, drug treatment and prophylaxis of influenza. Method This updated guideline has been developed in accordance with standards for trustworthy guidelines. The recommendations are based on systematic reviews on safety and effectiveness. They take into account the magnitude of benefits and harms of treatments, the reliability of the evidence, and the needs of pati...

Summary Background Molnupiravir and nirmatrelvir–ritonavir are oral antivirals that have shown efficacy in preventing disease progression in outpatients with COVID-19. We aimed to evaluate these treatments for patients hospitalised with COVID-19 pneumonia, for whom data on these antivirals are scarce. Methods The RECOVERY trial is a randomised, controlled, open-label, adaptive platform trial testing treatments for COVID-19 . In this study we report the molnupiravir and nirmatrelvir–ritonavir comparisons from the RECOVERY trial. In each comparison, participants aged 18 years and older were randomly allocated (1:1) to the relevant antiviral (5 days of molnupiravir 800 mg twice daily or 300 mg nirmatrelvir and 100 mg ritonavir twice daily) in addition to usual care, or to usual care alone. The molnupiravir comparison was conducted at 75 hospitals in the UK, two in Nepal, and two in Indonesia ; the nirmatrelvir–ritonavir comparison was conducted at 32 hospitals in the UK. Participants coul...