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Summary: Objectives: Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed. Methods: We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory. Results: Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC50 and high selectivity index. Additionally, ribavirin and interferons also exhibited in-vitro anti-MERS-CoV activity. The serum concentrations achievable at therapeutic doses of mycophenolic acid and interferon-β1b were 60–300 and 3–4 times higher than the concentrations at which in-vitro anti-MERS-CoV activities were demonstrated, whereas that of ribavirin was ∼2 times lower. Combination of mycophenolic acid and interferon-β1b lowered the EC50 of each drug by 1–3 times. Conclusions: Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS. [Copyright &y& Elsevier]

Abstract: Influenza vaccines are potentially the most efficacious means of mitigating the impact of influenza pandemic and might contribute to the rapid containment of an emerging pandemic virus. On the 12–13 February 2009, the Initiative For Vaccine Research (IVR) of the World Health Organisation convened the 5th meeting on the ‘Evaluation of pandemic influenza prototype vaccines in clinical trials’ in Geneva. This was a follow-up meeting to the 4th meeting held on 14–15 February 2008 [Girard M, Palkonyay L, Kieny MP. Report of the 4th meeting on the evaluation of pandemic influenza prototype vaccines in clinical trials. Vaccine 2008;26:4975–7], and presentations were made by representatives from industry, academia, and governmental organisations. This year''s meeting aimed to update the progress made during the past year on H5N1 and other prototype pandemic vaccines that have undergone clinical trials. A number of vaccine types were covered, including classical egg-derived inactivated vaccines, cell-derived inactivated vaccines, live-attenuated vaccines (LAIV) and vaccines developed using new technologies. The effects of different adjuvants and prime-boosting schedules were important topics, and further data were presented to show that children mount vigorous antibody responses to several H5N1 vaccines. Other subjects presented and discussed were standardisation, and regulatory issues concerning pandemic vaccines. [Copyright &y& Elsevier]

Available evidence indicates that the neuraminidase inhibitors (NAIs), particularly oseltamivir, are the preferred antiviral agents for treatment of influenza, although more data are needed from elderly and high-risk populations. Although widely available, amantadine has a narrower antiviral spectrum and therapeutic margin, greater need for individual dosing, and much higher risk for emergence of drug-resistant variants compared with NAIs. Despite documented efficacy and reasonable cost-effectiveness, the NAIs are under-utilized for treatment of acute influenza in most countries of the world. Cost and rapid access to care are major hurdles to broader application. Both of these country- or health care system-related impediments require solution, if patients are to benefit from available drugs. In addition to addressing these problems, stockpiling of antiviral agents will be essential to mount an effective antiviral response to the next major epidemic or pandemic. [Copyright &y& Elsevier]

It is more than 20 years since the neuraminidase inhibitors, oseltamivir and zanamivir were approved for the treatment and prevention of influenza. Guidelines for global surveillance and methods for evaluating resistance were established initially by the Neuraminidase Inhibitor Susceptibility Network (NISN), which merged 10 years ago with the International Society for influenza and other Respiratory Virus Diseases (isirv) to become the isirv-Antiviral Group (isirv-AVG). With the ongoing development of new influenza polymerase inhibitors and recent approval of baloxavir marboxil, the isirv-AVG held a closed meeting in August 2019 to discuss the impact of resistance to these inhibitors. Following this meeting and review of the current literature, this article is intended to summarize current knowledge regarding the clinical impact of resistance to polymerase inhibitors and approaches for surveillance and methods for laboratory evaluation of resistance, both in vitro and in animal models. We highlight limitations and gaps in current knowledge and suggest some strategies for addressing these gaps, including the need for additional clinical studies of influenza antiviral drug combinations. Lessons learned from influenza resistance monitoring may also be helpful for establishing future drug susceptibility surveillance and testing for SARS-CoV-2. • Current knowledge regarding the clinical impact of resistance to influenza polymerase inhibitors is summarized. • Current surveillance strategies for detection of variants with reduced susceptibility to polymerase inhibitors are discussed. • Methods for laboratory evaluation of resistance in vitro and in animal models, along with their limitations are presented. [ABSTRACT FROM AUTHOR]

Current influenza antivirals have limitations with regard to their effectiveness and the potential emergence of resistance. Encouragingly, several new compounds which inhibit the polymerase of influenza viruses have recently been shown to have enhanced pre-clinical and clinical effectiveness compared to the neuraminidase inhibitors, the mainstay of influenza antiviral therapy over the last two decades. In this review we focus on four compounds which inhibit polymerase function, baloxavir marboxil, favipiravir, pimodivir and AL-794 and discuss their clinical and virological effectiveness, their propensity to select for resistance and their potential for future combination therapy with the most commonly used neuraminidase inhibitor, oseltamivir. • Antiviral compounds targeting components of the polymerase complex PB1, PB2, and PA, are undergoing clinical investigation. • Baloxavir targets endonuclease activity of the PA polymerase subunit and was recently liscensed in Japan and USA for the treatment of influenza A and B viruses. • Favipiravir, a broad spectrum antiviral compound inhibits viral RNA polymerases and has limited licensure in Japan. • Pimodivir targets PB2 subunit of influenza A viruses preventing binding to 7-methyl GTP cap structures. • AL-794 binds to the endonuclease domain of PA but is no longer being evaluated for clinical use. [ABSTRACT FROM AUTHOR]

Abstract: Background: Live attenuated influenza vaccine (LAIV) is indicated for influenza prevention in persons 2–49 years of age. This study describes the incidence and duration of vaccine virus shedding and serum immune responses after receipt of LAIV. Methods: A single open-label dose of trivalent LAIV was administered intranasally to 344 subjects in 3 age cohorts: 5–8, 9–17, and 18–49 years of age. Shedding was determined by culture of nasal swabs (on days 1–7, daily; days 9–25, every other day; and day 28). Immunogenicity was measured as serum strain-specific hemagglutinin inhibition (HAI) titers (days 0, 28). Results: Among subjects aged 5–8 years, 9–17 years, and 18–49 years, 44%, 27%, and 17% of subjects, respectively, shed vaccine virus after vaccination, and the mean number of positive samples per subject was 2.2, 1.8, and 1.5, respectively. Shedding occurred on days 1–11 postvaccination. Shedding incidence peaked on day 2, and maximum observed titers were highest on days 2–3 (<5, <4, and <3 log10 TCID50/mL, respectively, by age group). Despite positive cultures, all titers were <1 log10 TCID50/mL after days 10, 6, and 6, respectively, by age group. Shedding incidence was inversely correlated to age and baseline serum HAI titer. The seroresponse rate (4-fold rise in HAI) to at least 1 strain was 59% (68%, 64%, and 47%, respectively, by age group), and strain-specific rates were higher in baseline seronegative/serosusceptible subjects. Reactogenicity, most commonly runny nose, headache, and sore throat, was not associated with shedding or seroresponse. Conclusions: This is the first study to comprehensively evaluate nasal shedding of LAIV in individuals 5–49 years of age. Shedding was generally of short duration and at low titers. Study findings support the current recommendation of the Advisory Committee on Immunization Practices that LAIV recipients should only avoid contact with severely immunosuppressed persons (e.g., hematopoietic stem cell transplant recipients) for 7 days after vaccination. [Copyright &y& Elsevier]

Abstract: Protective efficacy of the intranasal immunization with the neuraminidase (NA)-deficient mutant of the influenza A virus was investigated in ferrets. Despite the highly attenuated replication in vivo, the mutant completely protected the animals against the wild type virus challenge. When challenge was done with antigenic drift variants, significant reductions in the viral titers, inflammatory cell counts, and protein concentrations were observed in the nasal washes of the immunized animals. The genetically engineered NA-deficient mutant also protected animals against the challenge and induced humoral immune response against the foreign protein that replaced the NA. We conclude that the NA as antigen is dispensable in the live attenuated influenza virus vaccine and that the NA-lacking mutant can be used as a virus vector. [Copyright &y& Elsevier]

Background: Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications.Methods: We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011.Findings: 2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (-7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.Interpretation: Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications.Funding: Shionogi. [ABSTRACT FROM AUTHOR]

Summary Since the 18th century a wealth of knowledge regarding infectious disease pathogenesis, prevention, and treatment has been accumulated from findings of infection challenges in human beings. Partly because of improvements to ethical and regulatory guidance, human challenge studies—involving the deliberate exposure of participants to infectious substances—have had a resurgence in popularity in the past few years, in particular for the assessment of vaccines. To provide an overview of the potential use of challenge models, we present historical reports and contemporary views from experts in this type of research. A range of challenge models and practical approaches to generate important data exist and are used to expedite vaccine and therapeutic development and to support public health modelling and interventions. Although human challenge studies provide a unique opportunity to address complex research questions, participant and investigator safety is paramount. To increase the collaborative effort and future success of this area of research, we recommend the development of consensus frameworks and sharing of best practices between investigators. Furthermore, standardisation of challenge procedures and regulatory guidance will help with the feasibility for using challenge models in clinical testing of new disease intervention strategies. [ABSTRACT FROM AUTHOR]

Summary Observational data suggest that the treatment of influenza infection with neuraminidase inhibitors decreases progression to more severe illness, especially when treatment is started soon after symptom onset. However, even early treatment might fail to prevent complications in some patients, particularly those infected with novel viruses such as the 2009 pandemic influenza A H1N1, avian influenza A H5N1 virus subtype, or the avian influenza A H7N9 virus subtype. Furthermore, treatment with one antiviral drug might promote the development of antiviral resistance, especially in immunocompromised hosts and critically ill patients. An obvious strategy to optimise antiviral therapy is to combine drugs with different modes of action. Because host immune responses to infection might also contribute to illness pathogenesis, improved outcomes might be gained from the combination of antiviral therapy with drugs that modulate the immune response in an infected individual. We review available data from preclinical and clinical studies of combination antiviral therapy and of combined antiviral-immunomodulator therapy for influenza. Early-stage data draw attention to several promising antiviral combinations with therapeutic potential in severe infections, but there remains a need to substantiate clinical benefit. Combination therapies with favourable experimental data need to be tested in carefully designed aclinical trials to assess their efficacy. [ABSTRACT FROM AUTHOR]

Summary The emergence and spread of antimicrobial-resistant bacterial, viral, and fungal pathogens for which diminishing treatment options are available is of major global concern. New viral respiratory tract infections with epidemic potential, such as severe acute respiratory syndrome, swine-origin influenza A H1N1, and Middle East respiratory syndrome coronavirus infection, require development of new antiviral agents. The substantial rise in the global numbers of patients with respiratory tract infections caused by pan-antibiotic-resistant Gram-positive and Gram-negative bacteria, multidrug-resistant Mycobacterium tuberculosis , and multiazole-resistant fungi has focused attention on investments into development of new drugs and treatment regimens. Successful treatment outcomes for patients with respiratory tract infections across all health-care settings will necessitate rapid, precise diagnosis and more effective and pathogen-specific therapies. This Series paper describes the development and use of new antimicrobial agents and immune-based and host-directed therapies for a range of conventional and emerging viral, bacterial, and fungal causes of respiratory tract infections. [ABSTRACT FROM AUTHOR]

Summary: Influenza A H1N1 2009 virus caused the first pandemic in an era when neuraminidase inhibitor antiviral drugs were available in many countries. The experiences of detecting and responding to resistance during the pandemic provided important lessons for public health, laboratory testing, and clinical management. We propose recommendations for antiviral susceptibility testing, reporting results, and management of patients infected with 2009 pandemic influenza A H1N1. Sustained global monitoring for antiviral resistance among circulating influenza viruses is crucial to inform public health and clinical recommendations for antiviral use, especially since community spread of oseltamivir-resistant A H1N1 2009 virus remains a concern. Further studies are needed to better understand influenza management in specific patient groups, such as severely immunocompromised hosts, including optimisation of antiviral treatment, rapid sample testing, and timely reporting of susceptibility results. [Copyright &y& Elsevier]

The International Society for Influenza and other Respiratory Virus Diseases (isirv) and the WHO held a joint virtual conference from 19th-21st October 2021. While there was a major focus on the global response to the SARS-CoV-2 pandemic, including antivirals, vaccines and surveillance strategies, papers were also presented on treatment and prevention of influenza and respiratory syncytial virus (RSV). Potential therapeutics for SARS-CoV-2 included host-targeted therapies baricitinib, a JAK inhibitor, tocilizumab, an IL-6R inhibitor, verdinexor and direct acting antivirals ensovibep, S-217622, AT-527, and monoclonal antibodies casirivimab and imdevimab, directed against the spike protein. Data from trials of nirsevimab, a monoclonal antibody with a prolonged half-life which binds to the RSV F-protein, and an Ad26.RSV pre-F vaccine were also presented. The expanded role of the WHO Global Influenza Surveillance and Response System to address the SARS-CoV-2 pandemic was also discussed. This report summarizes the oral presentations given at this meeting for the benefit of the broader medical and scientific community involved in surveillance, treatment and prevention of respiratory virus diseases. • Presentations given at the recent joint isirv-WHO virtual conference held from 19th-21st October are summarized. • Due to the current global pandemic, SARS-CoV-2 was the primary focus, but influenza and RSV were also discussed. • Presentations on vaccines, immunotherapies and virus-targeted therapeutics were given. • Adaptation of the GISRS network from surveillance, sequencing and epidemiology of influenza to SARS-CoV-2 was highlighted. [ABSTRACT FROM AUTHOR]

Summary: Recent spread of avian influenza A (H5N1) virus to poultry and wild birds has increased the threat of human infections with H5N1 virus worldwide. Despite international agreement to stockpile antivirals, evidence-based guidelines for their use do not exist. WHO assembled an international multidisciplinary panel to develop rapid advice for the pharmacological management of human H5N1 virus infection in the current pandemic alert period. A transparent methodological guideline process on the basis of the Grading Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to develop evidence-based guidelines. Our development of specific recommendations for treatment and chemoprophylaxis of sporadic H5N1 infection resulted from the benefits, harms, burden, and cost of interventions in several patient and exposure groups. Overall, the quality of the underlying evidence for all recommendations was rated as very low because it was based on small case series of H5N1 patients, on extrapolation from preclinical studies, and high quality studies of seasonal influenza. A strong recommendation to treat H5N1 patients with oseltamivir was made in part because of the severity of the disease. Similarly, strong recommendations were made to use neuraminidase inhibitors as chemoprophylaxis in high-risk exposure populations. Emergence of other novel influenza A viral subtypes with pandemic potential, or changes in the pathogenicity of H5N1 virus strains, will require an update of these guidelines and WHO will be monitoring this closely. [Copyright &y& Elsevier]

The massive outbreak of Ebola virus disease in west Africa between 2013 and 2016 resulted in intense efforts to evaluate the efficacy of several specific countermeasures developed through years of preclinical work, including the first clinical trials for therapeutics and vaccines. In this Review, we discuss how the experience and data generated from that outbreak have helped to advance the understanding of the use of these countermeasures for post-exposure prophylaxis against Ebola virus infection. In future outbreaks, post-exposure prophylaxis could play an important part in reducing community transmission of Ebola virus by providing more immediate protection than does immunisation as well as providing additional protection for health-care workers who are inadvertently exposed over the course of their work. We propose provisional guidance for use of post-exposure prophylaxis in Ebola virus disease and identify the priorities for future preparedness and further research. [ABSTRACT FROM AUTHOR]