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Influenza and Other Respiratory Viruses Jan 2023External quality assessments (EQAs) for the molecular detection of human respiratory syncytial virus (RSV) are necessary to ensure the standardisation of reliable...
BACKGROUND
External quality assessments (EQAs) for the molecular detection of human respiratory syncytial virus (RSV) are necessary to ensure the standardisation of reliable results. The Phase II, 2019-2020 World Health Organization (WHO) RSV EQA included 28 laboratories in 26 countries. The EQA panel evaluated performance in the molecular detection and subtyping of RSV-A and RSV-B. This manuscript describes the preparation, distribution, and analysis of the 2019-2020 WHO RSV EQA.
METHODS
Panel isolates underwent whole genome sequencing and in silico primer matching. The final panel included nine contemporary, one historical virus and two negative controls. The EQA panel was manufactured and distributed by the UK National External Quality Assessment Service (UK NEQAS). National laboratories used WHO reference assays developed by the United States Centers for Disease Control and Prevention, an RSV subtyping assay developed by the Victorian Infectious Diseases Reference Laboratory (Australia), or other in-house or commercial assays already in use at their laboratories.
RESULTS
An in silico analysis of isolates showed a good match to assay primer/probes. The panel was distributed to 28 laboratories. Isolates were correctly identified in 98% of samples for detection and 99.6% for subtyping.
CONCLUSIONS
The WHO RSV EQA 2019-2020 showed that laboratories performed at high standards. Updating the composition of RSV molecular EQAs with contemporary strains to ensure representation of circulating strains, and ensuring primer matching with EQA panel viruses, is advantageous in assessing diagnostic competencies of laboratories. Ongoing EQAs are recommended because of continued evolution of mismatches between current circulating strains and existing primer sets.
Topics: United States; Humans; Respiratory Syncytial Virus, Human; Laboratories; Viruses; World Health Organization; Australia
PubMed: 36824313
DOI: 10.1111/irv.13073 -
The Lancet. Global Health May 2023
Topics: Humans; Infant; Developing Countries; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Poverty
PubMed: 37061306
DOI: 10.1016/S2214-109X(23)00165-1 -
American Journal of Respiratory and... Mar 2021
Topics: Child; Child, Preschool; Humans; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human; Vaccines, Attenuated
PubMed: 32986467
DOI: 10.1164/rccm.202009-3431ED -
Virus Research Jan 2020Human respiratory syncytial virus (hRSV) is one of the main etiological agents of diseases of the lower respiratory tract and is often responsible for the...
Human respiratory syncytial virus (hRSV) is one of the main etiological agents of diseases of the lower respiratory tract and is often responsible for the hospitalization of children and the elderly. To date, treatments are only palliative and there is no vaccine available. Natural products show exceptional structural diversity and they have played a vital role in drug research. Several investigations focused on applied structural modification of natural products to improved metabolic stability, solubility and biological actions them. Quercetin is a flavonoid that presents several biological activities, including anti-hRSV role. Some works criticize the pharmacological use of Quercetin because it has low solubility and low specificity. In this sense, we acetylated Quercetin structure and we used in vitro and in silico assays to compare anti-hRSV function between Quercetin (Q0) and its derivative molecule (Q1). Q1 shows lower cytotoxic effect than Q0 on HEp-2 cells. In addition, Q1 was more efficient than Q0 to protect HEp-2 cells infected with different multiplicity of infection (0.1-1 MOI). The virucidal effects of Q0 and Q1 suggest interaction between these molecules and viral particle. Dynamic molecular results suggest that Q0 and Q1 may interact with F-protein on hRSV surface in an important region to adhesion and viral infection. Q1 interaction with F-protein showed ΔG= -14.22 kcal/mol and it was more stable than Q0. Additional, MTT and plate assays confirmed that virucidal Q1 effects occurs during adhesion step of cycle hRSV replication. In conclusion, acetylation improves anti-hRSV Quercetin effects because Quercetin pentaacetate could interact with F-protein with lower binding energy and better stability to block viral adhesion. These results show alternative anti-hRSV strategy and contribute to drug discovery and development.
Topics: Acetylation; Antiviral Agents; Cell Line; Epithelial Cells; Humans; Molecular Dynamics Simulation; Quercetin; Respiratory Syncytial Virus, Human; Viral Fusion Proteins; Virus Attachment; Virus Replication
PubMed: 31712123
DOI: 10.1016/j.virusres.2019.197805 -
Viral Immunology 2021The resolution revolution of cryo-electron microscopy (cryo-EM) has made a significant impact on the structural analysis of the multifunctional RNA polymerases. In...
The resolution revolution of cryo-electron microscopy (cryo-EM) has made a significant impact on the structural analysis of the multifunctional RNA polymerases. In recent months, several high-resolution structures of RNA polymerases of , which includes the human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV), have been determined by single-particle cryo-EM. These structures illustrated high similarities and minor differences between the polymerases and revealed the potential mechanisms of the RNA synthesis.
Topics: Cryoelectron Microscopy; DNA-Directed RNA Polymerases; Humans; Pneumovirus; Respiratory Syncytial Virus, Human
PubMed: 32429800
DOI: 10.1089/vim.2020.0018 -
MSphere Feb 2022Streptococcus pneumoniae (the pneumococcus) is a leading cause of pneumonia in children under 5 years of age. Coinfection by pneumococci and respiratory viruses enhances...
Streptococcus pneumoniae (the pneumococcus) is a leading cause of pneumonia in children under 5 years of age. Coinfection by pneumococci and respiratory viruses enhances disease severity. Little is known about pneumococcal coinfections with respiratory syncytial virus (RSV). Here, we developed a novel infant mouse model of coinfection using pneumonia virus of mice (PVM), a murine analogue of RSV, to examine the dynamics of coinfection in the upper respiratory tract, an anatomical niche that is essential for host-to-host transmission and progression to disease. Coinfection increased damage to the nasal tissue and increased production of the chemokine CCL3. Nasopharyngeal pneumococcal density and shedding in nasal secretions were increased by coinfection. In contrast, coinfection reduced PVM loads in the nasopharynx, an effect that was independent of pneumococcal strain and the order of infection. We showed that this "antagonistic" effect was absent using either ethanol-killed pneumococci or a pneumococcal mutant deficient in capsule production and incapable of nasopharyngeal carriage. Colonization with a pneumococcal strain naturally unable to produce capsule also reduced viral loads. The pneumococcus-mediated reduction in PVM loads was caused by accelerated viral clearance from the nasopharynx. Although these synergistic and antagonistic effects occurred with both wild-type pneumococcal strains used in this study, the magnitude of the effects was strain dependent. Lastly, we showed that pneumococci can also antagonize influenza virus. Taken together, our study has uncovered multiple novel facets of bacterial-viral coinfection. Our findings have important public health implications, including for bacterial and viral vaccination strategies in young children. Respiratory bacterial-viral coinfections (such as pneumococci and influenza virus) are often synergistic, resulting in enhanced disease severity. Although colonization of the nasopharynx is the precursor to disease and transmission, little is known about bacterial-viral interactions that occur within this niche. In this study, we developed a novel mouse model to examine pneumococcal-viral interactions in the nasopharynx with pneumonia virus of mice (PVM) and influenza. We found that PVM infection benefits pneumococci by increasing their numbers in the nasopharynx and shedding of these bacteria in respiratory secretions. In contrast, we discovered that pneumococci decrease PVM numbers by accelerating viral clearance. We also report a similar effect of pneumococci on influenza. By showing that coinfections lead to both synergistic and antagonistic outcomes, our findings challenge the existing dogma in the field. Our work has important applications and implications for bacterial and viral vaccines that target these microbes.
Topics: Age Factors; Animals; Antibiosis; Coinfection; Cytokines; Disease Models, Animal; Influenza A virus; Mice; Mice, Inbred C57BL; Murine pneumonia virus; Nasopharynx; Orthomyxoviridae Infections; Pneumococcal Infections; Pneumovirus Infections; Respiratory System; Streptococcus pneumoniae; Viral Load
PubMed: 35044807
DOI: 10.1128/msphere.00984-21 -
American Journal of Physiology. Lung... Nov 2022
Topics: Female; Infant, Newborn; Humans; Anti-Bacterial Agents; Global Health; Premature Birth; Drug Resistance, Bacterial; Respiratory Syncytial Virus, Human; Infant, Premature, Diseases; Pneumonia; Pulmonary Disease, Chronic Obstructive
PubMed: 36193906
DOI: 10.1152/ajplung.00302.2022 -
BMC Pediatrics Jun 2023To undertake a systematic review of studies describing the proportion of children admitted to a paediatric intensive care unit (PICU) for respiratory syncytial virus... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To undertake a systematic review of studies describing the proportion of children admitted to a paediatric intensive care unit (PICU) for respiratory syncytial virus (RSV) and/or bronchiolitis who were born preterm, and compare their outcomes in PICU with children born at term.
METHODS
We searched Medline, Embase and Scopus. Citations and references of included articles were searched. We included studies published from the year 2000 onwards, from high-income countries, that examined children 0-18 years of age, admitted to PICU from the year 2000 onwards for RSV and/or bronchiolitis. The primary outcome was the percentage of PICU admissions born preterm, and secondary outcomes were observed relative risks of invasive mechanical ventilation and mortality within PICU. We used the Joanna Briggs Institute Checklist for Analytical Cross-Sectional Studies to assess risk of bias.
RESULTS
We included 31 studies, from 16 countries, including a total of 18,331 children. Following meta-analysis, the pooled estimate for percentage of PICU admissions for RSV/bronchiolitis who were born preterm was 31% (95% confidence interval: 27% to 35%). Children born preterm had a greater risk of requiring invasive ventilation compared to children born at term (relative risk 1.57, 95% confidence interval 1.25 to 1.97, I = 38%). However, we did not observe a significant increase in the relative risk for mortality within PICU for preterm-born children (relative risk 1.10, 95% confidence interval: 0.70 to 1.72, I = 0%), although the mortality rate was low across both groups. The majority of studies (n = 26, 84%) were at high risk of bias.
CONCLUSIONS
Among PICU admissions for bronchiolitis, preterm-born children are over-represented compared with the preterm birth rate (preterm birth rate 4.4% to 14.4% across countries included in review). Preterm-born children are at higher risk of mechanical ventilation compared to those born at term.
Topics: Infant, Newborn; Child; Humans; Pregnancy; Female; Cross-Sectional Studies; Premature Birth; Bronchiolitis; Parturition; Respiratory Syncytial Virus, Human; Critical Care
PubMed: 37386478
DOI: 10.1186/s12887-023-04150-7 -
Frontiers in Immunology 2023Nirsevimab is an extended half-life (M252Y/S254T/T256E [YTE]-modified) monoclonal antibody to the pre-fusion conformation of the respiratory syncytial virus (RSV) Fusion...
INTRODUCTION
Nirsevimab is an extended half-life (M252Y/S254T/T256E [YTE]-modified) monoclonal antibody to the pre-fusion conformation of the respiratory syncytial virus (RSV) Fusion protein, with established efficacy in preventing RSV-associated lower respiratory tract infection in infants for the duration of a typical RSV season. Previous studies suggest that nirsevimab confers protection via direct virus neutralization. Here we use preclinical models to explore whether fragment crystallizable (Fc)-mediated effector functions contribute to nirsevimab-mediated protection.
METHODS
Nirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897*-TM (i.e., MEDI8897* without Fc effector functions) binding to Fc γ receptors (FcγRs) was evaluated using surface plasmon resonance. Antibody-dependent neutrophil phagocytosis (ADNP), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent complement deposition (ADCD), and antibody-dependent cellular cytotoxicity (ADCC) were assessed through and serological analyses. A cotton rat challenge study was performed with MEDI8897* and MEDI8897*-TM to explore whether Fc effector functions contribute to protection from RSV.
RESULTS
Nirsevimab and MEDI8897* exhibited binding to a range of FcγRs, with expected reductions in FcγR binding affinities observed for MEDI8897*-TM. Nirsevimab exhibited ADNP, ADCP, ADCD, and ADCC activity above background levels, and similar ADNP, ADCP, and ADCD activity to palivizumab. Nirsevimab administration increased ADNP, ADCP, and ADCD activity in participant serum from the MELODY study (NCT03979313). However, ADCC levels remained similar between nirsevimab and placebo. MEDI8897* and MEDI8897*-TM exhibited similar dose-dependent reduction in lung and nasal turbinate RSV titers in the cotton rat model.
CONCLUSION
Nirsevimab possesses Fc effector activity comparable with the current standard of care, palivizumab. However, despite possessing the capacity for Fc effector activity, data from RSV challenge experiments illustrate that nirsevimab-mediated protection is primarily dependent on direct virus neutralization.
Topics: Infant; Humans; Animals; Palivizumab; Antibodies, Viral; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Complement System Proteins; Sigmodontinae
PubMed: 37901217
DOI: 10.3389/fimmu.2023.1283120 -
Influenza and Other Respiratory Viruses Jul 2023Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available.
METHODS
This was a Phase 2 study of the oral RSV fusion protein inhibitor AK0529 in infants aged 1-24 months, hospitalized with RSV infection. In Part 1, patients ( = 24) were randomized 2:1 to receive a single dose of AK0529 up to 4 mg/kg or placebo. In Part 2, patients ( = 48) were randomized 2:1 to receive AK0529 at 0.5, 1, or 2 mg/kg bid or placebo for 5 days. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modelling. Safety, tolerability, viral load, and respiratory signs and symptoms were assessed daily during treatment.
RESULTS
No safety or tolerability signals were detected for AK0529: grade ≥3 treatment-emergent adverse events occurring in 4.1% of patients in AK0529 and 4.2% in placebo groups, respectively, and none led to death or withdrawal from the study. In Part 2, targeted drug exposure was reached with 2 mg/kg bid. A numerically greater reduction in median viral load with 2 mg/kg bid AK0529 than with placebo at 96 h was observed. A -4.0 (95% CI: -4.51, -2.03) median reduction in Wang Respiratory Score from baseline to 96 h was observed in the 2 mg/kg group compared with -2.0 (95% CI: -3.42, -1.82) in the placebo group.
CONCLUSIONS
AK0529 was well tolerated in hospitalized RSV-infected infant patients. Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and Wang Respiratory Score.
CLINICAL TRIALS REGISTRATION
NCT02654171.
Topics: Child; Infant; Humans; Child, Preschool; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Sulfones; Quinazolines
PubMed: 37502622
DOI: 10.1111/irv.13176