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Communications Biology Oct 2023The respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap...
The respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap methylation via the RNA dependent RNA polymerase, capping, and Methyltransferase domains on L. Several nucleoside and non-nucleoside inhibitors have been reported to inhibit this polymerase complex, but the structural details of the exact inhibitor-polymerase interactions have been lacking. Here, we report a non-nucleoside inhibitor JNJ-8003 with sub-nanomolar inhibition potency in both antiviral and polymerase assays. Our 2.9 Å resolution cryo-EM structure revealed that JNJ-8003 binds to an induced-fit pocket on the capping domain, with multiple interactions consistent with its tight binding and resistance mutation profile. The minigenome and gel-based de novo RNA synthesis and primer extension assays demonstrated that JNJ-8003 inhibited nucleotide polymerization at the early stages of RNA transcription and replication. Our results support that JNJ-8003 binding modulates a functional interplay between the capping and RdRp domains, and this molecular insight could accelerate the design of broad-spectrum antiviral drugs.
Topics: Respiratory Syncytial Virus, Human; RNA-Dependent RNA Polymerase; Protein Binding; RNA; Nucleotides
PubMed: 37865687
DOI: 10.1038/s42003-023-05451-4 -
Jornal de Pediatria 2023To identify and assess the current evidence available about the costs of managing hospitalized pediatric patients diagnosed with Respiratory Syncytial Virus (RSV) and... (Review)
Review
OBJECTIVE
To identify and assess the current evidence available about the costs of managing hospitalized pediatric patients diagnosed with Respiratory Syncytial Virus (RSV) and Parainfluenza Virus Type 3 (PIV3) in upper-middle-income countries.
METHODS
The authors conducted a systematic review across seven key databases from database inception to July 2022. Costs extracted were converted into 2022 International Dollars using the Purchasing Power Parity-adjusted. PROSPERO identifier: CRD42020225757.
RESULTS
No eligible study for PIV3 was recovered. For RSV, cost analysis and COI studies were performed for populations in Colombia, China, Malaysia, and Mexico. Comparing the total economic impact, the lowest cost per patient at the pediatric ward was observed in Malaysia ($ 347.60), while the highest was in Colombia ($ 709.66). On the other hand, at pediatric ICU, the lowest cost was observed in China ($ 1068.26), while the highest was in Mexico ($ 3815.56). Although there is no consensus on the major cost driver, all included studies described that the medications (treatment) consumed over 30% of the total cost. A high rate of inappropriate prescription drugs was observed.
CONCLUSION
The present study highlighted how RSV infection represents a substantial economic burden to health care systems and to society. The findings of the included studies suggest a possible association between baseline risk status and expenditures. Moreover, it was observed that an important amount of the cost is destinated to treatments that have no evidence or support in most clinical practice guidelines.
Topics: Humans; Child; Infant; Developing Countries; Financial Stress; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Parainfluenza Virus 3, Human; Hospitalization
PubMed: 37247828
DOI: 10.1016/j.jped.2023.05.003 -
Expert Review of Vaccines Oct 2019: Human respiratory syncytial virus (RSV) is a major health threat both for the very young and the elderly. With yearly 3.2 million hospital admissions and approximately... (Review)
Review
: Human respiratory syncytial virus (RSV) is a major health threat both for the very young and the elderly. With yearly 3.2 million hospital admissions and approximately 118,000 deaths due to RSV in children across the globe, the impact of this infectious disease is very high. Development of a safe RSV vaccine is of utmost importance but has proven to be challenging for several reasons. Researchers are faced with the history of a failed RSV vaccine trial, difficult target populations, a virus that naturally does not induce a long-lasting immune response and ambiguity concerning the optimal correlate of protection. Many different vaccine formats are being tested in preclinical models and about 30 candidate RSV vaccines are being evaluated in clinical trials.: In this review we focus on the difficulties concerning the development of an effective RSV vaccine and discuss vaccines that are currently in clinical trials and how they have dealt with these challenges. We review live-attenuated vaccines, vectored vaccines, subunit vaccines and particle-based vaccines.: It is clear that this field is progressing rapidly with several promising RSV vaccine candidates. A safe and effective RSV vaccine might be on the brink of clinical implementation soon.
Topics: Animals; Clinical Trials as Topic; Humans; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human; Vaccination; Vaccines, Attenuated; Vaccines, Subunit
PubMed: 31587585
DOI: 10.1080/14760584.2019.1675520 -
Frontiers in Immunology 2023Respiratory syncytial virus (RSV) is a significant causative agent of bronchitis and pneumonia in infants and children. The identification and structural analysis of the... (Review)
Review
Respiratory syncytial virus (RSV) is a significant causative agent of bronchitis and pneumonia in infants and children. The identification and structural analysis of the surface fusion glycoprotein of RSV represents a pivotal advancement in the development of RSV prevention. This review provides a comprehensive summary of RSV monoclonal antibody (mAb) and vaccine clinical trials registered on ClinicalTrials.gov, emphasizing on the classification, name, target, phase, clinical outcomes, and safety data of RSV vaccination in newborns, infants and children. We also discuss the characteristics of the types of RSV vaccines for maternal immunity and summarize the current clinical research progress of RSV vaccination in pregnant women and their protective efficacy in infants. This review will provide new ideas for the development of RSV prevention for children in the future.
Topics: Humans; Infant, Newborn; Infant; Child; Female; Pregnancy; Pregnant Women; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Vaccines; Vaccination; Antibodies, Viral
PubMed: 38327765
DOI: 10.3389/fimmu.2023.1329426 -
Seminars in Respiratory and Critical... Dec 2021Biomedical research has long strived to improve our understanding of the immune response to respiratory viral infections, an effort that has become all the more... (Review)
Review
Biomedical research has long strived to improve our understanding of the immune response to respiratory viral infections, an effort that has become all the more important as we live through the consequences of a pandemic. The disease course of these infections is shaped in large part by the actions of various cells of the innate and adaptive immune systems. While these cells are crucial in clearing viral pathogens and establishing long-term immunity, their effector mechanisms may also escalate into excessive, tissue-destructive inflammation detrimental to the host. In this review, we describe the breadth of the immune response to infection with respiratory viruses such as influenza and respiratory syncytial virus. Throughout, we focus on the host rather than the pathogen and try to describe shared patterns in the host response to different viruses. We start with the local cells of the airways, onto the recruitment and activation of innate and adaptive immune cells, followed by the establishment of local and systemic memory cells key in protection against reinfection. We end by exploring how respiratory viral infections can predispose to bacterial superinfection.
Topics: Humans; Immunity; Influenza, Human; Respiratory Syncytial Virus, Human; Respiratory System
PubMed: 34918319
DOI: 10.1055/s-0041-1736459 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jun 2023To investigate the distribution characteristics of non-bacterial pathogens in community-acquired pneumonia (CAP) in children.
OBJECTIVES
To investigate the distribution characteristics of non-bacterial pathogens in community-acquired pneumonia (CAP) in children.
METHODS
A total of 1 788 CAP children admitted to Shenyang Children's Hospital from December 2021 to November 2022 were selected. Multiple RT-PCR and capillary electrophoresis were used to detect 10 viral pathogens and 2 atypical pathogens, and serum antibodies of (Ch) and (MP) were detected. The distribution characteristics of different pathogens were analyzed.
RESULTS
Among the 1 788 CAP children, 1 295 children were pathogen-positive, with a positive rate of 72.43% (1 295/1 788), including a viral pathogen positive rate of 59.68% (1 067/1 788) and an atypical pathogen positive rate of 22.04% (394/1 788). The positive rates from high to low were MP, respiratory syncytial virus (RSV), influenza B virus (IVB), human metapneumovirus (HMPV), human rhinovirus (HRV), human parainfluenza virus (HPIV), influenza A virus (IVA), bocavirus (BoV), human adenovirus (HADV), Ch, and human coronavirus (HCOV). RSV and MP were the main pathogens in spring; MP had the highest positive rate in summer, followed by IVA; HMPV had the highest positive rate in autumn; IVB and RSV were the main pathogens in winter. The positive rate of MP in girls was higher than that in boys (<0.05), and there were no significant differences in other pathogens between genders (>0.05). The positivity rates of certain pathogens differed among age groups (<0.05): the positivity rate of MP was highest in the >6 year-old group; the positivity rates of RSV and Ch were highest in the <1 year-old group; the positivity rates of HPIV and IVB were highest in the 1 to <3 year-old group. RSV, MP, HRV, and HMPV were the main pathogens in children with severe pneumonia, while MP was the primary pathogen in children with lobar pneumonia, and MP, IVB, HMPV, RSV, and HRV were the top 5 pathogens in acute bronchopneumonia.
CONCLUSIONS
MP, RSV, IVB, HMPV, and HRV are the main pathogens of CAP in children, and there are certain differences in the positive rates of respiratory pathogens among children of different ages, genders, and seasons.
Topics: Humans; Child; Female; Male; Infant; Child, Preschool; Pneumonia; Respiratory Syncytial Virus, Human; Antibodies; Community-Acquired Infections; Hospitalization; Influenza B virus; Mycoplasma pneumoniae
PubMed: 37382134
DOI: 10.7499/j.issn.1008-8830.2212079 -
The Journal of Infectious Diseases Aug 2022
Topics: Humans; Infection Control; N95 Respirators; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Viral Load
PubMed: 35535586
DOI: 10.1093/infdis/jiac197 -
Internal and Emergency Medicine Jan 2024The purpose of this study is to investigate the global epidemiological characteristics of lower respiratory infections (LRI) burden attributable to respiratory syncytial...
The global burden of lower respiratory infections attributable to respiratory syncytial virus in 204 countries and territories, 1990-2019: findings from the Global Burden of Disease Study 2019.
AIMS
The purpose of this study is to investigate the global epidemiological characteristics of lower respiratory infections (LRI) burden attributable to respiratory syncytial virus (RSV) from 1990 to 2019.
MATERIALS AND METHODS
We used the recent Global Burden of Disease Study (GBD) 2019 to systematically evaluate the current burden and temporal trend of LRI burden attributable to RSV by global, age, sex, geographic location, and socio-economic status.
RESULTS
Globally, the disability-adjusted life years (DALYs) cases of LRI attributable to RSV dropped from an estimated 39,964,488 [95% uncertainty interval (UI): 16,825, 572 to 68,800,553] in 1990 to 14,956,514 (95%UI: 6,271,751 to 25,910,753) in 2019 and estimated death cases droped from 541,172 (95%UI:226,614 to 958,596) to 338,495 (95%UI:126,555 to 667,109) from1990 to 2019. Similarly, age-standardized DALYs rate of LRI attributable to RSV decreased from an estimated 646.2 (95%UI: 276.9 to 1121.5) in 1990 to 218.3 (95%UI:92.1 to 376.8) in 2019 and estimated age-standardized deaths rate decreased from 10.3 (95%UI:4.1 to 18.5) to 4.8 (95%UI:1.8 to 9.3) between 1990 and 2019. In 2019, the highest age-standardized DALYs and death rates of LRI attributable to RSV were seen in the lower SDI regions, children and old people. From 1990 to 2019, age-standardized DALYs and death rates of LRI attributable to RSV decreased with increasing SDI.
CONCLUSIONS
In this study, we found that the LRI burden attributable to RSV decreased significantly from 1990 to 2019. However, the lower SDI regions, children and old people urgently require cost-effective interventions to prevent and reduce the LRI burden attributable to RSV.
Topics: Child; Humans; Global Burden of Disease; Respiratory Syncytial Viruses; Quality-Adjusted Life Years; Respiratory Tract Infections; Global Health
PubMed: 37789183
DOI: 10.1007/s11739-023-03438-x -
Influenza and Other Respiratory Viruses Sep 2023Despite the growing recognition of a potentially significant respiratory syncytial virus (RSV) disease burden in adults, relevant evidence in the United Kingdom (UK) is... (Review)
Review
Despite the growing recognition of a potentially significant respiratory syncytial virus (RSV) disease burden in adults, relevant evidence in the United Kingdom (UK) is limited. This systematic literature review (SLR) aimed to identify the disease burden of RSV in UK adults, including certain high-risk subgroups and existing evidence gaps. Published studies (2011 onwards) reporting epidemiological, economic and clinical burden outcomes in UK adults (≥15 years) with RSV were identified from indexed databases, including MEDLINE, Embase and the Cochrane library. High-risk groups included elderly (≥65 years), immunocompromised, co-morbid and co-infected patients. Outcomes included RSV incidence/prevalence, mortality, clinical presentation and direct/indirect resource use/costs. Twenty-eight publications on 28 unique studies were identified, mostly in general/respiratory indicator ( = 17), elderly ( = 10) and immunocompromised ( = 6) cohorts. Main outcomes reported in the general/respiratory indicator cohort were RSV infection incidence (seasonal/annual: 0.09-17.9%/6.6-15.1%), mortality (8,482 deaths/season) and direct resource use (including mean general practitioner [GP] episodes/season: 487,247). Seasonal/annual incidence was 14.6-26.5%/0.7-16% in high-risk cohorts. Attributed to RSV in the elderly were 7,915 deaths/season and 175,070 mean GP episodes/season. Only two studies reported on co-morbid cohorts. Clinical burden outcomes were only reported in general and immunocompromised patients, and no evidence was found in any cohort on indirect economic burden or RSV complications. Evidence captured suggests that RSV may have a substantial burden in UK adults. However, available data were limited and highly heterogenous, with further studies needed to characterise the burden of RSV in adults and to validate our findings.
Topics: Aged; Humans; Adult; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Cost of Illness; Databases, Factual; Evidence Gaps
PubMed: 37744994
DOI: 10.1111/irv.13188 -
Respirology (Carlton, Vic.) Nov 2021
Topics: Humans; Interleukin-17; Lung; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Virus Diseases
PubMed: 34580948
DOI: 10.1111/resp.14158