-
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 -
Infection Feb 2024Respiratory syncytial virus (RSV) inflicts severe illness and courses of infections not only in neonates, infants, and young children, but also causes significant... (Review)
Review
Respiratory syncytial virus (RSV) inflicts severe illness and courses of infections not only in neonates, infants, and young children, but also causes significant morbidity and mortality in older adults and in people with immunosuppression, hemato-oncologic disease, chronic lung disease, or cardiovascular disease. In June and August 2023, effective vaccines against RSV were approved for the first time by the European Medicines Agency (EMA) for the EU. The respective pivotal studies showed a very high efficacy of the vaccine in preventing severe RSV-associated respiratory infections. At this point, use of the respective vaccines is restricted to persons aged 60 years or older, according to the registration studies. We therefore recommend use of the vaccination in persons aged 60 years or older. In addition, we recommend use of the vaccination in adults of any age with severe pulmonary or cardiovascular pre-existing conditions, as well as in adults with significant immune compromise, after individual consultation with the treating physician. Cost coverage can be applied for individually with the responsible health insurance company.
Topics: Aged; Humans; Lung; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human; Vaccination; Middle Aged
PubMed: 38060068
DOI: 10.1007/s15010-023-02141-5 -
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 -
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 -
The Journal of Infectious Diseases Nov 2023Ebola virus (EBOV) and Marburg virus (MARV) made headlines in the past decade, causing outbreaks of human disease in previously nonendemic yet overlapping areas. While...
Ebola virus (EBOV) and Marburg virus (MARV) made headlines in the past decade, causing outbreaks of human disease in previously nonendemic yet overlapping areas. While EBOV outbreaks can be mitigated with licensed vaccines and treatments, there is not yet a licensed countermeasure for MARV. Here, we used nonhuman primates (NHPs) previously vaccinated with vesicular stomatitis virus (VSV)-MARV and protected against lethal MARV challenge. After a resting period of 9 months, these NHPs were revaccinated with VSV-EBOV and challenged with EBOV, resulting in 75% survival. Surviving NHPs developed EBOV glycoprotein (GP)-specific antibody titers and no viremia or clinical signs of disease. The single vaccinated NHP succumbing to challenge showed the lowest EBOV GP-specific antibody response after challenge, supporting previous findings with VSV-EBOV that antigen-specific antibodies are critical in mediating protection. This study again demonstrates that VSVΔG-based filovirus vaccine can be successfully used in individuals with preexisting VSV vector immunity, highlighting the platform's applicability for consecutive outbreak response.
Topics: Animals; Humans; Hemorrhagic Fever, Ebola; Vesicular Stomatitis; Ebola Vaccines; Ebolavirus; Vesiculovirus; Vesicular stomatitis Indiana virus; Marburgvirus; Antibodies, Viral; Glycoproteins; Primates
PubMed: 37290042
DOI: 10.1093/infdis/jiad208 -
Respiratory syncytial virus knowledge, attitudes, and perceptions among adults in the United States.Human Vaccines & Immunotherapeutics Dec 2024Respiratory syncytial virus (RSV) is associated with considerable morbidity and mortality among older adults (aged ≥60 years) and adults with certain chronic...
Respiratory syncytial virus (RSV) is associated with considerable morbidity and mortality among older adults (aged ≥60 years) and adults with certain chronic conditions in the United States (US). Despite this burden, no previous studies have assessed the knowledge, attitudes, and perceptions (KAP) of RSV among these populations. This study evaluates RSV-related KAP among US adults at increased risk of severe RSV infection. A cross-sectional, web-based survey was administered from May to June 2022 to better understand respiratory infection- and RSV-related KAP among US adults who are at risk of severe RSV infection. The survey included ≥200 adults in each of 4 subgroups: adults aged 60-89 years, and adults aged 18-59 years with ≥1 chronic cardiovascular condition, chronic pulmonary condition, or diabetes mellitus. Survey responses were analyzed descriptively overall and by subgroup, with exploratory logistic regression modeling used to evaluate characteristics associated with RSV awareness and concern. Among the 827 survey respondents, only 43.3% had ever heard of RSV ( = 358/827). The study identified key knowledge gaps (e.g. bacterial vs. viral nature of respiratory infections, RSV seasonality, common RSV symptoms, extent to which RSV causes respiratory infections in specific patient populations). Although 33.7% of RSV-aware adults ( = 120/356) reported being worried/very worried about RSV, 67.3% ( = 241/358) rarely consider RSV as a potential cause of their cold/flu-like symptoms. Results from this study highlight important knowledge gaps related to RSV, perceived risk, and severity of RSV. Findings can be used to support the development of tailored education efforts to support RSV prevention.
Topics: Humans; United States; Aged; Respiratory Syncytial Virus Infections; Health Knowledge, Attitudes, Practice; Cross-Sectional Studies; Respiratory Syncytial Virus, Human; Respiratory Tract Infections; Chronic Disease; Hospitalization
PubMed: 38297921
DOI: 10.1080/21645515.2024.2303796 -
Influenza and Other Respiratory Viruses Nov 2023A viral infection can modify the risk to subsequent viral infections via cross-protective immunity, increased immunopathology, or disease-driven behavioral change. There...
BACKGROUND
A viral infection can modify the risk to subsequent viral infections via cross-protective immunity, increased immunopathology, or disease-driven behavioral change. There is limited understanding of virus-virus interactions due to lack of long-term population-level data.
METHODS
Our study leverages passive surveillance data of 10 human acute respiratory viruses from Beijing, Chongqing, Guangzhou, and Shanghai collected during 2009 to 2019: influenza A and B viruses; respiratory syncytial virus A and B; human parainfluenza virus (HPIV), adenovirus, metapneumovirus (HMPV), coronavirus, bocavirus (HBoV), and rhinovirus (HRV). We used a multivariate Bayesian hierarchical model to evaluate correlations in monthly prevalence of test-positive samples between virus pairs, adjusting for potential confounders.
RESULTS
Of 101,643 lab-tested patients, 33,650 tested positive for any acute respiratory virus, and 4,113 were co-infected with multiple viruses. After adjusting for intrinsic seasonality, long-term trends and multiple comparisons, Bayesian multivariate modeling found positive correlations for HPIV/HRV in all cities and for HBoV/HRV and HBoV/HMPV in three cities. Models restricted to children further revealed statistically significant associations for another ten pairs in three of the four cities. In contrast, no consistent correlation across cities was found among adults. Most virus-virus interactions exhibited substantial spatial heterogeneity.
CONCLUSIONS
There was strong evidence for interactions among common respiratory viruses in highly populated urban settings. Consistent positive interactions across multiple cities were observed in viruses known to typically infect children. Future intervention programs such as development of combination vaccines may consider spatially consistent virus-virus interactions for more effective control.
Topics: Child; Adult; Humans; Infant; Beijing; Respiratory Tract Infections; Bayes Theorem; China; Viruses; Virus Diseases; Respiratory Syncytial Virus, Human
PubMed: 37964991
DOI: 10.1111/irv.13212 -
Frontiers in Immunology 2023The immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older...
INTRODUCTION
The immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older adults, symptoms are typically mild but can be serious in patients with comorbidities when the infection extends to the lower respiratory tract.
METHODS
This study formed part of the RESCEU older-adults prospective-cohort study in Northern Europe (2017-2019; NCT03621930) in which a thousand participants were followed over an RSV season. Peripheral-blood samples (taken pre-season, post-season, during illness and convalescence) were analyzed from participants who (i) had a symptomatic acute respiratory tract infection by RSV (RSV-ARTI; N=35) or (ii) asymptomatic RSV infection (RSV-Asymptomatic; N=16). These analyses included evaluations of antibody (Fc-mediated-) functional features and cell-mediated immunity, in which univariate and machine-learning (ML) models were used to explore differences between groups.
RESULTS
Pre-RSV-season peripheral-blood biomarkers were predictive of symptomatic RSV infection. T-cell data were more predictive than functional antibody data (area under receiver operating characteristic curve [AUROC] for the models were 99% and 76%, respectively). The pre-RSV season T-cell phenotypes which were selected by the ML modelling and which were more frequent in RSV-Asymptomatic group than in the RSV-ARTI group, coincided with prominent phenotypes identified during convalescence from RSV-ARTI (e.g., IFN-γ+, TNF-α+ and CD40L+ for CD4+, and IFN-γ+ and 4-1BB+ for CD8+).
CONCLUSION
The evaluation and statistical modelling of numerous immunological parameters over the RSV season suggests a primary role of cellular immunity in preventing symptomatic RSV infections in older adults.
Topics: Humans; Aged; Respiratory Syncytial Virus Infections; T-Lymphocytes; Cohort Studies; Prospective Studies; Convalescence; Respiratory Syncytial Virus, Human; Antibodies, Viral
PubMed: 37936699
DOI: 10.3389/fimmu.2023.1260146 -
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 -
Frontiers in Immunology 2023The primary goal of this work is to broaden and enhance the options for induction of protective CD8 T cells against HIV-1 and respiratory pathogens.
Combined intranasal and intramuscular parainfluenza 5-, simian adenovirus ChAdOx1- and poxvirus MVA-vectored vaccines induce synergistically HIV-1-specific T cells in the mucosa.
INTRODUCTION
The primary goal of this work is to broaden and enhance the options for induction of protective CD8 T cells against HIV-1 and respiratory pathogens.
METHODS
We explored the advantages of the parainfluenza virus 5 (PIV5) vector for delivery of pathogen-derived transgenes alone and in combination with the in-human potent regimen of simian adenovirus ChAdOx1 prime-poxvirus MVA boost delivering bi-valent mosaic of HIV-1 conserved regions designated HIVconsvX.
RESULTS
We showed in BALB/c mice that the PIV5 vector expressing the HIVconsvX immunogens could be readily incorporated with the other two vaccine modalities into a single regimen and that for specific vector combinations, mucosal CD8 T-cell induction was enhanced synergistically by a combination of the intranasal and intramuscular routes of administration.
DISCUSSION
Encouraging safety and immunogenicity data from phase 1 human trials of ChAdOx1- and MVA-vectored vaccines for HIV-1, and PIV5-vectored vaccines for SARS-CoV-2 and respiratory syncytial virus pave the way for combining these vectors for HIV-1 and other indications in humans.
Topics: Mice; Animals; Humans; Adenoviruses, Simian; HIV-1; CD8-Positive T-Lymphocytes; COVID-19 Vaccines; COVID-19; SARS-CoV-2; Respiratory Syncytial Virus, Human
PubMed: 37529048
DOI: 10.3389/fimmu.2023.1186478