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Influenza and Other Respiratory Viruses Apr 2024Human respiratory syncytial virus (RSV) is one of the most frequent causes of respiratory infections in children under 5 years of age, but its socioeconomic impact and...
INTRODUCTION
Human respiratory syncytial virus (RSV) is one of the most frequent causes of respiratory infections in children under 5 years of age, but its socioeconomic impact and burden in primary care settings is still little studied.
METHODS
During the 2022/2023 winter season, 55 pediatricians from five Italian regions participated in our community-based study. They collected a nasal swab for RSV molecular test from 650 patients under the age of 5 with acute respiratory infections (ARIs) and performed a baseline questionnaire. The clinical and socioeconomic burden of RSV disease in primary care was evaluated by two follow-up questionnaires completed by the parents of positive children on Days 14 and 30.
RESULTS
RSV laboratory-confirmed cases were 37.8% of the total recruited ARI cases, with RSV subtype B accounting for the majority (65.4%) of RSV-positive swabs. RSV-positive children were younger than RSV-negative ones (median 12.5 vs. 16.5 months). The mean duration of symptoms for all children infected by RSV was 11.47 ± 6.27 days. We did not observe substantial differences in clinical severity between the two RSV subtypes, but RSV-A positive patients required more additional pediatric examinations than RSV-B cases. The socioeconomic impact of RSV infection was considerable, causing 53% of children to be absent from school, 46% of parents to lose working days, and 25% of families to incur extra costs.
CONCLUSIONS
Our findings describe a baseline of the RSV disease burden in primary care in Italy before the introduction of upcoming immunization strategies.
Topics: Humans; Child; Infant; Child, Preschool; Respiratory Syncytial Virus Infections; Seasons; Respiratory Syncytial Virus, Human; Respiratory Tract Infections; Italy; Cost of Illness; Primary Health Care; Hospitalization
PubMed: 38622776
DOI: 10.1111/irv.13282 -
Human Vaccines & Immunotherapeutics Dec 2024Influenza remains a public health threat, partly due to suboptimal effectiveness of vaccines. One factor impacting vaccine effectiveness is strain mismatch, occurring... (Review)
Review
Influenza remains a public health threat, partly due to suboptimal effectiveness of vaccines. One factor impacting vaccine effectiveness is strain mismatch, occurring when vaccines no longer match circulating strains due to antigenic drift or the incorporation of inadvertent (eg, egg-adaptive) mutations during vaccine manufacturing. In this review, we summarize the evidence for antigenic drift of circulating viruses and/or egg-adaptive mutations occurring in vaccine strains during the 2011-2020 influenza seasons. Evidence suggests that antigenic drift led to vaccine mismatch during four seasons and that egg-adaptive mutations caused vaccine mismatch during six seasons. These findings highlight the need for alternative vaccine development platforms. Recently, vaccines based on mRNA technology have demonstrated efficacy against SARS-CoV-2 and respiratory syncytial virus and are under clinical evaluation for seasonal influenza. We discuss the potential for mRNA vaccines to address strain mismatch, as well as new multi-component strategies using the mRNA platform to improve vaccine effectiveness.
Topics: Humans; Influenza Vaccines; mRNA Vaccines; Seasons; Influenza, Human; RNA, Messenger; Respiratory Syncytial Virus, Human
PubMed: 38619079
DOI: 10.1080/21645515.2024.2336357 -
Influenza and Other Respiratory Viruses Apr 2024Pneumonia is a leading cause of morbidity and mortality in children < 5 years. We describe nasopharyngeal carriage of respiratory syncytial virus (RSV), human...
Predictors of Respiratory Syncytial Virus, Influenza Virus, and Human Metapneumovirus Carriage in Children Under 5 Years With WHO-Defined Fast-Breathing Pneumonia in Pakistan.
BACKGROUND
Pneumonia is a leading cause of morbidity and mortality in children < 5 years. We describe nasopharyngeal carriage of respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and influenza virus among children with fast-breathing pneumonia in Karachi, Pakistan.
METHODS
We performed a cross-sectional analysis of nasopharyngeal swabs from children aged 2-59 months with fast-breathing pneumonia, enrolled in the randomized trial of amoxicillin versus placebo for fast-breathing pneumonia (RETAPP) (NCT02372461) from 2014 to 2016. Swabs were collected using WHO standardized methods, processed at the Aga Khan University, Pakistan. Viral detection was performed using LUMINEX xTAG respiratory viral panel assay and logistic regression identified clinical and sociodemographic predictors.
FINDINGS
Of the 1000 children tested, 92.2% (n = 922) were positive for viral carriage. RSV, hMPV, and influenza virus were detected in 59 (6.4%), 56 (6.1%), and 58 (6.3%) children and co-infections in three samples (two RSV-hMPV and one influenza-hMPV). RSV carriage was common in infants (56%), we observed a higher occurrence of fever in children with hMPV and influenza virus (80% and 88%, respectively) and fast breathing in RSV (80%) carriage. RSV carriage was positively associated with a history of fast/difficulty breathing (aOR: 1.96, 95% CI 1.02-3.76) and low oxygen saturation (aOR: 2.52, 95% CI 1.32-4.82), hMPV carriage was positively associated with a complete vaccination status (aOR: 2.22, 95% CI 1.23-4.00) and body temperature ≥ 37.5°C (aOR: 2.34, 95% CI 1.35-4.04) whereas influenza viral carriage was associated with body temperature ≥ 37.5°C (aOR: 4.48, 95% CI 2.53-7.93).
CONCLUSION
We observed a high nasopharyngeal viral carriage among children with WHO-defined fast-breathing pneumonia in Pakistan. Fever, difficulty in breathing, hypoxia and vaccination status are important clinical predictors for viral nonsevere community-acquired pneumonia.
Topics: Child; Child, Preschool; Humans; Infant; Cross-Sectional Studies; Fever; Influenza, Human; Metapneumovirus; Orthomyxoviridae; Pakistan; Respiratory Syncytial Virus, Human; World Health Organization
PubMed: 38616564
DOI: 10.1111/irv.13285 -
Vaccine May 2024Bivalent RSV prefusion F subunit vaccine (RSVpreF), comprised of equal quantities of stabilized prefusion F antigens from the major circulating subgroups (RSV A, RSV B),... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Bivalent RSV prefusion F subunit vaccine (RSVpreF), comprised of equal quantities of stabilized prefusion F antigens from the major circulating subgroups (RSV A, RSV B), is licensed for prevention of RSV-associated lower respiratory tract illness (LRTI) in older adults and for maternal vaccination for prevention of RSV-associated LRTI in infants. To support licensure and large-scale manufacturing, this lot consistency study was conducted to demonstrate equivalence in immunogenicity across 3 RSVpreF lots.
METHODS
This phase 3, multicenter, parallel-group, placebo-controlled, randomized (1:1:1:1), double-blind study evaluated immunogenicity, safety, and tolerability of RSVpreF in healthy 18-49-year-old adults. Participants received a single 120-µg injection of 1 of 3RSVpreF lots or placebo. Geometric mean ratio (GMR) of RSV serum 50 % neutralizing geometric mean titers obtained 1 month after vaccination were compared between each vaccine lot for RSV A and RSV B, separately. Equivalence between lots was defined using a 1.5-fold criterion (GMR 95 % CIs for every lot pair within the 0.667-1.5 interval). Safety and tolerability were assessed.
RESULTS
Of 992participants vaccinated, 948 were included in the evaluable immunogenicity population. All 3 RSVpreF lots elicited strong immune responses, meeting the 1.5-fold equivalence criterion for all between-lot comparisons for both RSV A and RSV B. Across the 3 lots, RSV A and RSV B 50 % neutralizing geometric mean titers substantially increased from baseline (RSV A, 1671-1795; RSV B 1358-1429) to 1 month after RSVpreF vaccination (RSV A, 24,131-25,238; RSV B, 19,238-21,702), corresponding to ≥14-fold increases in 50 % neutralizing titers for both RSV A and RSV B from before to 1 month after vaccination. Single doses of RSVpreF were safe and well tolerated, with similar safety profiles across the 3 RSVpreF lots.
CONCLUSIONS
These findings support the reproducibility of RSVpreF vaccine manufacturing with similar safety and reactogenicity profiles (NCT05096208).
Topics: Humans; Respiratory Syncytial Virus Vaccines; Female; Male; Adult; Double-Blind Method; Young Adult; Adolescent; Antibodies, Viral; Middle Aged; Respiratory Syncytial Virus Infections; Immunogenicity, Vaccine; Respiratory Syncytial Virus, Human; Antibodies, Neutralizing; Vaccines, Subunit; Healthy Volunteers; Vaccination; Viral Fusion Proteins
PubMed: 38616438
DOI: 10.1016/j.vaccine.2024.03.070 -
Euro Surveillance : Bulletin Europeen... Apr 2024Since the end of November 2023, the European Mortality Monitoring Network (EuroMOMO) has observed excess mortality in Europe. During weeks 48 2023-6 2024, preliminary...
Since the end of November 2023, the European Mortality Monitoring Network (EuroMOMO) has observed excess mortality in Europe. During weeks 48 2023-6 2024, preliminary results show a substantially increased rate of 95.3 (95% CI: 91.7-98.9) excess all-cause deaths per 100,000 person-years for all ages. This excess mortality is seen in adults aged 45 years and older, and coincides with widespread presence of COVID-19, influenza and respiratory syncytial virus (RSV) observed in many European countries during the 2023/24 winter season.
Topics: Adult; Humans; Influenza, Human; COVID-19; Respiratory Syncytial Virus, Human; Europe; Seasons; Respiratory Syncytial Virus Infections
PubMed: 38606570
DOI: 10.2807/1560-7917.ES.2024.29.15.2400178 -
BMC Infectious Diseases Apr 2024Respiratory syncytial virus (RSV) infection in children under 5 years have a significant clinical burden, also in primary care settings. This study investigates the...
BACKGROUND
Respiratory syncytial virus (RSV) infection in children under 5 years have a significant clinical burden, also in primary care settings. This study investigates the epidemiology and burden of RSV in Italian children during the 2019/20 pre-pandemic winter season.
METHODS
A prospective cohort study was conducted in two Italian regions. Children with Acute Respiratory Infection (ARI) visiting pediatricians were eligible. Nasopharyngeal swabs were collected and analyzed via multiplex PCR for RSV detection. A follow-up questionnaire after 14 days assessed disease burden, encompassing healthcare utilization and illness duration. Statistical analyses, including regression models, explored associations between variables such as RSV subtype and regional variations.
RESULTS
Of 293 children with ARI, 41% (119) tested positive for RSV. Median illness duration for RSV-positive cases was 7 days; 6% required hospitalization (median stay: 7 days). Medication was prescribed to 95% (110/116) of RSV cases, with 31% (34/116) receiving antibiotics. RSV subtype B and regional factors predicted increased healthcare utilization. Children with shortness of breath experienced a 36% longer illness duration.
CONCLUSIONS
This study highlights a significant clinical burden and healthcare utilization associated with RSV in pre-pandemic Italian primary care settings. Identified predictors, including RSV subtype and symptomatology, indicate the need for targeted interventions and resource allocation strategies. RSV epidemiology can guide public health strategies for the implementation of preventive measures.
Topics: Child; Humans; Infant; Child, Preschool; Respiratory Syncytial Virus, Human; Hospitalization; Seasons; Prospective Studies; Pandemics; COVID-19; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Italy; Primary Health Care
PubMed: 38605310
DOI: 10.1186/s12879-024-09229-9 -
Clinical Infectious Diseases : An... Jun 2024Respiratory syncytial virus (RSV) circulation dropped markedly early in the COVID-19 pandemic, followed by a resurgence with heightened case counts. The "immunity debt"...
BACKGROUND
Respiratory syncytial virus (RSV) circulation dropped markedly early in the COVID-19 pandemic, followed by a resurgence with heightened case counts. The "immunity debt" hypothesis proposes that the RSV-naїve pediatric population increased during the period of low transmission. However, the evidence supporting this hypothesis is limited, and the role of changing testing practices in the perceived surge has not been comprehensively evaluated.
METHODS
We conducted a multicenter, retrospective analysis of 342 530 RSV encounters and 980 546 RSV diagnostic tests occurring at 32 US pediatric hospitals in 2013-2023. We used interrupted time series analysis to estimate pandemic-associated changes in RSV patient and test volume and to quantify changes in the proportions of patients requiring hospitalization, intensive care, or mechanical ventilation. We quantified the fraction of the shifts in case counts and in the age of diagnosed patients attributable to changes in testing.
RESULTS
RSV patient volume increased 2.4-fold (95% confidence interval [CI]: 1.7, 3.5) in 2021-2023 relative to the pre-pandemic phase and was accompanied by an 18.9-fold increase (95% CI: 15.0, 23.9) in RSV test volume. Shifts in patient volume and in patient age were largely attributable to increased testing. The proportions of patients with RSV that required hospitalization, intensive care, or mechanical ventilation declined significantly across all patient age groups.
CONCLUSIONS
A surge in RSV testing, rather than in viral circulation, likely underlies the increased case counts observed in 2021-2023. These findings warrant a critical assessment of the immunity debt hypothesis and highlight the importance of considering the testing denominator when surveillance strategies are dynamic.
Topics: Humans; Respiratory Syncytial Virus Infections; COVID-19; Infant; Retrospective Studies; Child, Preschool; Female; SARS-CoV-2; Male; Child; Respiratory Syncytial Virus, Human; Hospitalization; United States; Infant, Newborn; Adolescent; Respiration, Artificial; Hospitals, Pediatric; Interrupted Time Series Analysis
PubMed: 38602423
DOI: 10.1093/cid/ciae140 -
Frontiers in Immunology 2024The human orthopneumovirus, Respiratory Syncytial Virus (RSV), is the causative agent of severe lower respiratory tract infections (LRTI) and exacerbations of chronic...
INTRODUCTION
The human orthopneumovirus, Respiratory Syncytial Virus (RSV), is the causative agent of severe lower respiratory tract infections (LRTI) and exacerbations of chronic lung diseases. In immune competent hosts, RSV productively infects highly differentiated epithelial cells, where it elicits robust anti-viral, cytokine and remodeling programs. By contrast, basal cells are relatively resistant to RSV infection, in part, because of constitutive expression of an intrinsic innate immune response (IIR) consisting of a subgroup of interferon (IFN) responsive genes. The mechanisms controlling the intrinsic IIR are not known.
METHODS
Here, we use human small airway epithelial cell hSAECs as a multipotent airway stem cell model to examine regulatory control of an intrinsic IIR pathway.
RESULTS
We find hSAECs express patterns of intrinsic IIRs, highly conserved with pluri- and multi-potent stem cells. We demonstrate a core intrinsic IIR network consisting of Bone Marrow Stromal Cell Antigen 2 (), Interferon Induced Transmembrane Protein 1 () and Toll-like receptor () expression are directly under IRF1 control. Moreover, expression of this intrinsic core is rate-limited by ambient IRF1• phospho-Ser 2 CTD RNA Polymerase II (pSer2 Pol II) complexes binding to their proximal promoters. In response to RSV infection, the abundance of IRF1 and pSer2 Pol II binding is dramatically increased, with IRF1 complexing to the BRD4 chromatin remodeling complex (CRC). Using chromatin immunoprecipitation in IRF1 KD cells, we find that the binding of BRD4 is IRF1 independent. Using a small molecule inhibitor of the BRD4 acetyl lysine binding bromodomain (BRD4i), we further find that BRD4 bromodomain interactions are required for stable BRD4 promoter binding to the intrinsic IIR core promoters, as well as for RSV-inducible pSer2 Pol II recruitment. Surprisingly, BRD4i does not disrupt IRF1-BRD4 interactions, but disrupts both RSV-induced BRD4 and IRF1 interactions with pSer2 Pol II.
CONCLUSIONS
We conclude that the IRF1 functions in two modes- in absence of infection, ambient IRF1 mediates constitutive expression of the intrinsic IIR, whereas in response to RSV infection, the BRD4 CRC independently activates pSer2 Pol II to mediates robust expression of the intrinsic IIR. These data provide insight into molecular control of anti-viral defenses of airway basal cells.
Topics: Humans; Antiviral Agents; Bromodomain Containing Proteins; Cell Cycle Proteins; Immunity, Innate; Nuclear Proteins; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; RNA Polymerase II; Transcription Factors
PubMed: 38601157
DOI: 10.3389/fimmu.2024.1366235 -
Nature Communications Apr 2024Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in young children and the second leading cause of infant death worldwide....
Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in young children and the second leading cause of infant death worldwide. While global circulation has been extensively studied for respiratory viruses such as seasonal influenza, and more recently also in great detail for SARS-CoV-2, a lack of global multi-annual sampling of complete RSV genomes limits our understanding of RSV molecular epidemiology. Here, we capitalise on the genomic surveillance by the INFORM-RSV study and apply phylodynamic approaches to uncover how selection and neutral epidemiological processes shape RSV diversity. Using complete viral genome sequences, we show similar patterns of site-specific diversifying selection among RSVA and RSVB and recover the imprint of non-neutral epidemic processes on their genealogies. Using a phylogeographic approach, we provide evidence for air travel governing the global patterns of RSVA and RSVB spread, which results in a considerable degree of phylogenetic mixing across countries. Our findings highlight the potential of systematic global RSV genomic surveillance for transforming our understanding of global RSV spread.
Topics: Infant; Child; Humans; Child, Preschool; Respiratory Syncytial Virus Infections; Phylogeny; Respiratory Syncytial Virus, Human; Genomics; Respiratory Tract Infections
PubMed: 38600104
DOI: 10.1038/s41467-024-47118-6 -
PloS One 2024Respiratory syncytial virus (RSV) is the leading viral cause of bronchiolitis and pneumonia in infants and toddlers, but there currently is no licensed pediatric...
Mutations in the F protein of the live-attenuated respiratory syncytial virus vaccine candidate ΔNS2/Δ1313/I1314L increase the stability of infectivity and content of prefusion F protein.
Respiratory syncytial virus (RSV) is the leading viral cause of bronchiolitis and pneumonia in infants and toddlers, but there currently is no licensed pediatric vaccine. A leading vaccine candidate that has been evaluated for intranasal immunization in a recently completed phase 1/2 clinical trial is an attenuated version of RSV strain A2 called RSV/ΔNS2/Δ1313/I1314L (hereafter called ΔNS2). ΔNS2 is attenuated by deletion of the interferon antagonist NS2 gene and introduction into the L polymerase protein gene of a codon deletion (Δ1313) that confers temperature-sensitivity and is stabilized by a missense mutation (I1314L). Previously, introduction of four amino acid changes derived from a second RSV strain "line 19" (I79M, K191R, T357K, N371Y) into the F protein of strain A2 increased the stability of infectivity and the proportion of F protein in the highly immunogenic pre-fusion (pre-F) conformation. In the present study, these four "line 19" assignments were introduced into the ΔNS2 candidate, creating ΔNS2-L19F-4M. During in vitro growth in Vero cells, ΔNS2-L19F-4M had growth kinetics and peak titer similar to the ΔNS2 parent. ΔNS2-L19F-4M exhibited an enhanced proportion of pre-F protein, with a ratio of pre-F/total F that was 4.5- to 5.0-fold higher than that of the ΔNS2 parent. The stability of infectivity during incubation at 4°C, 25°C, 32°C and 37°C was greater for ΔNS2-L19F-4M; for example, after 28 days at 32°C, its titer was 100-fold greater than ΔNS2. ΔNS2-L19F-4M exhibited similar levels of replication in human airway epithelial (HAE) cells as ΔNS2. The four "line 19" F mutations were genetically stable during 10 rounds of serial passage in Vero cells. In African green monkeys, ΔNS2-L19F-4M and ΔNS2 had similar growth kinetics, peak titer, and immunogenicity. These results suggest that ΔNS2-L19F-4M is an improved live attenuated vaccine candidate whose enhanced stability may simplify its manufacture, storage and distribution, which merits further evaluation in a clinical trial in humans.
Topics: Animals; Humans; Chlorocebus aethiops; Child; Respiratory Syncytial Virus Vaccines; Vero Cells; Antibodies, Viral; Viral Fusion Proteins; Respiratory Syncytial Virus, Human; Antibodies, Neutralizing; Mutation, Missense; Respiratory Syncytial Virus Infections
PubMed: 38593167
DOI: 10.1371/journal.pone.0301773