scholarly journals 1409. Genomic Variation Among Respiratory Syncytial Viruses

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S712-S712
Author(s):  
Christopher S Anderson ◽  
Yun Zhang ◽  
Anthony Corbett ◽  
Chin-Yi Chu ◽  
Lu Wang ◽  
...  
Keyword(s):  
Protein Structure ◽  
Disease Severity ◽  
Genomic Variation ◽  
Structure Variation ◽  
Time Period ◽  
Nasal Swabs ◽  
Rsv Infection ◽  
Respiratory Syncytial Viruses ◽  
Syncytial Virus ◽  
Over Time

Abstract Background Respiratory Syncytial Virus (RSV) can be easily classified into two subtypes (A and B) based on the nucleic acid sequence of their genome. Phylogenic approaches have shown that within both subtypes separate lineages of viruses exist and new lineages continue to emerge. The role these genomic variations play in disease severity during RSV infection is largely unknown. Methods Next-generation viral RNA sequencing was performed on archived frozen nasal swabs of children infected with RSV in Rochester, NY between 1977-1998. Genomic variation was compared across year-of-isolation, age of host, and inpatient/outpatient status of host. Local RSV genomic variation was compared to variation of publicly available sequences isolated from hosts residing in other parts of the world. Results A and B subtypes demonstrated significant differences in the genetic sequence and primary-protein structure over time. G-protein was the most variable in both subtypes, but they differed in the number of unique genotypes detected. We found a significant association with disease severity (inpatient/outpatient status) and RSV phylogenetic topology, although the magnitude of the association differed by subtype. Variation in the primary protein structure of RSV viral proteins was also significantly associated with disease severity, but depended on which viral protein, and which subtype, was investigated. Lastly, local RSV genomic and protein-structure variation was similar to what was seen globally during this time period. Conclusion Overall, both subtypes demonstrated significant genetic change over time and these changes were associated with disease severity. These results suggest that the genetic variability of RSV may affect RSV disease in humans. Disclosures All Authors: No reported disclosures

scholarly journals 902. A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of a Single Immunization of Ad26.RSV.preF against RSV Infection in a Viral Challenge Model in Healthy Adults

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S27-S28 ◽  
Author(s):  
John DeVincenzo ◽  
Efi Gymnopoulou ◽  
Els De Paepe ◽  
Bryan Murray ◽  
Arangassery Rosemary Bastian ◽  
...  
Keyword(s):  
Disease Severity ◽  
Healthy Adults ◽  
Controlled Study ◽  
Clinical Strain ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Qrt Pcr ◽  
Rsv Infection ◽  
First Time ◽  
Over Time

Abstract Background Despite the high disease burden of RSV in older adults and children, there is currently no approved vaccine. Ad26.RSV.preF, an experimental RSV vaccine, has demonstrated immunogenicity and tolerability in first-in-human clinical studies. The aim of this study was to assess the potential of the Ad26.RSV.preF vaccine to protect against RSV infection and disease in an established RSV human challenge model, used for the first time to evaluate a vaccine. Methods We conducted a randomized, double-blind, placebo-controlled, human challenge study (NCT03334695). Healthy adults received 1 × 1011 vp Ad26.RSV.preF vaccine (active) or placebo (pbo) intramuscularly. After 28 days, volunteers were challenged intranasally with a low-passage clinical strain of RSV-A (0.8 mL of Memphis 37b) and then quarantined for 12 days. Nasal washes were collected twice daily throughout quarantine, starting 2 days post-challenge (viral load [VL] by qRT-PCR and quantitative cultures). Disease severity was recorded thrice daily using symptom diary cards. Results Fifty-three volunteers (active, n = 27; pbo, n = 26) were challenged with RSV-A. Quantitative viral assessments were consistently lower in active than pbo. The primary endpoint of the study was met: the area under the curve (AUC) for RSV VL over time (via qRT-PCR) was significantly lower in active pbo (P = 0.012). Median peak VL was lower for active (0 log10 copies/mL) than pbo (5.4 log10 copies/mL). Median AUC for RSV VL over time (quantitative culture) was lower for active than pbo (0 vs. 109, P = 0.002). Disease severity was lower for active than pbo, with a median AUC total symptom score of 35 (active) vs. 167 (pbo) (P = 0.002). Overall, RSV infection (defined by qRT-PCR alone or combined with symptoms) and disease severity over time were lower in active vs. pbo. Conclusion RSV infections, VL, and RSV disease severity were consistently lower in healthy adults receiving Ad26.RSV.preF vs. placebo, demonstrating promising protection from RSV infection and disease. This was the first time that antiviral prevention was observed against RSV after active immunization. Ad26.RSV.preF warrants further evaluation in field trials for efficacy against natural RSV infections in populations considered at risk of severe RSV disease. Disclosures All Authors: No reported Disclosures.

scholarly journals Temporal Dysbiosis of Infant Nasal Microbiota Relative to Respiratory Syncytial Virus Infection

2020 ◽  
Author(s):  
Alex Grier ◽  
Ann L Gill ◽  
Haeja A Kessler ◽  
Anthony Corbett ◽  
Sanjukta Bandyopadhyay ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Disease ◽  
Disease Severity ◽  
Temporal Dynamics ◽  
Disease Risk ◽  
Developmental Trajectory ◽  
Microbiota Composition ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Nasal Microbiota

Abstract Rationale Respiratory Syncytial Virus (RSV) is a leading cause of infant respiratory disease. Infant airway microbiota has been associated with respiratory disease risk and severity. The extent to which interactions between RSV and microbiota occur in the airway, and their impact on respiratory disease susceptibility and severity, are unknown. Objectives Characterize temporal associations between microbiota and RSV infection before, during, and after infants’ first respiratory illness. Methods 16S rRNA microbiota profiling of two infant cohorts in the first year of life: 1) a cross-sectional cohort of 89 RSV infected infants sampled during illness and 102 matched healthy controls, and 2) a matched longitudinal cohort of 12 infants who developed RSV infection and 12 who did not, sampled before, during, and after infection. Results We identified 12 taxa significantly associated with RSV infection. All 12 taxa were differentially abundant during infection, with 8 associated with disease severity. Nasal microbiota composition was more discriminative of healthy vs. infected than of disease severity. Conclusions Our findings elucidate the chronology of nasal microbiota dysbiosis and suggest an altered developmental trajectory associated with RSV infection. Microbial temporal dynamics reveal indicators of disease risk, correlates of illness and severity, and impact of RSV infection on microbiota composition.

scholarly journals Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection

PLoS ONE ◽  
2015 ◽  
Vol 10 (7) ◽  
pp. e0131927 ◽  
Author(s):  
H. K. Brand ◽  
I. M. L. Ahout ◽  
D. de Ridder ◽  
A. van Diepen ◽  
Y. Li ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Disease Severity ◽  
Rsv Infection ◽  
Syncytial Virus

scholarly journals The specific features of the developing T cell compartment of the neonatal lung are a determinant of respiratory syncytial virus immunopathogenesis

2021 ◽  
Vol 17 (4) ◽  
pp. e1009529
Author(s):  
Thomas Démoulins ◽  
Melanie Brügger ◽  
Beatrice Zumkehr ◽  
Blandina I. Oliveira Esteves ◽  
Kemal Mehinagic ◽  
...  
Keyword(s):  
T Cells ◽  
Respiratory Syncytial Virus ◽  
T Cell ◽  
Disease Severity ◽  
Early Life ◽  
Cell Compartment ◽  
Neonatal Lung ◽  
Rsv Infection ◽  
Syncytial Virus

The human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, possibly due to the properties of the immature neonatal pulmonary immune system. Using the newborn lamb, a classical model of human lung development and a translational model of RSV infection, we aimed to explore the role of cell-mediated immunity in RSV disease during early life. Remarkably, in healthy conditions, the developing T cell compartment of the neonatal lung showed major differences to that seen in the mature adult lung. The most striking observation being a high baseline frequency of bronchoalveolar IL-4-producing CD4 and CD8 T cells, which declined progressively over developmental age. RSV infection exacerbated this pro-type 2 environment in the bronchoalveolar space, rather than inducing a type 2 response per se. Moreover, regulatory T cell suppressive functions occurred very early to dampen this pro-type 2 environment, rather than shutting them down afterwards, while γδ T cells dropped and failed to produce IL-17. Importantly, RSV disease severity was related to the magnitude of those unconventional bronchoalveolar T cell responses. These findings provide novel insights in the mechanisms of RSV immunopathogenesis in early life, and constitute a major step for the understanding of RSV disease severity.

scholarly journals 1193. Mucosal Antibody Responses to Respiratory Syncytial Virus (RSV) in Infants and Young Children

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S688-S688
Author(s):  
Cristina Tomatis Souverbielle ◽  
Fang Ye ◽  
Sara Mertz ◽  
Mark E Peeples ◽  
Octavio Ramilo ◽  
...  
Keyword(s):  
Disease Severity ◽  
Panel Member ◽  
Healthy Children ◽  
Upper Respiratory Tract ◽  
Limited Information ◽  
Research Support ◽  
Review Panel ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Research Grant

Abstract Background The burden associated with RSV infection is substantial. Although RSV initially infects the upper respiratory tract, there is limited information of the mucosal concentrations of antibodies (Abs) directed to RSV specific proteins and whether patient’s age and disease severity influence production of mucosal Abs. Methods From 2017 to2019 we enrolled previously healthy children < 2 years of age hospitalized with RSV infection and obtained acute and convalescent (day; D30) nasopharyngeal (NP) samples to measure preF and postF specific IgG and IgA Abs by ELISA. Demographic and clinical data were collected and analyzed according to Abs responses. Results We enrolled 77 children (median [IQR] age: 2.8 [1.5-5.2] months; 49 % females) within the first 24 hours of hospitalization. Of those 25 (33%) patients required PICU care. A significant increase in convalescent IgG preF Abs titers was detected in 62 (81%) children, while IgA preF titers significantly increased in all but one child on D30. The magnitude of the increase was 56-fold higher for preF IgA versus preF IgG (p< 0.0001). PostF IgG and IgA titers were also increased on D30 but at significant lower levels. Infants < 3 months of age compared with those >3-24 months had significantly higher baseline preF and postF IgG Abs titers (p < 0.001) but not IgA antibodies. D30 preF and post F IgG titers were higher in children > 6 months of age (p < 0.0001) but only preF titers fold change significantly correlated with age (r=0.4, p< 0.0001). These correlations were not identified with IgA preF antibodies. There were no statistical differences in antibody titers at baseline and on D30 according to breastfeeding, and disease severity as defined by the need for PICU care. Conclusion Children hospitalized with RSV infection demonstrated significantly increased titers of mucosal preF and post F IgG and IgA specific Abs in convalescent samples. Baseline IgG Abs where higher in younger infants, which likely reflects maternally acquired antibodies. Age significantly correlated with Abs production, suggesting a more robust immune response in older children. Disclosures Mark E. Peeples, PhD, Janssen (Research Grant or Support)Pfizer (Research Grant or Support) Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member)

scholarly journals Airway gene expression correlates of RSV disease severity and microbiome composition in infants

2020 ◽  
Author(s):  
Chin-Yi Chu ◽  
Xing Qiu ◽  
Matthew N McCall ◽  
Lu Wang ◽  
Anthony Corbett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Disease Severity ◽  
Clinical Symptoms ◽  
Expression Patterns ◽  
Gene Expression Signature ◽  
Illness Severity ◽  
Severe Illness ◽  
Gene Expression Patterns ◽  
Rsv Infection ◽  
Syncytial Virus

Abstract Rationale Respiratory syncytial virus (RSV) is the leading cause of severe respiratory disease in infants. The causes and correlates of severe illness in the majority of infants are poorly defined. Objectives We identified molecular correlates of illness severity from the airways of infants infected with RSV. Methods We recruited a cohort of RSV-infected infants and simultaneously assayed the molecular status of their airways and the presence of airway microbiota. Rigorous statistical approaches identified gene expression patterns associated with disease severity and microbiota composition, separately and in combination. Measurements and Main Results We measured comprehensive airway gene expression patterns in 106 infants with primary RSV infection. We identified an airway gene expression signature of severe illness dominated by excessive chemokine expression. We also found an association between H. influenzae, disease severity and airway lymphocyte accumulation. Exploring the time of onset of clinical symptoms revealed acute activation of interferon (IFN) signaling following RSV infection in infants with mild or moderate illness, which was absent in subjects with severe illness. Conclusion Our data reveal that airway gene expression patterns distinguish mild/moderate from severe illness severity. Furthermore, our data identify biomarkers that may be therapeutic targets or useful for measuring efficacy of intervention responses.

Association of Viral Load With Disease Severity in Outpatient Children With Respiratory Syncytial Virus Infection

2020 ◽  
Vol 222 (2) ◽  
pp. 298-304 ◽  
Author(s):  
Erika Uusitupa ◽  
Matti Waris ◽  
Terho Heikkinen
Keyword(s):  
Viral Load ◽  
Respiratory Syncytial Virus ◽  
Disease Severity ◽  
Respiratory Infections ◽  
Respiratory Illness ◽  
Lower Viral Load ◽  
Primary Analysis ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Outpatient Children

Abstract Background There are scarce data on whether viral load affects the severity of respiratory syncytial virus (RSV) disease in outpatient children. Methods We analyzed the association between viral load and disease severity among children who participated in a prospective cohort study of respiratory infections. The children were examined and nasal swabs for the detection of RSV were obtained during each respiratory illness. Quantification of RSV load was based on the cycle threshold (Ct) value. For the primary analysis, the children were divided into 2 groups: higher (Ct < 27) and lower viral load (Ct ≥ 27). Results Among 201 episodes of RSV infection, children with higher viral load had significantly longer median durations of rhinitis (8 vs 6 days; P = .0008), cough (8 vs 6 days; P = .034), fever (2 vs 1 days; P = .018), and any symptom (10 vs 8 days; P = .024) than those with lower viral load. There were statistically significant negative correlations between the Ct values and durations of all measured symptoms. Conclusions Our findings support the concept that viral load drives the severity of RSV disease in children. Reducing the viral load by RSV antivirals might provide substantial benefits to outpatient children.

scholarly journals 118. Nasopharyngeal (NP) Bacterial Detection in Infants With Respiratory Syncytial Virus (RSV) Infection: Impact on Clinical Outcomes

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S4-S5 ◽  
Author(s):  
Alejandro Diaz ◽  
Eleonora Bunsow ◽  
Cristina Garcia-Maurino ◽  
Jeffrey Naples ◽  
Alexis Juergensen ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Disease Severity ◽  
Pathogenic Bacteria ◽  
Bacterial Colonization ◽  
Antibiotic Use ◽  
Clinical Disease ◽  
Outcomes Of Care ◽  
Severity Scores ◽  
Rsv Infection ◽  
Syncytial Virus

Abstract Background Previous studies suggest that RSV increases NP bacterial colonization and may facilitate infection. However, the role of NP colonization with potentially pathogenic bacteria (PPB) in the pathogenesis of RSV bronchiolitis is not well understood. We sought to determine the frequency, type, and density of NP PPB detection in infants with RSV infection compared with healthy controls (HC), and its association with clinical outcomes. Methods Single-center, prospective study of previously healthy infants with RSV infection and age-matched HC. Inpatients (IP) were enrolled within 24 hours of hospitalization, outpatients (OP) at the ED or primary clinics and HC at well-child visits. RSV infection and the following PPB: [S. pneumoniae, M. catarrhalis, H. influenzae, and S. aureus] were detected and quantified by PCR. We compared demographic, clinical characteristics, and outcomes of care according to NP PPB detection. Results From 2010 to 2018, we enrolled 815 infants: 664 with RSV infection [IP, 560; OP, 104] and 151 HC. RSV+ OP (6.1 [3.7–10.7] months) and HC (6.9 [3.8–10.8] months) were older than IP (2.5 [1.4–5.4] months; P < 0.001). Identification of ≥1 PPB was 89% in RSV+ infants [IP, 88%; OP, 90%] versus 63% of HC (P < 0.0001). While H. influenzae or >1 PPB detection was higher in RSV infection (P < 0.001), S. aureus detection predominated in HC (P < 0.05; Figure 1). Frequency of S. pneumoniae detection was comparable between groups; however, S. pneumoniae loads were one log higher in RSV+ infants versus HC (P = 0.001) adjusted for antibiotic use. Differences in colonization rates remained different in RSV+ infants versus HC across age ranges (<3, 3–6, >6–12, and >12–24 months; Figure 2). Last, RSV patients (both IP and OP) with S. pneumoniae or H. influenzae detection had fever more frequently (70%–74% vs. 25%–47%; P < 0.0001), higher clinical disease severity scores (P = 0.01), and higher blood neutrophil counts (34%–36% vs. 16%–19%; P < 0.001), versus those with M. catarrhalis, S. aureus detection or PCR negative. In addition, NP detection of H. influenzae in RSV children was associated with higher frequency of atelectasis/consolidation by chest X-ray (P < 0.005). Conclusion These data suggest that NP colonization with PPB is high in infants with RSV infection independent of age, and that specific bacteria, namely S. pneumoniae and H. influenzae, are associated with enhanced clinical disease severity. Disclosures A. Leber, Nationwide Children’s Hospital: Research Contractor, Research support. O. Ramilo, Janssen Scientific Affairs, LLC: Consultant, Consulting fee. A. Mejias, Janssen: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Abbvie: CME talks, Speaker honorarium.

Immune profiles provide insights into respiratory syncytial virus disease severity in young children

2020 ◽  
Vol 12 (540) ◽  
pp. eaaw0268 ◽  
Author(s):  
Santtu Heinonen ◽  
Victoria M. Velazquez ◽  
Fang Ye ◽  
Sara Mertz ◽  
Santiago Acero-Bedoya ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Disease Severity ◽  
Virus Disease ◽  
Severe Disease ◽  
Mild Disease ◽  
Hla Dr ◽  
Increased Risk ◽  
Determining Factors ◽  
Rsv Infection ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is associated with major morbidity in infants, although most cases result in mild disease. The pathogenesis of the disease is incompletely understood, especially the determining factors of disease severity. A better characterization of these factors may help with development of RSV vaccines and antivirals. Hence, identification of a “safe and protective” immunoprofile induced by natural RSV infection could be used as a as a surrogate of ideal vaccine-elicited responses in future clinical trials. In this study, we integrated blood transcriptional and cell immune profiling, RSV loads, and clinical data to identify factors associated with a mild disease phenotype in a cohort of 190 children <2 years of age. Children with mild disease (outpatients) showed higher RSV loads, greater induction of interferon (IFN) and plasma cell genes, and decreased expression of inflammation and neutrophil genes versus children with severe disease (inpatients). Additionally, only infants with severe disease had increased numbers of HLA-DRlow monocytes, not present in outpatients. Multivariable analyses confirmed that IFN overexpression was associated with decreased odds of hospitalization, whereas increased numbers of HLA-DRlow monocytes were associated with increased risk of hospitalization. These findings suggest that robust innate immune responses are associated with mild RSV infection in infants.

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