scholarly journals Anti-Respiratory Syncytial Virus (RSV) Neutralizing Antibody Decreases Lung Inflammation, Airway Obstruction, and Airway Hyperresponsiveness in a Murine RSV Model

2004 ◽  
Vol 48 (5) ◽  
pp. 1811-1822 ◽  
Author(s):  
Asunción Mejías ◽  
Susana Chávez-Bueno ◽  
Ana María Ríos ◽  
Jesús Saavedra-Lozano ◽  
Mónica Fonseca Aten ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Airway Obstruction ◽  
Airway Hyperresponsiveness ◽  
Strong Association ◽  
Neutralizing Antibody ◽  
Clinical Markers ◽  
Recurrent Wheezing ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT Numerous studies have described a strong association between respiratory syncytial virus (RSV) infection in infancy and the development of recurrent wheezing and airway hyperresponsiveness. We evaluated the effect of an anti-RSV neutralizing monoclonal antibody (palivizumab) on different aspects of RSV disease by using a murine model. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or an isotype-matched control antibody was administered once at 24 h before inoculation, 1 h after inoculation, or 48 h after inoculation. Regardless of the timing of administration, all mice treated with the neutralizing antibody showed significantly decreased RSV loads in bronchoalveolar lavage (BAL) and lung specimens compared with those of infected controls. Pulmonary histopathologic scores, airway obstruction measured by plethysmography, and airway hyperresponsiveness after methacholine challenge were significantly reduced in mice treated with the anti-RSV antibody 24 h before inoculation compared with those for untreated controls. Concentrations of interferon-gamma, interleukin-10, macrophage inflammatory protein 1α, regulated on activation normal T-cell expressed and secreted (RANTES), and eotaxin in BAL fluids were also significantly reduced in mice treated with palivizumab 24 h before inoculation. This study demonstrates that reduced RSV replication was associated with significant modulation of inflammatory and clinical markers of acute disease severity and significant improvement of the long-term pulmonary abnormalities. Studies to determine whether strategies aimed at preventing or reducing RSV replication could decrease the long-term morbidity associated with RSV infection in children should be considered.

scholarly journals A Durable Relationship: Respiratory Syncytial Virus Bronchiolitis and Asthma past Their Golden Anniversary

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 201 ◽  
Author(s):  
Ignacio Esteban ◽  
Renato T. Stein ◽  
Fernando P. Polack
Keyword(s):  
Respiratory Syncytial Virus ◽  
Acute Illness ◽  
Preventive Strategies ◽  
Biological Mechanisms ◽  
Recurrent Wheezing ◽  
Impaired Lung Function ◽  
Viral Illness ◽  
Rsv Infection ◽  
Syncytial Virus

Numerous preventive strategies against respiratory syncytial virus (RSV) are undergoing late stage evaluation in humans and, in addition to their intended benefit for acute illness, may impact long term consequences of infection in infants. Severe RSV infection has been repeatedly associated in the literature with long term complications, including impaired lung function, recurrent wheezing, and asthma. However, whether RSV lower respiratory tract infection (LRTI) causally affects the odds for developing wheezing and/or asthma during childhood requires further study, and the biological mechanisms underlying this hypothetical progression from viral illness to chronic lung disease are poorly characterized. In this review, we summarize the literature exploring the association between RSV LRTI in infancy and subsequent recurrent wheezing and pediatric asthma.

scholarly journals Comparative Effects of Two Neutralizing Anti-Respiratory Syncytial Virus (RSV) Monoclonal Antibodies in the RSV Murine Model: Time versus Potency

2005 ◽  
Vol 49 (11) ◽  
pp. 4700-4707 ◽  
Author(s):  
Asunción Mejías ◽  
Susana Chávez-Bueno ◽  
Ana María Ríos ◽  
Mónica Fonseca Aten ◽  
Brett Raynor ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Mouse Model ◽  
Airway Obstruction ◽  
Disease Severity ◽  
Murine Model ◽  
Airway Hyperresponsiveness ◽  
Plaque Assay ◽  
Clinical Markers ◽  
Viral Pathogen ◽  
Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is the leading viral pathogen responsible for bronchiolitis and pneumonia in infants and young children worldwide. We have previously shown in the mouse model that treatment with an anti-RSV neutralizing monoclonal antibody (MAb) against the F glycoprotein of RSV, palivizumab, decreased lung inflammation, airway obstruction, and postmethacholine airway hyperresponsiveness. MEDI-524, or Numax, is a new MAb derived from palivizumab with enhanced neutralizing activity against RSV. We compared the effects of these two MAbs on different markers of disease severity using the murine model of RSV infection. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or MEDI-524 was administered once at either 24 h before or 48 h after RSV inoculation. Regardless of the time of administration, all treated mice showed significantly decreased RSV loads in bronchoalveolar lavage samples measured by plaque assay. Only MEDI-524 given at −24 h significantly decreased lung RSV RNA loads on days 5 and 28 after RSV inoculation. Pulmonary histopathologic scores, airway obstruction, and postmethacholine airway hyperresponsiveness were significantly reduced in mice treated with MEDI-524 at 24 h before inoculation, compared with untreated controls and the other regimens evaluated. MEDI-524 was superior to palivizumab on several outcome variables of RSV disease assessed in the mouse model: viral replication, inflammatory and clinical markers of acute disease severity, and long-term pulmonary abnormalities.

scholarly journals Infantile respiratory syncytial virus and human rhinovirus infections: respective role in inception and persistence of wheezing

2014 ◽  
Vol 45 (3) ◽  
pp. 774-789 ◽  
Author(s):  
Giovanni A. Rossi ◽  
Andrew A. Colin
Keyword(s):  
Respiratory Syncytial Virus ◽  
Airway Disease ◽  
Epidemiological Studies ◽  
Human Rhinovirus ◽  
Allergic Sensitisation ◽  
Cytokines And Chemokines ◽  
Rsv Infection ◽  
History Of ◽  
Syncytial Virus

There is evidence that respiratory viruses play a key role in the development and exacerbation of obstructive respiratory diseases in children. This review attempts to juxtapose the separate profiles and prototypes of pathogenenetic mechanisms represented by the two most common amongst such viruses: respiratory syncytial virus (RSV) and human rhinovirus (HRV).RSV represents the most common agent of severe airway disease in infants and young children, and is predominant in winter months. Large epidemiological studies have revealed an unequivocal relationship between RSV infection and subsequent wheezing into childhood, thought to be related to long-term changes in neuroimmune control of the airways rather than allergic sensitisation.HRV is a highly diverse group of viruses that affect subjects of all ages, is ubiquitous and occurs year-round. In contrast to RSV, infections with HRV cause minimal cytotoxicity but induce a rapid production of cytokines and chemokines with amplification of the inflammatory response. The susceptibility to HRV-induced bronchiolitis and subsequent wheezing appears to be linked to individual predisposition since it is often associated with a family or personal history of asthma/atopy.Thus, RSV probably serves as an “inducer” rather than a “trigger”. Conversely, HRVs seem to serve as a “trigger” rather than an “inducer” in predisposed individuals.

scholarly journals Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection

2015 ◽  
Vol 90 (5) ◽  
pp. 2536-2543 ◽  
Author(s):  
Na Zang ◽  
Jianguo Zhuang ◽  
Yu Deng ◽  
Zhimei Yang ◽  
Zhixu Ye ◽  
...  
Keyword(s):  
Virus Infection ◽  
Airway Inflammation ◽  
Airway Hyperresponsiveness ◽  
Airway Resistance ◽  
Inflammatory Cells ◽  
C Fibers ◽  
Airway Diseases ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACTChildren with acute respiratory syncytial virus (RSV) infection often develop sequelae of persistent airway inflammation and wheezing. Pulmonary C fibers (PCFs) are involved in the generation of airway inflammation and resistance; however, their role in persistent airway diseases after RSV is unexplored. Here, we elucidated the pathogenesis of PCF activation in RSV-induced persistent airway disorders. PCF-degenerated and intact mice were used in the current study. Airway inflammation and airway resistance were evaluated. MMP408 and FSLLRY-NH2 were the selective antagonists for MMP-12 and PAR2, respectively, to investigate the roles of MMP-12 and PAR2 in PCFs mediating airway diseases. As a result, PCF degeneration significantly reduced the following responses to RSV infection: augmenting of inflammatory cells, especially macrophages, and infiltrating of inflammatory cells in lung tissues; specific airway resistance (sRaw) response to methacholine; and upregulation of MMP-12 and PAR2 expression. Moreover, the inhibition of MMP-12 reduced the total number of cells and macrophages in bronchiolar lavage fluid (BALF), as well infiltrating inflammatory cells, and decreased the sRaw response to methacholine. In addition, PAR2 was upregulated especially at the later stage of RSV infection. Downregulation of PAR2 ameliorated airway inflammation and resistance following RSV infection and suppressed the level of MMP-12. In all, the results suggest that PCF involvement in long-term airway inflammation and airway hyperresponsiveness occurred at least partially via modulating MMP-12, and the activation of PAR2 might be related to PCF-modulated MMP-12 production. Our initial findings indicated that the inhibition of PCF activity would be targeted therapeutically for virus infection-induced long-term airway disorders.IMPORTANCEThe current study is critical to understanding that PCFs are involved in long-term airway inflammation and airway resistance after RSV infection through mediating MMP-12 production via PAR2, indicating that the inhibition of PCF activity can be targeted therapeutically for virus infection-induced long-term airway disorders.

scholarly journals Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness

2015 ◽  
Vol 309 (3) ◽  
pp. L205-L210 ◽  
Author(s):  
Weifeng Song ◽  
Zhihong Yu ◽  
Stephen F. Doran ◽  
Namasivayam Ambalavanan ◽  
Chad Steele ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Lung Injury ◽  
Airway Hyperresponsiveness ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Infection Model ◽  
Type 2 Cytokines ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
First Time

Exposure to chlorine (Cl2) damages airway and alveolar epithelia resulting in acute lung injury and reactive airway hyperresponsiveness (AHR) to methacholine. However, little is known about the effect of preexisting respiratory disease on Cl2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1β, IL-10, IFN-γ, and RANTES concentrations in the bronchoalveolar lavage fluid (BALF). In contrast, levels of type 2 cytokines (i.e., IL-4, IL-5, IL-9, and IL-13) were not significantly affected by either RSV infection or Cl2 exposure. Cl2 exposure, but not RSV infection, induced AHR to methacholine challenge as measured by flexiVent. Moreover, preexisting RSV infection amplified BALF levels of hyaluronan (HA) and AHR. The Cl2-induced AHR was mitigated by treatment with inter-α-trypsin inhibitor antibody, which inhibits HA signaling, suggesting a mechanism of HA-mediated AHR from exacerbated oxidative injury. Our results show for the first time that preexisting RSV infection predisposes the lung to Cl2-induced injury. These data emphasize the necessity for further research on the effects of Cl2 in vulnerable populations and the development of appropriate treatments.

scholarly journals Prevention of Respiratory Syncytial Virus Infection in Healthy Adults by a Single Immunization of Ad26.RSV.preF in a Human Challenge Study

2021 ◽  
Author(s):  
Jerald Sadoff ◽  
Els De Paepe ◽  
John DeVincenzo ◽  
Efi Gymnopoulou ◽  
Joris Menten ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Geometric Mean ◽  
Area Under The Curve ◽  
Neutralizing Antibody ◽  
Healthy Adults ◽  
Controlled Study ◽  
Double Blind ◽  
Post Immunization ◽  
Rsv Infection ◽  
Syncytial Virus

Abstract Background Respiratory syncytial virus (RSV) is a significant cause of severe lower respiratory tract disease in children and older adults, but has no approved vaccine. This study assessed the potential of Ad26.RSV.preF to protect against RSV infection and disease in an RSV human challenge model. Methods In this double-blind, placebo-controlled study, healthy adults aged 18–50 years were randomized 1:1 to receive 1x1011 vp Ad26.RSV.preF or placebo intramuscularly. Twenty-eight days post-immunization, volunteers were challenged intranasally with RSV-A (Memphis 37b). Assesments included viral load (VL), RSV infections, clinical symptom score (CSS), safety and immunogenicity. Results Post-challenge, VL, RSV infections and disease severity were lower in Ad26.RSV.preF (n=27) versus placebo (n=26) recipients: median VL-AUC (area under the curve) qRT-PCR: 0.0 versus 236.0 (P=.012; predefined primary endpoint); median VL-AUC quantitative culture: 0.0 versus 109; RSV infections 11 (40.7%) versus 17 (65.4%); median RSV AUC-CSS 35 versus 167, respectively. From baseline to 28 days post-immunization, geometric mean fold-increases in RSV A2 neutralizing antibody titers of 5.8 and 0.9 were observed in Ad26.RSV.preF and placebo, respectively. Ad26.RSV.preF was well tolerated. Conclusions Ad26.RSV.preF demonstrated protection from RSV infection through immunization in a human challenge model, and therefore could potentially protect against natural RSV infection and disease. Clinical Trials Registration NCT03334695

scholarly journals Severe Morbidity and Short- and Mid- to Long-term Mortality in Older Adults Hospitalized with Respiratory Syncytial Virus Infection

2020 ◽  
Vol 222 (8) ◽  
pp. 1298-1310 ◽  
Author(s):  
Hung Fu Tseng ◽  
Lina S Sy ◽  
Bradley Ackerson ◽  
Zendi Solano ◽  
Jeff Slezak ◽  
...  
Keyword(s):  
Older Adults ◽  
Respiratory Syncytial Virus ◽  
Clinical Epidemiology ◽  
Ventilatory Support ◽  
The United States ◽  
Rsv Infection ◽  
Hospitalized Older Adults ◽  
Syncytial Virus ◽  
Long Term Mortality

Abstract Background We describe the clinical epidemiology and outcomes among a large cohort of older adults hospitalized with respiratory syncytial virus (RSV) infection in the United States. Methods Hospitalized adults aged ≥60 years who tested positive for RSV between 1 January 2011 and 30 June 2015 were identified from Kaiser Permanente Southern California. Patient-level demographics, comorbidities, clinical presentation, utilization, complications, and mortality were evaluated. Results There were 664 patients hospitalized with RSV (61% female, 64% aged ≥75 years). Baseline chronic diseases were prevalent (all >30%); 66% developed pneumonia, 80% of which were radiographically confirmed. Very severe tachypnea (≥26 breaths/minute) was common (56%); 21% required ventilator support and 18% were admitted to intensive care unit. Mortality during hospitalization was 5.6% overall (4.6% in 60–74 year olds and 6.1% in ≥75 year olds). Cumulative mortality within 1, 3, 6, and 12 months of admission was 8.6%, 12.3%, 17.2%, and 25.8%, respectively. Conclusion RSV infection in hospitalized older adults often manifested as severe, life-threatening lower respiratory tract illness with high rates of pneumonia, requirement for ventilatory support, and short- and long-term mortality. Increased recognition of the substantial RSV disease burden in adults will be important in evaluation and use of urgently needed interventions.

scholarly journals The Optimal Concentration of Formaldehyde is Key to Stabilizing the Pre-Fusion Conformation of Respiratory Syncytial Virus Fusion Protein

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 628 ◽  
Author(s):  
Wei Zhang ◽  
Lu-Jing Zhang ◽  
Lu-Ting Zhan ◽  
Min Zhao ◽  
Guang-Hua Wu ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Fusion Protein ◽  
Neutralizing Antibody ◽  
Neutralization Assay ◽  
Mean Value ◽  
Optimal Concentration ◽  
F Protein ◽  
Rsv Infection ◽  
Antibody Titers ◽  
Syncytial Virus

Background: To date, there is no licensed vaccine available to prevent respiratory syncytial virus (RSV) infection. The valuable pre-fusion conformation of the fusion protein (pre-F) is prone to lose high neutralizing antigenic sites. The goals of this study were to stabilize pre-F protein by fixatives and try to find the possibility of developing an inactivated RSV vaccine. Methods: The screen of the optimal fixative condition was performed with flow cytometry. BALB/c mice were immunized intramuscularly with different immunogens. The serum neutralizing antibody titers of immunized mice were determined by neutralization assay. The protection and safety of these immunogens were assessed. Results: Fixation in an optimal concentration of formaldehyde (0.0244%–0.0977%) or paraformaldehyde (0.0625%–1%) was able to stabilize pre-F. Additionally, BALB/c mice inoculated with optimally stabilized pre-F protein (opti-fixed) induced a higher anti-RSV neutralization (9.7 log2, mean value of dilution rate) than those inoculated with unstable (unfixed, 8.91 log2, p < 0.01) or excessively fixed (exce-fixed, 7.28 log2, p < 0.01) pre-F protein. Furthermore, the opti-fixed immunogen did not induce enhanced RSV disease. Conclusions: Only the proper concentration of fixatives could stabilize pre-F and the optimal formaldehyde condition provides a potential reference for development of an inactivated RSV vaccine.

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