scholarly journals In Vitro Enhancement of Respiratory Syncytial Virus Infection by Maternal Antibodies Does Not Explain Disease Severity in Infants

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Elisabeth A. van Erp ◽  
Puck B. van Kasteren ◽  
Teun Guichelaar ◽  
Inge M. L. Ahout ◽  
Cornelis A. M. de Haan ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Disease Severity ◽  
Respiratory Illness ◽  
Maternal Antibodies ◽  
Severe Illness ◽  
Antibody Dependent Enhancement ◽  
Cotton Rats ◽  
Syncytial Virus ◽  
The Impact

ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of severe respiratory illness in infants. At this young age, infants typically depend on maternally transferred antibodies (matAbs) and their innate immune system for protection against infections. RSV-specific matAbs are thought to protect from severe illness, yet severe RSV disease occurs mainly below 6 months of age, when neutralizing matAb levels are present. To investigate this discrepancy, we asked if disease severity is related to antibody properties other than neutralization. Some antibody effector functions are mediated via their Fc binding region. However, it has been shown that this binding may lead to antibody-dependent enhancement (ADE) of infection or reduction of neutralization, both possibly leading to more disease. In this study, we first showed that high levels of ADE of RSV infection occur in monocytic THP-1 cells in the presence of RSV antibodies and that neutralization by these antibodies was reduced in Vero cells when they were transduced with Fc gamma receptors. We then demonstrated that antibodies from cotton rats with formalin-inactivated (FI)-RSV-induced pulmonary pathology were capable of causing ADE. Human matAbs also caused ADE and were less neutralizing in vitro in cells that carry Fc receptors. However, these effects were unrelated to disease severity because they were seen both in uninfected controls and in infants hospitalized with different levels of RSV disease severity. We conclude that ADE and reduction of neutralization are unlikely to be involved in RSV disease in infants with neutralizing matAbs. IMPORTANCE It is unclear why severity of RSV disease peaks at the age when infants have neutralizing levels of maternal antibodies. Additionally, the exact reason for FI-RSV-induced enhanced disease, as seen in the 1960s vaccine trials, is still unclear. We hypothesized that antibodies present under either of these conditions could contribute to disease severity. Antibodies can have effects that may lead to more disease instead of protection. We investigated two of those effects: antibody-dependent enhancement of infection (ADE) and neutralization reduction. We show that ADE occurs in vitro with antibodies from FI-RSV-immunized RSV-infected cotton rats. Moreover, passively acquired maternal antibodies from infants had the capacity to induce ADE and reduction of neutralization. However, no clear association with disease severity was seen, ruling out that these properties explain disease in the presence of maternal antibodies. Our data contribute to a better understanding of the impact of antibodies on RSV disease in infants.

scholarly journals In Vitro and In Vivo Fitness of Respiratory Syncytial Virus Monoclonal Antibody Escape Mutants

2006 ◽  
Vol 80 (23) ◽  
pp. 11651-11657 ◽  
Author(s):  
Xiaodong Zhao ◽  
Enmei Liu ◽  
Fu-Ping Chen ◽  
Wayne M. Sullender
Keyword(s):  
Cell Culture ◽  
Monoclonal Antibody ◽  
Respiratory Syncytial Virus ◽  
Viral Population ◽  
Nucleotide Substitutions ◽  
Cotton Rats ◽  
Syncytial Virus ◽  
In Vivo Growth

ABSTRACT Respiratory syncytial virus (RSV) is the only infectious disease for which a monoclonal antibody (MAb) is used in humans. Palivizumab (PZ) is a humanized murine MAb to the F protein of RSV. PZ-resistant viruses appear after in vitro and in vivo growth of RSV in the presence of PZ. Fitness for replication could be a determinant of the likelihood of dissemination of resistant viruses. We assessed the fitness of two PZ-resistant viruses (F212 and MP4). F212 grew less well in cell culture than the parent A2 virus and was predicted to be less fit than A2. Equal amounts of F212 and A2 were mixed and passaged in cell culture. F212 disappeared from the viral population, indicating it was less fit than the A2 virus. The MP4 virus grew as well as A2 in culture and in cotton rats. A2/MP4 virus input ratios of 1:1, 10:1, 100:1, and 1,000:1 were compared in competitive replication. For all input ratios except 1,000:1, the MP4 virus became dominant, supplanting the A2 virus. The MP4 virus also dominated the A2 virus during growth in cotton rats. Thus, the mutant MP4 virus was more fit than A2 virus in both in vitro and in vivo competitive replication. Whether this fitness difference was due to the identified nucleotide substitutions in the F gene or to mutations elsewhere in the genome is unknown. Understanding the mechanisms by which mutant virus fitness increased or decreased could prove useful for consideration in attenuated vaccine design efforts.

scholarly journals Assessing Uncertainty in A2 Respiratory Syncytial Virus Viral Dynamics

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Gilberto González-Parra ◽  
Hana M. Dobrovolny
Keyword(s):  
Respiratory Syncytial Virus ◽  
Human Subjects ◽  
Respiratory Illness ◽  
The United States ◽  
Viral Kinetics ◽  
Phase Duration ◽  
Syncytial Virus ◽  
Parameter Values

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia in children younger than 1 year of age in the United States. Moreover, RSV is being recognized more often as a significant cause of respiratory illness in older adults. Although RSV has been studied both clinically and in vitro, a quantitative understanding of the infection dynamics is still lacking. In this paper, we study the effect of uncertainty in the main parameters of a viral kinetics model of RSV. We first characterize the RSV replication cycle and extract parameter values by fitting the mathematical model to in vivo data from eight human subjects. We then use Monte Carlo numerical simulations to determine how uncertainty in the parameter values will affect model predictions. We find that uncertainty in the infection rate, eclipse phase duration, and infectious lifespan most affect the predicted dynamics of RSV. This study provides the first estimate of in vivo RSV infection parameters, helping to quantify RSV dynamics. Our assessment of the effect of uncertainty will help guide future experimental design to obtain more precise parameter values.

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.

Human respiratory syncytial virus affects nonadrenergic noncholinergic inhibition in cotton rat airways

1995 ◽  
Vol 268 (6) ◽  
pp. L1006-L1011 ◽  
Author(s):  
G. N. Colasurdo ◽  
V. G. Hemming ◽  
G. A. Prince ◽  
J. E. Loader ◽  
J. P. Graves ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Human Respiratory Syncytial Virus ◽  
Control Group ◽  
Neurokinin A ◽  
Contractile Responses ◽  
Cotton Rat ◽  
Airway Function ◽  
Cotton Rats ◽  
Syncytial Virus

A dysfunction of the nonadrenergic noncholinergic inhibitory (NANCi) system has been invoked as a possible mechanism underlying or contributing to altered airway function. In the present study we assessed whether human respiratory syncytial virus (HRSV) infection affects the airways' neurally mediated contractile and relaxant (NANCi) responses in vitro. NANCi responses were studied on tracheal smooth muscle (TSM) segments obtained from young adult cotton rats, a well-established model for HRSV infection. To assess NANCi responses, TSM segments were removed and placed in tissue baths containing modified Krebs-Henseleit, atropine (1 x 10(-6) M) and propranolol (5 x 10(-6) M). After contraction with neurokinin A (1 x 10(-5) M), electrical field stimulation (EFS) was applied at stimulation frequencies ranging from 5 to 30 Hz. The NANCi responses were measured and expressed as the mean (+/- SE) percent relaxation. To evaluate neurally mediated contractile responses, full frequency response curves (0.5-30 Hz) to EFS were also performed. We found significantly decreased NANCi responses in TSM segments obtained from infected cotton rats (n = 12) compared with control animals (n = 9) (P < 0.002). Furthermore, the contractile responses to EFS were increased in infected animals compared with the control group (P = 0.0001). These findings demonstrate that HRSV infection leads to an enhanced contractile response to EFS and a significant decrease in NANCi response in cotton rat airways in vitro. This disruption of the neural control of airways may lead to the development of altered airway function.

scholarly journals The Impact of Human Immunodeficiency Virus Exposure on Respiratory Syncytial Virus–associated Severe Respiratory Illness in South African Infants, 2011–2016

2019 ◽  
Vol 69 (12) ◽  
pp. 2208-2211
Author(s):  
Meredith L McMorrow ◽  
Stefano Tempia ◽  
Sibongile Walaza ◽  
Florette K Treurnicht ◽  
Jocelyn Moyes ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Respiratory Syncytial Virus ◽  
South African ◽  
Respiratory Illness ◽  
Immunodeficiency Virus ◽  
Birth Dose ◽  
Virus Exposure ◽  
Syncytial Virus ◽  
The Impact ◽  
Severe Respiratory Illness

Abstract From 2011 through 2016, we conducted surveillance for severe respiratory illness in infants. Human immunodeficiency virus exposure significantly increased the risk of respiratory syncytial virus (RSV)–associated hospitalization in infants aged <5 months. More than 60% of RSV-associated hospitalizations occurred in the first 4 months of life and may be preventable through maternal vaccination or birth-dose monoclonal antibody.

scholarly journals The Impact of Maternal Human Immunodeficiency Virus Infection on the Burden of Respiratory Syncytial Virus Among Pregnant Women and Their Infants, Western Kenya

2020 ◽  
Author(s):  
Bryan O Nyawanda ◽  
Nancy A Otieno ◽  
Michael O Otieno ◽  
Gideon O Emukule ◽  
Godfrey Bigogo ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Respiratory Syncytial Virus ◽  
Hiv Infection ◽  
Pregnant Women ◽  
Respiratory Illness ◽  
Western Kenya ◽  
Immunodeficiency Virus ◽  
Maternal Hiv ◽  
Syncytial Virus ◽  
The Impact

Abstract Background Respiratory syncytial virus (RSV) is an important cause of respiratory illness worldwide; however, burden data on mother–infant pairs remain sparse in sub-Saharan Africa, where human immunodeficiency virus (HIV) is prevalent. We evaluated the impact of maternal HIV infection on the burden of RSV among mothers and their infants in western Kenya. Methods We enrolled pregnant women (≤20 weeks’ gestation) and followed them and their newborns weekly for up to 3–6 months postpartum, to document cases of acute respiratory illness (ARI). Nasal/oropharyngeal swabs were collected and tested for RSV using polymerase chain reaction. Analyses were stratified by maternal HIV status and incidence was computed per 1000 person-months. Results Compared to RSV-negative ARI cases, RSV-positive cases were associated with cough, apnea, and hospitalization among infants. RSV incidence per 1000 person-months among mothers was 4.0 (95% confidence interval [CI], 3.2–4.4), and was twice that among the HIV-infected mothers (8.4 [95% CI, 5.7–12.0]) compared to the HIV-uninfected mothers (3.1 [95% CI, 2.3–4.0]). Among infants, incidence per 1000 person-months was 15.4 (95% CI, 12.5–18.8); incidence did not differ by HIV exposure or prematurity. Conclusions HIV infection may increase the risk of RSV illness among pregnant women. Future maternal RSV vaccines may have added benefit in areas with high HIV prevalence.

scholarly journals Immunoprotective Activity and Safety of a RespiratorySyncytial Virus Vaccine: Mucosal Delivery of Fusion Glycoprotein with aCpG OligodeoxynucleotideAdjuvant

2003 ◽  
Vol 77 (24) ◽  
pp. 13156-13160 ◽  
Author(s):  
Gregory A. Prince ◽  
James J. Mond ◽  
David D. Porter ◽  
Kevin C. Yim ◽  
Steve J. Lan ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Neutralizing Antibody ◽  
Live Virus ◽  
Cotton Rat ◽  
F Protein ◽  
Virus Challenge ◽  
Cpg Oligodeoxynucleotides ◽  
Cotton Rats ◽  
Syncytial Virus

ABSTRACT CpG oligodeoxynucleotides (ODN) were identified that stimulated immunoglobulin production and cell proliferation in cotton rat cells in vitro. Three of these ODN were used as a mucosal adjuvant in the noses of cotton rats immunized via this route with respiratory syncytial virus fusion (F) protein. The CpG ODN markedly increased the cotton rat humoral neutralizing-antibody response to respiratory syncytial virus. Such immunized animals had a marked reduction in the production of infectious virus after a live-virus challenge. Animals immunized with the combination of F protein and CpG developed enhanced pulmonary pathology consisting of alveolitis and interstitial pneumonitis after a live-virus challenge. Similar enhanced disease has been seen in cotton rats and children immunized with formalin-inactivated respiratory syncytial virus.

Epidemiology of Respiratory Syncytial Virus Across Five Influenza Seasons Among Adults and Children One Year of Age and Older—Washington State, 2011/2012–2015/2016

2020 ◽  
Vol 223 (1) ◽  
pp. 147-156
Author(s):  
Michael L Jackson ◽  
Emily Scott ◽  
Jane Kuypers ◽  
Arun K Nalla ◽  
Pavitra Roychoudury ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Cumulative Incidence ◽  
Influenza Infection ◽  
Age Groups ◽  
Respiratory Illness ◽  
Kaiser Permanente ◽  
Subtype B ◽  
Syncytial Virus ◽  
The Impact ◽  
Virus Subtype

Abstract Background Vaccines and novel prophylactics against respiratory syncytial virus (RSV) are in development. To provide a baseline for evaluating these interventions, we characterized the incidence and molecular epidemiology of RSV in persons aged ≥1 year. Methods We identified patients with medically attended acute respiratory illness (MAARI) from the 2011/2012 through 2015/2016 influenza seasons among members of Kaiser Permanente Washington. We estimated the cumulative incidence of MAARI for laboratory-confirmed RSV or influenza infection. Results Annual cohorts ranged from 82 266 to 162 633 individuals, 14% of whom were children aged 1 to 17 years. Cumulative incidence of RSV each season ranged from 14 per 1000 population (95% confidence interval [CI], 12–16) to 22 per 1000 (95% CI, 19–25). Incidence of RSV was greater than influenza in children aged 12–23 months and 2–4 years; incidence of influenza was greater in other age groups. Respiratory syncytial virus subtype A dominated in 2011/2012, 2012/2013, and 2015/2016, with ON1 being the most common genotype. Respiratory syncytial virus subtype B dominated in 2013/2014 and 2014/2015, primarily of the BA genotype. Conclusions The burden of RSV is comparable to that of influenza across the life course. These results provide a baseline for evaluating the impact of new RSV interventions on the epidemiology of RSV.

scholarly journals RFI-641, a Potent Respiratory Syncytial Virus Inhibitor

2002 ◽  
Vol 46 (3) ◽  
pp. 841-847 ◽  
Author(s):  
Clayton C. Huntley ◽  
William J. Weiss ◽  
Anna Gazumyan ◽  
Aron Buklan ◽  
Boris Feld ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Tract Infections ◽  
Syncytium Formation ◽  
Therapeutic Window ◽  
Monkey Model ◽  
Cotton Rats ◽  
Syncytial Virus ◽  
Tract Infections

ABSTRACT Human respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. RFI-641 is a novel anti-RSV agent with potent in vitro and in vivo activity. RFI-641 is active against both RSV type A and B strains. The viral specificity and the large therapeutic window of RFI-641 (>100-fold) indicate that the antiviral activity of the compound is not due to adverse effects on normal cells. The potent in vitro activity of RFI-641 can be translated to efficacy in vivo: RFI-641 is efficacious when administered prophylactically by the intranasal route in mice, cotton rats, and African green monkeys. RFI-641 is also efficacious when administered therapeutically (24 h postinfection) in the monkey model. Mechanism of action studies indicate that RFI-641 blocks viral F protein-mediated fusion and cell syncytium formation.

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