Identification of epitopes on respiratory syncytial virus proteins by competitive binding immunoassay

Anderson, Larry J.; Hierholzer, John C.; Stone, Y O; Tsou, C; Fernie, Bruce F.

doi:10.1128/jcm.23.3.475-480.1986

Cited by 64 publications

(23 citation statements)

References 27 publications

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“…RSV-F BMAb competitive enzyme-linked immunosorbent assay (ELISA). Competitive binding of CR pooled sera versus biotin-labeled monoclonal antibodies (BMAbs) was performed using a panel of MAbs mapped previously, including anti-RSV-F antibodies 1121 (site A), 1129 (site A), 1107 (site AB), 1269 (site B), 1243 (site C), and 104-5 (anti-G MAb) (28,29). Homologous unlabeled MAbs were used as positive controls, and anti-PIV3-F b108 was used as a negative control in this assay.…”

Section: Fluorescence-activated Cell Sorter (Facs) Analysis Hek293 Cmentioning

confidence: 99%

Development of an Adenovirus-Based Respiratory Syncytial Virus Vaccine: Preclinical Evaluation of Efficacy, Immunogenicity, and Enhanced Disease in a Cotton Rat Model

Kim

Okada

Beeler

et al. 2014

J Virol

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The lack of a vaccine against respiratory syncytial virus (RSV) is a challenging and serious gap in preventive medicine. Herein, we characterize the immunogenicity of an adenovirus serotype 5-based RSV vaccine encoding the fusion (F) protein (Ad5.RSV-F) and the protection provided following immunization with Ad5.RSV-F and assess its potential for producing enhanced disease in a cotton rat (CR) model. Animals were immunized intranasally (i.n.) and/or intramuscularly (i.m.) and subsequently challenged with RSV/A/Tracy (i.n.) to assess protection. Robust immune responses were seen in CRs vaccinated with Ad5.RSV-F given i.m. or i.n., and these responses correlated with reduced replication of the virus in noses and lungs after challenge. Neutralizing antibody responses following immunization with a single dose of Ad5.RSV-F at 1 ؋ 10 11 viral particles (v.p.) elicited antibody titers 64-to 256-fold greater than those seen after natural infection. CRs boosted with Ad5.RSV-F i.n. 28 days after an i.m. dose also had significant increases in neutralizing antibody titers. Antibody affinity for different F-protein antigenic sites revealed substantial differences between antibodies elicited by Ad5.RSV-F and those seen after RSV infection; differences in antibody profiles were also seen between CRs given Ad5.RSV-F i.m. and CRs given Ad5.RSV-F i.n. Ad5.RSV-F priming did not result in enhanced disease following live-virus challenge, in contrast to the histopathology seen in CRs given the formalin-inactivated RSV/A/Burnett vaccine. IMPORTANCERespiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in infants and young children and a serious health threat in the immunocompromised and the elderly. Infection severity increased in children in an immunization trial, hampering the over 4-decade-long quest for a successful RSV vaccine. In this study, we show that a genetically engineered RSV-F-encoding adenoviral vector provides protective immunity against RSV challenge without enhanced lung disease in cotton rats (CRs). CRs were vaccinated under a number of different regimens, and the immunity induced by the recombinant adenoviral RSV vaccine administered by use of an intramuscular prime-intranasal boost regimen may provide the best protection for young infants and children at risk of RSV infection, since this population is naive to adenoviral preformed immunity. Overall, this report describes a potential RSV vaccine candidate that merits further evaluation in a phase I clinical study in humans.

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Section: Fluorescence-activated Cell Sorter (Facs) Analysis Hek293 Cmentioning

confidence: 99%

Development of an Adenovirus-Based Respiratory Syncytial Virus Vaccine: Preclinical Evaluation of Efficacy, Immunogenicity, and Enhanced Disease in a Cotton Rat Model

Kim

Okada

Beeler

et al. 2014

J Virol

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“…RSV4 and RS 102 were used as capture antibodies for detection of groups A + B and group A strains, respectively, with the indicator antibody NC4. MAb 130-8F, generated to RSV strain A2 and reactive with the F protein of both RSV groups, was obtained from L Anderson, CDC, Atlanta, GA, USA (20). RSlOl was generated to Randall strain of RSV and recognizes the F protein of both RSV groups (18).…”

Section: Virological Methodsmentioning

confidence: 99%

Incidence of acute otitis media associated with group A and B respiratory syncytial virus infections

Heikkinen

Waris²,

Ruuskanen

et al. 1995

Acta Paediatrica

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The comparative association of respiratory syncytial virus group A and B infections with acute otitis media was determined by analysing the hospital records of children with community-acquired respiratory syncytial virus infection during three successive outbreaks from 1987 to 1992. Of 326 episodes analysed, 192 (59%) were caused by group A and 134 (41%) by group B infections. Acute otitis media was diagnosed in 101 (75%) children with group B infection, compared with 119 (62%) with group A infection (p = 0.01). Group A infections were more often associated with wheezing (71% versus 59% in group B; p = 0.02) and oxygen therapy in inpatients (48% versus 31%, respectively; p = 0.008). The higher incidence of acute otitis media associated with group B infections was observed both after adjustment for potential confounding variables and during each outbreak.

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“…Structures of F proteins complexed with neutralizing antibodies have been solved for a number of pneumo-and paramyxovirus family members including RSV (Figure 3), HPIV3, and NiV. Distinct antigenic sites were identified on RSV F (Figure 4): conformation-dependent site Ø that is located at the apex of prefusion F and a dominant target for nAbs [36,[76][77][78]; sites II and IV that are present in both the pre-and postfusion F conformations [67,79]; site III that likewise exists in both F conformations, but undergoes rearrangement of secondary structure elements forming the epitope [80,81]; site V located between sites Ø and III on prefusion F [82,83]; and post-fusion F site I [84,85]. A cryo-EM structure of HPIV3 F complexed with nAb PIA174 likewise locates the binding site to the apex of the prefusion F trimer, establishing contact with residues of all three F protomers [37].…”

Section: Druggable Sites and Neutralizing Epitopesmentioning

confidence: 99%

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Aggarwal

Plemper

2020

Viruses

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Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre-and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.Viruses 2020, 12, 342 2 of 16 from its natural bat host to domestic animals, resulting in case/fatality rates reaching from 40% to over 90% [9]. Continued spillover into the human population must be expected, and human-to-human transmission through respiratory secretions, urine, and saliva has been documented [10].Of the pneumoviruses, RSV infects almost all children before two years of age and is responsible for over 100,000 hospitalizations yearly in the United States alone. The monoclonal antibody palivizumab has been approved for immunoprophylaxis against RSV infection [11], however, use is restricted to high-risk patients due to the high-cost and need for prophylactic administration.Given the health, medical and economic burden associated with paramyxo-and pneumovirus infections, a major and currently unmet clinical need exists to expedite the development of novel safe and effective therapeutics for improved disease management and outbreak control. Current direct-acting therapeutics predominantly focus on preventing viral entry through neutralizing antibodies (nAbs) and on small-molecules targeting the envelope glycoproteins or inhibiting the viral RNA-dependent RNA polymerase (RdRP) complex. Reflecting major efforts to identify a cost-effective alternative to high-price passive immunization with anti-RSV nAbs, a number of compounds have entered advanced preclinical development and clinical testing in recent years (Table 1). Breakthroughs in the structural and functional characterization of the viral entry machinery and polymerase complexes in the past decade [12][13][14][15][16][17][18][19][20][21] have furthermore created a novel opportunity for structure-informed mechanistic characterization and ligand optimization.

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Identification of epitopes on respiratory syncytial virus proteins by competitive binding immunoassay

Cited by 64 publications

References 27 publications

Development of an Adenovirus-Based Respiratory Syncytial Virus Vaccine: Preclinical Evaluation of Efficacy, Immunogenicity, and Enhanced Disease in a Cotton Rat Model

Development of an Adenovirus-Based Respiratory Syncytial Virus Vaccine: Preclinical Evaluation of Efficacy, Immunogenicity, and Enhanced Disease in a Cotton Rat Model

Incidence of acute otitis media associated with group A and B respiratory syncytial virus infections

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

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