Characterization of the epitope for anti-human respiratory syncytial virus F protein monoclonal antibody 101F using synthetic peptides and genetic approaches

Wu, Sheng‐Jiun; Schmidt, A.G.; Beil, E.; Day, Nicole D.; Branigan, Patrick; Liu, Changbao; Gutshall, Lester L.; Palomo, Concepción; Furze, Julie; Taylor, Geraldine; Melero, José A.; Tsui, Ping; Vecchio, Alfred M. Del; Kruszynski, Marian

doi:10.1099/vir.0.82753-0

Cited by 51 publications

(63 citation statements)

References 30 publications

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“…Whereas RSV-C4 and RSV-D3 VHHs readily competed with palivizumab for binding to recombinant RSV F TM -or inactivated RSV virions, RSV-E4 competed with 101 Fab, which is known to bind to the antigenic region IV-VI (Wu et al, 2007). These data are in line with the observation that AA substitutions within antigenic regions II and IV-VI, respectively, affected the binding of both RSV-D4 and RSV-C3 VHHs and RSV-E4 VHH.…”

Section: Rsv Binding Vhhs Antiviral Effect: Comparison With Synagis Mabsupporting

confidence: 80%

Single Domain Camelid Antibodies that Neutralize Negative Strand Viruses

Cardoso¹,

Ibáñez²,

Schepens³

et al. 2012

Antiviral Drugs - Aspects of Clinical Use and Recent Advances

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Section: Rsv Binding Vhhs Antiviral Effect: Comparison With Synagis Mabsupporting

confidence: 80%

Single Domain Camelid Antibodies that Neutralize Negative Strand Viruses

Cardoso¹,

Ibáñez²,

Schepens³

et al. 2012

Antiviral Drugs - Aspects of Clinical Use and Recent Advances

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“…The antigenic structure of the RSV F trimer has been mapped by a variety of techniques (7,17,(26)(27)(28)(29)(30)(31)(32)(33) (Table S2 and Fig. S1).…”

Section: Dilutions Of Seramentioning

confidence: 99%

Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers

Swanson¹,

Settembre²,

Shaw³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

248

246

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Respiratory syncytial virus (RSV), the main cause of infant bronchiolitis, remains a major unmet vaccine need despite more than 40 years of vaccine research. Vaccine candidates based on a chief RSV neutralization antigen, the fusion (F) glycoprotein, have foundered due to problems with stability, purity, reproducibility, and potency. Crystal structures of related parainfluenza F glycoproteins have revealed a large conformational change between the prefusion and postfusion states, suggesting that postfusion F antigens might not efficiently elicit neutralizing antibodies. We have generated a homogeneous, stable, and reproducible postfusion RSV F immunogen that elicits high titers of neutralizing antibodies in immunized animals. The 3.2-Å X-ray crystal structure of this substantially complete RSV F reveals important differences from homology-based structural models. Specifically, the RSV F crystal structure demonstrates the exposure of key neutralizing antibody binding sites on the surface of the postfusion RSV F trimer. This unanticipated structural feature explains the engineered RSV F antigen's efficiency as an immunogen. This work illustrates how structural-based antigen design can guide the rational optimization of candidate vaccine antigens.subunit | epitope

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“…An RSV F protein subunit vaccine candidate comprising aggregates of the postfusion conformation of RSV F is being tested currently in clinical trials (6), and serum antibody competition with palivizumab has been proposed as a potential serologic correlate of immunity for that vaccine (7,8). We and others have isolated and studied RSV F-specific mAbs using murine hybridomas (9), sorted macaque B cells (10), and transformed human B cells or human antibody gene phage-display libraries (11,12). Examples include mAbs 101F (9), D25 (13), and the next-generation site II mAb motavizumab (14).…”

mentioning

confidence: 99%

Structural basis for nonneutralizing antibody competition at antigenic site II of the respiratory syncytial virus fusion protein

Mousa

Sauer

Sevy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Palivizumab was the first antiviral monoclonal antibody (mAb) approved for therapeutic use in humans, and remains a prophylactic treatment for infants at risk for severe disease because of respiratory syncytial virus (RSV). Palivizumab is an engineered humanized version of a murine mAb targeting antigenic site II of the RSV fusion (F) protein, a key target in vaccine development. There are limited reported naturally occurring human mAbs to site II; therefore, the structural basis for human antibody recognition of this major antigenic site is poorly understood. Here, we describe a nonneutralizing class of site II-specific mAbs that competed for binding with palivizumab to postfusion RSV F protein. We also describe two classes of site II-specific neutralizing mAbs, one of which escaped competition with nonneutralizing mAbs. An X-ray crystal structure of the neutralizing mAb 14N4 in complex with F protein showed that the binding angle at which human neutralizing mAbs interact with antigenic site II determines whether or not nonneutralizing antibodies compete with their binding. Fine-mapping studies determined that nonneutralizing mAbs that interfere with binding of neutralizing mAbs recognize site II with a pose that facilitates binding to an epitope containing F surface residues on a neighboring protomer. Neutralizing antibodies, like motavizumab and a new mAb designated 3J20 that escape interference by the inhibiting mAbs, avoid such contact by binding at an angle that is shifted away from the nonneutralizing site. Furthermore, binding to rationally and computationally designed site II helixloop-helix epitope-scaffold vaccines distinguished neutralizing from nonneutralizing site II antibodies.F protein | human respiratory syncytial virus | neutralizing antibodies R espiratory syncytial virus (RSV) is a highly contagious human pathogen, infecting the majority of infants before age 2 y, and is the leading cause of viral bronchiolitis and viral pneumonia in infants and children (1, 2). RSV remains a top priority for vaccine development, as thousands of deaths are recorded worldwide each year because of complications from infection (3). To date, there is no licensed RSV vaccine. A major focus of RSV vaccine development has been inclusion of the RSV fusion (F) protein, a class I fusion glycoprotein that is synthesized as a precursor and cleaved into two disulfide-linked fragments upon maturation into a trimer (4). Although the RSV virion contains two additional surface proteins, the highly-glycosylated attachment (G) protein and the small hydrophobic protein, the F protein is highly conserved among strains of RSV strains and is the major target of protective neutralizing antibodies.The F protein is known to adopt at least two major conformations: the metastable prefusion conformation and the postfusion conformation. Following attachment of the virion to a cell by the G protein, the F protein undergoes a dramatic structural rearrangement, resulting in fusion of the viral and cell membranes, and in cultured cells causes...

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Characterization of the epitope for anti-human respiratory syncytial virus F protein monoclonal antibody 101F using synthetic peptides and genetic approaches

Cited by 51 publications

References 30 publications

Single Domain Camelid Antibodies that Neutralize Negative Strand Viruses

Single Domain Camelid Antibodies that Neutralize Negative Strand Viruses

Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers

Structural basis for nonneutralizing antibody competition at antigenic site II of the respiratory syncytial virus fusion protein

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