Prevalence and Significance of Substitutions in the Fusion Protein of Respiratory Syncytial Virus Resulting in Neutralization Escape From Antibody MEDI8897

Zhu, Qing; Lü, Bin; McTamney, Patrick M.; Palaszynski, Susan R.; Diallo, Seme; Ren, Kuishu; Ulbrandt, Nancy D.; Kallewaard, Nicole L.; Wang, Weijia; Fernandes, Fiona; Wong, Steve; Svabek, Catherine; Moldt, Brian; Esser, Mark T.; Jing, Hao; Suzich, JoAnn

doi:10.1093/infdis/jiy189

Cited by 55 publications

(48 citation statements)

References 26 publications

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“…In this scenario, the likelihood of an RSV strain emerging in response to the widespread administration of a monoclonal antibody is likely to be determined by the balance between benefits provided to the virus by particular mutations preventing antibody neutralisation, and the consequences to viral fitness of that mutation. This balance, as suggested by the varying proportions of mutations seen in different antigenic sites in our study, is likely to be antigenic site specific: a study examining site Ø escape mutants found no difference in fitness for the mutants [22] compared to circulating strains.…”

Section: Discussionmentioning

confidence: 59%

“…A precedent for generation of escape mutants exists both in vitro and in clinical settings. In a laboratory setting, prolonged treatment of hRSV with mAbs has been shown to select for mutants with reduced antibody binding affinities for antibodies binding to antigenic sites II, III, IV and Ø [18] , [19] , [20] , [21] , [22] , [23] , [24] . Clinically, cohorts of patients treated prophylactically with palivizumab or the related mAb motavizumab have been found to be infected with hRSV strains with mAb resistance-associate mutations [25] , [26] .…”

Section: Introductionmentioning

confidence: 99%

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Antigenic and sequence variability of the human respiratory syncytial virus F glycoprotein compared to related viruses in a comprehensive dataset

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Nair

Campbell

et al. 2018

Vaccine

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A comprehensive analysis of sequence variation was carried out comparing the fusion (F) protein of human respiratory syncytial viruses (hRSV) from antigenic groups A and B with the prototype sequence of the A2 strain, also belonging to antigenic group A. The limited number of full bovine RSV F sequences available were included, as well as an extensive set of F sequences from the related human metapneumovirus (hMPV). The results were analysed in the context of the recently determined three dimensional F protein structures, with antigenic sites mapped to these. Although a high degree of sequence conservation in hRSV F exists, and sequence changes did not correlate with location of antigenic sites, preferential accumulation of amino acid changes in certain antigenic sites was noted. When the analysis was extended to hMPV F, a high number of changes was noticed, in agreement with the limited degree of sequence conservation. However, some conserved regions were noted, which may account for the limited number of cross-reactive monoclonal antibodies described between hRSV F and hMPV F. These results provide information about the degree of sequence and antigenic variation currently found in the F protein of circulating viruses. They highlight the importance of establishing a baseline dataset to monitor for future changes that might evolve should preventative immunological measures be made widely available.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Antigenic and sequence variability of the human respiratory syncytial virus F glycoprotein compared to related viruses in a comprehensive dataset

Más

Nair

Campbell

et al. 2018

Vaccine

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show abstract

“…For example, palivizumab is a monoclonal antibody used in children less than 2 years old to prevent lower respiratory tract infections caused by respiratory syncytial virus (RSV). Palivizumab escape mutants have been isolated from approximately 5% of the patients where breakthrough disease occurred after monoclonal antibody treatment (Zhu et al, 2018). In this example, there is no evidence that monoclonal antibody escape in patients resulted in worsened disease or shedding of resistant virus; however, these possibilities cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Anti-HFRS Human IgG Produced in Transchromosomic Bovines Has Potent Hantavirus Neutralizing Activity and Is Protective in Animal Models

Perley

Brocato

et al. 2020

Front. Microbiol.

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We explored an emerging technology to produce anti-Hantaan virus (HTNV) and anti-Puumala virus (PUUV) neutralizing antibodies for use as pre-or post-exposure prophylactics. The technology involves hyperimmunization of transchomosomic bovines (TcB) engineered to express human polyclonal IgG antibodies with HTNV and PUUV DNA vaccines encoding G n G c glycoproteins. For the anti-HTNV product, TcB was hyperimmunized with HTNV DNA plus adjuvant or HTNV DNA formulated using lipid nanoparticles (LNP). The LNP-formulated vaccine yielded fivefold higher neutralizing antibody titers using 10-fold less DNA. Human IgG purified from the LNP-formulated animal (SAB-159), had anti-HTNV neutralizing antibody titers >100,000. SAB-159 was capable of neutralizing pseudovirions with monoclonal antibody escape mutations in G n and G c demonstrating neutralization escape resistance. SAB-159 protected hamsters from HTNV infection when administered pre-or post-exposure, and limited HTNV infection in a marmoset model. An LNP-formulated PUUV DNA vaccine generated purified anti-PUUV IgG, SAB-159P, with a neutralizing antibody titer >600,000. As little as 0.33 mg/kg of SAB-159P protected hamsters against PUUV infection for pre-exposure and 10 mg/kg SAB-159P protected PUUV-infected hamsters post-exposure. These data demonstrate that DNA vaccines combined with the TcB-based manufacturing platform can be used to rapidly produce potent, human, polyclonal, escaperesistant anti-HTNV, and anti-PUUV neutralizing antibodies that are protective in animal models.

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“…Future clinical use of therapeutics, vaccines and mAbs to prevent RSV raises concerns about the emergence of local resistant strains [9,10]. Therefore, RSV global surveillance is required.…”

Section: Introductionmentioning

confidence: 99%

“…The Observational US Targeted Surveillance of Monoclonal Antibody Resistance and Testing of RSV (OUTSMART-RSV) surveillance program characterized circulating RSV strains in the U.S. during the 2017-18 season [11]. RSV strains that are resistant to palivizumab were found to be rare [10]. The frequency of natural resistance-associated polymorphisms for nirsevimab was also low (in vitro < 1%).…”

Section: Introductionmentioning

confidence: 99%

Global molecular diversity of RSV – the “INFORM RSV” study

et al. 2020

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Background: Respiratory syncytial virus (RSV) is a global cause of severe respiratory morbidity and mortality in infants. While preventive and therapeutic interventions are being developed, including antivirals, vaccines and monoclonal antibodies, little is known about the global molecular epidemiology of RSV. INFORM is a prospective, multicenter, global clinical study performed by ReSViNET to investigate the worldwide molecular diversity of RSV isolates collected from children less than 5 years of age. Methods: The INFORM study is performed in 17 countries spanning all inhabited continents and will provide insight into the molecular epidemiology of circulating RSV strains worldwide. Sequencing of > 4000 RSV-positive respiratory samples is planned to detect temporal and geographical molecular patterns on a molecular level over five consecutive years. Additionally, RSV will be cultured from a subset of samples to study the functional implications of specific mutations in the viral genome including viral fitness and susceptibility to different monoclonal antibodies. Discussion: The sequencing and functional results will be used to investigate susceptibility and resistance to novel RSV preventive or therapeutic interventions. Finally, a repository of globally collected RSV strains and a database of RSV sequences will be created.

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Prevalence and Significance of Substitutions in the Fusion Protein of Respiratory Syncytial Virus Resulting in Neutralization Escape From Antibody MEDI8897

Abstract: Results from this study provide insights into the mechanism of MEDI8897 escape and the complexity of monitoring for emergence of resistance.

Cited by 55 publications

References 26 publications

Antigenic and sequence variability of the human respiratory syncytial virus F glycoprotein compared to related viruses in a comprehensive dataset

Antigenic and sequence variability of the human respiratory syncytial virus F glycoprotein compared to related viruses in a comprehensive dataset

Anti-HFRS Human IgG Produced in Transchromosomic Bovines Has Potent Hantavirus Neutralizing Activity and Is Protective in Animal Models

Global molecular diversity of RSV – the “INFORM RSV” study

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