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Article ; Online: Structural Characterization and Modeling of a Respiratory Syncytial Virus Fusion Glycoprotein Nanoparticle Vaccine in Solution.

Krueger, Susan / Curtis, Joseph E / Scott, Daniel R / Grishaev, Alexander / Glenn, Greg / Smith, Gale / Ellingsworth, Larry / Borisov, Oleg / Maynard, Ernest L

Molecular pharmaceutics

2020 Volume 18, Issue 1, Page(s) 359–376

Abstract: The respiratory syncytial virus (RSV) fusion (F) protein/polysorbate 80 (PS80) nanoparticle vaccine is the most clinically advanced vaccine for maternal immunization and protection of newborns against RSV infection. It is composed of a near-full-length ... ...

Abstract	The respiratory syncytial virus (RSV) fusion (F) protein/polysorbate 80 (PS80) nanoparticle vaccine is the most clinically advanced vaccine for maternal immunization and protection of newborns against RSV infection. It is composed of a near-full-length RSV F glycoprotein, with an intact membrane domain, formulated into a stable nanoparticle with PS80 detergent. To understand the structural basis for the efficacy of the vaccine, a comprehensive study of its structure and hydrodynamic properties in solution was performed. Small-angle neutron scattering experiments indicate that the nanoparticle contains an average of 350 PS80 molecules, which form a cylindrical micellar core structure and five RSV F trimers that are arranged around the long axis of the PS80 core. All-atom models of full-length RSV F trimers were built from crystal structures of the soluble ectodomain and arranged around the long axis of the PS80 core, allowing for the generation of an ensemble of conformations that agree with small-angle neutron and X-ray scattering data as well as transmission electron microscopy (TEM) images. Furthermore, the hydrodynamic size of the RSV F nanoparticle was found to be modulated by the molar ratio of PS80 to protein, suggesting a mechanism for nanoparticle assembly involving addition of RSV F trimers to and growth along the long axis of the PS80 core. This study provides structural details of antigen presentation and conformation in the RSV F nanoparticle vaccine, helping to explain the induction of broad immunity and observed clinical efficacy. Small-angle scattering methods provide a general strategy to visualize surface glycoproteins from other pathogens and to structurally characterize nanoparticle vaccines.
MeSH term(s)	Antibodies, Neutralizing/chemistry ; Antibodies, Neutralizing/immunology ; Glycoproteins/chemistry ; Glycoproteins/immunology ; Nanoparticles/chemistry ; Respiratory Syncytial Virus Infections/immunology ; Respiratory Syncytial Virus Vaccines/chemistry ; Respiratory Syncytial Virus Vaccines/immunology ; Respiratory Syncytial Virus, Human/chemistry ; Respiratory Syncytial Virus, Human/immunology ; Vaccination/methods
Chemical Substances	Antibodies, Neutralizing ; Glycoproteins ; Respiratory Syncytial Virus Vaccines
Language	English
Publishing date	2020-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.0c00986
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Article: Respiratory syncytial virus prefusogenic fusion (F) protein nanoparticle vaccine: Structure, antigenic profile, immunogenicity, and protection

Patel, Nita / Massare, Mike J / Tian, Jing-Hui / Guebre-Xabier, Mimi / Lu, Hanxin / Zhou, Haixia / Maynard, Ernest / Scott, Daniel / Ellingsworth, Larry / Glenn, Gregory / Smith, Gale

Vaccine. 2019 Sept. 24, v. 37, no. 41

2019

Abstract: Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in the very young, elderly, and immunocompromised for which there is no vaccine. The surface exposed RSV fusion (F) glycoprotein is required for membrane fusion and ... ...

Abstract	Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in the very young, elderly, and immunocompromised for which there is no vaccine. The surface exposed RSV fusion (F) glycoprotein is required for membrane fusion and infection and is a desirable vaccine candidate. RSV F glycoprotein structure is dynamic and undergoes significant rearrangements during virus assembly, fusion, and infection. We have previously described an RSV fusion-inactive prefusogenic F with a mutation of one of two furin cleavage sites resulting in the p27 region on the N-terminus of F1 with a truncated fusion peptide covalently linked to F2. A processing intermediate RSV prefusogenic F has been reported in infected cells, purified F, budded virus, and elicited a strong immune response against p27 in RSV infected young children. In this report, we demonstrate that prefusogenic F, when expressed on the cell surface of Sf9 insect and human 293T cells, binds monoclonal antibodies (mAbs) that target prefusion-specific antigenic sites Ø and VIII, and mAbs targeting epitopes common to pre- and postfusion F sites II and IV. Purified prefusogenic F bound prefusion F specific mAbs to antigenic sites Ø and VIII and mAbs targeting pre- and postfusion sites II, IV, and p27. Mice immunized with prefusogenic F antigen produced significantly higher levels of anti-F IgG and RSV neutralizing antibodies than prefusion or postfusion F antigens and induced antibodies competitive with mAbs to sites Ø, VIII, II, and IV. RSV prefusogenic F neutralization antibody responses were enhanced with aluminum phosphate adjuvant and significantly higher than prefusion F. Prefusogenic F vaccine protected cotton rats against upper and lower respiratory tract infection by RSV/A. For the first time, we present the structure, antigenic profile, immunogenicity, and protective efficacy of RSV prefusogenic F nanoparticle vaccine.
Keywords	Respiratory syncytial virus ; Sigmodon ; adjuvants ; aluminum phosphate ; antibody formation ; chemical bonding ; children ; elderly ; epitopes ; glycoproteins ; humans ; immunogenicity ; immunoglobulin G ; insects ; membrane fusion ; mice ; monoclonal antibodies ; mutation ; nanoparticles ; neutralization ; neutralizing antibodies ; peptides ; respiratory tract diseases ; vaccines ; virus assembly ; viruses
Language	English
Dates of publication	2019-0924
Size	p. 6112-6124.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2019.07.089
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Article ; Online: Respiratory syncytial virus fusion nanoparticle vaccine immune responses target multiple neutralizing epitopes that contribute to protection against wild-type and palivizumab-resistant mutant virus challenge.

Gilbert, Brian E / Patel, Nita / Lu, Hanxin / Liu, Ye / Guebre-Xabier, Mimi / Piedra, Pedro A / Glenn, Gregory / Ellingsworth, Larry / Smith, Gale

Vaccine

2018 Volume 36, Issue 52, Page(s) 8069–8078

Abstract: Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in newborns, young children, elderly, and immune-compromised. The RSV fusion (F) glycoprotein is a major focus of vaccine development and the target ...

Abstract	Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in newborns, young children, elderly, and immune-compromised. The RSV fusion (F) glycoprotein is a major focus of vaccine development and the target of palivizumab (Synagis®) which is licensed as an immuno-prophylactic for use in newborn children at high risk of infection. However, clinical use of a narrowly targeted monoclonal antibodies leads to the generation of escape mutant strains that are fully resistant to neutralization by the antibody. Herein, we evaluated the RSV F nanoparticle vaccine (RSV F vaccine), produced as near-full-length, pre-fusogenic F trimers that form stable protein-detergent nanoparticles. The RSV F vaccine induces polyclonal antibodies that bind to antigenic site II as well as other epitopes known to be broadly neutralizing. Cotton rats immunized with the RSV F vaccine produced antibodies that were both neutralizing and protected against wild-type RSV infection, as well as against a palivizumab-resistant mutant virus. Use of aluminum phosphate adjuvant with the RSV F vaccine increased site II antibody avidity 100 to 1000-fold, which correlated with enhanced protection against challenge. The breadth of the vaccine-induced antibody response was demonstrated using competitive binding with monoclonal antibodies targeting antigenic sites Ø, II, IV, and VIII found on pre-fusion and post-fusion conformations of RSV F. In summary, we found the RSV F vaccine induced antibodies that bind to conserved epitopes including those defined as pre-fusion F specific; that use of adjuvant increased antibody avidity that correlated with enhanced protection in the cotton rat challenge model; and the polyclonal, high-avidity antibodies neutralized and protected against both wild-type and palivizumab-resistant mutant virus. These data support the ongoing clinical development of the aluminum phosphate adjuvanted RSV F nanoparticle vaccine.
MeSH term(s)	Adjuvants, Immunologic/administration & dosage ; Aluminum Compounds/immunology ; Animals ; Antibodies, Neutralizing/blood ; Antibodies, Viral/blood ; Antibody Affinity ; Antiviral Agents/pharmacology ; Drug Resistance, Viral ; Epitopes/immunology ; Female ; Male ; Mutation ; Nanoparticles/administration & dosage ; Palivizumab/pharmacology ; Phosphates/immunology ; Rats ; Respiratory Syncytial Virus Infections/prevention & control ; Respiratory Syncytial Virus Vaccines/immunology ; Respiratory Syncytial Virus, Human/drug effects ; Respiratory Syncytial Virus, Human/genetics ; Sigmodontinae ; Vaccination ; Viral Fusion Proteins/immunology
Chemical Substances	Adjuvants, Immunologic ; Aluminum Compounds ; Antibodies, Neutralizing ; Antibodies, Viral ; Antiviral Agents ; Epitopes ; F protein, human respiratory syncytial virus ; Phosphates ; Respiratory Syncytial Virus Vaccines ; Viral Fusion Proteins ; Palivizumab (DQ448MW7KS) ; aluminum phosphate (F92V3S521O)
Language	English
Publishing date	2018-10-30
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2018.10.073
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Article: Flexible RSV Prefusogenic Fusion Glycoprotein Exposes Multiple Neutralizing Epitopes that May Collectively Contribute to Protective Immunity.

Patel, Nita / Tian, Jing-Hui / Flores, Rhonda / Jacobson, Kelsey / Walker, Michelle / Portnoff, Alyse / Gueber-Xabier, Mimi / Massare, Michael J / Glenn, Greg / Ellingsworth, Larry / Smith, Gale

Vaccines

2020 Volume 8, Issue 4

Abstract: Human respiratory syncytial virus (RSV) is a cause of lower respiratory tract infection in infants, young children, and older adults. There is no licensed vaccine and prophylactic treatment options are limited. The RSV fusion (F) glycoprotein is a target ...

Abstract	Human respiratory syncytial virus (RSV) is a cause of lower respiratory tract infection in infants, young children, and older adults. There is no licensed vaccine and prophylactic treatment options are limited. The RSV fusion (F) glycoprotein is a target of host immunity and thus a focus for vaccine development. F-trimers are metastable and undergo significant rearrangements from the prefusion to a stable postfusion structure with neutralizing epitopes on intermediate structures. We hypothesize that vaccine strategies that recapitulate the breathable F quaternary structure, and provide accessibility of B-cells to epitopes on intermediate conformations, may collectively contribute to protective immunity, while rigid prefusion F structures restrict access to key protective epitopes. To test this hypothesis, we used the near full-length prefusogenic F as a backbone to construct three prefusion F variants with substitutions in the hydrophobic head cavity: (1) disulfide bond mutant (DS), (2) space filling hydrophobic amino acid substitutions (Cav1), and (3) DS, Cav1 double mutant (DS-Cav1). In this study, we compared the immunogenicity of prefusogenic F to prefusion F variants in two animal models. Native prefusogenic F was significantly more immunogenic, producing high titer antibodies to prefusogenic, prefusion, and postfusion F structures, while animals immunized with DS or DS-Cav1 produced antibodies to prefusion F. Importantly, prefusogenic F elicited antibodies that target neutralizing epitopes including prefusion-specific site zero (Ø) and V and conformation-independent neutralizing sites II and IV. Immunization with DS or DS-Cav1 elicited antibodies primarily to prefusion-specific sites Ø and V with little or no antibodies to other key neutralizing sites. Animals immunized with prefusogenic F also had significantly higher levels of antibodies that cross-neutralized RSV A and B subtypes, while immunization with DS or DS-Cav1 produced antibodies primarily to the A subtype. We conclude that breathable trimeric vaccines that closely mimic the native F-structure, and incorporate strategies for B-cell accessibility to protective epitopes, are important considerations for vaccine design. F structures locked in a single conformation restrict access to neutralizing epitopes that may collectively contribute to destabilizing F-trimers important for broad protection. These results also have implications for vaccine strategies targeting other type 1 integral membrane proteins.
Language	English
Publishing date	2020-10-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines8040607
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Article ; Online: NVX-CoV2373 vaccine protects cynomolgus macaque upper and lower airways against SARS-CoV-2 challenge.

Guebre-Xabier, Mimi / Patel, Nita / Tian, Jing-Hui / Zhou, Bin / Maciejewski, Sonia / Lam, Kristal / Portnoff, Alyse D / Massare, Michael J / Frieman, Matthew B / Piedra, Pedro A / Ellingsworth, Larry / Glenn, Gregory / Smith, Gale

Vaccine

2020 Volume 38, Issue 50, Page(s) 7892–7896

Abstract: There is an urgent need for a safe and protective vaccine to control the global spread of SARS-CoV-2 and prevent COVID-19. Here, we report the immunogenicity and protective efficacy of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full- ... ...

Abstract	There is an urgent need for a safe and protective vaccine to control the global spread of SARS-CoV-2 and prevent COVID-19. Here, we report the immunogenicity and protective efficacy of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full-length SARS-CoV-2 spike (S) glycoprotein stabilized in the prefusion conformation. Cynomolgus macaques (Macaca fascicularis) immunized with NVX-CoV2373 and the saponin-based Matrix-M™ adjuvant induced anti-S antibody that was neutralizing and blocked binding to the human angiotensin-converting enzyme 2 (hACE2) receptor. Following intranasal and intratracheal challenge with SARS-CoV-2, immunized macaques were protected against upper and lower infection and pulmonary disease. These results support ongoing phase 1/2 clinical studies of the safety and immunogenicity of NVX-CoV2327 vaccine (NCT04368988).
MeSH term(s)	Adjuvants, Immunologic/pharmacology ; Adolescent ; Adult ; Aged ; Angiotensin-Converting Enzyme 2/immunology ; Angiotensin-Converting Enzyme 2/metabolism ; Animals ; Antibodies, Neutralizing ; COVID-19/immunology ; COVID-19/prevention & control ; COVID-19 Vaccines/genetics ; COVID-19 Vaccines/immunology ; COVID-19 Vaccines/pharmacology ; Chlorocebus aethiops ; Female ; Humans ; Immune Sera/drug effects ; Immune Sera/immunology ; Macaca fascicularis ; Male ; Middle Aged ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/genetics ; Vaccines, Synthetic/immunology ; Vaccines, Synthetic/pharmacology ; Vero Cells ; Viral Load ; Young Adult
Chemical Substances	Adjuvants, Immunologic ; Antibodies, Neutralizing ; COVID-19 Vaccines ; Immune Sera ; Spike Glycoprotein, Coronavirus ; Vaccines, Synthetic ; spike protein, SARS-CoV-2 ; NVX-CoV2373 adjuvated lipid nanoparticle (2SCD8Q63PF) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Keywords	covid19
Language	English
Publishing date	2020-10-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2020.10.064
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Article ; Online: Maternal immunization with RSV fusion glycoprotein vaccine and substantial protection of neonatal baboons against respiratory syncytial virus pulmonary challenge

Welliver, Robert C. / Papin, James F. / Preno, Alisha / Ivanov, Vadim / Tian, Jing-Hui / Lu, Hanxin / Guebre-Xabier, Mimi / Flyer, David / Massare, Michael J. / Glenn, Greg / Ellingsworth, Larry / Smith, Gale

Vaccine. 2020 Jan. 29, v. 38, no. 5 p.1258-1270

2020

Abstract: Globally, human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory infection in infants and young children. There are no licensed vaccines despite the high worldwide disease burden. RSV fusion (F) glycoprotein vaccine is the ... ...

Abstract	Globally, human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory infection in infants and young children. There are no licensed vaccines despite the high worldwide disease burden. RSV fusion (F) glycoprotein vaccine is the most advanced candidate for maternal immunization. In this report, a baboon maternal immunization model was used to assess the immunogenicity and protection of infants against pulmonary challenge with human RSV/A. Vaccination in the third trimester produced high anti-RSV F IgG titers and virus-neutralizing antibodies. Infants born to immunized females had high levels of serum RSV antibodies that were comparable to maternal levels at birth and persisted for over 50 days with a half-life of 14–24 days. Furthermore, infants from immunized females and challenged with RSV/A were healthy, developed less severe disease, and had only mild pulmonary inflammatory changes whereas infants born to non-vaccinated females developed more severe disease with marked to moderate interstitial pneumonia, pulmonary edema, and bronchiolar obstruction. These results support the further development of the RSV F vaccine for maternal immunization.
Keywords	Human orthopneumovirus ; Papio ; Respiratory syncytial virus ; antibodies ; blood serum ; burden of disease ; children ; disease severity ; edema ; females ; glycoproteins ; half life ; humans ; immunogenicity ; immunoglobulin G ; infant diseases ; infants ; models ; pneumonia ; vaccination ; vaccines ; BAL ; ELISA ; F ; FDA ; GMT ; IACUC ; IgG ; IM ; LRTI ; OUHSC ; PBS ; PCA ; RSV ; RSV F nanoparticle ; Vaccine ; Maternal immunization ; Baboon
Language	English
Dates of publication	2020-0129
Size	p. 1258-1270.
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2019.11.003
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Zs.A 1930: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: NVX-CoV2373 vaccine protects cynomolgus macaque upper and lower airways against SARS-CoV-2 challenge

Vaccine. 2020 Nov. 25, v. 38, no. 50

2020

Abstract	There is an urgent need for a safe and protective vaccine to control the global spread of SARS-CoV-2 and prevent COVID-19. Here, we report the immunogenicity and protective efficacy of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full-length SARS-CoV-2 spike (S) glycoprotein stabilized in the prefusion conformation. Cynomolgus macaques (Macaca fascicularis) immunized with NVX-CoV2373 and the saponin-based Matrix-M™ adjuvant induced anti-S antibody that was neutralizing and blocked binding to the human angiotensin-converting enzyme 2 (hACE2) receptor. Following intranasal and intratracheal challenge with SARS-CoV-2, immunized macaques were protected against upper and lower infection and pulmonary disease. These results support ongoing phase 1/2 clinical studies of the safety and immunogenicity of NVX-CoV2327 vaccine (NCT04368988).
Keywords	COVID-19 infection ; Macaca fascicularis ; Severe acute respiratory syndrome coronavirus 2 ; adjuvants ; antibodies ; glycoproteins ; humans ; immunogenicity ; peptidyl-dipeptidase A ; respiratory tract diseases ; subunit vaccines
Language	English
Dates of publication	2020-1125
Size	p. 7892-7896.
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2020.10.064
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 1930: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Structure basis of neutralization by a novel site II/IV antibody against respiratory syncytial virus fusion protein.

Xie, Qingqing / Wang, Zhao / Ni, Fengyun / Chen, Xiaorui / Ma, Jianpeng / Patel, Nita / Lu, Hanxin / Liu, Ye / Tian, Jing-Hui / Flyer, David / Massare, Michael J / Ellingsworth, Larry / Glenn, Gregory / Smith, Gale / Wang, Qinghua

PloS one

2019 Volume 14, Issue 2, Page(s) e0210749

Abstract: Globally, human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in newborns, young children, and the elderly for which there is no vaccine. The RSV fusion (F) glycoprotein is a major target for vaccine ... ...

Abstract	Globally, human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in newborns, young children, and the elderly for which there is no vaccine. The RSV fusion (F) glycoprotein is a major target for vaccine development. Here, we describe a novel monoclonal antibody (designated as R4.C6) that recognizes both pre-fusion and post-fusion RSV F, and binds with nanomole affinity to a unique neutralizing site comprised of antigenic sites II and IV on the globular head. A 3.9 Å-resolution structure of RSV F-R4.C6 Fab complex was obtained by single particle cryo-electron microscopy and 3D reconstruction. The structure unraveled detailed interactions of R4.C6 with antigenic site II on one protomer and site IV on a neighboring protomer of post-fusion RSV F protein. These findings significantly further our understanding of the antigenic complexity of the F protein and provide new insights into RSV vaccine design.
MeSH term(s)	Animals ; Antibodies, Neutralizing/chemistry ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/chemistry ; Antibodies, Viral/immunology ; Binding Sites, Antibody ; Cell Line ; Humans ; Immunoglobulin Fab Fragments/chemistry ; Immunoglobulin Fab Fragments/immunology ; Respiratory Syncytial Virus Infections/immunology ; Respiratory Syncytial Viruses/chemistry ; Respiratory Syncytial Viruses/immunology ; Spodoptera ; Viral Fusion Proteins/chemistry ; Viral Fusion Proteins/immunology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Immunoglobulin Fab Fragments ; Viral Fusion Proteins
Language	English
Publishing date	2019-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0210749
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Article ; Online: Maternal immunization with RSV fusion glycoprotein vaccine and substantial protection of neonatal baboons against respiratory syncytial virus pulmonary challenge.

Welliver, Robert C / Papin, James F / Preno, Alisha / Ivanov, Vadim / Tian, Jing-Hui / Lu, Hanxin / Guebre-Xabier, Mimi / Flyer, David / Massare, Michael J / Glenn, Greg / Ellingsworth, Larry / Smith, Gale

Vaccine

2019 Volume 38, Issue 5, Page(s) 1258–1270

Abstract	Globally, human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory infection in infants and young children. There are no licensed vaccines despite the high worldwide disease burden. RSV fusion (F) glycoprotein vaccine is the most advanced candidate for maternal immunization. In this report, a baboon maternal immunization model was used to assess the immunogenicity and protection of infants against pulmonary challenge with human RSV/A. Vaccination in the third trimester produced high anti-RSV F IgG titers and virus-neutralizing antibodies. Infants born to immunized females had high levels of serum RSV antibodies that were comparable to maternal levels at birth and persisted for over 50 days with a half-life of 14-24 days. Furthermore, infants from immunized females and challenged with RSV/A were healthy, developed less severe disease, and had only mild pulmonary inflammatory changes whereas infants born to non-vaccinated females developed more severe disease with marked to moderate interstitial pneumonia, pulmonary edema, and bronchiolar obstruction. These results support the further development of the RSV F vaccine for maternal immunization.
MeSH term(s)	Animals ; Antibodies, Neutralizing/blood ; Antibodies, Viral/blood ; Female ; Glycoproteins/administration & dosage ; Glycoproteins/immunology ; Mothers ; Papio ; Respiratory Syncytial Virus Infections/prevention & control ; Respiratory Syncytial Virus Vaccines/administration & dosage ; Respiratory Syncytial Virus, Human/immunology ; Vaccination ; Viral Fusion Proteins/administration & dosage ; Viral Fusion Proteins/immunology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Glycoproteins ; Respiratory Syncytial Virus Vaccines ; Viral Fusion Proteins
Language	English
Publishing date	2019-11-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2019.11.003
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Respiratory syncytial virus prefusogenic fusion (F) protein nanoparticle vaccine: Structure, antigenic profile, immunogenicity, and protection.

Patel, Nita / Massare, Mike J / Tian, Jing-Hui / Guebre-Xabier, Mimi / Lu, Hanxin / Zhou, Haixia / Maynard, Ernest / Scott, Daniel / Ellingsworth, Larry / Glenn, Gregory / Smith, Gale

Vaccine

2019 Volume 37, Issue 41, Page(s) 6112–6124

Abstract	Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in the very young, elderly, and immunocompromised for which there is no vaccine. The surface exposed RSV fusion (F) glycoprotein is required for membrane fusion and infection and is a desirable vaccine candidate. RSV F glycoprotein structure is dynamic and undergoes significant rearrangements during virus assembly, fusion, and infection. We have previously described an RSV fusion-inactive prefusogenic F with a mutation of one of two furin cleavage sites resulting in the p27 region on the N-terminus of F1 with a truncated fusion peptide covalently linked to F2. A processing intermediate RSV prefusogenic F has been reported in infected cells, purified F, budded virus, and elicited a strong immune response against p27 in RSV infected young children. In this report, we demonstrate that prefusogenic F, when expressed on the cell surface of Sf9 insect and human 293T cells, binds monoclonal antibodies (mAbs) that target prefusion-specific antigenic sites Ø and VIII, and mAbs targeting epitopes common to pre- and postfusion F sites II and IV. Purified prefusogenic F bound prefusion F specific mAbs to antigenic sites Ø and VIII and mAbs targeting pre- and postfusion sites II, IV, and p27. Mice immunized with prefusogenic F antigen produced significantly higher levels of anti-F IgG and RSV neutralizing antibodies than prefusion or postfusion F antigens and induced antibodies competitive with mAbs to sites Ø, VIII, II, and IV. RSV prefusogenic F neutralization antibody responses were enhanced with aluminum phosphate adjuvant and significantly higher than prefusion F. Prefusogenic F vaccine protected cotton rats against upper and lower respiratory tract infection by RSV/A. For the first time, we present the structure, antigenic profile, immunogenicity, and protective efficacy of RSV prefusogenic F nanoparticle vaccine.
MeSH term(s)	Animals ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Female ; HEK293 Cells ; Humans ; Male ; Mice ; Palivizumab/immunology ; Palivizumab/therapeutic use ; Rats ; Respiratory Syncytial Virus Infections/immunology ; Respiratory Syncytial Virus Infections/prevention & control ; Respiratory Syncytial Virus Vaccines/immunology ; Respiratory Syncytial Virus Vaccines/therapeutic use ; Respiratory Syncytial Virus, Human/immunology ; Respiratory Syncytial Virus, Human/pathogenicity ; Sf9 Cells ; Viral Fusion Proteins/immunology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Respiratory Syncytial Virus Vaccines ; Viral Fusion Proteins ; Palivizumab (DQ448MW7KS)
Language	English
Publishing date	2019-08-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2019.07.089
Database	MEDical Literature Analysis and Retrieval System OnLINE

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