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Structural basis for nonneutralizing antibody competition at antigenic site II of the respiratory syncytial virus fusion protein.
Mousa JJ, Sauer MF, Sevy AM, Finn JA, Bates JT, Alvarado G, King HG, Loerinc LB, Fong RH, Doranz BJ, Correia BE, Kalyuzhniy O, Wen X, Jardetzky TS, Schief WR, Ohi MD, Meiler J, Crowe JE
(2016) Proc Natl Acad Sci U S A 113: E6849-E6858
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Antibodies, Viral, Antiviral Agents, Cell Line, Crystallography, X-Ray, Epitope Mapping, Epitopes, Humans, Mice, Mutagenesis, Palivizumab, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Virus, Human, Viral Fusion Proteins
Show Abstract · Added April 8, 2017
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 helix-loop-helix epitope-scaffold vaccines distinguished neutralizing from nonneutralizing site II antibodies.
1 Communities
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17 MeSH Terms
Thermoresponsive Polymer Nanoparticles Co-deliver RSV F Trimers with a TLR-7/8 Adjuvant.
Francica JR, Lynn GM, Laga R, Joyce MG, Ruckwardt TJ, Morabito KM, Chen M, Chaudhuri R, Zhang B, Sastry M, Druz A, Ko K, Choe M, Pechar M, Georgiev IS, Kueltzo LA, Seymour LW, Mascola JR, Kwong PD, Graham BS, Seder RA
(2016) Bioconjug Chem 27: 2372-2385
MeSH Terms: Adjuvants, Immunologic, Animals, Antibodies, Neutralizing, Chemistry Techniques, Synthetic, Drug Delivery Systems, Female, Mice, Inbred Strains, Nanoparticles, Polymers, Respiratory Syncytial Virus Vaccines, Toll-Like Receptor 7, Toll-Like Receptor 8, Vaccines, Synthetic, Viral Fusion Proteins
Show Abstract · Added May 3, 2017
Structure-based vaccine design has been used to develop immunogens that display conserved neutralization sites on pathogens such as HIV-1, respiratory syncytial virus (RSV), and influenza. Improving the immunogenicity of these designed immunogens with adjuvants will require formulations that do not alter protein antigenicity. Here, we show that nanoparticle-forming thermoresponsive polymers (TRP) allow for co-delivery of RSV fusion (F) protein trimers with Toll-like receptor 7 and 8 agonists (TLR-7/8a) to enhance protective immunity. Although primary amine conjugation of TLR-7/8a to F trimers severely disrupted the recognition of critical neutralizing epitopes, F trimers site-selectively coupled to TRP nanoparticles retained appropriate antigenicity and elicited high titers of prefusion-specific, T1 isotype anti-RSV F antibodies following vaccination. Moreover, coupling F trimers to TRP delivering TLR-7/8a resulted in ∼3-fold higher binding and neutralizing antibody titers than soluble F trimers admixed with TLR-7/8a and conferred protection from intranasal RSV challenge. Overall, these data show that TRP nanoparticles may provide a broadly applicable platform for eliciting neutralizing antibodies to structure-dependent epitopes on RSV, influenza, HIV-1, or other pathogens.
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14 MeSH Terms
Proof of principle for epitope-focused vaccine design.
Correia BE, Bates JT, Loomis RJ, Baneyx G, Carrico C, Jardine JG, Rupert P, Correnti C, Kalyuzhniy O, Vittal V, Connell MJ, Stevens E, Schroeter A, Chen M, Macpherson S, Serra AM, Adachi Y, Holmes MA, Li Y, Klevit RE, Graham BS, Wyatt RT, Baker D, Strong RK, Crowe JE, Johnson PR, Schief WR
(2014) Nature 507: 201-6
MeSH Terms: Amino Acid Motifs, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antigens, Viral, Crystallography, X-Ray, Drug Design, Enzyme-Linked Immunosorbent Assay, Epitopes, Macaca mulatta, Male, Mice, Mice, Inbred BALB C, Models, Molecular, Neutralization Tests, Protein Conformation, Protein Stability, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Viruses
Show Abstract · Added March 20, 2014
Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.
0 Communities
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20 MeSH Terms
Enhancement of the CD8+ T cell response to a subdominant epitope of respiratory syncytial virus by deletion of an immunodominant epitope.
Mok H, Lee S, Wright DW, Crowe JE
(2008) Vaccine 26: 4775-82
MeSH Terms: Amino Acid Substitution, Animals, CD8-Positive T-Lymphocytes, Epitopes, T-Lymphocyte, Female, Immunodominant Epitopes, Mice, Mice, Inbred BALB C, Plasmids, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Viruses, Vaccines, DNA, Viral Proteins
Show Abstract · Added August 6, 2012
Cytotoxic T lymphocytes (CTLs) are critical for the control of respiratory syncytial virus infection (RSV) in humans and mice. Recently, we identified a new H-2K(d)-restricted subdominant epitope in the respiratory syncytial virus M2 protein. In this study, we investigated if modification of anchor residues at positions 2 and 9 in the dominant M2(82-90) epitope in the M2 protein would alter the CTL epitope dominance hierarchy following immunization with plasmid DNA encoding M2 proteins. We showed that immunogenicity of the subdominant epitope M2(127-135) was enhanced when the anchor residues of the dominant epitope were mutated, suggesting that the immunodominant epitope induces a suppression of response to the subdominant epitope.
0 Communities
1 Members
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13 MeSH Terms
Venezuelan equine encephalitis virus replicon particles encoding respiratory syncytial virus surface glycoproteins induce protective mucosal responses in mice and cotton rats.
Mok H, Lee S, Utley TJ, Shepherd BE, Polosukhin VV, Collier ML, Davis NL, Johnston RE, Crowe JE
(2007) J Virol 81: 13710-22
MeSH Terms: Animals, Cell Line, Cricetinae, Encephalitis Virus, Venezuelan Equine, Immunity, Mucosal, Lung, Mice, Mice, Inbred BALB C, Replicon, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Virus, Human, Sigmodontinae, Vaccination, Viral Envelope Proteins, Viral Fusion Proteins, Virion
Show Abstract · Added August 6, 2012
Respiratory syncytial virus (RSV) is an important viral pathogen that causes severe lower respiratory tract infection in infants, the elderly, and immunocompromised individuals. There are no licensed RSV vaccines to date. To prevent RSV infection, immune responses in both the upper and lower respiratory tracts are required. Previously, immunization with Venezuelan equine encephalitis virus replicon particles (VRPs) demonstrated effectiveness in inducing mucosal protection against various pathogens. In this study, we developed VRPs encoding RSV fusion (F) or attachment (G) glycoproteins and evaluated the immunogenicity and efficacy of these vaccine candidates in mice and cotton rats. VRPs, when administered intranasally, induced surface glycoprotein-specific virus neutralizing antibodies in serum and immunoglobulin A (IgA) antibodies in secretions at the respiratory mucosa. In addition, fusion protein-encoding VRPs induced gamma interferon (IFN-gamma)-secreting T cells in the lungs and spleen, as measured by reaction with an H-2K(d)-restricted CD8(+) T-cell epitope. In animals vaccinated with F protein VRPs, challenge virus replication was reduced below the level of detection in both the upper and lower respiratory tracts following intranasal RSV challenge, while in those vaccinated with G protein VRPs, challenge virus was detected in the upper but not the lower respiratory tract. Close examination of histopathology of the lungs of vaccinated animals following RSV challenge revealed no enhanced inflammation. Immunization with VRPs induced balanced Th1/Th2 immune responses, as measured by the cytokine profile in the lungs and antibody isotype of the humoral immune response. These results represent an important first step toward the use of VRPs encoding RSV proteins as a prophylactic vaccine for RSV.
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17 MeSH Terms
Recombinant Sendai virus as a novel vaccine candidate for respiratory syncytial virus.
Takimoto T, Hurwitz JL, Zhan X, Krishnamurthy S, Prouser C, Brown B, Coleclough C, Boyd K, Scroggs RA, Portner A, Slobod KS
(2005) Viral Immunol 18: 255-66
MeSH Terms: Animals, Child, Genetic Vectors, History, 21st Century, Humans, Mice, Recombination, Genetic, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Virus, Human, Sendai virus, Vaccines, Synthetic
Show Abstract · Added March 20, 2014
Respiratory syncytial virus (RSV) is among the most important and serious pediatric respiratory diseases, and yet after more than four decades of research an effective vaccine is still unavailable. This review examines the role of the immune response in reducing disease severity; considers the history of RSV vaccine development; and advocates the potential utility of Sendai virus (a murine paramyxovirus) as a xenogenic vaccine vector for the delivery of RSV antigens. The immunogenicity and protective efficacy of RSV-recombinant Sendai virus vectors constructed using reverse genetics is examined. RSV-recombinant Sendai virus is easy to grow (i.e., achieves extremely high titers in eggs), is easy to administer (intranasal drops), and elicits both B- and T-cell responses leading to protection from RSV challenge in a small-animal model. Unmodified Sendai virus is currently being studied in clinical trials as a vaccine for its closely related human cognate (human parainfluenza virus type 1). Sendai virus may prove an enormously valuable vaccine platform, permitting the delivery of recombinants targeting important pediatric respiratory pathogens, RSV chief among them.
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12 MeSH Terms
Recombinant Sendai virus expressing the G glycoprotein of respiratory syncytial virus (RSV) elicits immune protection against RSV.
Takimoto T, Hurwitz JL, Coleclough C, Prouser C, Krishnamurthy S, Zhan X, Boyd K, Scroggs RA, Brown B, Nagai Y, Portner A, Slobod KS
(2004) J Virol 78: 6043-7
MeSH Terms: Animals, Immunization, Respiratory Syncytial Virus Vaccines, Sendai virus, Sigmodontinae, Vaccines, Synthetic, Viral Proteins
Show Abstract · Added March 20, 2014
Although RSV causes serious pediatric respiratory disease, an effective vaccine does not exist. To capture the strengths of a live virus vaccine, we have used the murine parainfluenza virus type 1 (Sendai virus [SV]) as a xenogeneic vector to deliver the G glycoprotein of RSV. It was previously shown (J. L. Hurwitz, K. F. Soike, M. Y. Sangster, A. Portner, R. E. Sealy, D. H. Dawson, and C. Coleclough, Vaccine 15:533-540, 1997) that intranasal SV protected African green monkeys from challenge with the related human parainfluenza virus type 1 (hPIV1), and SV has advanced to clinical trials as a vaccine for hPIV1 (K. S. Slobod, J. L. Shenep, J. Lujan-Zilbermann, K. Allison, B. Brown, R. A. Scroggs, A. Portner, C. Coleclough, and J. L. Hurwitz, Vaccine, in press). Recombinant SV expressing RSV G glycoprotein was prepared by using reverse genetics, and intranasal inoculation of cotton rats elicited RSV-specific antibody and elicited protection from RSV challenge. RSV G-recombinant SV is thus a promising live virus vaccine candidate for RSV.
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7 MeSH Terms
NK T cells contribute to expansion of CD8(+) T cells and amplification of antiviral immune responses to respiratory syncytial virus.
Johnson TR, Hong S, Van Kaer L, Koezuka Y, Graham BS
(2002) J Virol 76: 4294-303
MeSH Terms: Animals, Antigen Presentation, Antigens, CD1, Antigens, CD1d, Galactosylceramides, Immunization, Killer Cells, Natural, Ligands, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Viruses, T-Lymphocytes, Cytotoxic, Viral Proteins
Show Abstract · Added December 10, 2013
CD1d-deficient mice have normal numbers of T lymphocytes and natural killer cells but lack Valpha14(+) natural killer T cells. Respiratory syncytial virus (RSV) immunopathogenesis was evaluated in 129xC57BL/6, C57BL/6, and BALB/c CD1d(-/-) mice. CD8(+) T lymphocytes were reduced in CD1d(-/-) mice of all strains, as shown by cell surface staining and major histocompatibility complex class I tetramer analysis, and resulted in strain-specific alterations in illness, viral clearance, and gamma interferon (IFN-gamma) production. Transient activation of NK T cells in CD1d(+/+) mice by alpha-GalCer resulted in reduced illness and delayed viral clearance. These data suggest that early IFN-gamma production and efficient induction of CD8(+)-T-cell responses during primary RSV infection require CD1d-dependent events. We also tested the ability of alpha-GalCer as an adjuvant to modulate the type 2 immune responses induced by RSV glycoprotein G or formalin-inactivated RSV immunization. However, immunized CD1-deficient or alpha-GalCer-treated wild-type mice did not exhibit diminished disease following RSV challenge. Rather, some disease parameters, including cytokine production, eosinophilia, and viral clearance, were increased. These findings indicate that CD1d-dependent NK T cells play a role in expansion of CD8(+) T cells and amplification of antiviral responses to RSV.
0 Communities
1 Members
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17 MeSH Terms
Influence of maternal antibodies on neonatal immunization against respiratory viruses.
Crowe JE
(2001) Clin Infect Dis 33: 1720-7
MeSH Terms: Antibodies, Viral, Female, Humans, Immunity, Maternally-Acquired, Immunization, Infant, Newborn, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus Vaccines, Respiratory Syncytial Viruses, Respiratory Tract Infections
Show Abstract · Added January 26, 2016
Vaccines that successfully prevent severe infant respiratory virus diseases should induce protection at a very young age because of the low age of patients who are hospitalized owing to these viruses. Candidate respiratory virus vaccines are being tested in infants who are naïve to infection but seropositive to the viral agents because they possess maternal IgG antibodies (Abs). Transplacental maternal Abs may be partially protective against disease caused by respiratory virus infections. Carefully conducted studies have shown that these Abs can also profoundly suppress or enhance infant immune responses to immunization. The mechanisms underlying regulation of immune responses to viruses by maternal Abs are under investigation. This article explores the current knowledge regarding the effect of maternal Abs on respiratory virus and measles virus immunization, and it reviews the current approaches to overcoming Ab-mediated immunosuppression.
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10 MeSH Terms
Respiratory syncytial virus vaccine development.
Crowe JE
(2001) Vaccine 20 Suppl 1: S32-7
MeSH Terms: Animals, Genetic Engineering, Humans, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus Vaccines, Vaccines, DNA, Vaccines, Inactivated, Vaccines, Subunit
Show Abstract · Added August 6, 2012
Development of an RSV vaccine for infants has been hindered by the lack of an ideal animal model that exhibits disease, and the challenge of effectively immunizing very young infants who are immunologically immature. Nevertheless, significant progress has been made recently in developing live attenuated viruses and protein subunit vaccine candidates. Numerous vaccine candidates are currently in early clinical trials. This paper reviews the significant obstacles to development of RSV vaccines, and the progress made to date.
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8 MeSH Terms