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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
Proc Natl Acad Sci U S A 113 E6849-E6858 (2016)
Cited: 27 times
EuropePMC logo PMID: 27791117

Abstract

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.

Reviews - 5j3d mentioned but not cited (1)

  1. Antibody Epitopes of Pneumovirus Fusion Proteins. Huang J, Diaz D, Mousa JJ. Front Immunol 10 2778 (2019)

Articles - 5j3d mentioned but not cited (2)

  1. 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. Proc Natl Acad Sci U S A 113 E6849-E6858 (2016)
  2. Structure basis of neutralization by a novel site II/IV antibody against respiratory syncytial virus fusion protein. Xie Q, Wang Z, Ni F, Chen X, Ma J, Patel N, Lu H, Liu Y, Tian JH, Flyer D, Massare MJ, Ellingsworth L, Glenn G, Smith G, Wang Q. PLoS One 14 e0210749 (2019)


Reviews citing this publication (6)

  1. Principles of Broad and Potent Antiviral Human Antibodies: Insights for Vaccine Design. Crowe JE. Cell Host Microbe 22 193-206 (2017)
  2. Respiratory syncytial virus infection and novel interventions. Langedijk AC, Bont LJ. Nat Rev Microbiol 21 734-749 (2023)
  3. Establishing Correlates of Protection for Vaccine Development: Considerations for the Respiratory Syncytial Virus Vaccine Field. Kulkarni PS, Hurwitz JL, Simões EAF, Piedra PA. Viral Immunol 31 195-203 (2018)
  4. Modeling Immunity with Rosetta: Methods for Antibody and Antigen Design. Schoeder CT, Schmitz S, Adolf-Bryfogle J, Sevy AM, Finn JA, Sauer MF, Bozhanova NG, Mueller BK, Sangha AK, Bonet J, Sheehan JH, Kuenze G, Marlow B, Smith ST, Woods H, Bender BJ, Martina CE, Del Alamo D, Kodali P, Gulsevin A, Schief WR, Correia BE, Crowe JE, Meiler J, Moretti R. Biochemistry 60 825-846 (2021)
  5. Mass Spectrometry-Based Structural Virology. Wörner TP, Shamorkina TM, Snijder J, Heck AJR. Anal Chem 93 620-640 (2021)
  6. Patterns of antibody response during natural hRSV infection: insights for the development of new antibody-based therapies. Muñoz-Durango N, Pizarro-Ortega MS, Rey-Jurado E, Díaz FE, Bueno SM, Kalergis AM. Expert Opin Investig Drugs 27 721-731 (2018)

Articles citing this publication (18)

  1. A novel pre-fusion conformation-specific neutralizing epitope on the respiratory syncytial virus fusion protein. Mousa JJ, Kose N, Matta P, Gilchuk P, Crowe JE. Nat Microbiol 2 16271 (2017)
  2. Protect, modify, deprotect (PMD): A strategy for creating vaccines to elicit antibodies targeting a specific epitope. Weidenbacher PA, Kim PS. Proc Natl Acad Sci U S A 116 9947-9952 (2019)
  3. Alternative conformations of a major antigenic site on RSV F. Jones HG, Battles MB, Lin CC, Bianchi S, Corti D, McLellan JS. PLoS Pathog 15 e1007944 (2019)
  4. Antibody recognition of the Pneumovirus fusion protein trimer interface. Huang J, Diaz D, Mousa JJ. PLoS Pathog 16 e1008942 (2020)
  5. Human antibody recognition of antigenic site IV on Pneumovirus fusion proteins. Mousa JJ, Binshtein E, Human S, Fong RH, Alvarado G, Doranz BJ, Moore ML, Ohi MD, Crowe JE. PLoS Pathog 14 e1006837 (2018)
  6. Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design. Sun F, Wang T, Jiang J, Wang Y, Ma Z, Li Z, Han Y, Pan M, Cai J, Wang M, Zhang J. Oncotarget 8 51238-51252 (2017)
  7. Epitope-Specific Serological Assays for RSV: Conformation Matters. Phung E, Chang LA, Morabito KM, Kanekiyo M, Chen M, Nair D, Kumar A, Chen GL, Ledgerwood JE, Graham BS, Ruckwardt TJ. Vaccines (Basel) 7 E23 (2019)
  8. A Potent Neutralizing Site III-Specific Human Antibody Neutralizes Human Metapneumovirus In Vivo. Bar-Peled Y, Diaz D, Pena-Briseno A, Murray J, Huang J, Tripp RA, Mousa JJ. J Virol 93 e00342-19 (2019)
  9. Development and Standardization of a High-Throughput Multiplex Immunoassay for the Simultaneous Quantification of Specific Antibodies to Five Respiratory Syncytial Virus Proteins. Schepp RM, de Haan CAM, Wilkins D, Layman H, Graham BS, Esser MT, Berbers GAM. mSphere 4 e00236-19 (2019)
  10. A prefusion-stabilized RSV F subunit vaccine elicits B cell responses with greater breadth and potency than a postfusion F vaccine. Chang LA, Phung E, Crank MC, Morabito KM, Villafana T, Dubovsky F, Falloon J, Esser MT, Lin BC, Chen GL, Graham BS, Ruckwardt TJ. Sci Transl Med 14 eade0424 (2022)
  11. A Single Shot Pre-fusion-Stabilized Bovine RSV F Vaccine is Safe and Effective in Newborn Calves with Maternally Derived Antibodies. Riffault S, Hägglund S, Guzman E, Näslund K, Jouneau L, Dubuquoy C, Pietralunga V, Laubreton D, Boulesteix O, Gauthier D, Remot A, Boukaridi A, Falk A, Shevchenko G, Lind SB, Vargmar K, Zhang B, Kwong PD, Rodriguez MJ, Duran MG, Schwartz-Cornil I, Eléouët JF, Taylor G, Valarcher JF. Vaccines (Basel) 8 E231 (2020)
  12. Comparison of Immune Responses to Different Versions of VLP Associated Stabilized RSV Pre-Fusion F Protein. Cullen LM, Schmidt MR, Torres GM, Capoferri AA, Morrison TG. Vaccines (Basel) 7 E21 (2019)
  13. Alternative Virus-Like Particle-Associated Prefusion F Proteins as Maternal Vaccines for Respiratory Syncytial Virus. Blanco JCG, Fernando LR, Zhang W, Kamali A, Boukhvalova MS, McGinnes-Cullen L, Morrison TG. J Virol 93 e00914-19 (2019)
  14. An epitope-specific chemically defined nanoparticle vaccine for respiratory syncytial virus. Zuniga A, Rassek O, Vrohlings M, Marrero-Nodarse A, Moehle K, Robinson JA, Ghasparian A. NPJ Vaccines 6 85 (2021)
  15. The Respiratory Syncytial Virus (RSV) G Protein Enhances the Immune Responses to the RSV F Protein in an Enveloped Virus-Like Particle Vaccine Candidate. McGinnes Cullen L, Luo B, Wen Z, Zhang L, Durr E, Morrison TG. J Virol 97 e0190022 (2023)
  16. Comparisons of Antibody Populations in Different Pre-Fusion F VLP-Immunized Cotton Rat Dams and Their Offspring. Cullen LM, Boukhvalova MS, Blanco JCG, Morrison TG. Vaccines (Basel) 8 E133 (2020)
  17. Double-Blind, Placebo-Controlled, Dose-Escalating Study Evaluating the Safety and Immunogenicity of an Epitope-Specific Chemically Defined Nanoparticle RSV Vaccine. Leroux-Roels I, Bruhwyler J, Stergiou L, Sumeray M, Joye J, Maes C, Lambert PH, Leroux-Roels G. Vaccines (Basel) 11 367 (2023)
  18. Computational epitope mapping of class I fusion proteins using low complexity supervised learning methods. Fischer MFS, Crowe JE, Meiler J. PLoS Comput Biol 18 e1010230 (2022)


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