A chimeric EBV gp350/220-based VLP replicates the virion B-cell attachment mechanism and elicits long-lasting neutralizing antibodies in mice

Journal of Translational Medicine

Joyce D Fingeroth¹  Trudy G Morrison¹  Robert W Finberg¹  Deep Agnani²  Juan Avendano²  Timelia Tison⁴  Rujapak Sutiwisesak⁴  Agapi Parcharidou²  Lori W McGinnes³  Matthew R Muraswki²  Javier Gordon Ogembo⁴ 

[1] Program in Immunology and Microbiology, University of Massachusetts Medical School, Worcester, MA, USA;Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, UK;Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA;Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB Room 323, Worcester 01605, MA, USA

关键词: Neutralization;    Vaccine;    VLP;    NDV;    EBV;   

Others  :  1137571
DOI  :  10.1186/s12967-015-0415-2

 received in 2014-12-01, accepted in 2015-01-20,  发布年份 2015

【 摘 要 】

Epstein-Barr virus (EBV), an oncogenic gammaherpesvirus, causes acute infectious mononucleosis (AIM) and is linked to the development of several human malignancies. There is an urgent need for a vaccine that is safe, prevents infection and/or limits disease. Unique among human herpesviruses, glycoprotein (gp)350/220, which initiates EBV attachment to susceptible host cells, is the major ligand on the EBV envelope and is highly conserved. Interaction between gp350/220 and complement receptor type 2 (CR2)/CD21 and/or (CR1)/CD35 on B-cells is required for infection. Potent antibody responses to gp350/220 occur in animal models and humans. Thus, gp350/220 provides an attractive candidate for prophylactic subunit vaccine development. However, in a recent Phase II clinical trial immunization with soluble recombinant gp350 reduced the incidence of AIM, but did not prevent infection. Despite various attempts to produce an EBV vaccine, no vaccine is licensed. Herein we describe a sub-unit vaccine against EBV based on a novel Newcastle disease virus (NDV)-virus-like particle (VLP) platform consisting of EBVgp350/220 ectodomain fused to NDV-fusion (F) protein. The chimeric protein EBVgp350/220-F is incorporated into the membrane of a VLP composed of the NDV matrix and nucleoprotein. The particles resemble native EBV in diameter and shape and bind CD21 and CD35. Immunization of BALB/c mice with EBVgp350/220-F VLPs elicited strong, long-lasting neutralizing antibody responses when assessed in vitro. This chimeric VLP is predicted to provide a superior safety profile as it is efficiently produced in Chinese hamster ovary (CHO) cells using a platform devoid of human nucleic acid and EBV-transforming genes.

【 授权许可】

   
2015 Ogembo et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Epstein-Barr Virus Rickinson AB, Kieff E: Epstein-Barr Virus. In Fields Virology. 5th edition. Edited by Knipe D, Howley P. Lippincott Wilkins and Williams, Philadelphia; 2007:2680-700.
• [2]Hjalgrim H, Friborg J, Melbye M: The epidemiology of EBV and its association with malignant disease. Cmbridge University Press, Cambridge; 2007.
• [3]Balfour HH Jr, Odumade OA, Schmeling DO, Mullan BD, Ed JA, Knight JA, et al.: Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis 2013, 207:80-8.
• [4]Luzuriaga K, Sullivan JL: Infectious mononucleosis. New England J Med 2010, 362:1993-2000.
• [5]Hochberg DR, Thorley-Lawson DA: Quantitative detection of viral gene expression in populations of Epstein-Barr virus-infected cells in vivo. Methods Mol Biol 2005, 292:39-56.
• [6]Carbone A, Vaccher E, Gloghini A, Pantanowitz L, Abayomi A, de Paoli P, et al.: Diagnosis and management of lymphomas and other cancers in HIV-infected patients. Nat Rev Clin Oncol 2014, 11:223-38.
• [7]Gottschalk S, Rooney CM, Heslop HE: Post-transplant lymphoproliferative disorders. Annu Rev Med 2005, 56:29-44.
• [8]Allen UD, Farkas G, Hebert D, Weitzman S, Stephens D, Petric M, et al.: Risk factors for post-transplant lymphoproliferative disorder in pediatric patients: a case–control study. Pediatr Transplant 2005, 9:450-5.
• [9]Paya C, Fung J, Nalesnik M, Kieff E, Green M, Gores G, et al.: ASTS/ASTP EBV-PTLD Task Force and The Mayo Clinic Organized International Consensus Development Meeting: Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. Transplantation 1999, 68:1517-25.
• [10]Schiller JT, Lowy DR: Vaccines to prevent infections by oncoviruses. Annu Rev Microbiol 2010, 64:23-41.
• [11]Kwak K, Yemelyanova A, Roden RB: Prevention of cancer by prophylactic human papillomavirus vaccines. Curr Opin Immunol 2011, 23:244-51.
• [12]Thorley-Lawson DA, Geilinger K: Monoclonal antibodies against the major glycoprotein (gp350/220) of Epstein-Barr virus neutralize infectivity. Proc Natl Acad Sci U S A 1980, 77:5307-11.
• [13]Fingeroth JD, Weis JJ, Tedder TF, Strominger JL, Biro PA, Fearon DT: Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc Natl Acad Sci U S A 1984, 81:4510-4.
• [14]Ogembo JG, Kannan L, Ghiran I, Nicholson-Weller A, Finberg RW, Tsokos GC, et al.: Human complement receptor type 1/CD35 is an Epstein-Barr Virus receptor. Cell Rep 2013, 3:371-85.
• [15]Tanner J, Weis J, Fearon D, Whang Y, Kieff E: Epstein-Barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping, and endocytosis. Cell 1987, 50:203-13.
• [16]Cohen JI, Fauci AS, Varmus H, Nabel GJ: Epstein-Barr virus: an important vaccine target for cancer prevention. Sci Transl Med 2011, 3:107fs107.
• [17]Sokal EM, Hoppenbrouwers K, Vandermeulen C, Moutschen M, Léonard P, Moreels A, et al.: Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis 2007, 196:1749-53.
• [18]Kingsman SM, Kingsman AJ: Polyvalent recombinant antigens: a new vaccine strategy. Vaccine 1988, 6:304-6.
• [19]Link A, Zabel F, Schnetzler Y, Titz A, Brombacher F, Bachmann MF: Innate immunity mediates follicular transport of particulate but not soluble protein antigen. J Immunol 2012, 188:3724-33.
• [20]Chackerian B: Virus-like particles: flexible platforms for vaccine development. Expert Rev Vaccines 2007, 6:381-90.
• [21]Pavlova S, Feederle R, Gartner K, Fuchs W, Granzow H, Delecluse HJ: An Epstein-Barr virus mutant produces immunogenic defective particles devoid of viral DNA. J Virol 2013, 87:2011-22.
• [22]Ruiss R, Jochum S, Wanner G, Reisbach G, Hammerschmidt W, Zeidler R: A virus-like particle-based Epstein-Barr virus vaccine. J Virol 2011, 85:13105-13.
• [23]Speck P, Longnecker R: Epstein-Barr virus (EBV) infection visualized by EGFP expression demonstrates dependence on known mediators of EBV entry. Arch Virol 1999, 144:1123-37.
• [24]Biggin M, Farrell PJ, Barrell BG: Transcription and DNA sequence of the BamHI L fragment of B95-8 Epstein-Barr virus. EMBO J 1984, 3:1083-90.
• [25]Jun-ichi M, Satoshi T, Kimi A, Fumi T, Akira T, Kiyoshi T, et al.: Expression vector system based on the chicken β-actin promoter directs efficient production of interleukin-5. Gene 1989, 79:269-77.
• [26]Pantua HD, McGinnes LW, Peeples ME, Morrison TG: Requirements for the assembly and release of Newcastle disease virus-like particles. J Virolol 2006, 80:11062-73.
• [27]McGinnes LW, Morrison TG: Newcastle disease virus‐like particles: preparation, purification, quantification, and incorporation of foreign glycoproteins. Curr Protoc Microbiol 2013, 18.12:11-8. 12. 21
• [28]Muratori C, D’Aloja P, Superti F, Tinari A, Sol-Foulon N, Sparacio S, et al.: Generation and characterization of a stable cell population releasing fluorescent HIV-1-based Virus Like Particles in an inducible way. BMC Biotechnol 2006, 6:52. BioMed Central Full Text
• [29]McGinnes LW, Reitter JN, Gravel K, Morrison TG: Evidence for mixed membrane topology of the newcastle disease virus fusion protein. J Virolol 2003, 77:1951-63.
• [30]Battisti AJ, Meng G, Winkler DC, McGinnes LW, Plevka P, Steven AC, et al.: Structure and assembly of a paramyxovirus matrix protein. Proc Natl Acad Sci 2012, 109:13996-4000.
• [31]Ghiran I, Glodek AM, Weaver G, Klickstein LB, Nicholson-Weller A: Ligation of erythrocyte CR1 induces its clustering in complex with scaffolding protein FAP-1. Blood 2008, 112:3465-73.
• [32]Murawski MR, McGinnes LW, Finberg RW, Kurt-Jones EA, Massare MJ, Smith G, et al.: Newcastle disease virus-like particles containing respiratory syncytial virus G protein induced protection in BALB/c mice, with no evidence of immunopathology. J Virol 2010, 84:1110-23.
• [33]Sashihara J, Burbelo PD, Savoldo B, Pierson TC, Cohen JI: Human antibody titers to Epstein-Barr Virus (EBV) gp350 correlate with neutralization of infectivity better than antibody titers to EBV gp42 using a rapid flow cytometry-based EBV neutralization assay. Virology 2009, 391:249-56.
• [34]Pantua H, McGinnes LW, Leszyk J, Morrison TG: Characterization of an alternate form of Newcastle disease virus fusion protein. J Virol 2005, 79:11660-70.
• [35]McGinnes LW, Gravel KA, Finberg RW, Kurt-Jones EA, Massare MJ, Smith G, et al.: Assembly and immunological properties of Newcastle disease virus-like particles containing the respiratory syncytial virus F and G proteins. J Virol 2011, 85:366-77.
• [36]Tanner J, Whang Y, Sample J, Sears A, Kieff E: Soluble gp350/220 and deletion mutant glycoproteins block Epstein-Barr virus adsorption to lymphocytes. J Virol 1988, 62:4452-64.
• [37]Germi R, Effantin G, Grossi L, Ruigrok RW, Morand P, Schoehn G: Three-dimensional structure of the Epstein–Barr virus capsid. J Gen Virol 2012, 93:1769-73.
• [38]Braun M, Jandus C, Maurer P, Hammann-Haenni A, Schwarz K, Bachmann MF, et al.: Virus-like particles induce robust human T-helper cell responses. Eur J Immunol 2012, 42:330-40.
• [39]Civoli F, Kroenke MA, Reynhardt K, Zhuang Y, Kaliyaperumal A, Gupta S: Development and optimization of neutralizing antibody assays to monitor clinical immunogenicity. Bioanalysis 2012, 4:2725-35.
• [40]Epstein MA: Epstein-Barr virus–is it time to develop a vaccine program? J Natl Cancer Inst 1976, 56:697-700.
• [41]Dudek T, Knipe DM: Replication-defective viruses as vaccines and vaccine vectors. Virology 2006, 344:230-9.
• [42]Mok H, Cheng X, Xu Q, Zengel JR, Parhy B, Zhao J, et al.: Evaluation of measles vaccine virus as a vector to deliver respiratory syncytial virus fusion protein or Epstein-Barr virus glycoprotein gp350. Open Virol J 2012, 6:12.
• [43]Taylor GS, Jia H, Harrington K, Lee LW, Turner J, Ladell K, et al.: A recombinant modified vaccinia Ankara vaccine encoding Epstein-Barr Virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer. Clin Cancer Res 2014, 20:5009-22.
• [44]Henson BW, Perkins EM, Cothran JE, Desai P: Self-assembly of Epstein-Barr virus capsids. J Virol 2009, 83:3877-90.
• [45]Cui X, Cao Z, Sen G, Chattopadhyay G, Fuller DH, Fuller JT, et al.: A novel tetrameric gp350 1–470 as a potential Epstein-Barr virus vaccine. Vaccine 2013, 31:3039-45.
• [46]Moutschen M, Leonard P, Sokal EM, Smets F, Haumont M, Mazzu P, et al.: Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein-Barr virus vaccine in healthy adults. Vaccine 2007, 25:4697-705.
• [47]Rees L, Tizard EJ, Morgan AJ, Cubitt WD, Finerty S, Oyewole-Eletu TA, et al.: A phase I trial of epstein-barr virus gp350 vaccine for children with chronic kidney disease awaiting transplantation. Transplantation 2009, 88:1025-9.
• [48]Walsh G: Biopharmaceutical benchmarks 2006. Nat Biotechnol 2006, 24:769-76.
• [49]Hesse F, Wagner R: Developments and improvements in the manufacturing of human therapeutics with mammalian cell cultures. Trends Biotechnol 2000, 18:173-80.
• [50]Chatterjee B, Leung CS, Münz C: Animal models of Epstein Barr virus infection. J Immunol Methods 2014, 410:80-7.
• [51]Yajima M, Imadome K, Nakagawa A, Watanabe S, Terashima K, Nakamura H, et al.: A new humanized mouse model of Epstein-Barr virus infection that reproduces persistent infection, lymphoproliferative disorder, and cell-mediated and humoral immune responses. J Infect Dis 2008, 198:673-82.
• [52]Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT: Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A 1992, 89:12180-4.
• [53]Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, et al.: A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002, 347:1645-51.