1887

Abstract

Human cytomegalovirus (HCMV) remains an important cause of mortality in immune-compromised transplant patients and following congenital infection. Such is the burden, an effective vaccine strategy is considered to be of the highest priority. The most successful vaccines to date have focused on generating immune responses against glycoprotein B (gB) – a protein essential for HCMV fusion and entry. We have previously reported that an important component of the humoral immune response elicited by gB/MF59 vaccination of patients awaiting transplant is the induction of non-neutralizing antibodies that target cell-associated virus with little evidence of concomitant classical neutralizing antibodies. Here we report that a modified neutralization assay that promotes prolonged binding of HCMV to the cell surface reveals the presence of neutralizing antibodies in sera taken from gB-vaccinated patients that cannot be detected using standard assays. We go on to show that this is not a general feature of gB-neutralizing antibodies, suggesting that specific antibody responses induced by vaccination could be important. Although we can find no evidence that these neutralizing antibody responses are a correlate of protection in transplant recipients their identification demonstrates the utility of the approach in identifying these responses. We hypothesize that further characterization has the potential to aid the identification of functions within gB that are important during the entry process and could potentially improve future vaccine strategies directed against gB if they prove to be effective against HCMV at higher concentrations.

Funding
This study was supported by the:
  • Rosetrees Trust (Award A2207)
    • Principle Award Recipient: MatthewB Reeves
  • Rosetrees Trust (Award A1601)
    • Principle Award Recipient: MatthewB Reeves
  • Wellcome Trust (Award WT204870/Z/16/Z)
    • Principle Award Recipient: PaulD Griffiths
  • Wellcome Trust (Award WT204870/Z/16/Z)
    • Principle Award Recipient: MatthewB Reeves
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2023-06-13
2024-05-23
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References

  1. Gatherer D, Depledge DP, Hartley CA, Szpara ML, Vaz PK et al. ICTV Virus Taxonomy Profile: Herpesviridae 2021. J Gen Virol 2021; 102:10 [View Article]
    [Google Scholar]
  2. Griffiths P, Reeves M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat Rev Microbiol 2021; 19:759–773 [View Article] [PubMed]
    [Google Scholar]
  3. Lazzarotto T, Guerra B, Gabrielli L, Lanari M, Landini MP. Update on the prevention, diagnosis and management of cytomegalovirus infection during pregnancy. Clin Microbiol Infect 2011; 17:1285–1293 [View Article] [PubMed]
    [Google Scholar]
  4. Arvin AM, Fast P, Myers M, Plotkin S, Rabinovich R et al. Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. Clin Infect Dis 2004; 39:233–239 [View Article] [PubMed]
    [Google Scholar]
  5. Isaacson MK, Compton T. Human cytomegalovirus glycoprotein B is required for virus entry and cell-to-cell spread but not for virion attachment, assembly, or egress. J Virol 2009; 83:3891–3903 [View Article] [PubMed]
    [Google Scholar]
  6. Isaacson MK, Juckem LK, Compton T. Virus entry and innate immune activation. Curr Top Microbiol Immunol 2008; 325:85–100 [View Article] [PubMed]
    [Google Scholar]
  7. Griffiths PD, Stanton A, McCarrell E, Smith C, Osman M et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet 2011; 377:1256–1263 [View Article] [PubMed]
    [Google Scholar]
  8. Bernstein DI, Munoz FM, Callahan ST, Rupp R, Wootton SH et al. Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: a randomized clinical trial. Vaccine 2016; 34:313–319 [View Article] [PubMed]
    [Google Scholar]
  9. Pass RF. Development and evidence for efficacy of CMV glycoprotein B vaccine with MF59 adjuvant. J Clin Virol 2009; 46 Suppl 4:S73–6 [View Article] [PubMed]
    [Google Scholar]
  10. Meyer H, Masuho Y, Mach M. The gp116 of the gp58/116 complex of human cytomegalovirus represents the amino-terminal part of the precursor molecule and contains a neutralizing epitope. J Gen Virol 1990; 71 (Pt 10):2443–2450 [View Article] [PubMed]
    [Google Scholar]
  11. Meyer H, Sundqvist VA, Pereira L, Mach M. Glycoprotein gp116 of human cytomegalovirus contains epitopes for strain-common and strain-specific antibodies. J Gen Virol 1992; 73 (Pt 9):2375–2383 [View Article] [PubMed]
    [Google Scholar]
  12. Spindler N, Diestel U, Stump JD, Wiegers A-K, Winkler TH et al. Structural basis for the recognition of human cytomegalovirus glycoprotein B by a neutralizing human antibody. PLoS Pathog 2014; 10:e1004377 [View Article] [PubMed]
    [Google Scholar]
  13. Spindler N, Rücker P, Pötzsch S, Diestel U, Sticht H et al. Characterization of a discontinuous neutralizing epitope on glycoprotein B of human cytomegalovirus. J Virol 2013; 87:8927–8939 [View Article] [PubMed]
    [Google Scholar]
  14. Pötzsch S, Spindler N, Wiegers A-K, Fisch T, Rücker P et al. B cell repertoire analysis identifies new antigenic domains on glycoprotein B of human cytomegalovirus which are target of neutralizing antibodies. PLoS Pathog 2011; 7:e1002172 [View Article] [PubMed]
    [Google Scholar]
  15. Ohlin M, Sundqvist VA, Mach M, Wahren B, Borrebaeck CA. Fine specificity of the human immune response to the major neutralization epitopes expressed on cytomegalovirus gp58/116 (gB), as determined with human monoclonal antibodies. J Virol 1993; 67:703–710 [View Article] [PubMed]
    [Google Scholar]
  16. Wagner B, Kropff B, Kalbacher H, Britt W, Sundqvist VA et al. A continuous sequence of more than 70 amino acids is essential for antibody binding to the dominant antigenic site of glycoprotein gp58 of human cytomegalovirus. J Virol 1992; 66:5290–5297 [View Article] [PubMed]
    [Google Scholar]
  17. Ai Y, Wu C, Zhang M, Jaijyan DK, Liu T et al. Neutralization epitopes in trimer and pentamer complexes recognized by potent cytomegalovirus-neutralizing human monoclonal antibodies. Microbiol Spectr 2022; 10:e0139322 [View Article] [PubMed]
    [Google Scholar]
  18. Vanarsdall AL, Chin AL, Liu J, Jardetzky TS, Mudd JO et al. HCMV trimer- and pentamer-specific antibodies synergize for virus neutralization but do not correlate with congenital transmission. Proc Natl Acad Sci 2019; 116:3728–3733 [View Article] [PubMed]
    [Google Scholar]
  19. Chandramouli S, Malito E, Nguyen T, Luisi K, Donnarumma D et al. Structural basis for potent antibody-mediated neutralization of human cytomegalovirus. Sci Immunol 2017; 2:12 [View Article] [PubMed]
    [Google Scholar]
  20. Kschonsak M, Rougé L, Arthur CP, Hoangdung H, Patel N et al. Structures of HCMV trimer reveal the basis for receptor recognition and cell entry. Cell 2021; 184:1232–1244 [View Article] [PubMed]
    [Google Scholar]
  21. Fouts AE, Comps-Agrar L, Stengel KF, Ellerman D, Schoeffler AJ et al. Mechanism for neutralizing activity by the anti-CMV gH/gL monoclonal antibody MSL-109. Proc Natl Acad Sci 2014; 111:8209–8214 [View Article] [PubMed]
    [Google Scholar]
  22. Chiuppesi F, Wussow F, Johnson E, Bian C, Zhuo M et al. Vaccine-derived neutralizing antibodies to the human cytomegalovirus gH/gL pentamer potently block primary cytotrophoblast infection. J Virol 2015; 89:11884–11898 [View Article] [PubMed]
    [Google Scholar]
  23. Speckner A, Glykofrydes D, Ohlin M, Mach M. Antigenic domain 1 of human cytomegalovirus glycoprotein B induces a multitude of different antibodies which, when combined, results in incomplete virus neutralization. J Gen Virol 1999; 80 (Pt 8):2183–2191 [View Article] [PubMed]
    [Google Scholar]
  24. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 2005; 202:673–685 [View Article] [PubMed]
    [Google Scholar]
  25. Jackson SE, Sedikides GX, Mason GM, Okecha G, Wills MR. Human cytomegalovirus (HCMV)-specific CD4+ T cells are polyfunctional and can respond to HCMV-infected dendritic cells In Vitro. J Virol 2017; 91:e02128-16 [View Article] [PubMed]
    [Google Scholar]
  26. Nelson CS, Baraniak I, Lilleri D, Reeves MB, Griffiths PD et al. Immune correlates of protection against human cytomegalovirus acquisition, replication, and disease. J Infect Dis 2020; 221:S45–S59 [View Article] [PubMed]
    [Google Scholar]
  27. Pass RF, Zhang C, Evans A, Simpson T, Andrews W et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med 2009; 360:1191–1199 [View Article] [PubMed]
    [Google Scholar]
  28. Baraniak I, Kropff B, Ambrose L, McIntosh M, McLean GR et al. Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies. Proc Natl Acad Sci 2018; 115:6273–6278 [View Article] [PubMed]
    [Google Scholar]
  29. Nelson CS, Huffman T, Jenks JA, Cisneros de la Rosa E, Xie G et al. HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions. Proc Natl Acad Sci 2018; 115:6267–6272 [View Article] [PubMed]
    [Google Scholar]
  30. Baraniak I, Kern F, Holenya P, Griffiths P, Reeves M. Original antigenic sin shapes the immunological repertoire evoked by human cytomegalovirus glycoprotein B/MF59 vaccine in seropositive recipients. J Infect Dis 2019; 220:228–232 [View Article] [PubMed]
    [Google Scholar]
  31. Baraniak I, Kropff B, McLean GR, Pichon S, Piras-Douce F et al. Epitope-specific humoral responses to human cytomegalovirus glycoprotein-B vaccine with MF59: anti-AD2 levels correlate with protection from Viremia. J Infect Dis 2018; 217:1907–1917 [View Article] [PubMed]
    [Google Scholar]
  32. Gomes AC, Baraniak IA, Lankina A, Moulder Z, Holenya P et al. The cytomegalovirus gB/MF59 vaccine candidate induces antibodies against an antigenic domain controlling cell-to-cell spread. Nat Commun 2023; 14:1041 [View Article] [PubMed]
    [Google Scholar]
  33. Baraniak I, Gomes AC, Sodi I, Langstone T, Rothwell E et al. Seronegative patients vaccinated with cytomegalovirus gB-MF59 vaccine have evidence of neutralising antibody responses against gB early post-transplantation. EBioMedicine 2019; 50:45–54 [View Article] [PubMed]
    [Google Scholar]
  34. Atabani SF, Emery VC, Smith C, Harber M, Thorburn D et al. Response to letter regarding “cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy.”. Am J Transplant 2012; 12:2859–2860 [View Article] [PubMed]
    [Google Scholar]
  35. Siddiqui S, Hackl S, Ghoddusi H, McIntosh MR, Gomes AC et al. IgA binds to the AD-2 epitope of glycoprotein B and neutralizes human cytomegalovirus. Immunology 2021; 162:314–327 [View Article] [PubMed]
    [Google Scholar]
  36. Murray MJ, Bonilla-Medrano NI, Lee QL, Oxenford SJ, Angell R et al. Evasion of a human cytomegalovirus entry inhibitor with potent cysteine reactivity is concomitant with the utilization of a heparan sulfate proteoglycan-independent route of entry. J Virol 2020; 94:e02012-19 [View Article] [PubMed]
    [Google Scholar]
  37. Kirchmeier M, Fluckiger A-C, Soare C, Bozic J, Ontsouka B et al. Enveloped virus-like particle expression of human cytomegalovirus glycoprotein B antigen induces antibodies with potent and broad neutralizing activity. Clin Vaccine Immunol 2014; 21:174–180 [View Article] [PubMed]
    [Google Scholar]
  38. Britt WJ, Vugler L, Butfiloski EJ, Stephens EB. Cell surface expression of human cytomegalovirus (HCMV) gp55-116 (gB): use of HCMV-recombinant vaccinia virus-infected cells in analysis of the human neutralizing antibody response. J Virol 1990; 64:1079–1085 [View Article] [PubMed]
    [Google Scholar]
  39. Britt WJ, Vugler L, Stephens EB. Induction of complement-dependent and -independent neutralizing antibodies by recombinant-derived human cytomegalovirus gp55-116 (gB). J Virol 1988; 62:3309–3318 [View Article] [PubMed]
    [Google Scholar]
  40. Li F, Freed DC, Tang A, Rustandi RR, Troutman MC et al. Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB/MF59 vaccination. NPJ Vaccines 2017; 2:36 [View Article] [PubMed]
    [Google Scholar]
  41. Britt WJ, Vugler LG. Oligomerization of the human cytomegalovirus major envelope glycoprotein complex gB (gp55-116). J Virol 1992; 66:6747–6754 [View Article] [PubMed]
    [Google Scholar]
  42. Lopper M, Compton T. Disulfide bond configuration of human cytomegalovirus glycoprotein B. J Virol 2002; 76:6073–6082 [View Article] [PubMed]
    [Google Scholar]
  43. Cui X, Cao Z, Wang S, Lee RB, Wang X et al. Novel trimeric human cytomegalovirus glycoprotein B elicits a high-titer neutralizing antibody response. Vaccine 2018; 36:5580–5590 [View Article] [PubMed]
    [Google Scholar]
  44. Liu Y, Heim KP, Che Y, Chi X, Qiu X et al. Prefusion structure of human cytomegalovirus glycoprotein B and structural basis for membrane fusion. Sci Adv 2021; 7:10 [View Article]
    [Google Scholar]
  45. Kelsey SM, Newland AC. Cytomegalovirus seroconversion in patients receiving intensive induction therapy prior to allogeneic bone marrow transplantation. Bone Marrow Transplant 1989; 4:543–546 [PubMed]
    [Google Scholar]
  46. Humar A, Mazzulli T, Moussa G, Razonable RR, Paya CV et al. Clinical utility of cytomegalovirus (CMV) serology testing in high-risk CMV D+/R- transplant recipients. Am J Transplant 2005; 5:1065–1070 [View Article] [PubMed]
    [Google Scholar]
  47. Johnstone RW, Andrew SM, Hogarth MP, Pietersz GA, McKenzie IF. The effect of temperature on the binding kinetics and equilibrium constants of monoclonal antibodies to cell surface antigens. Mol Immunol 1990; 27:327–333 [View Article] [PubMed]
    [Google Scholar]
  48. Ye X, Su H, Wrapp D, Freed DC, Li F et al. Recognition of a highly conserved glycoprotein B epitope by a bivalent antibody neutralizing HCMV at a post-attachment step. PLoS Pathog 2020; 16:e1008736 [View Article] [PubMed]
    [Google Scholar]
  49. Burke HG, Heldwein EE, Rey FA. Crystal structure of the human cytomegalovirus glycoprotein B. PLoS Pathog 2015; 11:e1005227 [View Article]
    [Google Scholar]
  50. Chandramouli S, Ciferri C, Nikitin PA, Caló S, Gerrein R et al. Structure of HCMV glycoprotein B in the postfusion conformation bound to a neutralizing human antibody. Nat Commun 2015; 6:8176 [View Article] [PubMed]
    [Google Scholar]
  51. Kwong PD, Doyle ML, Casper DJ, Cicala C, Leavitt SA et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 2002; 420:678–682 [View Article] [PubMed]
    [Google Scholar]
  52. Levitskaya J, Coram M, Levitsky V, Imreh S, Steigerwald-Mullen PM et al. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 1995; 375:685–688 [View Article] [PubMed]
    [Google Scholar]
  53. Murin CD, Wilson IA, Ward AB. Antibody responses to viral infections: a structural perspective across three different enveloped viruses. Nat Microbiol 2019; 4:734–747 [View Article] [PubMed]
    [Google Scholar]
  54. Jenks JA, Nelson CS, Roark HK, Goodwin ML, Pass RF et al. Antibody binding to native cytomegalovirus glycoprotein B predicts efficacy of the gB/MF59 vaccine in humans. Sci Transl Med 2020; 12:568 [View Article] [PubMed]
    [Google Scholar]
  55. Gomes AC, Griffiths PD, Reeves MB. The humoral immune response against the gB vaccine: lessons learnt from protection in solid organ transplantation. Vaccines 2019; 7:67 [View Article] [PubMed]
    [Google Scholar]
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