1887

Journal of General Virology header logo

Volume 102, Issue 3

A trimeric capable gB CMV vaccine provides limited protection against a highly cell associated and epithelial tropic strain of cytomegalovirus in guinea pigs Free

Abstract

Multiple strains of human cytomegalovirus (HCMV) can cause congenital cytomegalovirus (cCMV) by primary or secondary infection. The viral gB glycoprotein is a leading vaccine candidate, essential for infection of all cell-types, and immunodominant antibody target. Guinea pig cytomegalovirus (GPCMV) is the only small animal model for cCMV. Various gB vaccines have shown efficacy but studies have utilized truncated gB and protection against prototype strain 22122 with preferential tropism to fibroblasts despite encoding a gH-based pentamer complex for non-fibroblast infection. A highly cell-associated novel strain of GPCMV (TAMYC) with 99 % identity in gB sequence to 22122 exhibited preferred tropism to epithelial cells. An adenovirus vaccine encoding full-length gB (AdgB) was highly immunogenic and partially protected against 22122 strain challenge in vaccinated animals but not when challenged with TAMYC strain. GPCMV studies with AdgB vaccine sera on numerous cell-types demonstrated impaired neutralization (NA) compared to fibroblasts. GPCMV-convalescent sera including pentamer complex antibodies increased virus neutralization on non-fibroblasts and anti-gB depletion from GPCMV-convalescent sera had minimal impact on epithelial cell neutralization. GPCMV(PC+) 22122-convalescent animals challenged with TAMYC exhibited higher protection compared to AdgB vaccine. Overall, results suggest that antibody response to both gB and PC are important components of a GPCMV vaccine.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): antibody neutralization , CMV , CMV vaccine , congenital infection , cytomegalovirus , epithelial cell , glycoprotein gB , guinea pig , pentamer complex and virus tropism
Funding
This study was supported by the:
  • National Institute of Child Health and Human Development (Award R01HD090065)
    • Principle Award Recipient: AlistairMcGregor
  • National Institute of Allergy and Infectious Diseases (Award R01AI100933)
    • Principle Award Recipient: AlistairMcGregor
  • National Institute of Allergy and Infectious Diseases (Award R01AI098984)
    • Principle Award Recipient: AlistairMcGregor
© 2021 The Authors
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2021-03-17
2024-04-25
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References

  1. Ross SA, Boppana SB. Congenital cytomegalovirus infection: outcome and diagnosis. Semin Pediatr Infect Dis 2005; 16:44–49 [View Article][PubMed]
     [Google Scholar]
  2. Britt WJ. Congenital human cytomegalovirus infection and the enigma of maternal immunity. J Virol 2017; 91: 01 08 2017 [View Article][PubMed]
     [Google Scholar]
  3. Yue Y, Barry PA. Rhesus cytomegalovirus a nonhuman primate model for the study of human cytomegalovirus. Adv Virus Res 2008; 72:207–226 [View Article][PubMed]
     [Google Scholar]
  4. Griffith BP, McCormick SR, Fong CK, Lavallee JT, Lucia HL et al. The placenta as a site of cytomegalovirus infection in guinea pigs. J Virol 1985; 55:402–409 [View Article][PubMed]
     [Google Scholar]
  5. Kaufmann P. Guinea Pig Cavia procellus http://placentation.ucsd.edu/guinea.htm2004 (updated July 10, 2004).
  6. Mess A. The guinea pig placenta: model of placental growth dynamics. Placenta 2007; 28:812–815 [View Article][PubMed]
     [Google Scholar]
  7. Woolf NK, Koehrn FJ, Harris JP, Richman DD. Congenital cytomegalovirus labyrinthitis and sensorineural hearing loss in guinea pigs. J Infect Dis 1989; 160:929–937 [View Article][PubMed]
     [Google Scholar]
  8. Coleman S, Hornig J, Maddux S, Choi KY, McGregor A. Viral glycoprotein complex formation, essential function and immunogenicity in the guinea pig model for cytomegalovirus. PLoS One 2015; 10:e0135567 [View Article][PubMed]
     [Google Scholar]
  9. Coleman S, Choi KY, Root M, McGregor A. A homolog pentameric complex dictates viral epithelial tropism, pathogenicity and congenital infection rate in guinea pig cytomegalovirus. PLoS Pathog 2016; 12:e1005755 [View Article][PubMed]
     [Google Scholar]
  10. Auerbach M, Yan D, Fouts A, Xu M, Estevez A et al. Characterization of the guinea pig CMV gH/gL/GP129/GP131/GP133 complex in infection and spread. Virology 2013; 441:75–84 [View Article][PubMed]
     [Google Scholar]
  11. Coleman S, Choi KY, McGregor A. Cytomegalovirus UL128 homolog mutants that form a pentameric complex produce virus with impaired epithelial and trophoblast cell tropism and altered pathogenicity in the guinea pig. Virology 2017; 509:205–221 [View Article][PubMed]
     [Google Scholar]
  12. Choi KY, El-Hamdi NS, McGregor A. Neutralizing antibodies to gB based CMV vaccine requires full length antigen but reduced virus neutralization on non-fibroblast cells limits vaccine efficacy in the guinea pig model. Vaccine 2020; 38:2340–2349 [View Article][PubMed]
     [Google Scholar]
  13. Wu Y, Prager A, Boos S, Resch M, Brizic I et al. Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry. PLoS Pathog 2017; 13:e1006281 [View Article][PubMed]
     [Google Scholar]
  14. Choi KY, El-Hamdi NS, McGregor A. Inclusion of the viral pentamer complex in a vaccine design greatly improves protection against congenital cytomegalovirus in the guinea pig model. J Virol 2019; 93: [View Article]
     [Google Scholar]
  15. El-Hamdi NS, Choi KY, McGregor A. Guinea pig cytomegalovirus trimer complex gH/gL/gO uses PDGFRA as universal receptor for cell fusion and entry. Virology 2020; 548:236–249 [View Article][PubMed]
     [Google Scholar]
  16. Gerna G, Kabanova A, Lilleri D. Human cytomegalovirus cell tropism and host cell receptors. Vaccines 2019; 7:E70 22 07 2019 [View Article][PubMed]
     [Google Scholar]
  17. Choi KY, Root M, McGregor A. A novel non-replication-competent cytomegalovirus capsid mutant vaccine strategy is effective in reducing congenital infection. J Virol 2016; 90:7902–7919 [View Article][PubMed]
     [Google Scholar]
  18. Britt WJ, Harrison C. Identification of an abundant disulfide-linked complex of glycoproteins in the envelope of guinea pig cytomegalovirus. Virology 1994; 201:294–302 [View Article][PubMed]
     [Google Scholar]
  19. Schleiss MR, Jensen NJ. Cloning and expression of the guinea pig cytomegalovirus glycoprotein B (gB) in a recombinant baculovirus: utility for vaccine studies for the prevention of experimental infection. J Virol Methods 2003; 108:59–65 [View Article][PubMed]
     [Google Scholar]
  20. Si Z, Zhang J, Shivakoti S, Atanasov I, Tao C-L et al. Different functional states of fusion protein gB revealed on human cytomegalovirus by cryo electron tomography with Volta phase plate. PLoS Pathog 2018; 14:e1007452 [View Article][PubMed]
     [Google Scholar]
  21. Perotti M, Marcandalli J, Demurtas D, Sallusto F, Perez L. Rationally designed human cytomegalovirus gB nanoparticle vaccine with improved immunogenicity. PLoS Pathog 2020; 16:e1009169 [View Article][PubMed]
     [Google Scholar]
  22. Britt WJ, Jarvis MA, Drummond DD, Mach M. Antigenic domain 1 is required for oligomerization of human cytomegalovirus glycoprotein B. J Virol 2005; 79:4066–4079 [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; 80:2183–2191 [View Article][PubMed]
     [Google Scholar]
  24. Schleiss MR, Permar SR, Plotkin SA. Progress toward development of a vaccine against congenital cytomegalovirus infection. Clin Vaccine Immunol 2017; 24: 05 12 2017 [View Article][PubMed]
     [Google Scholar]
  25. Plotkin SA, Boppana SB. Vaccination against the human cytomegalovirus. Vaccine 2019; 37:7437–7442 [View Article][PubMed]
     [Google Scholar]
  26. Cui X, Snapper CM. Development of novel vaccines against human cytomegalovirus. Hum Vaccin Immunother 2019; 15:2673–2683 [View Article][PubMed]
     [Google Scholar]
  27. 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]
  28. 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]
  29. Vincenti F, Budde K, Merville P, Shihab F, Ram Peddi V et al. A randomized, phase 2 study of ASP0113, a DNA-based vaccine, for the prevention of CMV in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor. Am J Transplant 2018; 18:2945–2954 [View Article][PubMed]
     [Google Scholar]
  30. Kharfan-Dabaja MA, Boeckh M, Wilck MB, Langston AA, Chu AH et al. A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis 2012; 12:290–299 [View Article][PubMed]
     [Google Scholar]
  31. Nelson CS, Jenks JA, Pardi N, Goodwin M, Roark H et al. Human cytomegalovirus glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization. J Virol 2020; 94: 16 04 2020 [View Article][PubMed]
     [Google Scholar]
  32. Plotkin SA, Wang D, Oualim A, Diamond DJ, Kotton CN et al. The status of vaccine development against the human cytomegalovirus. J Infect Dis 2020; 221:S113–S122 [View Article][PubMed]
     [Google Scholar]
  33. 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]
  34. 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 U S A 2018; 115:6273–6278 [View Article][PubMed]
     [Google Scholar]
  35. Cui X, Meza BP, Adler SP, McVoy MA. Cytomegalovirus vaccines fail to induce epithelial entry neutralizing antibodies comparable to natural infection. Vaccine 2008; 26:5760–5766 [View Article][PubMed]
     [Google Scholar]
  36. Schleiss MR, Bourne N, Stroup G, Bravo FJ, Jensen NJ et al. Protection against congenital cytomegalovirus infection and disease in guinea pigs, conferred by a purified recombinant glycoprotein B vaccine. J Infect Dis 2004; 189:1374–1381 [View Article][PubMed]
     [Google Scholar]
  37. Hashimoto K, Yamada S, Katano H, Fukuchi S, Sato Y et al. Effects of immunization of pregnant guinea pigs with guinea pig cytomegalovirus glycoprotein B on viral spread in the placenta. Vaccine 2013; 31:3199–3205 [View Article][PubMed]
     [Google Scholar]
  38. Cardin RD, Bravo FJ, Pullum DA, Orlinger K, Watson EM et al. Replication-defective lymphocytic choriomeningitis virus vectors expressing guinea pig cytomegalovirus gB and pp65 homologs are protective against congenital guinea pig cytomegalovirus infection. Vaccine 2016; 34:1993–1999 [View Article][PubMed]
     [Google Scholar]
  39. Swanson EC, Gillis P, Hernandez-Alvarado N, Fernández-Alarcón C, Schmit M et al. Comparison of monovalent glycoprotein B with bivalent gB/pp65 (gp83) vaccine for congenital cytomegalovirus infection in a guinea pig model: inclusion of gp83 reduces GB antibody response but both vaccine approaches provide equivalent protection against pup mortality. Vaccine 2015; 33:4013–4018 [View Article][PubMed]
     [Google Scholar]
  40. 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]
  41. Choi KY, El-Hamdi NS, McGregor A. Requirements for guinea pig cytomegalovirus tropism and antibody neutralization on placental amniotic sac cells. J Gen Virol 2020; 101:426–439 [View Article][PubMed]
     [Google Scholar]
  42. Macagno A, Bernasconi NL, Vanzetta F, Dander E, Sarasini A et al. Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex. J Virol 2010; 84:1005–1013 [View Article][PubMed]
     [Google Scholar]
  43. 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]
  44. Kabanova A, Perez L, Lilleri D, Marcandalli J, Agatic G et al. Antibody-driven design of a human cytomegalovirus gHgLpUL128L subunit vaccine that selectively elicits potent neutralizing antibodies. Proc Natl Acad Sci U S A 2014; 111:17965–17970 [View Article][PubMed]
     [Google Scholar]
  45. Wussow F, Chiuppesi F, Martinez J, Campo J, Johnson E et al. Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex. PLoS Pathog 2014; 10:e1004524 [View Article][PubMed]
     [Google Scholar]
  46. Cui X, McGregor A, Schleiss MR, McVoy MA. Cloning the complete guinea pig cytomegalovirus genome as an infectious bacterial artificial chromosome with excisable origin of replication. J Virol Methods 2008; 149:231–239 [View Article][PubMed]
     [Google Scholar]
  47. Tabata T, Petitt M, Fang-Hoover J, Freed DC, Li F et al. Neutralizing monoclonal antibodies reduce human cytomegalovirus infection and spread in developing placentas. Vaccines 2019; 7:E135135 29 09 2019 [View Article][PubMed]
     [Google Scholar]
  48. Fouts AE, Chan P, Stephan J-P, Vandlen R, Feierbach B. Antibodies against the gH/gL/UL128/UL130/UL131 complex comprise the majority of the anti-cytomegalovirus (anti-CMV) neutralizing antibody response in CMV hyperimmune globulin. J Virol 2012; 86:7444–7447 [View Article][PubMed]
     [Google Scholar]
  49. 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]
  50. Zydek M, Petitt M, Fang-Hoover J, Adler B, Kauvar LM et al. Hcmv infection of human trophoblast progenitor cells of the placenta is neutralized by a human monoclonal antibody to glycoprotein B and not by antibodies to the pentamer complex. Viruses 2014; 6:1346–1364 [View Article][PubMed]
     [Google Scholar]
  51. Choi KY, El-Hamdi NS, McGregor A. Convalescent immunity to guinea pig cytomegalovirus induces limited cross strain protection against re-infection but high-level protection against congenital disease. Int J Mol Sci 2020; 21:5997 20 Aug 2020 [View Article][PubMed]
     [Google Scholar]
  52. Zhou M, Yu Q, Wechsler A, Ryckman BJ. Comparative analysis of Go isoforms reveals that strains of human cytomegalovirus differ in the ratio of gH/gL/gO and gH/gL/UL128-131 in the virion envelope. J Virol 2013; 87:9680–9690 [View Article][PubMed]
     [Google Scholar]
  53. Schleiss MR. Cloning and characterization of the guinea pig cytomegalovirus glycoprotein B gene. Virology 1994; 202:173–185 [View Article][PubMed]
     [Google Scholar]
  54. 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]
  55. Utz U, Britt W, Vugler L, Mach M. Identification of a neutralizing epitope on glycoprotein gp58 of human cytomegalovirus. J Virol 1989; 63:1995–2001 [View Article][PubMed]
     [Google Scholar]
  56. Burke HG, Heldwein EE. Crystal structure of the human cytomegalovirus glycoprotein B. PLoS Pathog 2015; 11:e1005227 [View Article][PubMed]
     [Google Scholar]
  57. McGregor A, Liu F, Schleiss MR. Identification of essential and non-essential genes of the guinea pig cytomegalovirus (GPCMV) genome via transposome mutagenesis of an infectious BAC clone. Virus Res 2004; 101:101–108 [View Article][PubMed]
     [Google Scholar]
  58. Yue Y, Zhou SS, Barry PA. Antibody responses to rhesus cytomegalovirus glycoprotein B in naturally infected rhesus macaques. J Gen Virol 2003; 84:3371–3379 [View Article][PubMed]
     [Google Scholar]
  59. Ryckman BJ, Chase MC, Johnson DC. HCMV gH/gL/UL128-131 interferes with virus entry into epithelial cells: evidence for cell type-specific receptors. Proc Natl Acad Sci U S A 2008; 105:14118–14123 [View Article][PubMed]
     [Google Scholar]
  60. McGregor A, Choi KY, Schleiss MR. Guinea pig cytomegalovirus GP84 is a functional homolog of the human cytomegalovirus (HCMV) UL84 gene that can complement for the loss of UL84 in a chimeric HCMV. Virology 2011; 410:76–87 [View Article][PubMed]
     [Google Scholar]
  61. Falk JJ, Winkelmann M, Laib Sampaio K, Paal C, Schrezenmeier H et al. Large-Scale screening of HCMV-Seropositive blood donors indicates that HCMV effectively escapes from antibodies by cell-associated spread. Viruses 2018; 10:500 14 09 2018 [View Article][PubMed]
     [Google Scholar]
  62. 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]
  63. Marshall GS, Rabalais GP, Stout GG, Waldeyer SL. Antibodies to recombinant-derived glycoprotein B after natural human cytomegalovirus infection correlate with neutralizing activity. J Infect Dis 1992; 165:381–384 [View Article][PubMed]
     [Google Scholar]
  64. Schleiss MR, Choi KY, Anderson J, Mash JG, Wettendorff M et al. Glycoprotein B (gB) vaccines adjuvanted with AS01 or AS02 protect female guinea pigs against cytomegalovirus (CMV) viremia and offspring mortality in a CMV-challenge model. Vaccine 2014; 32:2756–2762 [View Article][PubMed]
     [Google Scholar]
  65. Ha S, Li F, Troutman MC, Freed DC, Tang A et al. Neutralization of diverse human cytomegalovirus strains conferred by antibodies targeting viral gH/gL/pUL128-131 pentameric complex. J Virol 2017; 91: 01 04 2017 [View Article][PubMed]
     [Google Scholar]
  66. Loughney JW, Rustandi RR, Wang D, Troutman MC, Dick LW et al. Soluble human cytomegalovirus gH/gL/pUL128–131 pentameric complex, but not gH/gL, inhibits viral entry to epithelial cells and presents dominant native neutralizing epitopes. J Biol Chem 2015; 290:15985–15995 [View Article]
     [Google Scholar]
  67. Murrell I, Bedford C, Ladell K, Miners KL, Price DA et al. The pentameric complex drives immunologically covert cell-cell transmission of wild-type human cytomegalovirus. Proc Natl Acad Sci U S A 2017; 114:6104–6109 [View Article][PubMed]
     [Google Scholar]
  68. Schleiss MR, Berka U, Watson E, Aistleithner M, Kiefmann B et al. Additive protection against congenital cytomegalovirus conferred by combined glycoprotein B/pp65 vaccination using a lymphocytic choriomeningitis virus vector. Clin Vaccine Immunol 2017; 24: 05 01 2017 [View Article][PubMed]
     [Google Scholar]
  69. Schleiss MR, Bourne N, Bernstein DI. Preconception vaccination with a glycoprotein B (gB) DNA vaccine protects against cytomegalovirus (CMV) transmission in the guinea pig model of congenital CMV infection. J Infect Dis 2003; 188:1868–1874 [View Article][PubMed]
     [Google Scholar]
  70. Hartley JW, Rowe WP, Huebner RJ. Serial propagation of the guinea pig salivary gland virus in tissue culture. Proc Soc Exp Biol Med 1957; 96:281–285 [View Article][PubMed]
     [Google Scholar]
  71. Abel K, Martinez J, Yue Y, Lacey SF, Wang Z et al. Vaccine-induced control of viral shedding following rhesus cytomegalovirus challenge in rhesus macaques. J Virol 2011; 85:2878–2890 [View Article][PubMed]
     [Google Scholar]
  72. Valencia S, Gill RB, Dowdell KC, Wang Y, Hornung R et al. Comparison of vaccination with rhesus CMV (RhCMV) soluble gB with a RhCMV replication-defective virus deleted for MHC class I immune evasion genes in a RhCMV challenge model. Vaccine 2019; 37:333–342 [View Article][PubMed]
     [Google Scholar]
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A trimeric capable gB CMV vaccine provides limited protection against a highly cell associated and epithelial tropic strain of cytomegalovirus in guinea pigs
J. Gen. Virol. 102, 001579 (2021); https://doi.org/10.1099/jgv.0.001579
/content/journal/jgv/10.1099/jgv.0.001579
/content/journal/jgv/10.1099/jgv.0.001579
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