The Journal of Pediatrics
Volume 151, Issue 6 , Pages 564-570 , December 2007

Prospects for Development and Potential Impact of a Vaccine Against Congenital Cytomegalovirus (CMV) Infection

  • Mark R. Schleiss, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Dr. Mark R. Schleiss, Division of Pediatric Infectious Diseases, Department of Pediatrics, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, 2001 6th Street SE, Minneapolis, MN 55455.

Received 6 February 2007 ,Revised 29 May 2007 ,Accepted 6 July 2007.

References 

  1. Griffiths PD. Happy anniversary for human cytomegalovirus. Rev Med Virol. 2006;16:349–352
  2. Boeckh M, Fries B, Nichols WG. Recent advances in the prevention of CMV infection and disease after hematopoietic stem cell transplantation. Pediatr Transplant. 2004;8(Suppl 5):19–27
  3. Boeckh M, Riddell SR. Immunologic predictors of late cytomegalovirus disease after solid organ transplantation: an elusive goal?. J Infect Dis. 2007;195:615–617
  4. Reischig T, Jindra P, Svecova M, Kormunda S, Opatrny K, Treska V. The impact of cytomegalovirus disease and asymptomatic infection on acute renal allograft rejection. J Clin Virol. 2006;36:146–151
  5. Whitley RJ. Congenital cytomegalovirus infection: epidemiology and treatment. Adv Exp Med Biol. 2004;549:155–160
  6. Ross DS, Dollard SC, Victor M, Sumartojo E, Cannon MJ. The epidemiology and prevention of congenital cytomegalovirus infection and disease: activities of the Centers for Disease Control and Prevention Workgroup. J Womens Health (Larchmt). 2006;15:224–229
  7. Stagno S, Pass RF, Cloud G, Britt WJ, Henderson RE, Walton PD, et al. Primary cytomegalovirus infection in pregnancy: incidence, transmission to fetus, and clinical outcome. JAMA. 1986;256:1904–1908
  8. Pass RF, Hutto C, Ricks R, Cloud GA. Increased rate of cytomegalovirus infection among parents of children attending day-care centers. N Engl J Med. 1986;314:1414–1418
  9. Adler SP, Finney JW, Manganello AM, Best AM. Prevention of child-to-mother transmission of cytomegalovirus among pregnant women. J Pediatr. 2004;145:485–491
  10. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA. The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med. 1992;326:663–667
  11. Fowler KB, Stagno S, Pass RF. Maternal immunity and prevention of congenital cytomegalovirus infection. JAMA. 2003;289:1008–1011
  12. Pass RF, Fowler KB, Boppana SB, Britt WJ, Stagno S. Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome. J Clin Virol. 2006;35:216–220
  13. Lazzarotto T, Gabrielli L, Lanari M, Guerra B, Bellucci T, Sassi M, et al. Congenital cytomegalovirus infection: recent advances in the diagnosis of maternal infection. Hum Immunol. 2004;65:410–415
  14. Bodeus M, Van Ranst M, Bernard P, Hubinont C, Goubau P. Anticytomegalovirus IgG avidity in pregnancy: a 2-year prospective study. Fetal Diagn Ther. 2002;17:362–366
  15. Arav-Boger R, Battaglia CA, Lazzarotto T, Gabrielli L, Zong JC, Hayward GS, et al. Cytomegalovirus (CMV)-encoded UL144 (truncated tumor necrosis factor receptor) and outcome of congenital CMV infection. J Infect Dis. 2006;194:464–473
  16. Arvin AM, Fast P, Myers M, Plotkin S, Rabinovich R National Vaccine Advisory Committee. Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. Clin Infect Dis. 2004;39:233–239
  17. Pass RF. Immunization strategy for prevention of congenital cytomegalovirus infection. Infect Agents Dis. 1996;5:240–244
  18. Fowler KB, McCollister FP, Dahle AJ, Boppana S, Britt WJ, Pass RF. Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. J Pediatr. 1997;130:624–630
  19. Williamson WD, Demmler GJ, Percy AK, Catlin FI. Progressive hearing loss in infants with asymptomatic congenital cytomegalovirus infection. Pediatrics. 1992;90:862–866
  20. Fowler KB, Dahle AJ, Boppana SB, Pass RF. Newborn hearing screening: will children with hearing loss caused by congenital cytomegalovirus infection be missed?. J Pediatr. 1999;135:60–64
  21. Nance WE, Lim BG, Dodson KM. Importance of congenital cytomegalovirus infections as a cause for pre-lingual hearing loss. J Clin Virol. 2006;35:221–225
  22. Dolan A, Cunningham C, Hector RD, Hassan-Walker AF, Lee L, Addison C, et al. Genetic content of wild-type human cytomegalovirus. J Gen Virol. 2004;85:1301–1312
  23. Varnum SM, Streblow DN, Monroe ME, Smith P, Auberry KJ, Pasa-Tolic L, et al. Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome. J Virol. 2004;78:10960–10966
  24. 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
  25. Marshall GS, Stout GG, Knights ME, Rabalais GP, Ashley R, Miller H, et al. Ontogeny of glycoprotein gB-specific antibody and neutralizing activity during natural cytomegalovirus infection. J Med Virol. 1994;43:77–83
  26. Kniess N, Mach M, Fay J, Britt WJ. Distribution of linear antigenic sites on glycoprotein gp55 of human cytomegalovirus. J Virol. 1991;65:138–146
  27. 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
  28. Kari B, Gehrz R. Analysis of human antibody responses to human cytomegalovirus envelope glycoproteins found in two families of disulfide linked glycoprotein complexes designated gC-I and gC-II. Arch Virol. 1990;114:213–228
  29. Mach M, Kropff B, Dal Monte P, Britt W. Complex formation by human cytomegalovirus glycoproteins M (gpUL100) and N (gpUL73). J Virol. 2000;74:11881–11892
  30. Mach M, Kropff B, Kryzaniak M, Britt W. Complex formation by glycoproteins M and N of human cytomegalovirus: structural and functional aspects. J Virol. 2005;79:2160–2170
  31. Urban M, Klein M, Britt WJ, Hassfurther E, Mach M. Glycoprotein H of human cytomegalovirus is a major antigen for the neutralizing humoral immune response. J Gen Virol. 1996;77:1537–1547
  32. Simpson JA, Chow JC, Baker J, Avdalovic N, Yuan S, Au D, et al. Neutralizing monoclonal antibodies that distinguish three antigenic sites on human cytomegalovirus glycoprotein H have conformationally distinct binding sites. J Virol. 1993;67:489–496
  33. Shimamura M, Mach M, Britt WJ. Human cytomegalovirus infection elicits a glycoprotein M (gM)/gN-specific virus-neutralizing antibody response. J Virol. 2006;80:4591–4600
  34. McLaughlin-Taylor E, Pande H, Forman SJ, Tanamachi B, Li CR, Zaia JA, et al. Identification of the major late human cytomegalovirus matrix protein pp65 as a target antigen for CD8+ virus-specific cytotoxic T lymphocytes. J Med Virol. 1994;43:103–110
  35. Wills MR, Carmichael AJ, Mynard K, Jin X, Weekes MP, Plachter B, et al. The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J Virol. 1996;70:7569–7579
  36. Lacey SF, Gallez-Hawkins G, Crooks M, Martinez J, Senitzer D, Forman SJ, et al. Characterization of cytotoxic function of CMV-pp65-specific CD8+ T-lymphocytes identified by HLA tetramers in recipients and donors of stem-cell transplants. Transplantation. 2002;74:722–732
  37. Kern F, Bunde T, Faulhaber N, Kiecker F, Khatamzas E, Rudawski IM, et al. Cytomegalovirus (CMV) phosphoprotein 65 makes a large contribution to shaping the T cell repertoire in CMV-exposed individuals. J Infect Dis. 2002;185:1709–1716
  38. Gyulai Z, Endresz V, Burian K, Pincus S, Toldy J, Cox WI, et al. Cytotoxic T lymphocyte (CTL) responses to human cytomegalovirus pp65, IE1-Exon4, gB, pp150, and pp28 in healthy individuals: reevaluation of prevalence of IE1-specific CTLs. J Infect Dis. 2000;181:1537–1546
  39. Gibson L, Piccinini G, Lilleri D, Revello MG, Wang Z, Markel S, et al. Human cytomegalovirus proteins pp65 and immediate early protein 1 are common targets for CD8+ T cell responses in children with congenital or postnatal human cytomegalovirus infection. J Immunol. 2004;172:2256–2264
  40. Wang Z, La Rosa C, Maas R, Ly H, Brewer J, Mekhoubad S, et al. Recombinant modified vaccinia virus Ankara expressing a soluble form of glycoprotein B causes durable immunity and neutralizing antibodies against multiple strains of human cytomegalovirus. J Virol. 2004;78:3965–3976
  41. La Rosa C, Wang Z, Lacey SF, Markel SF, Sharma MC, Martinez J, et al. Characterization of host immunity to cytomegalovirus pp150 (UL32). Hum Immunol. 2005;66:116–126
  42. Elkington R, Walker S, Crough T, Menzies M, Tellam J, Bharadwaj M, et al. Ex vivo profiling of CD8+-T-cell responses to human cytomegalovirus reveals broad and multispecific reactivities in healthy virus carriers. J Virol. 2003;77:5226–5240
  43. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, 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
  44. Neff BJ, Weibel RE, Buynak EB, McLean AA, Hilleman MR. Clinical and laboratory studies of live cytomegalovirus vaccine Ad-169. Proc Soc Exp Biol Med. 1979;160:32–37
  45. Gonczol E, Ianacone J, Furlini G, Ho W, Plotkin SA. Humoral immune response to cytomegalovirus Towne vaccine strain and to Toledo low-passage strain. J Infect Dis. 1989;159:851–859
  46. Adler SP, Starr SE, Plotkin SA, Hempfling SH, Buis J, Manning ML, et al. Immunity induced by primary human cytomegalovirus infection protects against secondary infection among women of childbearing age. J Infect Dis. 1995;171:26–32
  47. Adler SP, Hempfling SH, Starr SE, Plotkin SA, Riddell S. Safety and immunogenicity of the Towne strain cytomegalovirus vaccine. Pediatr Infect Dis J. 1998;17:200–206
  48. Gehrz RC, Christianson WR, Linner KM, Groth KE, Balfour HH. Cytomegalovirus vaccine: specific humoral and cellular immune responses in human volunteers. Arch Intern Med. 1980;140:936–939
  49. Starr SE, Glazer JP, Friedman HM, Farquhar JD, Plotkin SA. Specific cellular and humoral immunity after immunization with live Towne strain cytomegalovirus vaccine. J Infect Dis. 1981;143:585–589
  50. Fleisher GR, Starr SE, Friedman HM, Plotkin SA. Vaccination of pediatric nurses with live attenuated cytomegalovirus. Am J Dis Child. 1982;136:294–296
  51. Plotkin SA, Starr SE, Friedman HM, Gonczol E, Weibel RE. Protective effects of Towne cytomegalovirus vaccine against low-passage cytomegalovirus administered as a challenge. J Infect Dis. 1989;159:860–865
  52. Quinnan GV, Delery M, Rook AH, Frederick WR, Epstein JS, Manischewitz JF, et al Comparative virulence and immunogenicity of the Towne strain and a nonattenuated strain of cytomegalovirus. Ann Intern Med. 1984;101:478–483
  53. Plotkin SA, Starr SE, Friedman HM, Brayman K, Harris S, Jackson S, et al. Effect of Towne live virus vaccine on cytomegalovirus disease after renal transplant: a controlled trial. Ann Intern Med. 1991;114:525–531
  54. Plotkin SA, Higgins R, Kurtz JB, Morris PJ, Campbell DA, Shope TC, et al. Multicenter trial of Towne strain attenuated virus vaccine in seronegative renal transplant recipients. Transplantation. 1994;58:1176–1178
  55. Balfour HH, Sachs GW, Welo P, Gehrz RC, Simmons R. Cytomegalovirus vaccine in renal transplant candidates: progress report of a randomized, placebo-controlled, double-blind trial. Birth Defects Orig Artic Ser. 1984;20:289–304
  56. Sachs GW, Simmons RL, Balfour HH. Cytomegalovirus vaccine: persistence of humoral immunity following immunization of renal transplant candidates. Vaccine. 1984;2:215–218
  57. Kemble G, Duke G, Winter R, Spaete R. Defined large-scale alterations of the human cytomegalovirus genome constructed by cotransfection of overlapping cosmids. J Virol. 1996;70:2044–2048
  58. Schleiss MR, Heineman TC. Progress toward an elusive goal: current status of cytomegalovirus vaccines. Expert Rev Vaccines. 2005;4:381–406
  59. Heineman TC, Schleiss M, Bernstein DI, Spaete RR, Yan L, Duke G, et al. A phase 1 study of 4 live, recombinant human cytomegalovirus Towne/Toledo chimeric vaccines. J Infect Dis. 2006;193:1350–1360
  60. Spaete RR, Thayer RM, Probert WS, Masiarz FR, Chamberlain SH, Rasmussen L, et al. Human cytomegalovirus strain Towne glycoprotein B is processed by proteolytic cleavage. Virology. 1988;167:207–225
  61. Spaete RR. A recombinant subunit vaccine approach to HCMV vaccine development. Transplant Proc. 1991;23(3 Suppl 3):90–96
  62. Pass RF, Duliege AM, Boppana S, Sekulovich R, Percell S, Britt W, et al. A subunit cytomegalovirus vaccine based on recombinant envelope glycoprotein B and a new adjuvant. J Infect Dis. 1999;180:970–975
  63. Frey SE, Harrison C, Pass RF, Yang E, Boken D, Sekulovich RE, et al. Effects of antigen dose and immunization regimens on antibody responses to a cytomegalovirus glycoprotein B subunit vaccine. J Infect Dis. 1999;180:1700–1703
  64. Mitchell DK, Holmes SJ, Burke RL, Duliege AM, Adler SP. Immunogenicity of a recombinant human cytomegalovirus gB vaccine in seronegative toddlers. Pediatr Infect Dis J. 2002;21:133–138
  65. Zhang C, Pass RF. Detection of cytomegalovirus infection during clinical trials of glycoprotein B vaccine. Vaccine. 2004;23:507–510
  66. Temperton NJ. DNA vaccines against cytomegalovirus: current progress. Int J Antimicrob Agents. 2002;19:169–172
  67. Vilalta A, Mahajan RK, Hartikka J, Rusalov D, Martin T, Bozoukova V, et al. Poloxamer-formulated plasmid DNA-based human cytomegalovirus vaccine: evaluation of plasmid DNA biodistribution/persistence and integration. Hum Gene Ther. 2005;16:1143–1150
  68. Selinsky C, Luke C, Wloch M, Geall A, Hermanson G, Kaslow D, et al. A DNA-based vaccine for the prevention of human cytomegalovirus-associated diseases. Hum Vaccines. 2005;1:16–23
  69. Adler SP, Plotkin SA, Gonczol E, Cadoz M, Meric C, Wang JB, et al. A canarypox vector expressing cytomegalovirus (CMV) glycoprotein B primes for antibody responses to a live attenuated CMV vaccine (Towne). J Infect Dis. 1999;180:843–846
  70. Bernstein DI, Schleiss MR, Berencsi K, Gonczol E, Dickey M, Khoury P, et al. Effect of previous or simultaneous immunization with canarypox expressing cytomegalovirus (CMV) glycoprotein B (gB) on response to subunit gB vaccine plus MF59 in healthy CMV-seronegative adults. J Infect Dis. 2002;185:686–690
  71. Berencsi K, Gyulai Z, Gonczol E, Pincus S, Cox WI, Michelson S, et al. A canarypox vector-expressing cytomegalovirus (CMV) phosphoprotein 65 induces long-lasting cytotoxic T cell responses in human CMV-seronegative subjects. J Infect Dis. 2001;183:1171–1179
  72. Wang Z, Rosa CL, Li Z, Ly H, Krishnan A, Martinez J, et al. Vaccine properties of a novel marker gene-free recombinant modified vaccinia Ankara expressing immunodominant CMV antigens pp65 and IE1. Vaccine. 2007;25:1132–1141
  73. Schleiss MR, Lacayo J, Belkaid Y, McGregor A, Stroup G, Rayner J, et al. Preconceptual administration of an alphavirus replicon UL83 (pp65 homolog) vaccine induces humoral and cellular immunity and improves pregnancy outcome in the guinea pig model of congenital cytomegalovirus infection. J Infect Dis. 2007;195:789–798
  74. Nigro G, Adler SP, La Torre R, Best AM Congenital Cytomegalovirus Collaborating Group. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med. 2005;353:1350–1362
  75. La Torre R, Nigro G, Mazzocco M, Best AM, Adler SP. Placental enlargement in women with primary maternal cytomegalovirus infection is associated with fetal and neonatal disease. Clin Infect Dis. 2006;43:994–1000
  76. Schleiss MR. The role of the placenta in the pathogenesis of congenital cytomegalovirus infection: is the benefit of cytomegalovirus immune globulin for the newborn mediated through improved placental health and function?. Clin Infect Dis. 2006;43:1001–1003
  77. Zanghellini F, Boppana SB, Emery VC, Griffiths PD, Pass RF. Asymptomatic primary cytomegalovirus infection: virologic and immunologic features. J Infect Dis. 1999;180:702–707
  78. Stanberry LR, Rosenthal SL, Mills L, Succop PA, Biro FM, Morrow RA, et al. Longitudinal risk of herpes simplex virus (HSV) type 1, HSV type 2, and cytomegalovirus infections among young adolescent girls. Clin Infect Dis. 2004;39:1433–1438
  79. Kumar ML, Gold E, Jacobs IB, Ernhart CB, Nankervis GA. Primary cytomegalovirus infection in adolescent pregnancy. Pediatrics. 1984;74:493–500
  80. In:  Stratton KR,  Durch JS,  Lawrence RS editor. Vaccines for the 21st Century: A Tool for Decision making, Committee to Study Priorities for Vaccine Development, Division of Health Promotion and Disease Prevention, Institute of Medicine, Washington, DC. 1999;
  81. Meissner HC, Reef SE, Cochi S. Elimination of rubella from the United States: a milestone on the road to global elimination. Pediatrics. 2006;117:933–935
  82. Griffiths PD, McLean A, Emery VC. Encouraging prospects for immunisation against primary cytomegalovirus infection. Vaccine. 2001;19:1356–1362
  83. Soderberg-Naucler C. Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer?. J Intern Med. 2006;259:219–246
  84. Cannon MJ, Davis KF. Washing our hands of the congenital cytomegalovirus disease epidemic. BMC Public Health. 2005;5:70
  85. Casteels A, Naessens A, Gordts F, De Catte L, Bougatef A, Foulon W. Neonatal screening for congenital cytomegalovirus infections. J Perinatal Med. 1999;27:116–121
  86. Barbi M, Binda S, Caroppo S, Primache V. Neonatal screening for congenital cytomegalovirus infection and hearing loss. J Clin Virol. 2006;35:206–209
  87. Collinet P, Subtil D, Houfflin-Debarge V, Kacet N, Dewilde A, Puech F. Routine CMV screening during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2004;114:3–11
  88. ACOG practice bulletin (Perinatal viral and parasitic infections. Number 20, September 2000. ACOG). International J Gynaecol Obstet. 2002;76:95–107

 Supported by grants NIH HD38416-01 and HD44864-01 and a grant from the March of Dimes Birth Defects Foundation.

PII: S0022-3476(07)00667-1

doi: 10.1016/j.jpeds.2007.07.015

The Journal of Pediatrics
Volume 151, Issue 6 , Pages 564-570 , December 2007

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