, Volume 76, Issue 17, pp 1625–1645 | Cite as

Cytomegalovirus Vaccines: Current Status and Future Prospects

  • K. M. Anderholm
  • C. J. Bierle
  • M. R. Schleiss
Review Article


Congenital human cytomegalovirus (HCMV) infection can result in severe and permanent neurological injury in newborns, and vaccine development is accordingly a major public health priority. HCMV can also cause disease in solid organ transplant (SOT) and hematopoietic stem-cell transplant (HSCT) recipients, and a vaccine would be valuable in prevention of viremia and end-organ disease in these populations. Currently there is no licensed HCMV vaccine, but progress toward this goal has been made in recent clinical trials. A recombinant HCMV glycoprotein B (gB) vaccine has been shown to have some efficacy in prevention of infection in young women and adolescents, and has provided benefit to HCMV-seronegative SOT recipients. Similarly, DNA vaccines based on gB and the immunodominant T-cell target, pp65 (ppUL83), have been shown to reduce viremia in HSCT patients. This review provides an overview of HCMV vaccine candidates in various stages of development, as well as an update on the current status of ongoing clinical trials. Protective correlates of vaccine-induced immunity may be different for pregnant woman and transplant patients. As more knowledge emerges about correlates of protection, the ultimate licensure of HCMV vaccines may reflect the uniqueness of the target populations being immunized.


Bacterial Artificial Chromosome Hematopoietic Stem Cell Transplantation HCMV Infection Neutralize Antibody Titer Neutralize Antibody Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with Ethical Standards

Conflict of interest

K.M.A. has no conflicts of interest related to the content of this manuscript. C.J.B. has no conflicts of interest related to the content of this manuscript. M.R.S. has received a consultant fee from Merck vaccines.


Funding support from NIH awards HD044864, HD079918, AI114013 and HD082273 (to M.R.S.) and DE022732 (supporting C.J.B.) is acknowledged.


  1. 1.
    Bialas KM, Swamy GK, Permar SR. Perinatal cytomegalovirus and varicella zoster virus infections: epidemiology, prevention, and treatment. Clin Perinatol. 2015;42(1):61–75, viii.Google Scholar
  2. 2.
    Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988–2004. Clin Infect Dis. 2010;50(11):1439–47.PubMedCrossRefGoogle Scholar
  3. 3.
    Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17(4):253–76.PubMedCrossRefGoogle Scholar
  4. 4.
    Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5):355–63.PubMedCrossRefGoogle Scholar
  5. 5.
    Bristow BN, O’Keefe KA, Shafir SC, Sorvillo FJ. Congenital cytomegalovirus mortality in the United States, 1990-2006. PLoS Negl Trop Dis. 2011;5(4):e1140.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Nyholm JL, Schleiss MR. Prevention of maternal cytomegalovirus infection: current status and future prospects. Int J Womens Health. 2010;2:23–35.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Wang C, Zhang X, Bialek S, Cannon MJ. Attribution of congenital cytomegalovirus infection to primary versus non-primary maternal infection. Clin Infect Dis. 2011;52(2):e11–3.PubMedCrossRefGoogle Scholar
  8. 8.
    Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357(25):2601–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Hoover DR, Saah AJ, Bacellar H, Phair J, Detels R, Anderson R, et al. Clinical manifestations of AIDS in the era of pneumocystis prophylaxis. Multicenter AIDS Cohort Study. N Engl J Med. 1993;329(26):1922–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Schönberger S, Meisel R, Adams O, Pufal Y, Laws HJ, Enczmann J, et al. Prospective, comprehensive, and effective viral monitoring in children undergoing allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2010;16(10):1428–35.CrossRefGoogle Scholar
  11. 11.
    Roman A, Manito N, Campistol JM, Cuervas-Mons V, Almenar L, Arias M, et al. The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients. Transpl Rev (Orlando). 2014;28(2):84–91.CrossRefGoogle Scholar
  12. 12.
    Lönnqvist B, Ringdén O, Wahren B, Gahrton G, Lundgren G. Cytomegalovirus infection associated with and preceding chronic graft-versus-host disease. Transplantation. 1984;38(5):465–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Stratton KR, Durch J, Lawrence RS, eds. Vaccines for the 21st century: a tool for decision making. Washington, DC: National Academy Press; 2000.Google Scholar
  14. 14.
    Adler SP. The molecular epidemiology of cytomegalovirus transmission among children attending a day care center. J Infect Dis. 1985;152(4):760–8.PubMedCrossRefGoogle Scholar
  15. 15.
    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(22):1414–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Söderberg-Nauclér C. Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer? J Intern Med. 2006;259(3):219–46.PubMedCrossRefGoogle Scholar
  17. 17.
    Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300(4):413–22.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Osawa R, Singh N. Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care. 2009;13(3):R68.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Derhovanessian E, Maier AB, Hähnel K, McElhaney JE, Slagboom EP, Pawelec G. Latent infection with cytomegalovirus is associated with poor memory CD4 responses to influenza A core proteins in the elderly. J Immunol. 2014;193(7):3624–31.PubMedCrossRefGoogle Scholar
  20. 20.
    Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine. Vaccine. 2015;33(12):1433–9.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Nielsen CM, White MJ, Bottomley C, Lusa C, Rodríguez-Galán A, Turner SE, et al. Impaired NK cell responses to pertussis and H1N1 influenza vaccine antigens in human cytomegalovirus-infected individuals. J Immunol. 2015;194(10):4657–67.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Furman D, Jojic V, Sharma S, Shen-Orr SS, Angel CJ, Onengut-Gumuscu S, et al. Cytomegalovirus infection enhances the immune response to influenza. Sci Transl Med. 2015;7(281):281ra43.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Griffiths PD, Mahungu T. Why CMV is a candidate for elimination and then eradication. J Virus Erad. 2016;2(3):131–5.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Elek SD, Stern H. Development of a vaccine against mental retardation caused by cytomegalovirus infection in utero. Lancet. 1974;1(7845):1–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Prichard MN, Penfold ME, Duke GM, Spaete RR, Kemble GW. A review of genetic differences between limited and extensively passaged human cytomegalovirus strains. Rev Med Virol. 2001;11(3):191–200.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang D, Shenk T. Human cytomegalovirus UL131 open reading frame is required for epithelial cell tropism. J Virol. 2005;79(16):10330–8.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Hahn G, Revello MG, Patrone M, Percivalle E, Campanini G, Sarasini A, et al. Human cytomegalovirus UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. J Virol. 2004;78(18):10023–33.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Ryckman BJ, Rainish BL, Chase MC, Borton JA, Nelson JA, Jarvis MA, et al. Characterization of the human cytomegalovirus gH/gL/UL128-131 complex that mediates entry into epithelial and endothelial cells. J Virol. 2008;82(1):60–70.PubMedCrossRefGoogle Scholar
  29. 29.
    Cha TA, Tom E, Kemble GW, Duke GM, Mocarski ES, Spaete RR. Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J Virol. 1996;70(1):78–83.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Heineman TC. Human cytomegalovirus vaccines. In: Arvin A, Gabriella C-F, Mocarski E, et al., editors. Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge: Cambridge University Press; 2007.Google Scholar
  31. 31.
    Stern H. Live cytomegalovirus vaccination of healthy volunteers: eight-year follow-up studies. Birth Defects Orig Artic Ser. 1984;20(1):263–9.PubMedGoogle Scholar
  32. 32.
    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(1):32–7.PubMedCrossRefGoogle Scholar
  33. 33.
    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(4):585–9.PubMedCrossRefGoogle Scholar
  34. 34.
    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(11):1176–8.PubMedCrossRefGoogle Scholar
  35. 35.
    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(1):26–32.PubMedCrossRefGoogle Scholar
  36. 36.
    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(10):1350–60.PubMedCrossRefGoogle Scholar
  37. 37.
    Adler SP, Manganello AM, Lee R, McVoy MA, Nixon DE, Plotkin S, et al. A phase 1 study of four live, recombinant human cytomegalovirus towne/toledo chimera vaccines in CMV seronegative men. J Infect Dis. 2016;214(9):1341–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Fu TM, An Z, Wang D. Progress on pursuit of human cytomegalovirus vaccines for prevention of congenital infection and disease. Vaccine. 2014;32(22):2525–33.PubMedCrossRefGoogle Scholar
  39. 39.
    Banaszynski LA, Chen LC, Maynard-Smith LA, Ooi AG, Wandless TJ. A rapid, reversible, and tunable method to regulate protein function in living cells using synthetic small molecules. Cell. 2006;126(5):995–1004.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Glass M, Busche A, Wagner K, Messerle M, Borst EM. Conditional and reversible disruption of essential herpesvirus proteins. Nat Methods. 2009;6(8):577–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Borst EM, Kleine-Albers J, Gabaev I, Babic M, Wagner K, Binz A, et al. The human cytomegalovirus UL51 protein is essential for viral genome cleavage-packaging and interacts with the terminase subunits pUL56 and pUL89. J Virol. 2013;87(3):1720–32.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Paulus C, Nevels M. The human cytomegalovirus major immediate-early proteins as antagonists of intrinsic and innate antiviral host responses. Viruses. 2009;1(3):760–79.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Borst EM, Wagner K, Binz A, Sodeik B, Messerle M. The essential human cytomegalovirus gene UL52 is required for cleavage-packaging of the viral genome. J Virol. 2008;82(5):2065–78.PubMedCrossRefGoogle Scholar
  44. 44.
    Colletti KS, Xu Y, Yamboliev I, Pari GS. Human cytomegalovirus UL84 is a phosphoprotein that exhibits UTPase activity and is a putative member of the DExD/H box family of proteins. J Biol Chem. 2005;280(12):11955–60.PubMedCrossRefGoogle Scholar
  45. 45.
    Isaacson MK, Juckem LK, Compton T. Virus entry and innate immune activation. Curr Top Microbiol Immunol. 2008;325:85–100.PubMedGoogle Scholar
  46. 46.
    Wille PT, Wisner TW, Ryckman B, Johnson DC. Human cytomegalovirus (HCMV) glycoprotein gB promotes virus entry in trans acting as the viral fusion protein rather than as a receptor-binding protein. MBio. 2013;4(3):e00332-13.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    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(8):3891–903.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    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(3):1079–85.PubMedPubMedCentralGoogle Scholar
  49. 49.
    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(2):381–4.PubMedCrossRefGoogle Scholar
  50. 50.
    Navarro D, Lennette E, Tugizov S, Pereira L. Humoral immune response to functional regions of human cytomegalovirus glycoprotein B. J Med Virol. 1997;52(4):451–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Shanley JD, Wu CA. Mucosal immunization with a replication-deficient adenovirus vector expressing murine cytomegalovirus glycoprotein B induces mucosal and systemic immunity. Vaccine. 2003;21(19–20):2632–42.PubMedCrossRefGoogle Scholar
  52. 52.
    Wilson SR, Wilson JH, Buonocore L, Palin A, Rose JK, Reuter JD. Intranasal immunization with recombinant vesicular stomatitis virus expressing murine cytomegalovirus glycoprotein B induces humoral and cellular immunity. Comp Med. 2008;58(2):129–39.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Schleiss MR, Bourne N, Stroup G, Bravo FJ, Jensen NJ, Bernstein DI. Protection against congenital cytomegalovirus infection and disease in guinea pigs, conferred by a purified recombinant glycoprotein B vaccine. J Infect Dis. 2004;189(8):1374–81.PubMedCrossRefGoogle Scholar
  54. 54.
    Vesikari T, Groth N, Karvonen A, Borkowski A, Pellegrini M. MF59-adjuvanted influenza vaccine (FLUAD) in children: safety and immunogenicity following a second year seasonal vaccination. Vaccine. 2009;27(45):6291–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Pass RF, Zhang C, Evans A, Simpson T, Andrews W, Huang ML, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med. 2009;360(12):1191–9.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Pass RF. Development and evidence for efficacy of CMV glycoprotein B vaccine with MF59 adjuvant. J Clin Virol. 2009;46(Suppl 4):S73–6.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Griffiths PD, Stanton A, McCarrell E, Smith C, Osman M, Harber M, et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet. 2011;377(9773):1256–63.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Sabbaj S, Pass RF, Goepfert PA, Pichon S. Glycoprotein B vaccine is capable of boosting both antibody and CD4 T-cell responses to cytomegalovirus in chronically infected women. J Infect Dis. 2011;203(11):1534–41.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Pass RF, Duliegè 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(4):970–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Bernstein DI, Munoz FM, Callahan ST, Rupp R, Wootton SH, Edwards KM, et al. Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: a randomized clinical trial. Vaccine. 2016;34(3):313–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Baudoux GJMFP, Blais N, Marchand M, inventors. 2012.
  62. 62.
    Gheysen D, inventor. Fusion glycoprotein from hcmv and hsv. 1995.
  63. 63.
    Dasari V, Smith C, Zhong J, Scott G, Rawlinson W, Khanna R. Recombinant glycoprotein B vaccine formulation with Toll-like receptor 9 agonist and immune-stimulating complex induces specific immunity against multiple strains of cytomegalovirus. J Gen Virol. 2011;92(Pt 5):1021–31.PubMedCrossRefGoogle Scholar
  64. 64.
    Schleiss MR, Choi KY, Anderson J, Mash JG, Wettendorff M, Mossman S, 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(23):2756–62.PubMedCrossRefGoogle Scholar
  65. 65.
    Pötzsch S, Spindler N, Wiegers AK, Fisch T, Rücker P, Sticht H, 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(8):e1002172.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    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):2183–91.PubMedCrossRefGoogle Scholar
  67. 67.
    Lantto J, Fletcher JM, Ohlin M. Binding characteristics determine the neutralizing potential of antibody fragments specific for antigenic domain 2 on glycoprotein B of human cytomegalovirus. Virology. 2003;305(1):201–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Finnefrock AC, Freed DC, Tang A, Li F, He X, Wu C, et al. Preclinical evaluations of peptide-conjugate vaccines targeting the antigenic domain-2 of glycoprotein B of human cytomegalovirus. Hum Vaccin Immunother. 2016;17:1–7 (PMID 26986197).Google Scholar
  69. 69.
    Schrader JW, McLean GR. Location, location, timing: analysis of cytomegalovirus epitopes for neutralizing antibodies. Immunol Lett. 2007;112(1):58–60.PubMedCrossRefGoogle Scholar
  70. 70.
    CBER/FDA. Guidance for industry: considerations for plasmid DNA vaccines for infectious disease indications. Rockville, MD; 2007. p. 13.Google Scholar
  71. 71.
    Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990;247(4949 Pt 1):1465–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Tang DC, DeVit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature. 1992;356(6365):152–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Ulmer JB, Donnelly JJ, Parker SE, Rhodes GH, Felgner PL, Dwarki VJ, et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science. 1993;259(5102):1745–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Smith LR, Wloch MK, Chaplin JA, Gerber M, Rolland AP. Clinical development of a cytomegalovirus DNA vaccine: from product concept to pivotal phase 3 trial. Vaccines (Basel). 2013;1(4):398–414.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Wloch MK, Smith LR, Boutsaboualoy S, Reyes L, Han C, Kehler J, et al. Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects. J Infect Dis. 2008;197(12):1634–42.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Kharfan-Dabaja MA, Boeckh M, Wilck MB, Langston AA, Chu AH, Wloch MK, 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(4):290–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Jacobson MA, Adler SP, Sinclair E, Black D, Smith A, Chu A, et al. A CMV DNA vaccine primes for memory immune responses to live-attenuated CMV (Towne strain). Vaccine. 2009;27(10):1540–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Sullivan SM, Doukas J, Hartikka J, Smith L, Rolland A. Vaxfectin: a versatile adjuvant for plasmid DNA- and protein-based vaccines. Expert Opin Drug Deliv. 2010;7(12):1433–46.PubMedCrossRefGoogle Scholar
  79. 79.
    McVoy MA, Lee R, Saccoccio FM, Hartikka J, Smith LR, Mahajan R, et al. A cytomegalovirus DNA vaccine induces antibodies that block viral entry into fibroblasts and epithelial cells. Vaccine. 2015;33(51):7328–36.PubMedCrossRefGoogle Scholar
  80. 80.
    Hartikka J, Bozoukova V, Morrow J, Rusalov D, Shlapobersky M, Wei Q, et al. Preclinical evaluation of the immunogenicity and safety of plasmid DNA-based prophylactic vaccines for human cytomegalovirus. Hum Vaccin Immunother. 2012;8(11):1595–606.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Ramanathan MP, Kuo YC, Selling BH, Li Q, Sardesai NY, Kim JJ, et al. Development of a novel DNA SynCon tetravalent dengue vaccine that elicits immune responses against four serotypes. Vaccine. 2009;27(46):6444–53.PubMedCrossRefGoogle Scholar
  82. 82.
    Obeng-Adjei N, Hutnick NA, Yan J, Chu JS, Myles DJ, Morrow MP, et al. DNA vaccine cocktail expressing genotype A and C HBV surface and consensus core antigens generates robust cytotoxic and antibody responses in mice and Rhesus macaques. Cancer Gene Ther. 2013;20(12):652–62.PubMedCrossRefGoogle Scholar
  83. 83.
    Flingai S, Czerwonko M, Goodman J, Kudchodkar SB, Muthumani K, Weiner DB. Synthetic DNA vaccines: improved vaccine potency by electroporation and co-delivered genetic adjuvants. Front Immunol. 2013;4:354.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Babiuk S, Baca-Estrada ME, Foldvari M, Middleton DM, Rabussay D, Widera G, et al. Increased gene expression and inflammatory cell infiltration caused by electroporation are both important for improving the efficacy of DNA vaccines. J Biotechnol. 2004;110(1):1–10.PubMedCrossRefGoogle Scholar
  85. 85.
    Huang C, Wang H, Wu S, Chang H, Liu L, Peng B, et al. Comparison of multiple DNA vaccines for protection against cytomegalovirus infection in BALB/c mice. Virol J. 2014;11:104.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Flingai S, Plummer EM, Patel A, Shresta S, Mendoza JM, Broderick KE, et al. Protection against dengue disease by synthetic nucleic acid antibody prophylaxis/immunotherapy. Sci Rep. 2015;5:12616.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Shedlock DJ, Talbott KT, Cress C, Ferraro B, Tuyishme S, Mallilankaraman K, et al. A highly optimized DNA vaccine confers complete protective immunity against high-dose lethal lymphocytic choriomeningitis virus challenge. Vaccine. 2011;29(39):6755–62.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Mallilankaraman K, Shedlock DJ, Bao H, Kawalekar OU, Fagone P, Ramanathan AA, et al. A DNA vaccine against chikungunya virus is protective in mice and induces neutralizing antibodies in mice and nonhuman primates. PLoS Negl Trop Dis. 2011;5(1):e928.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Lang Kuhs KA, Ginsberg AA, Yan J, Wiseman RW, Khan AS, Sardesai NY, et al. Hepatitis C virus NS3/NS4A DNA vaccine induces multiepitope T cell responses in rhesus macaques mimicking human immune responses [corrected]. Mol Ther. 2012;20(3):669–78.PubMedCrossRefGoogle Scholar
  90. 90.
    Shen X, Söderholm J, Lin F, Kobinger G, Bello A, Gregg DA, et al. Influenza A vaccines using linear expression cassettes delivered via electroporation afford full protection against challenge in a mouse model. Vaccine. 2012;30(48):6946–54.PubMedCrossRefGoogle Scholar
  91. 91.
    Loomis RJ, Lilja AE, Monroe J, Balabanis KA, Brito LA, Palladino G, et al. Vectored co-delivery of human cytomegalovirus gH and gL proteins elicits potent complement-independent neutralizing antibodies. Vaccine. 2013;31(6):919–26.PubMedCrossRefGoogle Scholar
  92. 92.
    Geall AJ, Verma A, Otten GR, Shaw CA, Hekele A, Banerjee K, et al. Nonviral delivery of self-amplifying RNA vaccines. Proc Natl Acad Sci USA. 2012;109(36):14604–9.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Plotkin S. The history of vaccination against cytomegalovirus. Med Microbiol Immunol. 2015;204(3):247–54.PubMedCrossRefGoogle Scholar
  94. 94.
    Brito LA, Chan M, Shaw CA, Hekele A, Carsillo T, Schaefer M, et al. A cationic nanoemulsion for the delivery of next-generation RNA vaccines. Mol Ther. 2014;22(12):2118–29.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    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(3):843–6.PubMedCrossRefGoogle Scholar
  96. 96.
    Berencsi K, Gyulai Z, Gönczöl 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(8):1171–9.PubMedCrossRefGoogle Scholar
  97. 97.
    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(5):686–90.PubMedCrossRefGoogle Scholar
  98. 98.
    Schleiss MR, Lacayo JC, 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(6):789–98.PubMedCrossRefGoogle Scholar
  99. 99.
    Bernstein DI, Reap EA, Katen K, Watson A, Smith K, Norberg P, et al. Randomized, double-blind, Phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers. Vaccine. 2009;28(2):484–93.PubMedCrossRefGoogle Scholar
  100. 100.
    Wussow F, Chiuppesi F, Martinez J, Campo J, Johnson E, Flechsig C, et al. Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex. PLoS Pathog. 2014;10(11):e1004524.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Wussow F, Yue Y, Martinez J, Deere JD, Longmate J, Herrmann A, et al. A vaccine based on the rhesus cytomegalovirus UL128 complex induces broadly neutralizing antibodies in Rhesus macaques. J Virol. 2013;87(3):1322–32.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Gillis PA, Hernandez-Alvarado N, Gnanandarajah JS, Wussow F, Diamond DJ, Schleiss MR. Development of a novel, guinea pig-specific IFN-γ ELISPOT assay and characterization of guinea pig cytomegalovirus GP83-specific cellular immune responses following immunization with a modified vaccinia virus Ankara (MVA)-vectored GP83 vaccine. Vaccine. 2014;32(31):3963–70.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Abel K, Martinez J, Yue Y, Lacey SF, Wang Z, Strelow L, et al. Vaccine-induced control of viral shedding following rhesus cytomegalovirus challenge in Rhesus macaques. J Virol. 2011;85(6):2878–90.PubMedCrossRefGoogle Scholar
  104. 104.
    Macagno A, Bernasconi NL, Vanzetta F, Dander E, Sarasini A, Revello MG, 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(2):1005–13.PubMedCrossRefGoogle Scholar
  105. 105.
    Kabanova A, Perez L, Lilleri D, Marcandalli J, Agatic G, Becattini S, et al. Antibody-driven design of a human cytomegalovirus gHgLpUL128L subunit vaccine that selectively elicits potent neutralizing antibodies. Proc Natl Acad Sci USA. 2014;111(50):17965–70.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Flatz L, Hegazy AN, Bergthaler A, Verschoor A, Claus C, Fernandez M, et al. Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity. Nat Med. 2010;16(3):339–45.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Vicente T, Burri S, Wellnitz S, Walsh K, Rothe S, Liderfelt J. Fully aseptic single-use cross flow filtration system for clarification and concentration of cytomegalovirus-like particles. Eng Life Sci. 2014;14(3):318–26.CrossRefGoogle Scholar
  108. 108.
    Kirchmeier M, Fluckiger AC, Soare C, Bozic J, Ontsouka B, Ahmed T, 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(2):174–80.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Soare C, Ahmed T, Fluckiger A, et al. CMV gB/pp65 eVLPs formulated with GM-CSF as a therapeutic vaccine against GBM. Abstracts of the Keystone Cancer Vaccine Symposium; 2016.Google Scholar
  110. 110.
    Cayatte C, Schneider-Ohrum K, Wang Z, Irrinki A, Nguyen N, Lu J, et al. Cytomegalovirus vaccine strain towne-derived dense bodies induce broad cellular immune responses and neutralizing antibodies that prevent infection of fibroblasts and epithelial cells. J Virol. 2013;87(20):11107–20.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Becke S, Aue S, Thomas D, Schader S, Podlech J, Bopp T, et al. Optimized recombinant dense bodies of human cytomegalovirus efficiently prime virus specific lymphocytes and neutralizing antibodies without the addition of adjuvant. Vaccine. 2010;28(38):6191–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Pepperl S, Münster J, Mach M, Harris JR, Plachter B. Dense bodies of human cytomegalovirus induce both humoral and cellular immune responses in the absence of viral gene expression. J Virol. 2000;74(13):6132–46.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Gratama JW, Boeckh M, Nakamura R, Cornelissen JJ, Brooimans RA, Zaia JA, et al. Immune monitoring with iTAg MHC Tetramers for prediction of recurrent or persistent cytomegalovirus infection or disease in allogeneic hematopoietic stem cell transplant recipients: a prospective multicenter study. Blood. 2010;116(10):1655–62.PubMedCrossRefGoogle Scholar
  114. 114.
    CpG 7909: PF 3512676, PF-3512676. Drugs R D. 2006;7(5):312–6.Google Scholar
  115. 115.
    La Rosa C, Longmate J, Lacey SF, Kaltcheva T, Sharan R, Marsano D, et al. Clinical evaluation of safety and immunogenicity of PADRE-cytomegalovirus (CMV) and tetanus-CMV fusion peptide vaccines with or without PF03512676 adjuvant. J Infect Dis. 2012;205(8):1294–304.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Nakamura R, Rosa CL, Longmate J, Drake J, Slape C, Zhou Q, et al. Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Lancet Haematol. 2016;3(2):e87–98.PubMedCrossRefGoogle Scholar
  117. 117.
    Chircop V. BPA Backs CMV Vaccine Project. QIMR Berghofer Medical Research Institute;, 2015.
  118. 118.
    Dasari V, Smith C, Khanna R. Recent advances in designing an effective vaccine to prevent cytomegalovirus-associated clinical diseases. Expert Rev Vaccines. 2013;12(6):661–76.PubMedCrossRefGoogle Scholar
  119. 119.
    Zhong J, Rist M, Cooper L, Smith C, Khanna R. Induction of pluripotent protective immunity following immunisation with a chimeric vaccine against human cytomegalovirus. PLoS One. 2008;3(9):e3256.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Freed DC, Tang Q, Tang A, Li F, He X, Huang Z, et al. Pentameric complex of viral glycoprotein H is the primary target for potent neutralization by a human cytomegalovirus vaccine. Proc Natl Acad Sci USA. 2013;110(51):E4997–5005.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Fu TM, Wang D, Freed DC, Tang A, Li F, He X, et al. Restoration of viral epithelial tropism improves immunogenicity in rabbits and rhesus macaques for a whole virion vaccine of human cytomegalovirus. Vaccine. 2012;30(52):7469–74.PubMedCrossRefGoogle Scholar
  122. 122.
    Genini E, Percivalle E, Sarasini A, Revello MG, Baldanti F, Gerna G. Serum antibody response to the gH/gL/pUL128-131 five-protein complex of human cytomegalovirus (HCMV) in primary and reactivated HCMV infections. J Clin Virol. 2011;52(2):113–8.PubMedCrossRefGoogle Scholar
  123. 123.
    Wen Y, Monroe J, Linton C, Archer J, Beard CW, Barnett SW, et al. Human cytomegalovirus gH/gL/UL128/UL130/UL131A complex elicits potently neutralizing antibodies in mice. Vaccine. 2014;32(30):3796–804.PubMedCrossRefGoogle Scholar
  124. 124.
    Assaf BT, Mansfield KG, Strelow L, Westmoreland SV, Barry PA, Kaur A. Limited dissemination and shedding of the UL128 complex-intact, UL/b′-defective rhesus cytomegalovirus strain 180.92. J Virol. 2014;88(16):9310–20.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Jacob CL, Lamorte L, Sepulveda E, Lorenz IC, Gauthier A, Franti M. Neutralizing antibodies are unable to inhibit direct viral cell-to-cell spread of human cytomegalovirus. Virology. 2013;444(1–2):140–7.PubMedCrossRefGoogle Scholar
  126. 126.
    Cui X, Lee R, Adler SP, McVoy MA. Antibody inhibition of human cytomegalovirus spread in epithelial cell cultures. J Virol Methods. 2013;192(1–2):44–50.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Chiuppesi F, Wussow F, Johnson E, Bian C, Zhuo M, Rajakumar A, Barry PA, Britt WJ, Chakraborty R, Diamond DJ. Vaccine-derived neutralizing antibodies to the human cytomegalovirus gH/gL pentamer potently block primary cytotrophoblast infection. J Virol. 2015;89(23):11884–98.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Revello MG, Lazzarotto T, Guerra B, Spinillo A, Ferrazzi E, Kustermann A, et al. A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. N Engl J Med. 2014;370(14):1316–26.PubMedCrossRefGoogle Scholar
  129. 129.
    Nigro G, Adler SP, La Torre R, Best AM, Group CCC. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med. 2005;353(13):1350–62.Google Scholar
  130. 130.
    Arav-Boger R, Wojcik GL, Duggal P, Ingersoll RG, Beaty T, Pass RF, et al. Polymorphisms in Toll-like receptor genes influence antibody responses to cytomegalovirus glycoprotein B vaccine. BMC Res Notes. 2012;5:140.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Boehme KW, Guerrero M, Compton T. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells. J Immunol. 2006;177(10):7094–102.PubMedCrossRefGoogle Scholar
  132. 132.
    Yurochko AD, Hwang ES, Rasmussen L, Keay S, Pereira L, Huang ES. The human cytomegalovirus UL55 (gB) and UL75 (gH) glycoprotein ligands initiate the rapid activation of Sp1 and NF-kappaB during infection. J Virol. 1997;71(7):5051–9.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Kijpittayarit S, Eid AJ, Brown RA, Paya CV, Razonable RR. Relationship between Toll-like receptor 2 polymorphism and cytomegalovirus disease after liver transplantation. Clin Infect Dis. 2007;44(10):1315–20.PubMedCrossRefGoogle Scholar
  134. 134.
    Schleiss MR. Does public perception of exposure risks and transmission mechanisms drive antiviral vaccine awareness? What if cytomegalovirus was transmitted by mosquitoes? Curr Opin Virol. 2016;17:126–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • K. M. Anderholm
    • 1
  • C. J. Bierle
    • 1
  • M. R. Schleiss
    • 1
  1. 1.Division of Pediatric Infectious Diseases and Immunology, Department of Pediatrics, Center for Infectious Diseases and Microbiology Translational ResearchUniversity of Minnesota Medical SchoolMinneapolisUSA

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