Nothing Special   »   [go: up one dir, main page]

Skip to main content

Vaccine Development for Cytomegalovirus

  • Chapter
  • First Online:
Human Herpesviruses

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1045))

Abstract

The development of a cytomegalovirus (CMV) vaccine has become a top priority due to its potential cost-effectiveness and associated public health benefits. However, there are a number of challenges facing vaccine development including the following: (1) CMV has many mechanisms for evading immune responses , and natural immunity is not perfect, (2) the immune correlates for protection are unclear, (3) a narrow range of CMV hosts limits the value of animal models, and (4) the placenta is a specialized organ formed transiently and its immunological status changes with time. In spite of these limitations, several types of CMV vaccine candidate, including live-attenuated, DISC , subunit, DNA, vectored, and peptide vaccines, have been developed or are currently under development. The recognition of the pentameric complex as the major neutralization target and identification of various strategies to block viral immune response evasion mechanisms have opened new avenues to CMV vaccine development. Here, we discuss the immune correlates for protection, the characteristics of the various vaccine candidates and their clinical trials, and the relevant animal models.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Abel K, Martinez J, Yue Y et al (2011) Vaccine-induced control of viral shedding following rhesus cytomegalovirus challenge in rhesus macaques. J Virol 85:2878–2890

    Article  PubMed  CAS  Google Scholar 

  • Adler SP (2008) Human CMV vaccine trials: what if CMV caused a rash? J Clin Virol 41:231–236

    Article  PubMed  CAS  Google Scholar 

  • Adler SP, Starr SE, Plotkin SA et al (1995) Immunity induced by primary human cytomegalovirus-infection protects against secondary infection among women of childbearing age. J Infect Dis 171:26–32

    Article  PubMed  CAS  Google Scholar 

  • Adler SP, Plotkin SA, Gonczol E et al (1999) A canarypox vector expressing cytomegalovirus (CMV) glycoprotein B primes for antibody responses to a live attenuated CMV vaccine (Towne). J Infect Dis 180:843–846

    Article  PubMed  CAS  Google Scholar 

  • Adler SP, Manganello AM, Lee R et al (2016) A phase 1 study of 4 live, recombinant human cytomegalovirus Towne/Toledo chimera vaccines in cytomegalovirus-seronegative men. J Infect Dis 214:1341–1348

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Adler S, Lewis N, Conlon A et al (2017) Phase 1 clinical trial of a replication-defective human cytomegalovirus (CMV) vaccine. ID Week 2017 presentation

    Google Scholar 

  • Arav-Boger R, Wojcik GL, Duggal P et al (2012) Polymorphisms in toll-like receptor genes influence antibody responses to cytomegalovirus glycoprotein B vaccine. BMC Res Notes 5:140

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arvin AM, Fast P, Myers M et al (2004) Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. Clin Infect Dis 39:233–239

    Article  PubMed  Google Scholar 

  • Assaf BT, Mansfield KG, Strelow L et al (2014) Limited dissemination and shedding of the UL128 complex-intact, UL/b’-defective rhesus cytomegalovirus strain 180.92. J Virol 88:9310–9320

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Auerbach MR, Yan D, Vij R et al (2014) A neutralizing anti-gH/gL monoclonal antibody is protective in the guinea pig model of congenital CMV infection. PLoS Pathog 10:e1004060

    Article  PubMed  PubMed Central  Google Scholar 

  • Barry PA, Lockridge KM, Salamat S et al (2006) Nonhuman primate models of intrauterine cytomegalovirus infection. ILAR J 47:49–64

    Article  PubMed  CAS  Google Scholar 

  • Berencsi K, Gyulai Z, Gönczöl E et al (2001) A canarypox vector-expressing cytomegalovirus (CMV) phosphoprotein 65 induces long-lasting cytotoxic T cell responses in human CMV-seronegative subjects. J Infect Dis 183:1171–1179

    Article  PubMed  CAS  Google Scholar 

  • Bernstein DI, Reap EA, Katen K et al (2009) Randomized, double-blind, phase 1 trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers. Vaccine 28:484–493

    Article  PubMed  CAS  Google Scholar 

  • Bernstein DI, Munoz FM, Callahan ST et al (2016) Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: a randomized clinical trial. Vaccine 34:313–319

    Article  PubMed  CAS  Google Scholar 

  • Bialas KM, Tanaka T, Tran D et al (2015) Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission. Proc Natl Acad Sci U S A 112:13645–13650

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boppana SB, Britt WJ (1995) Antiviral antibody responses and intrauterine transmission after primary maternal cytomegalovirus infection. J Infect Dis 171:1115–1121

    Article  PubMed  CAS  Google Scholar 

  • Britt WJ (2017) Congenital human cytomegalovirus infection and the enigma of maternal immunity. J Virol 91:e02392-16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bunde T, Kirchner A, Hoffmeister B et al (2005) Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J Exp Med 201:1031–1036

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Burwitz BJ, Malouli D, Bimber BN et al (2016) Cross-species rhesus cytomegalovirus infection of cynomolgus macaques. PLoS Pathog 12:e1006014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cardin RD, Bravo FJ, Pullum DA et al (2016) Replication-defective lymphocytic choriomeningitis virus vectors expressing guinea pig cytomegalovirus gB and pp65 homologs are protective against congenital guinea pig cytomegalovirus infection. Vaccine 34:1993–1999

    Article  PubMed  CAS  Google Scholar 

  • Cayatte C, Schneider-Ohrum K, Wang Z et al (2013) 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 87:11107–11120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cha TA, Tom E, Kemble GW et al (1996) Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J Virol 70:78–83

    PubMed  PubMed Central  CAS  Google Scholar 

  • Chandramouli S, Malito E, Nguyen T et al (2017) Structural basis for potent antibody-mediated neutralization of human cytomegalovirus. Sci Immunol 2:eaan1457

    Article  PubMed  Google Scholar 

  • Chang WLW, Barry PA (2010) Attenuation of innate immunity by cytomegalovirus IL-10 establishes a long-term deficit of adaptive antiviral immunity. Proc Natl Acad Sci U S A 107:22647–22652

    Article  PubMed  PubMed Central  Google Scholar 

  • Chang WL, Baumgarth N, Yu D, Barry PA (2004) Human cytomegalovirus-encoded interleukin-10 homolog inhibits maturation of dendritic cells and alters their functionality. J Virol 78:8720–8731

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chatterjee A, Harrison CJ, Britt WJ, Bewtra C (2001) Modification of maternal and congenital cytomegalovirus infection by anti-glycoprotein b antibody transfer in guinea pigs. J Infect Dis 183:1547–1553

    Article  PubMed  CAS  Google Scholar 

  • Chaudhuri S, Lowen B, Chan G et al (2009) Human cytomegalovirus interacts with toll-like receptor 2 and CD14 on syncytiotrophoblasts to stimulate expression of TNFα mRNA and apoptosis. Placenta 30:994–1001

    Article  PubMed  CAS  Google Scholar 

  • Chiuppesi F, Wussow F, Johnson E et al (2015) Vaccine-derived neutralizing antibodies to the human cytomegalovirus gH/gL pentamer potently block primary cytotrophoblast infection. J Virol 89:11884–11898

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chiuppesi F, Kaltcheva T, Meng Z et al (2017) Identification of a continuous neutralizing epitope within UL128 of human cytomegalovirus. J Virol 91:e01857–e01816

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ciferri C, Chandramouli S, Donnarumma D et al (2015a) Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes. Proc Natl Acad Sci U S A 112:1767–1772

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ciferri C, Chandramouli S, Leitner A et al (2015b) Antigenic characterization of the HCMV gH/gL/gO and Pentamer cell entry complexes reveals binding sites for potently neutralizing human antibodies. PLoS Pathog 11:e1005230

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Coaquette A, Bourgeois A, Dirand C et al (2004) Mixed cytomegalovirus glycoprotein B genotypes in immunocompromised patients. Clin Infect Dis 39:155–161

    Article  PubMed  Google Scholar 

  • Corrales-Aguilar E, Trilling M, Hunold K et al (2014) Human cytomegalovirus Fcγ binding proteins gp34 and gp68 antagonize Fcγ receptors I, II and III. PLoS Pathog 10:e1004131

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Crumpler MM, Choi KY, McVoy MA, Schleiss MR (2009) A live guinea pig cytomegalovirus vaccine deleted of three putative immune evasion genes is highly attenuated but remains immunogenic in a vaccine/challenge model of congenital cytomegalovirus infection. Vaccine 27:4209–4218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cui X, Meza BP, Adler SP, McVoy MA (2008) Cytomegalovirus vaccines fail to induce epithelial entry neutralizing antibodies comparable to natural infection. Vaccine 26:5760–5766

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dempsey AF, Pangborn HM, Prosser LA (2012) Cost-effectiveness of routine vaccination of adolescent females against cytomegalovirus. Vaccine 30:4060–4066

    Article  PubMed  Google Scholar 

  • Dropulic LK, Cohen JI (2012) The challenge of developing a herpes simplex virus 2 vaccine. Expert Rev Vaccines 11:1429–1440

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eberhardt MK, Deshpande A, Chang WLW et al (2013) Vaccination against a virus-encoded cytokine significantly restricts viral challenge. J Virol 87:11323–11331

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Elkington R, Walker S, Crough T et al (2003) Ex vivo profiling of CD8+-T-cell responses to human cytomegalovirus reveals broad and multispecific reactivities in healthy virus carriers. J Virol 77:5226–5240

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fan Q, Nelson CS, Bialas KM et al (2017) Plasmablast response to primary rhesus cytomegalovirus infection in a monkey model of congenital CMV transmission. Clin Vaccine Immunol 24:e00510-16

    Google Scholar 

  • Fornara C, Cassaniti I, Zavattoni M et al (2017) Human cytomegalovirus-specific memory CD4+ T-Cell response and its correlation with virus transmission to the fetus in pregnant women with primary infection. Clin Infect Dis 65:1659–1665

    Article  PubMed  Google Scholar 

  • Fouts AE, Chan P, Stephan J-PP et al (2012) 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 86:7444–7447

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fowler KB, Stagno S, Pass RF et al (1992) The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med 326:663–667

    Article  PubMed  CAS  Google Scholar 

  • Fowler KB, Stagno S, Pass RF (2003) Maternal immunity and prevention of congenital cytomegalovirus infection. J Am Med Assoc 289:1008–1011

    Article  Google Scholar 

  • Freed DC, Tang Q, Tang A et al (2013) Pentameric complex of viral glycoprotein H is the primary target for potent neutralization by a human cytomegalovirus vaccine. Proc Natl Acad Sci U S A 110:E4997–E5005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fu TM, Wang D, Freed DC et al (2012) Restoration of viral epithelial tropism improves immunogenicity in rabbits and rhesus macaques for a whole virion vaccine of human cytomegalovirus. Vaccine 30:7469–7474

    Article  PubMed  CAS  Google Scholar 

  • Fukui Y, Shindoh K, Yamamoto Y et al (2008) Establishment of a cell-based assay for screening of compounds inhibiting very early events in the cytomegalovirus replication cycle and characterization of a compound identified using the assay. Antimicrob Agents Chemother 52:2420–2427

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gerna G, Sarasini A, Patrone M et al (2008) Human cytomegalovirus serum neutralizing antibodies block virus infection of endothelial/epithelial cells, but not fibroblasts, early during primary infection. J Gen Virol 89:853–865

    Article  PubMed  CAS  Google Scholar 

  • Gillis PA, Hernandez-Alvarado N, Gnanandarajah JS et al (2014) Development of a novel, guinea pig-specific IFN-gamma 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 32:3963–3970

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Griffiths PD, Stanton A, McCarrell E et al (2011) Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet 377:1256–1263

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ha S, Li F, Troutman MC et al (2017) Neutralization of diverse human cytomegalovirus strains conferred by antibodies targets viral gH/gL/pUL128-131 pentameric complex. J Virol 91:e02033–e02016

    PubMed  PubMed Central  Google Scholar 

  • Hahn G, Revello MG, Patrone M et al (2004) Human cytomegalovirus UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. J Virol 78:10023–10033

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hansen SG, Strelow LI, Franchi DC et al (2003) Complete sequence and genomic analysis of rhesus cytomegalovirus. J Virol 77:6620–6636

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hashimoto K, Yamada S, Katano H et al (2013) Effects of immunization of pregnant guinea pigs with guinea pig cytomegalovirus glycoprotein B on viral spread in the placenta. Vaccine 31:3199–3205

    Article  PubMed  CAS  Google Scholar 

  • Heineman TC, Schleiss M, Bernstein DI et al (2006) A phase 1 study of 4 live, recombinant human cytomegalovirus Towne/Toledo chimeric vaccines. J Infect Dis 193:1350–1360

    Article  PubMed  CAS  Google Scholar 

  • Ikuta K, Minematsu T, Inoue N et al (2013) Cytomegalovirus (CMV) glycoprotein H-based serological analysis in Japanese healthy pregnant women, and in neonates with congenital CMV infection and their mothers. J Clin Virol 58:474–478

    Article  PubMed  CAS  Google Scholar 

  • Ishibashi K, Tokumoto T, Tanabe K et al (2007) Association of the outcome of renal transplantation with antibody response to cytomegalovirus strain-specific glycoprotein H epitopes. Clin Infect Dis 45:60–67

    Article  PubMed  CAS  Google Scholar 

  • Jacobson MA, Adler SP, Sinclair E et al (2009) A CMV DNA vaccine primes for memory immune responses to live-attenuated CMV (Towne strain). Vaccine 27:1540–1548

    Article  PubMed  CAS  Google Scholar 

  • Kabanova A, Perez L, Lilleri D et al (2014) Antibody-driven design of a human cytomegalovirus gHgLpUL128L subunit vaccine that selectively elicits potent neutralizing antibodies. Proc Natl Acad Sci U S A 111:17965–17970

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kang SH, Abdel-Massih RC, Brown RA et al (2012) Homozygosity for the toll-like receptor 2 R753Q single-nucleotide polymorphism is a risk factor for cytomegalovirus disease after liver transplantation. J Infect Dis 205:639–646

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Katano H, Sato Y, Tsutsui Y et al (2007) Pathogenesis of cytomegalovirus-associated labyrinthitis in a guinea pig model. Microbes Infect 9:183–191

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann P, Davidoff M (1977) The guinea-pig placenta. Adv Anat Embryol Cell Biol 53:5–91

    PubMed  CAS  Google Scholar 

  • Kenneson A, Cannon MJ (2007) Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol 17:253–276

    Article  PubMed  Google Scholar 

  • Kharfan-Dabaja MA, Boeckh M, Wilck MB et al (2012) A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis 12:290–299

    Article  PubMed  CAS  Google Scholar 

  • Kirchmeier M, Fluckiger AC, Soare C et al (2014) Enveloped virus-like particle expression of human cytomegalovirus glycoprotein B antigen induces antibodies with potent and broad neutralizing activity. Clin Vaccine Immunol 21:174–180

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Koyano S, Inoue N, Nagamori T et al (2009) Dried umbilical cords in the retrospective diagnosis of congenital cytomegalovirus infection as a cause of developmental delays. Clin Infect Dis 48:e93–e95

    Article  PubMed  Google Scholar 

  • Koyano S, Inoue N, Oka A et al (2011) Screening for congenital cytomegalovirus infection using newborn urine samples collected on filter paper: feasibility and outcomes from a multicentre study. BMJ Open 1:e000118

    Article  PubMed  PubMed Central  Google Scholar 

  • Krause PR, Bialek SR, Boppana SB et al (2013) Priorities for CMV vaccine development. Vaccine 32:4–10

    Article  PubMed  PubMed Central  Google Scholar 

  • La Rosa C, Longmate J, Lacey SF et al (2012) Clinical evaluation of safety and immunogenicity of PADRE-cytomegalovirus (CMV) and tetanus-CMV fusion peptide vaccines with or without PF03512676 adjuvant. J Infect Dis 205:1294–1302

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • La Rosa C, Longmate J, Martinez J et al (2017) MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults. Blood 129:114–125

    Article  PubMed  PubMed Central  Google Scholar 

  • La Torre R, Nigro G, Mazzocco M et al (2006) Placental enlargement in women with primary maternal cytomegalovirus infection is associated with fetal and neonatal disease. Clin Infect Dis 43:994–1000

    Article  PubMed  Google Scholar 

  • Lacey SF, La Rosa C, Zhou W et al (2006) Functional comparison of T cells recognizing cytomegalovirus pp65 and intermediate-early antigen polypeptides in hematopoietic stem-cell transplant and solid organ transplant recipients. J Infect Dis 194:1410–1421

    Article  PubMed  CAS  Google Scholar 

  • Landais I, Pelton C, Streblow D et al (2015) Human cytomegalovirus miR-UL112-3p targets TLR2 and modulates the TLR2/IRAK1/NFκB signaling pathway. PLoS Pathog 11:e1004881

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Leviton MP, Lacayo JC, Choi KY et al (2013) An attenuated cytomegalovirus vaccine with a deletion of a viral chemokine gene is protective against congenital CMV transmission in a guinea pig model. Clin Dev Immunol 2013:906948

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lilja AE, Shenk T (2008) Efficient replication of rhesus cytomegalovirus variants in multiple rhesus and human cell types. Proc Natl Acad Sci U S A 105:19950–19955

    Article  PubMed  PubMed Central  Google Scholar 

  • Lilleri D, Fornara C, Furione M et al (2007) Development of human cytomegalovirus-specific T cell immunity during primary infection of pregnant women and its correlation with virus transmission to the fetus. J Infect Dis 195:1062–1070

    Article  PubMed  Google Scholar 

  • Lilleri D, Kabanova A, Lanzavecchia A, Gerna G (2012) Antibodies against neutralization epitopes of human cytomegalovirus gH/gL/pUL128-130-131 complex and virus spreading may correlate with virus control in vivo. J Clin Immunol 32:1324–1331

    Article  PubMed  CAS  Google Scholar 

  • Lilleri D, Kabanova A, Revello MG et al (2013) Fetal human cytomegalovirus transmission correlates with delayed maternal antibodies to gH/gL/pUL128-130-131 complex during primary infection. PLoS One 8:e0059863

    Article  CAS  Google Scholar 

  • Loomis RJ, Lilja AE, Monroe J et al (2013) Vectored co-delivery of human cytomegalovirus gH and gL proteins elicits potent complement-independent neutralizing antibodies. Vaccine 31:919–926

    Article  PubMed  CAS  Google Scholar 

  • Loughney JW, Rustandi RR, Wang D et al (2015) 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 290:15985–15995

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Macagno A, Bernasconi NL, Vanzetta F et al (2010) Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex. J Virol 84:1005–1013

    Article  PubMed  CAS  Google Scholar 

  • Maidji E, McDonagh S, Genbacev O et al (2006) Maternal antibodies enhance or prevent cytomegalovirus infection in the placenta by neonatal Fc receptor-mediated transcytosis. Am J Pathol 168:1210–1226

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Majima R, Shindoh K, Yamaguchi T, Inoue N (2017) Characterization of a thienylcarboxamide derivative that inhibits the transactivation functions of cytomegalovirus IE2 and varicella zoster virus IE62. Antivir Res 140:142–150

    Article  PubMed  CAS  Google Scholar 

  • Malouli D, Nakayasu ES, Viswanathan K et al (2012) Reevaluation of the coding potential and proteomic analysis of the BAC-derived rhesus cytomegalovirus strain 68-1. J Virol 86:8959–8973

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Marsh AK, Willer DO, Ambagala APN et al (2011) Genomic sequencing and characterization of cynomolgus macaque cytomegalovirus. J Virol 85:12995–13009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mele F, Fornara C, Jarrossay D et al (2017) Phenotype and specificity of T cells in primary human cytomegalovirus infection during pregnancy: IL-7Rpos long-term memory phenotype is associated with protection from vertical transmission. PLoS One 12:e0187731

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • McDonagh S, Maidji E, Chang HT, Pereira L (2006) Patterns of human cytomegalovirus infection in term placentas: a preliminary analysis. J Clin Virol 35:210–215

    Article  PubMed  CAS  Google Scholar 

  • Mori T, Kanda Y, Takenaka K et al (2017) Safety of ASP0113, a cytomegalovirus DNA vaccine, in recipients undergoing allogeneic hematopoietic cell transplantation: an open-label phase 2 trial. Int J Hematol 105:206–212

    Article  PubMed  CAS  Google Scholar 

  • Nahum A, Dadi H, Bates A, Roifman CM (2012) The biological significance of TLR3 variant, L412F, in conferring susceptibility to cutaneous candidiasis, CMV and autoimmunity. Autoimmun Rev 11:341–347

    Article  PubMed  CAS  Google Scholar 

  • Nakamura R, Rosa C, La LJ et al (2016) 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 3:e87–e98

    Article  Google Scholar 

  • NCT01974206 News release (2016) HP of Vical (www.vical.com/investors/news-releases/News-Release-Details/2016/Vical-and-Astellas-Announce-Topline-Results-from-a-Phase-2-Study-of-Investigational-Cytomegalovirus-CMV-Vaccine-ASP0113-in-Kidney-Transplant-Patients/default.aspx)

  • NCT01877655 News release (2017) HP of Vical (www.vical.com/investors/news-releases/News-Release-Details/2017/Vical-Announces-Completion-of-the-Phase-3-ASP0113-CMV-Vaccine-Trial/default.aspx)

  • NCT02798692 News release (2017) HP of Hooki (www.29c5yd3ksizu1pn67922fy74.wpengine.netdna-cdn.com/wp-content/uploads/2017/05/Hookipa-press-release-HB-101-Data-at-CMV-Conference-4-May-2017.pdf)

  • NCT02826798 News release (2017) HP of VBI vacinnes (www.vbivaccines.com/wire/cmv-phase-i-clinical-study-update-may-2017/)

  • Nelson CS, Cruz DV, Tran D et al (2017) Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys. JCI Insight 2:94002

    Google Scholar 

  • Nozawa N, Koyano S, Yamamoto Y et al (2007) Real-time PCR assay using specimens on filter disks as a template for detection of cytomegalovirus in urine. J Clin Microbiol 45:1305–1307

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nozawa N, Yamamoto Y, Fukui Y et al (2008) Identification of a 1.6 kb genome locus of guinea pig cytomegalovirus required for efficient viral growth in animals but not in cell culture. Virology 379:45–54

    Article  PubMed  CAS  Google Scholar 

  • Nozawa N, Fang-Hoover J, Tabata T et al (2009) Cytomegalovirus-specific, high-avidity IgG with neutralizing activity in maternal circulation enriched in the fetal bloodstream. J Clin Virol 46:S58–S63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ogawa H, Suzutani T, Baba Y et al (2007) Etiology of severe sensorineural hearing loss in children: independent impact of congenital cytomegalovirus infection and mutations. J Infect Dis 195:782–788

    Article  PubMed  CAS  Google Scholar 

  • Pass RF, Duliegè AM, Boppana S et al (1999) A subunit cytomegalovirus vaccine based on recombinant envelope glycoprotein B and a new adjuvant. J Infect Dis 180:970–975

    Article  PubMed  CAS  Google Scholar 

  • Pass RF, Zhang C, Evans A et al (2009) Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med 360:1191–1199

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Peggs KS, Verfuerth S, Pizzey A et al (2003) Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet 362:1375–1377

    Article  PubMed  Google Scholar 

  • Pepperl S, Münster J, Mach M et al (2000) Dense bodies of human cytomegalovirus induce both humoral and cellular immune responses in the absence of viral gene expression. J Virol 74:6132–6146

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pereira L, Maidji E, McDonagh S et al (2003) Human cytomegalovirus transmission from the uterus to the placenta correlates with the presence of pathogenic bacteria and maternal immunity. J Virol 77:13301–13314

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Petty TJ, Todd Callahan S, Chen Q et al (2010) Assessment of parental acceptance of a potential cytomegalovirus vaccine for adolescent females. Vaccine 28:5686–5690

    Article  PubMed  PubMed Central  Google Scholar 

  • Puchhammer-Stockl E, Gorzer I (2006) Cytomegalovirus and Epstein-Barr virus subtypes--the search for clinical significance. J ClinVirol 36:239–248

    Google Scholar 

  • Raftery MJ, Wieland D, Gronewald S et al (2004) Shaping phenotype, function, and survival of dendritic cells by cytomegalovirus-encoded IL-10. J Immunol 173:3383–3391

    Article  PubMed  CAS  Google Scholar 

  • Reap EA, Morris J, Dryga SA et al (2007) Development and preclinical evaluation of an alphavirus replicon particle vaccine for cytomegalovirus. Vaccine 25:7441–7449

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Revello MG, Lilleri D, Zavattoni M et al (2006) Lymphoproliferative response in primary human cytomegalovirus (HCMV) infection is delayed in HCMV transmitter mothers. J Infect Dis 193:269–276

    Article  PubMed  Google Scholar 

  • Revello MG, Lazzarotto T, Guerra B et al (2014) A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. N Engl J Med 370:1316–1326

    Article  PubMed  CAS  Google Scholar 

  • Riddell SR, Watanabe KS, Goodrich JM et al (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257:238–241

    Article  PubMed  CAS  Google Scholar 

  • Ross SA, Arora N, Novak Z et al (2010) Cytomegalovirus reinfections in healthy seroimmune women. J Infect Dis 201:386–389

    Article  PubMed  Google Scholar 

  • Russell JNH, Marsh AK, Willer DO et al (2016) A novel strain of cynomolgus macaque cytomegalovirus: implications for host-virus co-evolution. BMC Genomics 17:1–17

    Article  CAS  Google Scholar 

  • Schleiss MR, Bourne N, Bernstein DI (2003) 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 188:1868–1874

    Article  PubMed  CAS  Google Scholar 

  • Schleiss MR, Bourne N, Stroup G et al (2004) Protection against congenital cytomegalovirus infection and disease in guinea pigs, conferred by a purified recombinant glycoprotein B vaccine. J Infect Dis 189:1374–1381

    Article  PubMed  CAS  Google Scholar 

  • Schleiss MR, Stroup G, Pogorzelski K, McGregor A (2006) Protection against congenital cytomegalovirus (CMV) disease, conferred by a replication-disabled, bacterial artificial chromosome (BAC)-based DNA vaccine. Vaccine 24:6175–6186

    Article  PubMed  CAS  Google Scholar 

  • Schleiss MR, Lacayo JC, Belkaid Y et al (2007) 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 195:789–798

    Article  PubMed  CAS  Google Scholar 

  • Schleiss MR, Choi KY, Anderson J et al (2014) 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 32:2756–2762

    Article  PubMed  CAS  Google Scholar 

  • Schleiss MR, Bierle CJ, Swanson EC et al (2015) Vaccination with a live attenuated cytomegalovirus devoid of a protein kinase R inhibitory gene results in reduced maternal viremia and improved pregnancy outcome in a guinea pig congenital infection model. J Virol 89:9727–9738

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schleiss MR, Berka U, Watson E et al (2017) Additive protection against congenital cytomegalovirus conferred by combined glycoprotein B/pp65 vaccination using a lymphocytic choriomeningitis virus vector. ClinVaccine Immunol 24:e00300–e00316

    CAS  Google Scholar 

  • Schneider-Ohrum K, Cayatte C, Liu Y et al (2016) Production of cytomegalovirus dense bodies by scalable bioprocess methods maintains immunogenicity and improves neutralizing antibody titers. J Virol 90:10133–10144

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Scott GM, Chow SS, Craig ME et al (2012) Cytomegalovirus infection during pregnancy with maternofetal transmission induces a proinflammatory cytokine bias in placenta and amniotic fluid. J Infect Dis 205:1305–1310

    Article  PubMed  CAS  Google Scholar 

  • Siewiera J, El Costa H, Tabiasco J et al (2013) Human cytomegalovirus infection elicits new decidual natural killer cell effector functions. PLoS Pathog 9:e1003257

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Slavuljica I, Busche A, Babić M et al (2010) Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties. J Clin Invest 120:4532–4545

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stratton KR, Durch JS, Lawrence RS (2000) Vaccines for the 21st century. National Academy Press, Washington, DC

    Google Scholar 

  • Swanson EC, Gillis P, Hernandez-Alvarado N et al (2015) 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 p. Vaccine 33:4013–4018

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sylwester A, Mitchell B, Edgar J et al (2005) Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 202:673–685

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Taniguchi R, Koyano S, Suzutani T et al (2013) Polymorphisms in TLR-2 are associated with congenital cytomegalovirus (CMV) infection but not with congenital CMV disease. Int J Infect Dis 17:e1092–e1097

    Article  PubMed  CAS  Google Scholar 

  • Tomić A, Varanasi PR, Golemac M et al (2016) Activation of innate and adaptive immunity by a recombinant human cytomegalovirus strain expressing an NKG2D ligand. PLoS Pathog 12:e1006015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Walter EA, Greenberg PD, Gilbert MJ et al (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333:1038–1044

    Article  PubMed  CAS  Google Scholar 

  • Wang D, Shenk T (2005a) Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc Natl Acad Sci U S A 102:18153–18158

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang D, Shenk T (2005b) Human cytomegalovirus UL131 open reading frame is required for epithelial cell tropism. J Virol 79:10330–10338

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang Z, La Rosa C, Maas R et al (2004) 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 78:3965–3976

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang D, Li F, Freed DC et al (2011) Quantitative analysis of neutralizing antibody response to human cytomegalovirus in natural infection. Vaccine 29:9075–9080

    Article  PubMed  CAS  Google Scholar 

  • Wang D, Freed DC, He X et al (2016) A replication-defective human cytomegalovirus vaccine for prevention of congenital infection. Sci Transl Med 8:362ra145

    Article  PubMed  CAS  Google Scholar 

  • Weisblum Y, Panet A, Zakay-Rones Z et al (2011) Modeling of human cytomegalovirus maternal-fetal transmission in a novel decidual organ culture. J Virol 85:13204–13213

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weisblum Y, Panet A, Zakay-Rones Z et al (2015) Human cytomegalovirus induces a distinct innate immune response in the maternal-fetal interface. Virology 485:289–296

    Article  PubMed  CAS  Google Scholar 

  • Wen Y, Monroe J, Linton C et al (2014) Human cytomegalovirus gH/gL/UL128/UL130/UL131A complex elicits potently neutralizing antibodies in mice. Vaccine 32:3796–3804

    Article  PubMed  CAS  Google Scholar 

  • Wussow F, Yue Y, Martinez J et al (2013) A vaccine based on the rhesus cytomegalovirus UL128 complex induces broadly neutralizing antibodies in rhesus macaques. J Virol 87:1322–1332

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wussow F, Chiuppesi F, Martinez J et al (2014) Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex. PLoS Pathog 10:e1004524

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yamada S, Nozawa N, Katano H et al (2009) Characterization of the guinea pig cytomegalovirus genome locus that encodes homologs of human cytomegalovirus major immediate-early genes, UL128, and UL130. Virology 391:99–106

    Article  PubMed  CAS  Google Scholar 

  • Yamada S, Fukuchi S, Hashimoto K et al (2014) Guinea pig cytomegalovirus GP129/131/133, homologues of human cytomegalovirus UL128/130/131A, are necessary for infection of monocytes and macrophages. J Gen Virol 95:1376–1382

    Article  PubMed  CAS  Google Scholar 

  • Yue Y, Kaur A, Zhou SS, Barry PA (2006) Characterization and immunological analysis of the rhesus cytomegalovirus homologue (Rh112) of the human cytomegalovirus UL83 lower matrix phosphoprotein (pp65). J Gen Virol 87:777–787

    Article  PubMed  CAS  Google Scholar 

  • Yue Y, Kaur A, Eberhardt MK et al (2007) Immunogenicity and protective efficacy of DNA vaccines expressing rhesus cytomegalovirus glycoprotein B, phosphoprotein 65-2, and viral interleukin-10 in rhesus macaques. J Virol 81:1095–1109

    Article  PubMed  CAS  Google Scholar 

  • Yue Y, Wang Z, Abel K et al (2008) Evaluation of recombinant modified vaccinia Ankara virus-based rhesus cytomegalovirus vaccines in rhesus macaques. Med Microbiol Immunol 197:117–123

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Naoki Inoue .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Inoue, N., Abe, M., Kobayashi, R., Yamada, S. (2018). Vaccine Development for Cytomegalovirus. In: Kawaguchi, Y., Mori, Y., Kimura, H. (eds) Human Herpesviruses. Advances in Experimental Medicine and Biology, vol 1045. Springer, Singapore. https://doi.org/10.1007/978-981-10-7230-7_13

Download citation

Publish with us

Policies and ethics