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Vol. 29. Núm. S6.
La infección por citomegalovirus en el trasplante de órgano sólido: nuevas evidencias de un patógeno clásico
Páginas 28-32 (diciembre 2011)
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Vol. 29. Núm. S6.
La infección por citomegalovirus en el trasplante de órgano sólido: nuevas evidencias de un patógeno clásico
Páginas 28-32 (diciembre 2011)
Acceso a texto completo
Estrategias de monitorización inmunológica para la infección por citomegalovirus. Tratamientos de base inmunológica
Immunological monitoring strategies for cytomegalovirus infection. Immune-based therapies
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4310
Sara Cantisán Bohórqueza,
Autor para correspondencia
sacanti@hotmail.com

Autor para correspondencia.
, David Navarro Ortegab,c
a Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC) - Hospital Reina Sofía - Universidad de Córdoba, Córdoba, España
b Servicio de Microbiología, Hospital Clínico Universitario de Valencia, Valencia, España
c Departamento de Microbiología, Facultad de Medicina de Valencia, Valencia España
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Resumen

La respuesta inmunitaria T frente al citomegalovirus (CMV) es esencial en el control de la replicación viral. La cuantificación de linfocitos T CD4+ y T CD8+ funcionales frente a ciertas especificidades antigénicas del CMV mediante citometría de flujo, ELISPOT o el método comercializado QuantiFERON®-CMV permite estimar con relativa precisión el riesgo de infección activa y enfermedad por el CMV en el marco del trasplante de órgano sólido (TOS). La monitorización virológica e inmunológica conjunta de la infección por el CMV podría permitir individualizar y optimizar los tratamientos antivirales en el TOS, aunque no hay experiencia clínica contrastada al respecto. La transferencia adoptiva de células T autólogas específicas frente al CMV, previa selección con multímeros HLA-péptidos o después de ser activadas y expandidas ex vivo, puede ser una alternativa terapéutica eficaz en el manejo de la infección activa o enfermedad orgánica por el CMV refractario al tratamiento antiviral. Se han desarrollado varias vacunas frente al CMV que se han mostrado seguras e inmunogénicas en ensayos preclínicos o clínicos fase I, pero hasta el momento ninguna ha sido evaluada en ensayos clínicos fase III, por lo que no están licenciadas para uso clínico.

Palabras clave:
Citomegalovirus
Inmunidad celular
Cuantificación de linfocitos T
Infección activa por CMV
Transferencia adoptiva de linfocitos T
Vacunación
Abstract

T-cell response to cytomegalovirus (CMV) is essential in the control of viral replication. Quantification of functional CD4+ and CD8+ T lymphocytes against certain CMV-antigen specificities through flow cytometry, ELISPOT or the QuantiFERON®-CMV kit allows fairly accurate estimation of the risk of active infection and CMV disease in solid organ transplantation (SOT). Combined virological and immunological monitoring of CMV infection could allow antiviral treatments to be individually tailored and optimized in SOT, although clinical experience is currently lacking. The adoptive transfer of CMV-specific T cells before selection with multimer HLA peptides or after activation and expansion ex vivo could be an effective therapeutic alternative in the management of active infection or organic CMV disease refractory to antiviral therapy. Several CMV vaccines have been developed, which have been shown to be safe and immunogenic in preclinical and Phase I clinical trials. However, to date, none of these vaccines has been evaluated in Phase III clinical trials and consequently none has been approved for clinical use.

Keywords:
Cytomegalovirus
Cellular immunity
T-lymphocyte quantification
Active CMV infection
Adoptive T-lymphocyte transfer
Vaccination
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Bibliografía
[1.]
P. Moss, N. Khan.
CD8(+) T-cell immunity to cytomegalovirus.
Hum Immunol, 65 (2004), pp. 456-464
[2.]
R. Vescovini, C. Biasini, F.F. Fagnoni, A.R. Telera, L. Zanlari, M. Pedrazzoni, et al.
Massive load of functional effector CD4+ and CD8+ T cells against cytomegalovirus in very old subjects.
J Immunol, 179 (2007), pp. 4283-4291
[3.]
R. Elkington, S. Walker, T. Crough, M. Menzies, J. Tellam, M. Bharadwaj, et al.
Ex vivo profiling of CD8+-T-cell responses to human cytomegalovirus reveals broad and multispecific reactivities in healthy virus carriers.
J Virol, 77 (2003), pp. 5226-5240
[4.]
A.W. Sylwester, B.L. Mitchell, J.B. Edgar, C. Taormina, C. Pelte, F. Ruchti, et al.
Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects.
J Exp Med, 202 (2005), pp. 673-685
[5.]
S. Cantisán, J. Torre-Cisneros, R. Lara, A. Rodríguez-Benot, F. Santos, J. Gutiérrez-Aroca, et al.
Age-dependent association between low frequency of CD27/CD28 expression on pp65 CD8+ T cells and cytomegalovirus replication after transplantation.
Clin Vaccine Immunol, 16 (2009), pp. 1429-1438
[6.]
E. Derhovanessian, A. Larbi, G. Pawelec.
Biomarkers of human immunosenescence: impact of Cytomegalovirus infection.
Curr Opin Immunol, 21 (2009), pp. 440-445
[7.]
L. Couzi, X. Lafarge, V. Pitard, M. Neau-Cransac, C. Dromer, M.A. Billes, et al.
Gammadelta T cell expansion is closely associated with cytomegalovirus infection in all solid organ transplant recipients.
Transpl Int, 24 (2011), pp. e40-e42
[8.]
J. Dechanet, P. Merville, F. Berge, G. Bone-Mane, J.L. Taupin, P. Michel, et al.
Major expansion of gammadelta T lymphocytes following cytomegalovirus infection in kidney allograft recipients.
J Infect Dis, 179 (1999), pp. 1-8
[9.]
X. Lafarge, P. Merville, M.C. Cazin, F. Berge, L. Potaux, J.F. Moreau, et al.
Cytomegalovirus infection in transplant recipients resolves when circulating gammadelta T lymphocytes expand, suggesting a protective antiviral role.
J Infect Dis, 184 (2001), pp. 533-541
[10.]
T. Crough, R. Khanna.
Immunobiology of human cytomegalovirus: from bench to bedside.
Clin Microbiol Rev, 22 (2009), pp. 76-98
[11.]
M.K. Gandhi, R. Khanna.
Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments.
Lancet Infect Dis, 4 (2004), pp. 725-738
[12.]
S. Kijpittayarit, A.J. Eid, R.A. Brown, C.V. Paya, R.R. Razonable.
Relationship between Toll-like receptor 2 polymorphism and cytomegalovirus disease after liver transplantation.
Clin Infect Dis, 44 (2007), pp. 1315-1320
[13.]
K. Hadaya, C. De Rham, C. Bandelier, S. Ferrari-Lacraz, S. Jendly, T. Berney, et al.
Natural killer cell receptor repertoire and their ligands, and the risk of CMV infection after kidney transplantation.
Am J Transplant, 8 (2008), pp. 2674-2683
[14.]
M. Stern, H. Elsasser, G. Honger, J. Steiger, S. Schaub, C. Hess.
The number of activating KIR genes inversely correlates with the rate of CMV infection/reactivation in kidney transplant recipients.
Am J Transplant, 8 (2008), pp. 1312-1317
[15.]
T.W. Kuijpers, P.A. Baars, C. Dantin, M. Van den Burg, R.A. Van Lier, E. Roosnek.
Human NK cells can control CMV infection in the absence of T cells.
[16.]
D. Navarro, P. Paz, S. Tugizov, K. Topp, J. La Vail, L. Pereira.
Glycoprotein B of human cytomegalovirus promotes virion penetration into cells, transmission of infection from cell to cell, and fusion of infected cells.
Virology, 197 (1993), pp. 143-158
[17.]
J.F. Navarro, C. Mora-Fernández.
Antibody level after hepatitis B vaccination.
Nephrol Dial Transplant, 12 (1997), pp. 2207
[18.]
L. Pereira, E. Lennette, P. Paz, D. Navarro.
Humoral immunity to glycoprotein B in primary and recurrent cytomegalovirus infection.
Progress in Cytomegalovirus Research, pp. 145-148
[19.]
J. Alberola, A. Tamarit, R. Igual, D. Navarro.
Early neutralizing and glycoprotein B (gB)-specific antibody responses to human cytomegalovirus (HCMV) in immunocompetent individuals with distinct clinical presentations of primary HCMV infection.
J Clin Virol, 16 (2000), pp. 113-122
[20.]
D. Di Martino, M.P. Terranova, A. Valetto, L. Scarso, M. Faraci, E. Lanino, et al.
An unusual pattern of B-cell immunological reconstitution after allogeneic stem cell transplantation: A possible correlation with CMV reactivation?.
Pediatr Transplant, 13 (2008), pp. 1050-1052
[21.]
I. Muñoz, A. Gutiérrez, C. Gimeno, A. Farga, J. Alberola, C. Solano, et al.
Lack of association between the kinetics of human cytomegalovirus (HCMV) glycoprotein B (gB)-specific and neutralizing serum antibodies and development or recovery from HCMV active infection in patients undergoing allogeneic stem cell transplant.
J Med Virol, 65 (2001), pp. 77-84
[22.]
D.R. Snydman, B.G. Werner, B. Heinze-Lacey, V.P. Berardi, N.L. Tilney, R.L. Kirkman, et al.
Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients.
N Engl J Med, 317 (1987), pp. 1049-1054
[23.]
M.E. Falagas, D.R. Snydman, R. Ruthazer, J. Griffith, B.G. Werner, R. Freeman, et al.
Cytomegalovirus immune globulin (CMVIG) prophylaxis is associated with increased survival after orthotopic liver transplantation. The Boston Center for Liver Transplantation CMVIG Study Group.
Clin Transplant, 11 (1997), pp. 432-437
[24.]
N.S. Goldfarb, R.K. Avery, M. Goormastic, A.C. Mehta, R. Schilz, N. Smedira, et al.
Hypogammaglobulinemia in lung transplant recipients.
Transplantation, 71 (2001), pp. 242-246
[25.]
S. Doron, R. Ruthazer, B.G. Werner, A. Rabson, D.R. Snydman.
Hypogammaglobulinemia in liver transplant recipients: incidence, timing, risk factors, and outcomes.
Transplantation, 81 (2006), pp. 697-703
[26.]
A. Humar, C. Paya, M.D. Pescovitz, E. Domínguez, K. Washburn, E. Blumberg, et al.
Clinical utility of cytomegalovirus viral load testing for predicting CMV disease in D+/R– solid organ transplant recipients.
Am J Transplant, 4 (2004), pp. 644-649
[27.]
A. Humar, T. Mazzulli, G. Moussa, R.R. Razonable, C.V. Paya, M.D. Pescovitz, et al.
Clinical utility of cytomegalovirus (CMV) serology testing in high-risk CMV D+/R–transplant recipients.
Am J Transplant, 5 (2005), pp. 1065-1070
[28.]
G. Gerna, E. Percivalle, D. Lilleri, L. Lozza, C. Fornara, G. Hahn, et al.
Dendritic-cell infection by human cytomegalovirus is restricted to strains carrying functional UL131-128 genes and mediates efficient viral antigen presentation to CD8+ T cells.
J Gen Virol, 86 (2005), pp. 275-284
[29.]
G. Gerna, A. Sarasini, M. Patrone, E. Percivalle, L. Fiorina, G. Campanini, et al.
Human cytomegalovirus serum neutralizing antibodies block virus infection of endothelial/epithelial cells, but not fibroblasts, early during primary infection.
J Gen Virol, 89 (2008), pp. 853-865
[30.]
S. Giulieri, O. Manuel.
QuantiFERON(R)-CMV assay for the assessment of cytomegalovirus cell-mediated immunity.
Expert Rev Mol Diagn, 11 (2011), pp. 17-25
[31.]
D. Kumar, S. Chernenko, G. Moussa, I. Cobos, O. Manuel, J. Preiksaitis, et al.
Cellmediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients.
Am J Transplant, 9 (2009), pp. 1214-1222
[32.]
S. Walker, C. Fazou, T. Crough, R. Holdsworth, P. Kiely, M. Veale, et al.
Ex vivo monitoring of human cytomegalovirus-specific CD8+ T-cell responses using QuantiFERON-CMV.
Transpl Infect Dis, 9 (2007), pp. 165-170
[33.]
G.P. Westall, N.A. Mifsud, T. Kotsimbos.
Linking CMV serostatus to episodes of CMV reactivation following lung transplantation by measuring CMV-specific CD8+ T-cell immunity.
Am J Transplant, 8 (2008), pp. 1749-1754
[34.]
J. Torre-Cisneros.
Toward the individualization of cytomegalovirus control after solid-organ transplantation: the importance of the “individual pathogenic balance”.
Clin Infect Dis, 49 (2009), pp. 1167-1168
[35.]
C. Solano, I. Benet, M.A. Clari, J. Nieto, R. De la Cámara, J. López, et al.
Enumeration of cytomegalovirus-specific interferongamma CD8+ and CD4+ T cells early after allogeneic stem cell transplantation may identify patients at risk of active cytomegalovirus infection.
Haematologica, 93 (2008), pp. 1434-1436
[36.]
C. Solano, D. Navarro.
Clinical virology of cytomegalovirus infection following hematopoietic transplantation.
Future Virology, 5 (2010), pp. 1-14
[37.]
N. Tormo, C. Solano, I. Benet, M.A. Clari, J. Nieto, R. De la Cámara, et al.
Lack of prompt expansion of cytomegalovirus pp65 and IE-1-specific IFNgamma CD8+ and CD4+ T cells is associated with rising levels of pp65 antigenemia and DNAemia during pre-emptive therapy in allogeneic hematopoietic stem cell transplant recipients.
Bone Marrow Transplant, 45 (2009), pp. 543-549
[38.]
T. Bunde, A. Kirchner, B. Hoffmeister, D. Habedank, R. Hetzer, G. Cherepnev, et al.
Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells.
J Exp Med, 201 (2005), pp. 1031-1036
[39.]
T. Crough, C. Fazou, J. Weiss, S. Campbell, M.P. Davenport, S.C. Bell, et al.
Symptomatic and asymptomatic viral recrudescence in solid-organ transplant recipients and its relationship with the antigen-specific CD8(+) T-cell response.
J Virol, 81 (2007), pp. 11538-11542
[40.]
L.E. Gamadia, E.B. Remmerswaal, J.F. Weel, F. Bemelman, R.A. Van Lier, I.J. Ten Berge.
Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease.
Blood, 101 (2003), pp. 2686-2692
[41.]
G. Gerna, D. Lilleri, C. Fornara, G. Comolli, L. Lozza, C. Campana, et al.
Monitoring of human cytomegalovirus-specific CD4 and CD8 T-cell immunity in patients receiving solid organ transplantation.
Am J Transplant, 6 (2006), pp. 2356-2364
[42.]
D. Lilleri, P. Zelini, C. Fornara, G. Comolli, G. Gerna.
Inconsistent responses of cytomegalovirus-specific T cells to pp65 and IE-1 versus infected dendritic cells in organ transplant recipients.
Am J Transplant, 7 (2007), pp. 1997-2005
[43.]
F.M. Mattes, A. Vargas, J. Kopycinski, E.G. Hainsworth, P. Sweny, G. Nebbia, et al.
Functional impairment of cytomegalovirus specific CD8 T cells predicts high-level replication after renal transplantation.
Am J Transplant, 8 (2008), pp. 990-999
[44.]
G. Nebbia, F.M. Mattes, C. Smith, E. Hainsworth, J. Kopycinski, A. Burroughs, et al.
Polyfunctional cytomegalovirus-specific CD4+ and pp65 CD8+ T cells protect against high-level replication after liver transplantation.
Am J Transplant, 8 (2008), pp. 2590-2599
[45.]
R. Radha, S. Jordan, D. Puliyanda, S. Bunnapradist, A. Petrosyan, N. Amet, et al.
Cellular immune responses to cytomegalovirus in renal transplant recipients.
Am J Transplant, 5 (2005), pp. 110-117
[46.]
M. Sester, U. Sester, B.C. Gartner, M. Girndt, A. Meyerhans, H. Kohler.
Dominance of virus-specific CD8 T cells in human primary cytomegalovirus infection.
J Am Soc Nephrol, 13 (2002), pp. 2577-2584
[47.]
U. Sester, B.C. Gartner, H. Wilkens, B. Schwaab, R. Wossner, I. Kindermann, et al.
Differences in CMV-specific T-cell levels and long-term susceptibility to CMV infection after kidney, heart and lung transplantation.
Am J Transplant, 5 (2005), pp. 1483-1489
[48.]
O.A. Shlobin, E.E. West, N. Lechtzin, S.M. Miller, M. Borja, J.B. Orens, et al.
Persistent cytomegalovirus-specific memory responses in the lung allograft and blood following primary infection in lung transplant recipients.
J Immunol, 176 (2006), pp. 2625-2634
[49.]
A. Krishnan, W. Zhou, S.F. Lacey, A.P. Limaye, D.J. Diamond, C. La Rosa.
Programmed death-1 receptor and interleukin-10 in liver transplant recipients at high risk for late cytomegalovirus disease.
Transpl Infect Dis, 12 (2010), pp. 363-370
[50.]
C. La Rosa, A. Krishnan, J. Longmate, J. Martínez, P. Manchanda, S.F. Lacey, et al.
Programmed death-1 expression in liver transplant recipients as a prognostic indicator of cytomegalovirus disease.
J Infect Dis, 197 (2008), pp. 25-33
[51.]
T.W. Hoffmann, J.M. Halimi, M. Buchler, F. Velge-Roussel, A. Goudeau, A. Al-Najjar, et al.
Association between a polymorphism in the human programmed death-1 (PD-1) gene and cytomegalovirus infection after kidney transplantation.
J Med Genet, 47 (2009), pp. 54-58
[52.]
H. Einsele, E. Roosnek, N. Rufer, C. Sinzger, S. Riegler, J. Loffler, et al.
Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy.
Blood, 99 (2002), pp. 3916-3922
[53.]
L. Dong, Z.Y. Gao, L.J. Chang, Y. Liang, X.Y. Tan, J.H. Liu, et al.
Adoptive transfer of cytomegalovirus/Epstein-Barr virus-specific immune effector cells for therapeutic and preventive/preemptive treatment of pediatric allogeneic cell transplant recipients.
J Pediatr Hematol Oncol, 32 (2010), pp. e31-e37
[54.]
H. Einsele, M. Kapp, G.U. Grigoleit.
CMV-specific T cell therapy.
Blood Cells Mol Dis, 40 (2008), pp. 71-75
[55.]
K.P. Micklethwaite, L. Clancy, U. Sandher, A.M. Hansen, E. Blyth, V. Antonenas, et al.
Prophylactic infusion of cytomegalovirus-specific cytotoxic T lymphocytes stimulated with Ad5f35pp65 gene-modified dendritic cells after allogeneic hemopoietic stem cell transplantation.
Blood, 112 (2008), pp. 3974-3981
[56.]
B. Horn, L. Bao, K. Dunham, M. Stamer, S. Adler, M. Cowan, et al.
Infusion of cytomegalovirus specific cytotoxic T lymphocytes from a sero-negative donor can facilitate resolution of infection and immune reconstitution.
Pediatr Infect Dis J, 28 (2009), pp. 65-67
[57.]
G.R. Hill, S.K. Tey, L. Beagley, T. Crough, J.A. Morton, A.D. Clouston, et al.
Successful immunotherapy of HCMV disease using virus-specific T cells expanded from an allogeneic stem cell transplant recipient.
Am J Transplant, 10 (2009), pp. 173-179
[58.]
P. Scheinberg, J.J. Melenhorst, J.M. Brenchley, B.J. Hill, N.F. Hensel, P.K. Chattopadhyay, et al.
The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor.
Blood, 114 (2009), pp. 5071-5080
[59.]
G. Brestrich, S. Zwinger, A. Fischer, M. Schmuck, A. Rohmhild, M.H. Hammer, et al.
Adoptive T-cell therapy of a lung transplanted patient with severe CMV disease and resistance to antiviral therapy.
Am J Transplant, 9 (2009), pp. 1679-1684
[60.]
M.R. Schleiss.
Prospects for development and potential impact of a vaccine against congenital cytomegalovirus (CMV) infection.
J Pediatr, 151 (2007), pp. 564-570
[61.]
S.P. Adler.
Immunoprophylaxis against cytomegalovirus disease.
Scand J Infect Dis Suppl, 99 (1995), pp. 105-109
[62.]
S.A. Plotkin, M.L. Smiley, H.M. Friedman, S.E. Starr, G.R. Fleisher, C. Wlodaver, et al.
Towne-vaccine-induced prevention of cytomegalovirus disease after renal transplants.
Lancet, 1 (1984), pp. 528-530
[63.]
S.P. Adler, S.A. Plotkin, E. Gonczol, M. Cadoz, C. Meric, J.B. Wang, et al.
A canarypox vector expressing cytomegalovirus (CMV) glycoprotein B primes for antibody responses to a live attenuated CMV vaccine (Towne).
J Infect Dis, 180 (1999), pp. 843-846
[64.]
K. Berencsi, Z. Gyulai, E. Gonczol, S. Pincus, W.I. Cox, S. Michelson, 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, 183 (2001), pp. 1171-1179
[65.]
D.I. Bernstein, M.R. Schleiss, K. Berencsi, E. Gonczol, M. Dickey, P. Khoury, 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, 185 (2002), pp. 686-690
[66.]
R.F. Pass, A.M. Duliege, S. Boppana, R. Sekulovich, S. Percell, W. Britt, et al.
A subunit cytomegalovirus vaccine based on recombinant envelope glycoprotein B and a new adjuvant.
J Infect Dis, 180 (1999), pp. 970-975
[67.]
R.F. Pass, C. Zhang, A. Evans, T. Simpson, W. Andrews, M.L. Huang, et al.
Vaccine prevention of maternal cytomegalovirus infection.
N Engl J Med, 360 (2009), pp. 1191-1199
[68.]
E.A. Reap, J. Morris, S.A. Dryga, M. Maughan, T. Talarico, R.E. Esch, et al.
Development and preclinical evaluation of an alphavirus replicon particle vaccine for cytomegalovirus.
Vaccine, 25 (2007), pp. 7441-7449
[69.]
M.R. Schleiss, J.C. Lacayo, Y. Belkaid, A. McGregor, G. Stroup, J. Rayner, 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, 195 (2007), pp. 789-798
[70.]
J. Zhong, M. Rist, L. Cooper, C. Smith, R. Khanna.
Induction of pluripotent protective immunity following immunisation with a chimeric vaccine against human cytomegalovirus.
[71.]
M.R. Schleiss.
VCL-CB01, an injectable bivalent plasmid DNA vaccine for potential protection against CMV disease and infection.
Curr Opin Mol Ther, 11 (2009), pp. 572-578
[72.]
M.K. Wloch, L.R. Smith, S. Boutsaboualoy, L. Reyes, C. Han, J. Kehler, et al.
Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects.
J Infect Dis, 197 (2008), pp. 1634-1642
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