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array:23 [ "pii" => "S2445146020300224" "issn" => "24451460" "doi" => "10.1016/j.vacune.2020.10.005" "estado" => "S300" "fechaPublicacion" => "2020-07-01" "aid" => "158" "copyrightAnyo" => "2020" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Vacunas. 2020;21:111-20" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S157698872030039X" "issn" => "15769887" "doi" => "10.1016/j.vacun.2020.07.004" "estado" => "S300" "fechaPublicacion" => "2020-07-01" "aid" => "158" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Vacunas. 2020;21:111-20" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Revisión</span>" "titulo" => "Estado actual de las vacunas frente a la infección congénita por citomegalovirus: la paradoja de la inmunidad previa" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "111" "paginaFinal" => "120" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Current status of vaccines against congenital cytomegalovirus infection: The paradox of previous immunity" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1250 "Ancho" => 2167 "Tamanyo" => 129838 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Representación esquemática de los complejos glicoproteicos (CG) de la superficie del citomegalovirus humano. El complejo pentamérico (CP) está formado por las glicoproteínas gH, gL y las proteínas UL128, UL130 y UL131.</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Fuente: modificado de Gardner y Tortorella<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">17</span></a>.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Reina" "autores" => array:1 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Reina" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2445146020300224" "doi" => "10.1016/j.vacune.2020.10.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146020300224?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S157698872030039X?idApp=UINPBA00004N" "url" => "/15769887/0000002100000002/v2_202010210933/S157698872030039X/v2_202010210933/es/main.assets" ] ] "itemSiguiente" => array:17 [ "pii" => "S2445146020300261" "issn" => "24451460" "doi" => "10.1016/j.vacune.2020.10.009" "estado" => "S300" "fechaPublicacion" => "2020-07-01" "aid" => "153" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Vacunas. 2020;21:121-8" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Revisión</span>" "titulo" => "A review on Promising vaccine development progress for COVID-19 disease" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "121" "paginaFinal" => "128" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Revisión sobre el avance prometedor del desarrollo de vacunas frente a la enfermedad por COVID-19" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1952 "Ancho" => 2155 "Tamanyo" => 403190 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Coronavirus structure.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Tafere Mulaw Belete" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Tafere Mulaw" "apellidos" => "Belete" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146020300261?idApp=UINPBA00004N" "url" => "/24451460/0000002100000002/v1_202011280950/S2445146020300261/v1_202011280950/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S2445146020300182" "issn" => "24451460" "doi" => "10.1016/j.vacune.2020.10.001" "estado" => "S300" "fechaPublicacion" => "2020-07-01" "aid" => "151" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Vacunas. 2020;21:105-10" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Fever and childhood vaccination" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "105" "paginaFinal" => "110" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Fiebre y vacunación infantil" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "V. Pineda Solas" "autores" => array:1 [ 0 => array:2 [ "nombre" => "V." "apellidos" => "Pineda Solas" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1576988720300248" "doi" => "10.1016/j.vacun.2020.05.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1576988720300248?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146020300182?idApp=UINPBA00004N" "url" => "/24451460/0000002100000002/v1_202011280950/S2445146020300182/v1_202011280950/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Current status of vaccines against congenital cytomegalovirus infection: The paradox of previous immunity" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "111" "paginaFinal" => "120" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "J. Reina" "autores" => array:1 [ 0 => array:3 [ "nombre" => "J." "apellidos" => "Reina" "email" => array:1 [ 0 => "jorge.reina@ssib.es" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Virología, Hospital Universitario Son Espases, Facultad de Medicina, Universitat Illes Balears, Palma de Mallorca, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estado actual de las vacunas frente a la infección congénita por citomegalovirus: la paradoja de la inmunidad previa" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1250 "Ancho" => 2167 "Tamanyo" => 129923 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Diagrammatic representation of the glycoprotein complexes (GC) of the human cytomegalovirus surface. The pentameric complex (PC) is composed of glycoproteins gH and gL, and the UL128, UL130 and UL131 proteins.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Source: modified, from Gardner and Tortorella.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Human cytomegalovirus (CMV) is very common and is transmitted within the population very efficiently by means of saliva, urine, breast feeding or blood transfusion. Around 75% of individuals are already seropositive at the age of 15 years and have acquired immunity against this virus. Like all of the members of the herpes virus family, after the primary infection, which is generally asymptomatic or with a self-limiting febrile syndrome, it will remain latent within the human organism. Situations that involve alteration to the immune system, which controls its latency in vascular endothelial cells, will therefore favour the reactivation of CMV and the appearance of febrile or localised symptoms (retinitis or colitis).<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In pregnant women we may find two different situations: (a) seronegative mothers, i.e., those who have never been in contact with CMV (15% of the population) and who are therefore at risk of their primary infection during pregnancy; and (b) seropositive mothers, i.e., who already have latent CMV (85% of the population), whose gestational immune tolerance may favour the reactivation of the virus, which is generally asymptomatic; however, nor can the possibility of repeat infection be ruled out in seropositive mothers (17.5%).<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3–6</span></a> In all of these situations CMV causes viraemia which allows it to infect placenta cells and then access the embryo or foetus, where it may affect multiple organ structures, giving rise to the so-called congenital infection. The majority (85%) of congenital CMV infections are due to reactivation during pregnancy and reinfection by different strains of CMV, and only 15% of cases involve a primary infection during this time. Placental transmission in seronegative mothers have been calculated to stand at 32%, while in seropositive mothers this figure is harder to establish, although it would stand at from 5% to 20%.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6–8</span></a> These data support the concept of the previous immunity paradox, i.e., that the risk of congenital CMV infection is higher in seropositive expectant mothers; moreover, and in spite of the protective effect of maternal immunity, it is in populations with high rates of seroprevalence (80%–100%) where the highest rates of congenital CMV infection are detected. Thus infection rates of congenital infections in populations with low levels of seroprevalence (30%) have been found to stand at around 0.3%, while in populations with rates of seroprevalence above 80%, the infection rate amounts to 2%.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8–10</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Pre-existing immunity must therefore be considered hardly beneficial in protecting against intrauterine infection by CMV, so that its role is not very relevant in establishing the disease burden for this virus. This lack of maternal immune protection against CMV is unique and exclusive to this virus, and it has not been possible to detect it in other viruses or pathogens that are also transmitted placentally (rubella, toxoplasmosis).<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a> All of these data must be taken into consideration when designing a vaccine, as the immunity it induces may not be sufficient to prevent it passing through the placenta. However, if the vaccine is given prior to pregnancy it will avoid latency and reactivation, but not the repeat infections that appear to be equally or more frequent than primary infections.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10–14</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Due to these virological and epidemiological circumstances the following questions have to be raised initially regarding the prevention by vaccination of congenital CMV infections: (a) in seronegative women, will the vaccine give sufficient immunity (in terms of quantity and quality) to prevent a primary infection?; (b) in seropositive women, will the vaccine increase their pre-existing immunity up to levels where it will be able to prevent viral reactivation and repeat infections? Will this post-vaccination immunity be enough to prevent placental transmission and the intrauterine infection of the embryo or foetus? and (c) will the vaccine prevent neurological sequelae in those who are born with asymptomatic congenital infection? All of these questions must be asked and resolved when analysing the results obtained with the different vaccination platforms that are under study or in clinical trial.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,16</span></a></p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Viral structure</span><p id="par0025" class="elsevierStylePara elsevierViewall">CMV is a virus that belongs to the beta subfamily of the <span class="elsevierStyleItalic">Herpesviridae</span> family. It has an icosahedral capsid approximately 120 nm in diameter, surrounded by a lipid envelope; there is a protein layer denominated the tegument between both structures, which is basically composed of phosphoprotein 65 (pp65) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The virus has a lineal DNA double helix genome of approximately 235 Kbs that codifies about 200 different proteins. Of the latter some 65 unique proteins known as glycoproteins (gps) stand out; some 20 of these are located on the viral envelope and their main function is to bind to the cellular receptors of host cells, as well as taking part in the processes of evasion and immunological induction.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–5</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The surface or external envelope of CMV has a large number of proteins and gps that are grouped in different functional structures denominated glycoprotein complexes (GC). These are classified into 4 groups according to their antigenecity: GCI, which contains the gB oligomer, composed of gp58 and gp116; GCII, which contains the gM/gN dimer; GCIII, which contains the gH/gL/gO trimer; and the pentameric complex (PC) that contains glycoproteins gH/gL and the unique proteins UL128/UL130/UL131 (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Of all these, gB, gH and gL are present and conserved in all of the herpes viruses and constitute the necessary viral fusion mechanism for binding and cell infection.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,5,6,12</span></a> Knowledge of these structures and their antigenicity is the key to the design and development of any vaccine against this virus, as neutralising antibodies aimed against them will be those that prevent CMV binding to a host cell, thereby preventing infection by this virus.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,17</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Maternal immunity</span><p id="par0035" class="elsevierStylePara elsevierViewall">The development of an effective vaccine to prevent congenital infections by CMV will have to be based on knowledge and correlated immunological protection that are necessary to prevent the virus being transmitted to the foetus.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18,19</span></a> The first studies onwards provided evidence that maternal antibodies and their responses in T cells were associated with protection against viral transmission. Being seropositive against CMV prior to pregnancy seems to be insufficient (low avidity IgGs) to obtain complete protection against CMV reactivation, as this process is the main cause of the majority of congenital infections, although there is also the possibility of exogenous reinfection by new strains of CMV during pregnancy.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,20</span></a> Although being seropositive (natural immunity) does not protect completely, it has been shown to reduce the risk and consequences, i.e., immunity in a pregnant woman acts as a barrier in the vertical transmission process in approximately 69% of cases.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13–15</span></a> It has therefore been confirmed that the risk and progression of neurosensorial deficit and postnatal deafness are more severe in women with a primary infection than in those who are seropositive, indicating once again the importance of prior immunity.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Different experimental studies in mice have shown that neutralising antibodies against the immunodominant gB antigen of CMV, as well as against the PC (gH/gL), are able to prevent the transmission of CMV in the murine gestation model.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21,22</span></a> The administration of polyclonal IgG, even in the absence of T cell responses, was also proven to have protective capacity in the gestational model of Rhesus monkeys against RhCMV.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,15</span></a> Likewise, it was possible to prove that antibodies against the PC were capable of developing crossed protection against different human strains of CMV. This datum is highly important, as recurring infections, due to reinfection by another viral strain, may also be the cause of human transplacental infection.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Anti-PC antibodies have therefore been considered, together with the degree of avidity of the IgGs against CMV, to be potential protection markers against the congenital transmission of this virus. They constitute the protection correlates that would have to be monitored prospectively in clinical trials of different vaccines.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12,20,23</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">As well as the humoral response in antibodies, the cellular response of T/CD4+ has been shown to play an essential role in protection against the transplacental transmission of RhCMV.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> One study was able to prove that the magnitude of the T/CD4+ cell immune response to the tegument pp65 antigen was far higher in pregnant women who had not transmitted CMV to the foetus.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25,26</span></a> These data showed for the first time the essential role played by T/CD4+/pp65 cells in preventing infection or the congenital transmission of CMV in humans. It therefore seems necessary that a vaccine against this virus should contain at least the pp65 antigen.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,26</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Together with maternal immunity, another datum that deserves mention is the magnitude of the CMV to which the mother is exposed, and its association with transplacental transmission. Different studies have shown that high loads of this virus in primary infection induce a more intense immune response than cases in which suffer a low load infection.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18–22</span></a> The speed and intensity with which CMV replication is prevented or reduced and the magnitude of viraemia therefore play a significant role in predicting transplacental transmission.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,19</span></a> Although CMV is described as a slow replication virus (about 72 h.) in cell cultures, current analyses of its replication dynamic in vivo suggest that the time needed to double the initial infective dose is far shorter, and it may be close to 24 h in immunodepressed patients.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13,17</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Genetic analyses in pregnant women with viraemia have shown the existence of a dynamic population of particles within the CMV itself.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,8</span></a> It is possible that this occurs during pregnancy, and perhaps due to hormonal or immunological mechanisms a selection of strains or clones occurs which are especially able to infect placenta cells before passing to embryonic tissues.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18,19</span></a> If these experimental data are confirmed in women, these clones will have to be analysed to check whether natural immunity or vaccine-induced immunity are able to prevent their proliferation or reduce their presence within the viral population.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,8</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">The target population for the CMV vaccine</span><p id="par0060" class="elsevierStylePara elsevierViewall">If the primary epidemiological aim of the CMV vaccine is to prevent congenital infection by the virus, then immunisation of the pre-adolescent population should be the chief target; this would prevent the sexual transmission of CMV in young adults and hinder vertical transmission from mother to foetus once adolescents become of fertile age with possible pregnancies.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,11,12,15</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Another target group for vaccination would be seronegative women of fertile age, based on the evidence that primary infection during pregnancy directly affects foetal development. The target group could be expanded to include the universal vaccination of all women of fertile age, or at the start of the same (10–14 years old), regardless of their serological status for CMV, based on the studies which indicate that reactivations or reinfections directly affect the foetus in spite of previous maternal immunity, and that the increase in the antibody titer and cellular response due to vaccination would restrict or reduce the viral burden and its possible effect on the foetus. A strategy based on a vaccine able to induce an intense immune response in seronegative women and increase the response (the reinforcement effect) in seropositive women would require a CMV vaccine able to stimulate previous natural immunity, as was shown by the vaccine based on gB/MF59.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The possibility of vaccinating all girls and boys (universal vaccination) in the first months of life may be the best epidemiological option, as it would reduce the transmission of CMV in the first stages of life, when the horizontal spread of the virus is very widespread due to contacts (kindergartens and schools) in this age group. This process would impede the increase in girls infected externally by CMV so that they would reach fertile age with increased immunity that would be reinforced by subsequent exposures. Nevertheless, it would have to be checked whether post-vaccination immunity were sufficient to prevent congenital infections, or whether a booster dose would be necessary at some stage of pregnancy; in this case the requisites for vaccine safety would have to be extreme, as any possible adverse effects of vaccination could affect embryonic development, with teratogenic results.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,8,9,11</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Attenuated vaccines</span><p id="par0075" class="elsevierStylePara elsevierViewall">The first vaccines designed against CMV were no more than human strains attenuated in cell cultures (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>), such as the Towne strain which was isolated from the urine of a child with congenital infection. This strain is defective in several genes and therefore does not develop latency in the host. However, these vaccines were unable to prevent infection and reactivation of the virus when it was administered to adults, and moreover they were not recommendable for pregnant women.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Chimerical vaccines were developed to improve immunogenicity by using recombinant genome regions of the new viral strain, Toledo.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,4</span></a> In this way the Towne/Toledo vaccines demonstrated the capacity to induce powerful T cell immunity in a Phase I trial.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,12,15,27</span></a> In a second trial the DNA-CMV (VCL-CT02) vaccine, which codified pp65 (tegument protein) and IE1 <span class="elsevierStyleItalic">(</span>immediately early protein<span class="elsevierStyleItalic">)</span>-gB, was tested in seronegative subjects, confirming that specific T type memory against CMV was obtained in approximately 60% of subjects, and this was correlated with effective immunity against the Towne strain.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> A third trial of the Towne vaccine strain was administered conjointly with recombinant interleukin 2 (IL-2). This type of combination showed a significant increase in antibody titers against the CMV gB and a memory cell response. Nevertheless, one of the main problems with chimerical vaccines of this type is that the presence of the UL130 mutation in the Towne strain and UL128 in the Toledo strain prevent the expression of PC in them, this being one of the main targets of neutralising antibodies, and this explain its low degree of vaccination efficacy.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28–30</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">A new platform based on artificial bacterial chromosomes (ABC) was developed to obtain an attenuated vaccine against CMV. The application of this technology in the genetic modification of herpes virus has meant that it may be used in vaccine development. This ABC structure was tested in a murine model, in which the murine CMV genome was deleted in 32 genes. This mutant is conventionally replicated in cell cultures and in mice, and it induces specific antibodies and an intense cellular response. Although there are genetic differences between murine and human CMV, the formation of these ABC could be a new approach in the preparation of new attenuated vaccines for human beings.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Towne vaccine virus ABC clones have recently been prepared and their immunity is being trialled in mice.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31–33</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">gB subunit recombinant vaccines</span><p id="par0085" class="elsevierStylePara elsevierViewall">gB (codified by UL55) is one of the glycoproteins that have been studied the most as a candidate CMV vaccine as its behaviour is immunodominant, and it is also essential in the process of cellular fixation and fusion. This glycoprotein is a dimer that contains a surface (ectodermic domain) subunit (gp116) and a small protein (gp58) similar to type I membrane proteins (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> 5 antigenic domains have been described in gB (AD-1-AD-5) that are able to induce neutralising antibodies.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,4,17,23</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">gB is a powerful inducer of specific neutralising antibodies against this virus. It is responsible for 50% of them as well as the T-CD4+ and T-CD8+ cellular immune response in natural infection (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The subunit gB associated with an adjuvant is also capable of protecting guinea pigs against congenital infection by CMV.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Recombinant gB is different from the natural type, composed of 2 subunits joined by a disulphide bridge, as it is a single molecule in which the furin hydrolysis point has mutated and the transmembrane domain has been eliminated to convert it into a monomer protein that is more stable for use in vaccines.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32–34</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">The vaccine composed of gB and the MF59 adjuvant or aluminium hydroxide, administered to adults and young people was found to be safe and immunogenic in a Phase I trial, significantly increasing the previous antibody titer.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> This vaccine was studied in 2 double blind randomised Phase II trials in comparison with a placebo. 3 doses were administered in one of these trials, of 5, 30 or 100 μg gB with MF59 or 100 μg of gB with aluminium hydroxide on days 0, 30 and 180. The antibody peak was detected 2 weeks after the third dose, obtaining the maximum response with 30 μg gB/MF59 and the minimum response with 100 μg of gB/aluminium hydroxide.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,23</span></a> 6 months after the last dose a significant fall in the antibody titer was observed in all of the groups except for the one that had received the dose of 30 μg/MF59; the administration of a fourth dose led once again to a significant increase in antibody titers, especially neutralising antibodies, which demonstrates the capacity of the induced response and memory of the vaccine, which would probably have been able to neutralise a natural CMV infection in these subjects.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,23</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The vaccine in the other trial was composed of 20 μg of gB and 13.25 mg of MF59, administered at 0, 1 and 6 months. The response in seronegative women of fertile age was studied in a subgroup. Primary infection occurred in 8% of the women vaccinated with gB/MF59 and in 14% of the placebo group; vaccination efficacy was estimated to stand at 50% (CI 95%:7−73) and rates of congenital infection per 100 individuals/year stood at 1% of the vaccinated subjects and 3% of the placebo group.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,23</span></a> This vaccine was subsequently trialled in CMV seropositive women of fertile age, to observe its efficacy in preventing reactivations. In this group the gB/MF59 vaccine acted as a powerful booster by increasing the previous antibody titers and cellular response in these women, who had latent CMV in their organism. However, it was not possible to evaluate whether this important immune response was able to prevent the transmission of CMV to a foetus.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,26</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Another combination with an adjuvant that was studied is composed of gB/AS03, the preliminary results of which seem to indicate that it induces high protective (neutralising) titers with great avidity, superior even to natural infection.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> This vaccine was also found (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) to be capable of inducing gB-specific cellular memory and intense responses in CD4+ and CD8+ cells in the seronegative subjects studied.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23,34–37</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Genetic and recombinant vaccines</span><p id="par0110" class="elsevierStylePara elsevierViewall">The use of DNA-based vaccines has shown a possible application against CMV. A bivalent DNA vaccine has therefore been developed (VCL-CB01, ASP0113 or TransVax) which contains 2 plasmids that codify pp65 protein (of the tegument) (VCL-6368) and gB (of the envelope) (VCL-635) with the poloxamer adjuvant CRL100.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5</span></a> The first studies showed that this vaccine was well-tolerated with hardly any adverse reactions, and immunogenicity was detected after 16 weeks (antibody induction) in 45.5% of seronegative patients and in 25% of the seropositive ones who received this vaccine against CMV.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,11</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The VCL-CB01 vaccine induced an intense response in T cells against both of the antigens used, as well as immunological memory beyond week 32 in the seronegative subjects. Nevertheless, in the seropositive subjects the induced titers did not increase to more than double pre-existing levels. A new trivalent DNA vaccine has also been evaluated in Phase I (VCL-CT02) which contains pp65, IE1 and gB expressed in plasmids, followed by a booster with attenuated Towne vaccine. The preliminary results seem to show an important immune induction and reinforcement in the seropositive subjects.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,15</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Use of the canarypox virus (a bird poxvirus) as a candidate vaccine is based on the fact that it is able to include a large amount of genetic material in its interior, infecting mammal cells and expressing all of the proteins it codifies without replicating itself in them, inducing humoral and cellular immunological responses in healthy volunteers without causing adverse effects.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,11,12</span></a> A recombinant vaccine has therefore been developed using attenuated canarypox (ALVAC) that expresses CMV gB (ALVAC-gb) alone or in combination with pp65, and this has been studied in 3 Phase I trials. In 2 of these it did not induce any specific response, while in the third it only obtained an antibody response but no neutralising one after inoculation with Towne vaccine.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38,39</span></a> In spite of initial signs of immunogenicity, the data corresponding to use in humans indicate inefficacy.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,15</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Another possibility that has been tested was the use of the replicon vectorial system (virus-like replicon particles, VRPs) of Venezuelan equine encephalitis (alphavirus) to vehiculise CMV antigens. The trialled vaccine was the one that expressed the extracellular domain of gB and pp65EI1 (AVX601); it showed itself able to induce neutralising antibodies and immunological cellular memory. 93% of those who received a low dose and 100% of those who received a high dose of this vaccines showed high protective titers 4 weeks after vaccination.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Replicon VRPs were subsequently developed which express gH and gL and the PC; these VRPs induce high titers of neutralising antibodies which are superior to those that only express gB.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> The use has also been described of gene vectors based on non-replicator lymphocytic choriomeningitis virus (rLCMV) in which gB and pp65 were inserted; the first studies indicate 90% seroconversion in seronegative subjects.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41,42</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Different modifications of the vaccinia Ankara virus (MVA) have been used to design vaccines against CMV. A recombinant that expresses pp65 protein, exon IE1 4 and exon IE2 5 (Triplex), has been tested in seronegative and seropositive mice to check its capacity to induce humoral and cellular immunity.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42,43</span></a> Rhesus monkey recombinant MVA (RhCMV) containing gB, gB-pp65 or IE1 has been tested in these animals, and once again this confirmed its capacity to induce immunity.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,15</span></a> These studies show that multiantigenic vaccines are more effective, in terms of reducing the replicator capacity of the virus as well as its capacity to be excreted.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Another vector studied was defective adenovirus (AS169) into which the genes that will express immunodominant CMV antigens are inserted (vaccine V160). Within this context vaccine AD5F35-AD-1 which expresses the gB AD-1 antigen and AD-gBCMV were developed. Studies in animal models were hopeful, although they have not even progressed to non-human primates.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,13,15</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">A new vaccine platform uses dense CMV bodies (DB, dense bodies) which form in human fibroblast cultures; they are not infective and have an envelope, but they are unable to replicate and are basically composed of pp65 and gB. In fibroblasts and epithelial cells the antibodies they induce prevent the in vitro infection of the same. In mice they have displayed a certain capacity to induce a neutralising antibody response as well as cytotoxic T lymphocytes.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,31</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">VLP (virus-like particle) and cytotoxic lymphocyte vaccines</span><p id="par0145" class="elsevierStylePara elsevierViewall">A vaccine against CMV has been prepared using VLP technology obtained in infected mammal cells. These contain the extracellular domain of gB (gp116) fused with the transmembrane and cytoplasmatic domains of vesicular stomatitis virus G protein (VSV-G/gB). The induced antibodies were preferentially neutralising in mice and T lymphocytes stimulators, and their total concentration was superior to that obtained with each one of the separate antigens (the immunoamplifying effect).<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,16</span></a> In a Phase I assay in 128 seronegative adults this aluminium-adjuvated vaccine (eVLP/gB-G or VBI-1501) was well tolerated, did not cause adverse effects and induced a 90% seroconversion with the first dose and 100% in the second, preferentially of neutralising antibodies.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,4</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The chimerical vaccine PepVax is composed of the immunodominant zone HLA-A*0201 of CMV pp65 (between amino acids 495–503), as an epitope detected by T/CD8+ cytotoxic lymphocytes, and the synthetic epitope derived from pan-DR (PADRE) protein or with natural tetanus T-helper cell epitope. This vaccine has been tested with and without adjuvant PF-03512676; the initial data seem to indicate that without the presence of the adjuvant no effective cellular immunity responses are obtained. Moreover, even in the presence of the adjuvant it does not induce an immune response in seronegative individuals. It therefore and for now does not seem to be a good candidate for the future prevention of CMV.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,15,44</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pentameric complex vaccines (PC)</span><p id="par0155" class="elsevierStylePara elsevierViewall">Several studies have evaluated the efficacy of a recombinant vaccine based on the PC located in the external envelope of CMV, which is essential for viral infection (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>); this vaccine contains the gH/gL/ antigens and UL128-UL130-UL131 proteins.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,17</span></a> Using PC as the vaccine platform gives rise to an 85% increase in the neutralising antibody titer, antagonically reducing the specific proportion of antibodies against gB. It is postulated that these neutralising antibodies would act by blocking CMV binding to cellular receptors and the viral fusion process. Specific monoclonal antibodies against PC have shown the capacity to prevent primary infection by CMV in animal models by significantly reducing the percentages of placental transmission of this virus, although not the congenital infection it causes.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,45–47</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Animal studies have shown strong humoral as well as cellular immunological induction, and it seems to be one of the best-placed candidates for the future vaccine to be trialled in humans.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5,11</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">The demand is for a vaccine against CMV that prevents congenital infections and therefore stimulates humoral as well as cellular immunity, so that an ideal vaccines would have to fulfil the following requirements: (a) it would have to express the main antigens and epitopes (gB and PC) which have been confirmed to induce an intense neutralising antibody response that prevents human infection in multiple cell types; (b) it would have to express the main targets (pp65, IE1 and IE2) which stimulates the cellular immunity that controls the elimination and lysis of CMV-infected cells; (c) it would have to have an extremely safe profile so that it could be administered to pregnant women; and (d) it would preferentially have to use a vaccine platform that makes it possible to scale up vaccine production, as well as producing it quickly and cheaply so that it could be used in any country in the world.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,13,15,48</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">In spite of the large amount of work with this aim during the past 40 years, there is still no vaccine against CMV that can be used effectively in human beings. Only 6 of all the multiple platforms that have been developed (attenuated Towne vaccine, subunits gB/MF59, gB/AS03, bivalent DNA, viral vector recombinant vaccine and the peptide vaccine) have been tested in humans, and recently gB/MF59 and bivalent DNA vaccine (TransVax) have finalised Phase II trials<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,15</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Due to safety problems the attenuated vaccines and those based on vectors seem to have been ruled out for future use; it is therefore highly possible that vaccines in the future will be based on recombinant proteins and especially those formed by the PC.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">Several studies confirm the need for clinical trials of vaccines against CMV to prove that they work safely, effectively and significantly in providing immunological protection that is able to reduce placental transmission and therefore the transmission of congenital infections.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7–9</span></a> This datum is far easier to detect and confirm than is the case for any possible long-term capacity of the vaccine to prevent the neurosensorial sequelae associated with this congenital infection.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7–9</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">It has to be said that the specific immune responses induced by the subunit vaccines (gB or pp65) or the vectorial vaccines are qualitatively and quantitatively very different from those obtained during natural infection by CMV. Initial exposure to the complete virus gives rise to a broad spectrum immune response against multiple antigens and epitopes, making it more universal. This is why vaccination with these vaccines will strengthen any previous natural immunity in the immunodominant antigens that play a more direct role in the replicator dynamics of CMV.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13,15</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">One of the data to be considered is the duration of the immune response obtained with the new vaccine platforms, given that women may have several pregnancies throughout their fertile life, separated by long intervals of time. A worrying datum is that a study of gB/MF59 vaccine found that the antibody titer fell very intensely 12 months after vaccination, so that its protective effect also fell over time.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> These data must be taken into consideration when evaluating each new vaccine, as it is possible that they will require the addition of other adjuvants to especially strengthen cellular memory immunity, ensuring the capacity to respond to subsequent exposure to CMV.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Other aspects that have to be taken into account are the acceptability of the new vaccine in infancy or adolescence, preferentially for girls of fertile age. The study by Petty et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> analyses the attitude of the parents of these populations to the new vaccine and its acceptability for them. It finds that the new hypothetical vaccine would be reasonably well-accepted, even though the general population has little information about CMV and the congenital infections which it causes.</p><p id="par0195" class="elsevierStylePara elsevierViewall">Whenever a study commences of any new vaccine it is always necessary to perform a cost-effectiveness analysis of its possible use, even if this is only theoretical. Thus Dempsey et al.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> have developed a mathematical model for this datum, based on the premises that it would be given to 100% of adolescent girls of fertile age and at a cost of 180 dollars per dose. Their study concludes that vaccinating this age group is less costly and brings about more health benefits than would the decision not to vaccinate. Nevertheless, it also predicts that when effect of the vaccine in protecting against primary infection by CMV is lower than 61%, then non-vaccination would be the best strategy, as the consequences of infection are less costly than a universal vaccination program. As the sole clinical trial to date of gB/MF59 showed an efficacy of only 50%,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,23</span></a> this could not be recommended as a universal clinical candidate. Only if a moderately effective vaccine were able to induce significant group immunity to make it more effective overall than 61% would it be cost-effective.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">It seems that currently the process of obtaining an effective safe vaccine to prevent congenital CMV infections is quite advanced, although it is still distant on the horizon. Although the main target group would have to be defined according to immune response parameters, it would be ideal for the vaccine to be of universal use for both sexes during the first year of life. This strategy would prevent the majority of the population against infection and drastically reduce the number of seropositive expectant mothers and those with viral latency, as well as the circulation of CMV.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interests</span><p id="par0205" class="elsevierStylePara elsevierViewall">The author is a member of the editorial committee of the journal <span class="elsevierStyleItalic">Vacunas</span>.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:3 [ "identificador" => "xres1423015" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1300919" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1423016" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1300920" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Viral structure" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Maternal immunity" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "The target population for the CMV vaccine" ] 3 => array:2 [ "identificador" => "sec0025" "titulo" => "Attenuated vaccines" ] 4 => array:2 [ "identificador" => "sec0030" "titulo" => "gB subunit recombinant vaccines" ] 5 => array:2 [ "identificador" => "sec0035" "titulo" => "Genetic and recombinant vaccines" ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "VLP (virus-like particle) and cytotoxic lymphocyte vaccines" ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Pentameric complex vaccines (PC)" ] ] ] 5 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of interests" ] 6 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1300919" "palabras" => array:5 [ 0 => "Cytomegalovirus" 1 => "Congenital infection" 2 => "Vaccination" 3 => "gB glycoprotein" 4 => "Pentameric complex" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1300920" "palabras" => array:5 [ 0 => "Citomegalovirus" 1 => "Infección congénita" 2 => "Vacunación" 3 => "Glicoproteína gB" 4 => "Complejo pentamérico" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Human cytomegalovirus (CMV) is a very ubiquitous virus that is transmitted very efficiently among the population through saliva, urine, lactation or blood transfusions. Around 75% of people at age 15 are already seropositive, have acquired immunity, against this virus. The majority (85%) of congenital CMV infections are due to gestational reactivation (latency) and reinfection by different CMV strains and only 15% to a primary infection during it. These data support the concept of the paradox of previous immunity, that is, the risk of congenital CMV infection is higher in seropositive pregnant women.</p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">One of the possibilities of avoiding congenital CMV infections is universal vaccination in the first months of life. In this way women would reach fertile age with immunity and without CMV in their body.</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Despite the efforts made in the last forty years, there is still no vaccine against CMV that can be applied effectively in humans. Of all the multiple platforms developed, only six of them (attenuated Towne vaccine, gB/MF59 subunits, gB/AS03, DNA bivalent, viral vector recombinant and peptide vaccine) have been tested in humans and recently the gB / MF59 and the bivalent DNA have completed Phase II assays. Due to safety concerns, attenuated and vector-based vaccines seem to be ruled out for the future; Therefore it is very possible that the future is in vaccines based on recombinant proteins (gB) and especially those formed by the pentameric complex. Keywords: cytomegalovirus; congenital infection; vaccination; gB glycoprotein; pentameric complex.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">El citomegalovirus (CMV) humano es un virus muy ubicuo que se trasmite de forma muy eficiente entre la población a través de la saliva, orina, lactancia o transfusiones sanguíneas. Alrededor del 75% de las personas a los 15 años ya son seropositivas, presentan inmunidad adquirida, frente a este virus. La mayoría (85%) de las infecciones congénitas por CMV son debidas a la reactivación gestacional (latencia) y a la reinfección por cepas de CMV distintas y sólo el 15% a una primoinfección durante la misma. Estos datos apoyan el concepto de la paradoja de la inmunidad previa, es decir el riesgo de infección congénita por CMV es superior en las gestantes seropositivas.</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Una de las posibilidades de evitar las infecciones congénitas por CMV es la vacunación universal en los primeros meses de vida. De este modo las mujeres llegarían a la edad fértil con inmunidad y sin CMV en su organismo.</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">A pesar de los esfuerzos realizados en los últimos cuarenta años, todavía no se dispone de una vacuna frente al CMV que pueda aplicarse de forma efectiva en el ser humano. De todas las múltiples plataformas desarrolladas sólo seis de ellas (vacuna Towne atenuada, subunidades gB/MF59, gB/AS03, bivalente de ADN, recombinante de vector viral y vacuna de péptidos) se han llegado a probar en humanos y recientemente la gB/MF59 y la bivalente de ADN han finalizado los ensayos Fase II. Debido a los problemas de seguridad las vacunas atenuadas y basadas en vectores parecen descartarse de cara al futuro; por ello es muy posible que el futuro se encuentre en vacunas basadas en proteínas recombinantes (gB) y especialmente las formadas por el complejo pentamérico.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Reina J. Estado actual de las vacunas frente a la infección congénita por citomegalovirus: la paradoja de la inmunidad previa. Vacunas. 2020;21:111–120.</p>" ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 946 "Ancho" => 1624 "Tamanyo" => 146240 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Diagrammatic structure of human cytomegalovirus.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Source: modified, from Gardner and Tortorella.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1250 "Ancho" => 2167 "Tamanyo" => 129923 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Diagrammatic representation of the glycoprotein complexes (GC) of the human cytomegalovirus surface. The pentameric complex (PC) is composed of glycoproteins gH and gL, and the UL128, UL130 and UL131 proteins.</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Source: modified, from Gardner and Tortorella.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p>" ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1698 "Ancho" => 3074 "Tamanyo" => 289748 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">History of cytomegalovirus vaccines following its initial isolation in humans.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">ALVAC: canarypox vector; CAB: bacterial artificial chromosome; VAM: modified Ankara virus.</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Source: modified, from Dasari et al.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p>" ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">AcNeu: neutralising antibodies; NA: not studied.</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Source: modified, from Dasari et al.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Vaccine \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">AcNeu \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">T/CD4+ \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">T/CD8+ \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated Towne \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Towne + rhIL-2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chimerical Towne/Toledo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trivalent DNA Towne \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">gB/MF59 subunits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">gB/AS03 subunits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bivalent DNA gB/pp65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ALVAC-gb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ALVAC-pp65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AlphavirusgB/pp65-IE1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vaccine pp65 alone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2440570.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Humoral and cellular immune response induction of the main vaccines against CMV tested in clinical trials.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">VAM: Modified Ankara virus; VLP: Virus-like particles.</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Source: modified, from Luisi et al.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Components \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Situation \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chimerical Towne/Toledo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase I \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">V160 (defective virus with pentamer) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase I \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subunits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">gB/MF59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase II \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">gB/AS01 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase I \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pentameric complex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preclinical \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VLP- pentameric complex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preclinical \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Genetic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">gB/pp65 (TransVax) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase II \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">gB/pp65 (DNA vector) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preclinical \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VAM pentamer/pp65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preclinical \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">gB/pp65-IE1 (alphavirus AVX601) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase I \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2440571.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Experimental vaccines against CMV under clinical or preclinical evaluation (up to 2018).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:50 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cytomegalovirus vaccines" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M.A. McVoy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/cid/cit587" "Revista" => array:7 [ "tituloSerie" => "Clin Infect Dis" "fecha" => "2013" "volumen" => "57" "numero" => "S4" "paginaInicial" => "S196" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24257427" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cytomegalovirus (Chapter 62)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "E.S. 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