Review article
Current situation of intranasal attenuated vaccines against respiratory syncytial virus in the child population
Situación actual de las vacunas atenuadas intranasales frente al virus respiratorio sincitial en la población infantil
Read
Not available
Timeswas read the article
Total PDF
Total HTML
Share statistics
array:23 [ "pii" => "S2445146024000190" "issn" => "24451460" "doi" => "10.1016/j.vacune.2024.02.016" "estado" => "S300" "fechaPublicacion" => "2024-01-01" "aid" => "334" "copyrightAnyo" => "2024" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Vacunas. 2024;25:140-6" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "es" => array:18 [ "pii" => "S1576988723001048" "issn" => "15769887" "doi" => "10.1016/j.vacun.2023.12.001" "estado" => "S300" "fechaPublicacion" => "2024-01-01" "aid" => "334" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Vacunas. 2024;25:140-6" "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" => "Situación actual de las vacunas atenuadas intranasales frente al virus respiratorio sincitial en la población infantil" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "140" "paginaFinal" => "146" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Current situation of intranasal attenuated vaccines against respiratory syncytial virus in the child population" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "f0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 640 "Ancho" => 2175 "Tamanyo" => 142709 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Figura " "rol" => "short" ] ] "descripcion" => array:1 [ "es" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Posible estrategia de vacunación e inmunización frente al virus respiratorio sincitial en las diferentes etapas de la vida (modificado de Mejias et al.<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a>).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jordi Reina, Andrés Suárez" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Jordi" "apellidos" => "Reina" ] 1 => array:2 [ "nombre" => "Andrés" "apellidos" => "Suárez" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2445146024000190" "doi" => "10.1016/j.vacune.2024.02.016" "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/S2445146024000190?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1576988723001048?idApp=UINPBA00004N" "url" => "/15769887/0000002500000001/v1_202402130601/S1576988723001048/v1_202402130601/es/main.assets" ] ] "itemSiguiente" => array:17 [ "pii" => "S2445146024000086" "issn" => "24451460" "doi" => "10.1016/j.vacune.2024.02.005" "estado" => "S300" "fechaPublicacion" => "2024-01-01" "aid" => "305" "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "cor" "cita" => "Vacunas. 2024;25:147-8" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter to the editor</span>" "titulo" => "Vaccination impact on long COVID sequelae; a perspective view" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "147" "paginaFinal" => "148" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Impacto de la vacunación en las secuelas del COVID de larga duración; una visión en perspectiva" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Farhad Dadgar, Fatemeh Dehghani, Farzaneh Peikfalak, Masoud Keikha" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Farhad" "apellidos" => "Dadgar" ] 1 => array:2 [ "nombre" => "Fatemeh" "apellidos" => "Dehghani" ] 2 => array:2 [ "nombre" => "Farzaneh" "apellidos" => "Peikfalak" ] 3 => array:2 [ "nombre" => "Masoud" "apellidos" => "Keikha" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146024000086?idApp=UINPBA00004N" "url" => "/24451460/0000002500000001/v1_202403150618/S2445146024000086/v1_202403150618/en/main.assets" ] "itemAnterior" => array:17 [ "pii" => "S2445146024000177" "issn" => "24451460" "doi" => "10.1016/j.vacune.2024.02.014" "estado" => "S300" "fechaPublicacion" => "2024-01-01" "aid" => "316" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Vacunas. 2024;25:128-39" "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" => "Prevalence of HCV among patients with HIV in Iran: A systematic review and meta-analysis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "128" "paginaFinal" => "139" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "f0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3947 "Ancho" => 2590 "Tamanyo" => 1001405 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Forest plot showing the observed outcomes and the estimate of the random-effects model.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Maedeh Hajizadeh, Maryam Moradi Binabaj, Arezoo Asadi, Milad Abdi, Abolfazl Shakiba, Masoumeh Beig, Mohsen Heidary, Mohammad Sholeh" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Maedeh" "apellidos" => "Hajizadeh" ] 1 => array:2 [ "nombre" => "Maryam Moradi" "apellidos" => "Binabaj" ] 2 => array:2 [ "nombre" => "Arezoo" "apellidos" => "Asadi" ] 3 => array:2 [ "nombre" => "Milad" "apellidos" => "Abdi" ] 4 => array:2 [ "nombre" => "Abolfazl" "apellidos" => "Shakiba" ] 5 => array:2 [ "nombre" => "Masoumeh" "apellidos" => "Beig" ] 6 => array:2 [ "nombre" => "Mohsen" "apellidos" => "Heidary" ] 7 => array:2 [ "nombre" => "Mohammad" "apellidos" => "Sholeh" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146024000177?idApp=UINPBA00004N" "url" => "/24451460/0000002500000001/v1_202403150618/S2445146024000177/v1_202403150618/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Current situation of intranasal attenuated vaccines against respiratory syncytial virus in the child population" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "140" "paginaFinal" => "146" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Jordi Reina, Andrés Suárez" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Jordi" "apellidos" => "Reina" "email" => array:1 [ 0 => "jorge.reina@ssib.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "af0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "af0010" ] ] ] 1 => array:3 [ "nombre" => "Andrés" "apellidos" => "Suárez" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "af0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "af0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cr0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Virología, Servicio de Microbiología, Hospital Universitario Son Espases, Palma de Mallorca, Spain" "etiqueta" => "a" "identificador" => "af0005" ] 1 => array:3 [ "entidad" => "Facultad de Medicina, Universitat Illes Balears, Palma de Mallorca, Spain" "etiqueta" => "b" "identificador" => "af0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cr0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Situación actual de las vacunas atenuadas intranasales frente al virus respiratorio sincitial en la población infantil" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "f0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1991 "Ancho" => 2120 "Tamanyo" => 258142 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">General structure an distribution of the different genes in the genoma of the syncytial respiratory virus (modified from Plemper et al<a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a>).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">Respiratory syncytial virus (RSV) was discovered in 1955, designated as <span class="elsevierStyleItalic">chimpanzee coryza</span> agent and associated with bronchiolitis in children in 1957.<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0010"><span class="elsevierStyleSup">2</span></a> It causes acute respiratory illnesses (bronchiolitis and pneumonias) that occur most commonly as an epidemic in the winter months. Despite the fact that it can affect the entire population, its pathological impact is much greater in children (under 5 years of age) and in the elderly (over 65 years of age).<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a> As such, it is estimated to account for 22% of all acute respiratory infections (ARIs) in the paediatric population. A 2015 worldwide study estimated that RSV was responsible for 33.1 million ARIs per year, leading to some 3.2 million hospitalisations and 59 000 hospital deaths in children under the age of 5 years. Furthermore, in infants under 6 months of age, RSV is responsible for approximately 1.4 million hospitalisations and about 27 300 deaths per year.<a class="elsevierStyleCrossRefs" href="#bb0020"><span class="elsevierStyleSup">4–6</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">In the paediatric population, the peak for hospitalisations is between the ages of 2 and 3 months, although the risk of severe infection continues until the age of 5 years. It has been estimated that by the age of 3, almost the entire population has been infected with RSV, with reinfections occurring annually or every 3–5 years,<a class="elsevierStyleCrossRefs" href="#bb0030"><span class="elsevierStyleSup">6–9</span></a> suggesting an immune response that fails to protect for long periods of time. Given that the aim of RSV vaccination is to prevent severe infection and its consequences, the target population to be vaccinated would ideally be children over the age of 6 months, given that infants younger than this would be vaccinated with a long-lasting monoclonal antibody or by vaccinating pregnant women<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRefs" href="#bb0050"><span class="elsevierStyleSup">10–12</span></a> (<a class="elsevierStyleCrossRef" href="#f0005">Fig. 1</a>).</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0015" class="elsevierStylePara elsevierViewall">Of the various vaccines available, attenuated vaccines (AVs) are defined as those that contain a virus that has been altered or modified to reduce its pathogenic potential as much as possible, while maintaining its immunological response capacity.<a class="elsevierStyleCrossRefs" href="#bb0050"><span class="elsevierStyleSup">10–12</span></a> They can be obtained by classical methods (low-temperature/<span class="elsevierStyleItalic">cold-adapted</span> or by chemical modifications) or by reverse genetics techniques that impede viral replication.<a class="elsevierStyleCrossRefs" href="#bb0030"><span class="elsevierStyleSup">6–8</span></a> Their intranasal (INV) delivery route makes them very attractive to immunise young children (><span class="elsevierStyleHsp" style=""></span>6 months–5 years) because they mimic natural moderate infection and, moreover, contain a wide range of proteins that induce a broad spectrum of innate and adaptive immunity both in the nasal and oropharyngeal mucosa and systemically.<a class="elsevierStyleCrossRefs" href="#bb0045"><span class="elsevierStyleSup">9–11</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">These attenuated vaccines have a number of advantages, such as: (a) the ability to replicate in the respiratory tract despite the presence of maternal antibodies, (b) the capability to induce humoral and cellular immune responses, and (c) the possibility of nasal administration, which is much better tolerated by the paediatric population. Over the course of the last 25 years, this type of vaccine has been evaluated in more than 500 HIV-negative children.<a class="elsevierStyleCrossRef" href="#bb0065"><span class="elsevierStyleSup">13</span></a> These studies have failed to establish any evidence that they induce the phenomenon of increased vaccine-associated disease, as occurred in children who received the formalin-inactivated RSV vaccine.<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">14</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">The ideal INV should be able to replicate enough to elicit protective immunity with a minimum of adverse effects. The use of reverse genetics and a better understanding of the function of the various RSV genes has made it possible to develop new candidates. The basic requirements of these candidates include stabilising the point mutations that make it temperature-sensitive, preferably by restricting its replication capacity in the lower respiratory tract, and deletion/delection of non-essential viral genes such as NS2, a type I/III interferon antagonist.<a class="elsevierStyleCrossRef" href="#bb0065"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Vaccines in which the M2-2 domain has been deleted</span><p id="p0030" class="elsevierStylePara elsevierViewall">The RSV is an enveloped virus with a single-stranded, negative, unsegmented RNA genome of some 15 200 nucleotides that belongs to the Pneumoviridae family and the Orthopneumovirus genus. It contains 10 genes and encodes for 11 distinct proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), RNA polymerase (L), polymerase factors (M2-1 and M2-2), fusion glycoprotein (F), adhesion glycoprotein (G), small hydrophobic protein (SH), and the non-structural proteins NS1 and NS2 (<a class="elsevierStyleCrossRef" href="#f0010">Fig. 2</a>).<a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a></p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0035" class="elsevierStylePara elsevierViewall">Since 1995, the use of reverse genetics has enabled us to understand the function of the different RSV genes, enabling the development of vaccine candidates. The first attenuated vaccine for intranasal administration against this virus was designated rA2cp248/404/1030ΔSH (RSVcps2) obtained by culture passages at suboptimal temperatures to select variants adapted to low temperatures (<span class="elsevierStyleItalic">cold-adapted</span>) and introduction of point mutations in the SH gene to attenuate its replicative capacity. This vaccine contained: (a) 5 amino acid substitutions obtained in <span class="elsevierStyleItalic">cold-passage</span> (cp) in the nucleoprotein (N), fusion protein (F), and polymerase (L); (b) the attenuation (<span class="elsevierStyleItalic">att</span>) and temperature-sensitive (<span class="elsevierStyleItalic">ts</span>) point mutation at position 404 of the gene encoding the M2-1 and M2-2 proteins; (c) substitutions at positions 248 and 1030 of the L protein (<span class="elsevierStyleItalic">att</span> and <span class="elsevierStyleItalic">ts</span>), and (d) deletion of the gene encoding the SH protein. This combination of genetic modifications rendered the vaccine strain highly attenuated and unable to infect above 35 °C (<span class="elsevierStyleItalic">ts</span>).<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a> This vaccine was proven to be well tolerated in humans, but moderately immunogenic.<a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a> Based on this vaccine, the MEDI-559 vaccine was developed but exhibited genetic instability and reversion to the wild-type form; hence, the decision was made to modify it by introducing changes in the M2-2 protein.<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a></p><p id="p0040" class="elsevierStylePara elsevierViewall">RSV M2-2 is a small, non-abundant protein encoded by the second RNA-messenger of the ORF of the M2 gene, located in close proximity to the other M2-1 gene. Loss of the M2-2 protein (gene deletion) leads to increased transcription of viral RNA genes and their heightened antigenic expression, but associated with significantly decreased viral replication. This elevated antigenic expression produces high immunogenicity with low viral replication (attenuation).<a class="elsevierStyleCrossRefs" href="#bb0080"><span class="elsevierStyleSup">16–18</span></a></p><p id="p0045" class="elsevierStylePara elsevierViewall">In recent years, 2 vaccine candidates based on the M2-2 gene deletion have been evaluated: MEDI/ΔM2 and LID/ΔM2-2 (cDNA from the A2 strain of RSV subgroup A).<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a> Both are derived from two recombinant cDNAs that differ by 21 nucleotides. They differ in their design in the M2-2 domain; thus, the LID/ΔM2-2 vaccine contains a set of silent mutations in the SH gene. Nevertheless, both vaccines exhibit a similar phenotype in <span class="elsevierStyleItalic">in-vitro</span> and animal studies. However, when administered to seronegative children (aged 6–24 months), the MEDI/ΔM2 vaccine induced a substantial neutralising antibody response with little RSV present in nasal wash, whereas the LID/ΔM2-2 vaccine resulted in a high viral load present in nasal swabs.<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a> The degree of vaccine virus shedding in the nasopharynx is a strong marker of attenuation; although the optimal level has yet to be ascertained, titres of between 4.0 and 4.9 log10 PFU/ml have been found to correlate with marked nasal congestion, hindering feeding and sleep in children.<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a></p><p id="p0050" class="elsevierStylePara elsevierViewall">As a result of this behaviour, the LID/ΔM2-2 vaccine was poorly tolerated by some recipients when administered on a large scale. That is why McFarland et al<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a> developed a new vaccine strain designated LID/ΔM2-2/1030s that contains the missense mutations at position 1030 providing greater stability and attenuation (ts) to the vaccine.</p><p id="p0055" class="elsevierStylePara elsevierViewall">In the study conducted in 21 seronegative children (6–24 months), participants received an intranasal dose (105 PFU) of the new LID/ΔM2-2/1030s vaccine vs. a placebo group. 85% of those vaccinated developed a 4-fold higher neutralising antibody titre than before; fever or respiratory symptoms were fairly common adverse effects in the vaccinated group (67% vs. 25% placebo). 20% of those vaccinated maintained the protective titre in the following epidemic season. These results support the notion that this new vaccine strain is a promising candidate for application in future clinical trials.<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a></p><p id="p0060" class="elsevierStylePara elsevierViewall">This same group has developed a second modification of the LID/ΔM2-2 vaccine by deleting 234 nucleotides in the M2-2 gene and designating it D46/NS2/ΔM2-2-HindIII, in addition to maintaining the deletion in the SH protein that was eliminated in the prior vaccine. In this trial, 95% of seronegatives had a very positive neutralising antibody response that remained between 6 and 9 months post-vaccination.<a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Vaccines with ΔNS2/Δ1313 deletion</span><p id="p0065" class="elsevierStylePara elsevierViewall">RSV with the Δ1313 deletion replicates in cell culture at 32 °C with the same efficiency as the wild-type strain, yet is restricted to do so at 37 °C and 50–150 times more in mouse respiratory tract cells.<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a> This strain is far more <span class="elsevierStyleItalic">ts</span> than the previous strain described with the L protein mutations at positions 248 (Q831L) and 1030 (Y1321N).<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a> Despite being an attenuated strain, it is able to elicit an increase of up to 4 titres in RSV antibody levels in 100% of the non-human primates studied. Nevertheless, the Δ1313 deletion is not enough to achieve the attenuation needed to be applied in the paediatric population (immunological immaturity). For this reason, and based on the MEDI-59 vaccine prototype, Luongo et al<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a> combined this deletion with the following mutations: (a) <span class="elsevierStyleItalic">non-ts cp</span> mutation previously identified in a virus adapted to low temperatures (32 °C); (b) the <span class="elsevierStyleItalic">non-ts</span> deletion of the SH gene, whose function is unknown; (c) the ts mutations at the 1030 and 404 loci, and (d) the <span class="elsevierStyleItalic">non-ts</span> deletion of the NS2 gene.</p><p id="p0070" class="elsevierStylePara elsevierViewall">Based on the different <span class="elsevierStyleItalic">in-vitro</span> assays, Luongo et al<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a> concluded that the combination of the Δ131313 deletion with the NS2 deletion was the best combination to develop an attenuated recombinant RSV vaccine candidate (ΔNS2/Δ1313). NS2 is an interferon antagonist and facilitates RSV excretion from infected cells, contributing to bronchial obstruction. Its deletion results in an increased interferon response that decreases viral replication (attenuation), respiratory tract injury, and, possibly, increases the adaptive immune response. During <span class="elsevierStyleItalic">in-vitro</span> testing with temperature increments, a second compensatory mutation was detected in the vicinity of Δ1313, designated I1314T. This mutation could be genetically and phenotypically stabilised with the I1314L substitution. Thus, the combination of the I1314L with the ΔNS2/Δ1313 deletions resulted in the RSV/ΔNS2/Δ1313/I1314L that was genetically stable with respect to physiological temperature changes.</p><p id="p0075" class="elsevierStylePara elsevierViewall">In this study, the RSV/ΔNS2/Δ1313/I1314L vaccine containing the NS2 deletion (deletion of nucleotides 577–1098) and the introduction of a stabilisation codon (I1314L) in the polymerase (L) gene had proven to be highly attenuated and immunogenic in seronegative children.<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a> However, this vaccine was found to be excessively attenuated <span class="elsevierStyleItalic">in-vivo</span> and did not replicate sufficiently to provide effective immunity. For this reason, Cunningham et al<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a> developed 2 new vaccines: (a) RSV/6120/ΔNS2/1030s, which is identical to the previous one except that the Δ131313/I1314L mutations in the polymerase gene have been replaced by missense mutations 1321 K (AAA) and S1321 (GGT), located next to the deleted Δ131313 codon and (b) RSV/276 only deleted in the M2–2 protein (28). These vaccines were less ts and were less restricted in their ability to replicate in non-human primates and primary human respiratory tract cells; as a result, they should be substantially more immunogenic in children.<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a> However, the RSV/276 vaccine caused excessive nasal adverse effects and was therefore abandoned.</p><p id="p0080" class="elsevierStylePara elsevierViewall">Based on these data, in 2021, Karron et al<a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">24</span></a> conducted a phase I evaluation of RSV/6120/ΔNS2/1030s in seronegative and seropositive children with RSV strain RSV/6120/ΔNS2/1030s. This vaccine proved that it elicited an immune response with a titre equal to or greater than 1/40, which was deemed predictive of its efficacy in protecting against RSV infections in both the upper (67% efficacy) and lower (88% efficacy) respiratory tract of the paediatric population (aged 6–24 months). Moreover, the duration of vaccine-induced neutralising antibodies and their concentration was found to be maintained up to 12 months, albeit with a non-significant decrease. This suggests that a single dose would be sufficient to protect children over the course of a seasonal window, although it is more than likely that it would have to be administered periodically in each season thereafter.</p><p id="p0085" class="elsevierStylePara elsevierViewall">In 2022, Karron et al<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a> developed a new vaccine candidate designated RSV/6120/ΔNS2/1030s that is identical to the previous RSV/ΔNS2/Δ1313/I1314L virus, except that the Δ131313/I1314L mutations in polymerase L were replaced by the missense mutations S1313 (TCA) and Y1321K (AAA) near codon Δ131313 (<a class="elsevierStyleCrossRef" href="#f0015">Fig. 3</a>).</p><elsevierMultimedia ident="f0015"></elsevierMultimedia><p id="p0090" class="elsevierStylePara elsevierViewall">An intranasal dose of this new vaccine (10<span class="elsevierStyleSup">5.7</span> PFU, <span class="elsevierStyleItalic">plaque-forming units</span>) was administered to 15 seropositive children aged 12–59 months and 30 seronegative children aged 6–24 months. The vaccine virus infected 100% of the seronegative subjects, was immunogenic, and genetically stable. Moderate rhinorrhoea was detected in 90% of those vaccinated (40% placebo). A 4-fold increase in F-protein antibody titre or neutralising antibody titre was observed in 0% of the seropositive individuals. These findings confirm vaccine attenuation and are similar to those observed with other attenuated vaccines in seropositive children.<a class="elsevierStyleCrossRefs" href="#bb0090"><span class="elsevierStyleSup">18–21</span></a> In the seronegative sample, the results were different, with 73% of the cohort receiving a dose of 105 PFU experiencing respiratory or febrile illness. In terms of immune response, 53% of the children who received the dose of 105 PFU developed neutralising antibodies to the F protein, while 85% of those who received the higher vaccine dose also produced neutralising antibodies to the F protein. There was no good correlation between antibody titre and shedding of vaccine virus in nasal washes. During the first RSV season, the vaccinated individuals had neutralising antibody titres 14 times higher than the placebo group; during the second season, immunological memory was detected as a result of the earlier imprinting. These data would indicate that a second dose would not be necessary after the first season. Nevertheless, one aspect that must be examined is the frequency and nature of the respiratory symptoms detected in the vaccinated subjects and whether (the vaccines) are responsible for them or whether they are caused by other respiratory viruses.<a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a></p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Attenuated single replicative cycle vaccines</span><p id="p0095" class="elsevierStylePara elsevierViewall">Live single-cycle (SCR) viruses have been developed as potential attenuated candidate vaccines for different viruses, including influenza.<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a> These viruses are attenuated through a genetic modification that precludes the formation of mature virions capable of spreading infection to contiguous cells. This strategy is highly advantageous as the antiviral immune response is initiated in the absence of disease produced by the wild-type virus. Mitra et al<a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">27</span></a> have developed an RSV with SCR by deleting the matrix (M) protein encoding gene and labelled it RSV-M-null. The M protein is only required to assemble mature RSV virions following infection of the host cell; for this reason, it is not essential for genome replication or full expression. In this way, RSV M-null is not able to form infectious viral particles after initial infection and only undergoes a single replicative cycle. Originally, this type of virus was not very effective because the M gene was absent; therefore, a second generation of RSV M-null was developed in cell cultures to which a tet transactivator gene was added in place of the ORF of the M gene. The viral titres that were obtained with this modification were very similar to those produced by the wild-type RSV in <span class="elsevierStyleItalic">in-vivo</span> studies.<a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">27</span></a></p><p id="p0100" class="elsevierStylePara elsevierViewall">Schmidt et al<a class="elsevierStyleCrossRef" href="#bb0140"><span class="elsevierStyleSup">28</span></a> have evaluated this second generation of attenuated RSV M-null virus as a potential candidate vaccine and its ability to prevent infection in murine (BALB/c) models. First of all, they analysed the behaviour of this virus in natural infection. Compared to the control strain, RSV M-null demonstrated a significant decrease in viral titres and pulmonary impairment. Subsequent immunisation with the RSV M-null resulted in a strong immune response, both CD4 and CD8 cell-mediated and humoral immune responses, which afforded protection against external infection by the control strain. Thus, the RSV M-null strain was proven to combine a highly attenuated phenotype within itself without any loss of its immunogenicity, providing a highly efficient immunological protection. The absence of the M gene in this strain prevents it from recovering its function and, therefore, eliminates the risk that it will revert to the wild-type form, as could occur in strains attenuated by point mutations. The conclusion is that the RSV SCR M-null is a very promising prototype from which a future intranasal attenuated RSV vaccine could be developed.<a class="elsevierStyleCrossRef" href="#bb0140"><span class="elsevierStyleSup">28</span></a></p><p id="p0105" class="elsevierStylePara elsevierViewall">To enhance vaccine safety and efficacy, Lamichhane et al<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a> have developed an SCR-type RSV vaccine that primarily expresses the prefusion (preF)(RSV-preF<span class="elsevierStyleSup">ΔCT</span>) form of RSV, either on its membrane or secreted by infected cells. The preF-secreting vaccine was unable to induce a protective immune response in mice after vaccination. However, the viral membrane-anchored preF vaccine did elicit high levels of antibodies against preF, as well as cell-mediated immunity, which subsequently protected infected mice. These data illustrate the ability of this strain to protect against RSV infection and to do so with a high degree of safety and tolerability in mice.</p><p id="p0110" class="elsevierStylePara elsevierViewall">There are many intranasal attenuated RSV vaccines in phase I trials and only a few in phase II trials, due to the higher safety requirements. For the time being and thanks to their efficacy and safety, these vaccines appear to be the prime candidates for population-based vaccination programmes in children over the age of 6 months.</p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Funding</span><p id="p0115" class="elsevierStylePara elsevierViewall">This review article has not received any funding from any public or private entity.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres2108185" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1796013" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2108184" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1796012" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "s0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "s0010" "titulo" => "Vaccines in which the M2-2 domain has been deleted" ] 6 => array:2 [ "identificador" => "s0015" "titulo" => "Vaccines with ΔNS2/Δ1313 deletion" ] 7 => array:2 [ "identificador" => "s0020" "titulo" => "Attenuated single replicative cycle vaccines" ] 8 => array:2 [ "identificador" => "s0025" "titulo" => "Funding" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-12-01" "fechaAceptado" => "2023-12-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1796013" "palabras" => array:3 [ 0 => "Respiratory syncytial virus" 1 => "Attenuated vaccines" 2 => "Deletions" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1796012" "palabras" => array:3 [ 0 => "Virus respiratorio sincitial" 1 => "Vacunas atenuadas" 2 => "Delecciones genéticas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">The respiratory syncytial virus (RSV) is the cause of acute respiratory pathologies (bronchiolitis and pneumonia), which occur preferably in the paediatric population in an epidemic manner. The only way to prevent these infections is through prior vaccination ><span class="elsevierStyleHsp" style=""></span>6 months. Of the different existing vaccines, attenuated vaccines, defined as those that contain an altered or modified virus to minimise its pathogenic capacity while maintaining its immunological response capacity, seem to represent an important advance. In recent years, 2 vaccine candidates based on the M2-2 gene deletion have been evaluated, those designated MEDI/ΔM2 and LID/ΔM2-2/1030s. In the study carried out in 21 seronegative children (6–24 months), they received an intranasal dose (105 PFU) of the new vaccine compared to a placebo group. 85% of those vaccinated developed a neutralising antibody titre ><span class="elsevierStyleHsp" style=""></span>4 times the previous one. The combination of the Δ1313 deletion with the NS2 deletion was shown to be better for the development of an attenuated RSV recombinant vaccine candidate (ΔNS2/Δ1313), with good protective results. A new vaccine candidate designated RSV/6120/ΔNS2/1030s was developed that is identical to the previous virus RSV/ΔNS2/Δ1313/I1314L but with additional mutations. Finally, a VRS with a single replicative cycle has been developed by eliminating the gene encoding the matrix (M) protein (VRS-M-null). Most of these vaccines are still in phase 2/3 and very good results are expected.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">El Virus Respiratorio Sincitial (VRS) es el causante de patologías respiratorias agudas (bronquiolitis y neumonías), que se presentan preferentemente en la población infantil de forma epidémica. La única forma de prevenir estas infecciones es mediante la vacunación previa de los ><span class="elsevierStyleHsp" style=""></span>6 meses. De las diferentes vacunas existentes, las vacunas atenuadas, definidas como aquellas que contienen un virus alterado o modificado para disminuir al máximo su capacidad patogénica pero manteniendo su capacidad de respuesta inmunológica, parecen representar un importante avance. En los últimos años se han evaluado dos candidatas vacunales basadas en la delección de gen M2–2, las designadas como MEDI/ΔM2 y la LID/ΔM2–2/1030s. En el estudio realizado en 21 niños seronegativos (6–24 meses), éstos recibieron una dosis intranasal (10<span class="elsevierStyleSup">5</span> PFU) de la nueva vacuna frente a un grupo placebo. El 85% de los vacunados desarrollaron un título de anticuerpos neutralizantes ><span class="elsevierStyleHsp" style=""></span>4 veces al previo. La combinación de la delección Δ1313 con la delección de la NS2 se mostró mejor para la elaboración un candidato vacunal recombinante atenuado del VRS (ΔNS2/Δ1313), con buenos resultados protectores. Se desarrolló un nuevo candidato vacunal designado como RSV/6120/ΔNS2/1030s que es idéntico al virus previo RSV/ΔNS2/Δ1313/I1314L pero con mutaciones adicionales. Finalmente se ha desarrollado un VRS de un solo ciclo replicativo eliminando el gen codificador de la proteína de matriz (M) (VRS-M-null). La mayoría de estas vacunas están todavía en fase 2/3 y se esperan muy buenos resultados.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="np4005">Please cite this article as: Reina J, Suárez A. Situación actual de las vacunas atenuadas intranasales frente al virus respiratorio sincitial en la población infantil. Vacunas. 2024. <span class="elsevierStyleInterRef" id="ir3005" href="https://doi.org/10.1016/j.vacun.2023.12.001">https://doi.org/10.1016/j.vacun.2023.12.001</span>.</p>" ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "f0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 565 "Ancho" => 2174 "Tamanyo" => 98545 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Possible vaccination and immunisation strategy against the syncitial respiratory virus during the different stages of life (modified from Mejias et al<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a>).</p>" ] ] 1 => array:8 [ "identificador" => "f0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1991 "Ancho" => 2120 "Tamanyo" => 258142 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">General structure an distribution of the different genes in the genoma of the syncytial respiratory virus (modified from Plemper et al<a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a>).</p>" ] ] 2 => array:8 [ "identificador" => "f0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1777 "Ancho" => 2175 "Tamanyo" => 166665 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Evolution of the genetic modifications introduced into the syncytial respiratory virus genoma to obtain better vaccine candidates.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bb0005" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent (CCA). I. Isolation properties and characterization" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R. Chanock" 1 => "B. Roizman" 2 => "R. Myers" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/oxfordjournals.aje.a119901" "Revista" => array:7 [ "tituloSerie" => "Am J Hyg" "fecha" => "1957" "volumen" => "66" "paginaInicial" => "281" "paginaFinal" => "290" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13478578" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0140673611607812" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bb0010" "etiqueta" => "2." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent (CCA). II. Epidemiologic aspects of infection in infants and Young children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R. Chanock" 1 => "L. Finberg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/oxfordjournals.aje.a119902" "Revista" => array:6 [ "tituloSerie" => "Am J Hyg" "fecha" => "1957" "volumen" => "66" "paginaInicial" => "291" "paginaFinal" => "300" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13478579" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bb0015" "etiqueta" => "3." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Respiratory syncytial virus subunit vaccines base on the viral envelope glycoproteins intended for pregnant women and the elderly" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M. Beugeling" 1 => "J. De Zee" 2 => "H.J. Woerdenbarg" 3 => "H.W. Frijlink" 4 => "J.C. Wilschut" 5 => "W.L. Hinrichs" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/14760584.2019.1657013" "Revista" => array:5 [ "tituloSerie" => "Expert Rev Vaccines" "fecha" => "2019" "volumen" => "18" "paginaInicial" => "935" "paginaFinal" => "950" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bb0020" "etiqueta" => "4." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global, regional and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in Young children in 2015: a systematic review and modelling study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Shi" 1 => "D.A. McAllister" 2 => "K.L. O´Brien" 3 => "E.A. Simoes" 4 => "A. Shabir" 5 => "T. Shi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(17)30938" "Revista" => array:6 [ "tituloSerie" => "Lancet." "fecha" => "2017" "volumen" => "390" "paginaInicial" => "946" "paginaFinal" => "958" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28689664" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bb0025" "etiqueta" => "5." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Current strategies and perspectives for active and passive immunization against respiratory syncytial virus in childhood" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.C. Scotta" 1 => "R.T. Stein" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jped.2022.10.004" "Revista" => array:5 [ "tituloSerie" => "J Pediatr" "fecha" => "2023" "volumen" => "99" "paginaInicial" => "S4" "paginaFinal" => "S11" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bb0030" "etiqueta" => "6." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Respiratory syncytial virus infection in the modern era" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M. Ludlow" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/QCO.0000000000000917" "Revista" => array:7 [ "tituloSerie" => "Curr Opin Infect Dis" "fecha" => "2023" "volumen" => "36" "paginaInicial" => "155" "paginaFinal" => "163" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36939556" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0002870314007388" "estado" => "S300" "issn" => "00028703" ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bb0035" "etiqueta" => "7." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vaccine development for respiratory syncytial virus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "B.S. Graham" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.coviro.2017.03.012" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Virol" "fecha" => "2017" "volumen" => "23" "paginaInicial" => "107" "paginaFinal" => "112" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28525878" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bb0040" "etiqueta" => "8." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Respiratory syncytial virus: current treatment strategies and vaccine approaches" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E.M. Thornhill" 1 => "J. Salpor" 2 => "D. Verhoeven" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Antivir Chem Chemother" "fecha" => "2020" "volumen" => "28" "paginaInicial" => "1" "paginaFinal" => "12" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bb0045" "etiqueta" => "9." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The immunogenicity and safety of respiratory syncytial virus vaccines in development: a systematic review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J. Shan" 1 => "P.N. Britton" 2 => "C.L. King" 3 => "R. Booy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/irv.12850" "Revista" => array:5 [ "tituloSerie" => "Influenza Other Respi Viruses" "fecha" => "2021" "volumen" => "15" "paginaInicial" => "539" "paginaFinal" => "551" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bb0050" "etiqueta" => "10." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The journey to a respiratory syncytial virus vaccine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A. Mejias" 1 => "R. Rodriguez-Fernandez" 2 => "S. Oliva" 3 => "M.E. Peeples" 4 => "O. Ramilo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.anai.2020.03.017" "Revista" => array:6 [ "tituloSerie" => "Ann Allergy Asthma Immunol" "fecha" => "2020" "volumen" => "125" "paginaInicial" => "36" "paginaFinal" => "46" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32217187" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bb0055" "etiqueta" => "11." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Current state and challenges in developing respiratory syncytial virus vaccines" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Biagi" 1 => "A. Dondi" 2 => "S. Scarpini" 3 => "A. Rocca" 4 => "S. Vandini" 5 => "G. Poletti" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/vaccines8040772" "Revista" => array:5 [ "tituloSerie" => "Vaccines" "fecha" => "2020" "volumen" => "8" "paginaInicial" => "672" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33187337" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bb0060" "etiqueta" => "12." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Situación actual y perspectivas de futuro de las vacunas frente al Virus Respiratorio Sincitial" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Reina" 1 => "E. González de Herrero" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.vacun.2022.12.005" "Revista" => array:5 [ "tituloSerie" => "Vacunas." "fecha" => "2023" "volumen" => "24" "paginaInicial" => "150" "paginaFinal" => "157" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bb0065" "etiqueta" => "13." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Crafting live-attenuated vaccines against respiratory syncytial virus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "F.P. Polack" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/infdis/jiy038" "Revista" => array:6 [ "tituloSerie" => "J Infect Dis" "fecha" => "2018" "volumen" => "217" "paginaInicial" => "1335" "paginaFinal" => "1337" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29509928" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bb0070" "etiqueta" => "14." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.W. Kim" 1 => "J.G. Canchola" 2 => "C.D. Brandt" 3 => "G. Pyles" 4 => "R.M. Chanock" 5 => "K. Jensen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/oxfordjournals.aje.a120955" "Revista" => array:6 [ "tituloSerie" => "Am J Epidemiol" "fecha" => "1969" "volumen" => "89" "paginaInicial" => "422" "paginaFinal" => "434" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4305198" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bb0075" "etiqueta" => "15." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Respiratory suncytial virus modified by deletions of the NS2 gene and amino acid S1313 of the L polymerase protein is a temperatura-sensitive, live-attenuated vaccine candidate that is phenotypically stable at physiological temperatura" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "C. Luongo" 1 => "C.C. Winter" 2 => "P.L. Collins" 3 => "U.J. Buchholz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/JVI.02769-12" "Revista" => array:6 [ "tituloSerie" => "J Virol" "fecha" => "2013" "volumen" => "87" "paginaInicial" => "1985" "paginaFinal" => "1996" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23236065" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bb0080" "etiqueta" => "16." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Paramyxociridae: the viruses and their replication" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.K. Plemper" 1 => "R.A. Lamb" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "P.M.Howley, D.M.Knipe" "titulo" => "Fields Virology" "paginaInicial" => "504" "paginaFinal" => "558" "serieVolumen" => "vol. 1" "serieFecha" => "2021" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bb0085" "etiqueta" => "17." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Live-attenuated respiratory syncytial virus vaccine candidate with deletion of RNA synthesis regulatory M2-2 is highly immunogenic in children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.J. MacFarland" 1 => "R.A. Karron" 2 => "P. Muresan" 3 => "C.K. Cunningham" 4 => "M.E. Valentine" 5 => "C. Perlowski" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/infdis/jiy040" "Revista" => array:6 [ "tituloSerie" => "J Infect Dis" "fecha" => "2018" "volumen" => "217" "paginaInicial" => "1347" "paginaFinal" => "1355" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29509911" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bb0090" "etiqueta" => "18." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Live respiratory syncytial virus (RSV) vaccine candidate containing stabilized temperatura-sensitivity mutations is highly attenuated in RSV-seronegative infants and children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "U.J. Buchholz" 1 => "C.K. Cunningham" 2 => "P. Muresan" 3 => "D. Gnanashanmugan" 4 => "P. Sato" 5 => "G.K. Siberry" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/infdis/jiy066" "Revista" => array:6 [ "tituloSerie" => "J Infect Dis" "fecha" => "2018" "volumen" => "217" "paginaInicial" => "1338" "paginaFinal" => "1346" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29509929" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bb0095" "etiqueta" => "19." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Live-attenuated respiratory syncytial virus vaccine with M2-2 deletion and with small hydrophobic noncoding región is highly immunogenic in children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.J. McFarland" 1 => "R.A. Karron" 2 => "P. Muresan" 3 => "C.K. Cunningham" 4 => "C. Perlowsky" 5 => "J. Libous" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/infdis/jiaa049" "Revista" => array:6 [ "tituloSerie" => "J Infect Dis" "fecha" => "2020" "volumen" => "221" "paginaInicial" => "2050" "paginaFinal" => "2059" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32006006" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bb0100" "etiqueta" => "20." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Live respiratory syncytial virus attenuated by M2-2 deletion and stabilized temperatura sensitivity mutation 1030s is a promising vaccine candidate in children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.J. McFarland" 1 => "R.A. Karron" 2 => "P. Muresan" 3 => "C.K. Cunningham" 4 => "J. Libous" 5 => "C. Perlowsky" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/infdis/jiz603" "Revista" => array:6 [ "tituloSerie" => "J Infect Dis" "fecha" => "2020" "volumen" => "221" "paginaInicial" => "534" "paginaFinal" => "543" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31758177" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bb0105" "etiqueta" => "21." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of the live-attenuated intranasal respiratory syncytial virus (RSV) vaccine RSV/6120/ΔNS2/1030s in RSV-seronegative Young children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.A. Karron" 1 => "C. Luongo" 2 => "S. Woods" 3 => "J. Oliva" 4 => "P.L. Collins" 5 => "U.J. Bucholz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/infdis/jiad281" "Revista" => array:2 [ "tituloSerie" => "J Infect Dis" "fecha" => "2023" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bb0110" "etiqueta" => "22." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Altered growth characteristics of recombinant respiratory syncytial viruses which do not produce NS2 protein" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.N. Teng" 1 => "P.L. Collins" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/JVI.73.1.466-473" "Revista" => array:6 [ "tituloSerie" => "J Virol" "fecha" => "1999" "volumen" => "73" "paginaInicial" => "466" "paginaFinal" => "473" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9847352" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bb0115" "etiqueta" => "23." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of recombinant live-attenuated respiratory syncytial virus (RSV) vaccines RSV/ΔNS2/Δ1313/I1314L and RSV/276 in RSV-seronegative children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.K. Cunningham" 1 => "R.A. Karron" 2 => "P. Muresan" 3 => "M.S. Kelly" 4 => "E.J. McFarland" 5 => "C. Perlowski" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/infdis/jiac253" "Revista" => array:6 [ "tituloSerie" => "J Infect Dis" "fecha" => "2022" "volumen" => "226" "paginaInicial" => "2069" "paginaFinal" => "2078" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35732186" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bb0120" "etiqueta" => "24." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Live-attenuated vaccines prevent respiratory syncytial virus-associated illness in Young children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.A. Karron" 1 => "J.E. Atwell" 2 => "E.J. McFarland" 3 => "C.K. Cunningham" 4 => "P. Muresan" 5 => "C. Perlowski" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.202005-1660OC" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med." "fecha" => "2021" "volumen" => "203" "paginaInicial" => "594" "paginaFinal" => "603" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32871092" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bb0125" "etiqueta" => "25." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Advanced live attenuated vaccines for the prevention of respiratory syncytial virus infections in Young children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "O. Ramilo" 1 => "R. Rodriguez-Fernandez" 2 => "M.E. Peeples" 3 => "A. Mejias" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/infdis/jiz409" "Revista" => array:6 [ "tituloSerie" => "J Infect Dis" "fecha" => "2020" "volumen" => "222" "paginaInicial" => "4" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31549154" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bb0130" "etiqueta" => "26." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Induction of CD8 T cell hetrologous protection by a single dose of single-cycle infectious influenza virus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H. Guo" 1 => "S.F. Baker" 2 => "L. Martinez-Sobrino" 3 => "D.J. Topham" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/JVI.01847-14" "Revista" => array:6 [ "tituloSerie" => "J Virol" "fecha" => "2014" "volumen" => "88" "paginaInicial" => "12006" "paginaFinal" => "12016" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25100831" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bb0135" "etiqueta" => "27." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The human respiratory syncytial virus matrix protein is required for maturation of viral filaments" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Mitra" 1 => "P. Baviskar" 2 => "R.R. Duncan-Deccoq" 3 => "D. Patel" 4 => "A.G. Ooomens" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/JVI.06744-11" "Revista" => array:6 [ "tituloSerie" => "J Virol" "fecha" => "2012" "volumen" => "86" "paginaInicial" => "4432" "paginaFinal" => "4443" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22318136" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bb0140" "etiqueta" => "28." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vaccination with a single-cycle respiratory syncytial virus is immunogenic and protective in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.E. Schmidt" 1 => "A.G. Ooomens" 2 => "S.M. Varga" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4049/jimmunol.1900050" "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "2019" "volumen" => "202" "paginaInicial" => "3234" "paginaFinal" => "3245" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31004010" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bb0145" "etiqueta" => "29." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A live single-cycle RSV vaccine expressing prefusion F protein" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Lamichhane" 1 => "M.E. Schmidt" 2 => "M. Terhüja" 3 => "S.M. Varga" 4 => "T.A. Snider" 5 => "C.A. Rostad" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.virol.2022.10.003" "Revista" => array:6 [ "tituloSerie" => "Virology." "fecha" => "2022" "volumen" => "577" "paginaInicial" => "51" "paginaFinal" => "64" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36306605" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/24451460/0000002500000001/v1_202403150618/S2445146024000190/v1_202403150618/en/main.assets" "Apartado" => array:4 [ "identificador" => "87216" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Reviews" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/24451460/0000002500000001/v1_202403150618/S2445146024000190/v1_202403150618/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146024000190?idApp=UINPBA00004N" ]