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Los puntos negros corresponden a los cambios de aminoácidos y la zona entre las flechas al nuevo puente disulfuro creado con ellos.</p> <p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">HRA: heptados repetidos tipo A; HRB: heptados repetidos tipo B; PF: péptido fusión; PS: péptido señal; PT: péptido transmembrana (modificado de Espeseth et al.<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a>).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jordi Reina, María Fernández-Billón" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Jordi" "apellidos" => "Reina" ] 1 => array:2 [ "nombre" => "María" "apellidos" => "Fernández-Billón" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2445146022000760" "doi" => "10.1016/j.vacune.2022.10.007" "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/S2445146022000760?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1576988722000322?idApp=UINPBA00004N" "url" => "/15769887/0000002300000003/v1_202210261809/S1576988722000322/v1_202210261809/es/main.assets" ] ] "itemSiguiente" => array:18 [ "pii" => "S2445146022000772" "issn" => "24451460" "doi" => "10.1016/j.vacune.2022.10.008" "estado" => "S300" "fechaPublicacion" => "2022-09-01" "aid" => "226" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Vacunas. 2022;23:222-33" "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">Review article</span>" "titulo" => "Genomic instability, origin and evolution of cancer, and personalized immunotherapy" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "222" "paginaFinal" => "233" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Inestabilidad genética, origen y evolución del cáncer y la inmunoterapia personalizada" ] ] "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" => "f0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2723 "Ancho" => 3389 "Tamanyo" => 375800 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Mechanisms of neoepitope generation in tumour cells. Mutations in DNA such as insertions and deletions lead to a change in the sequence and reading frame (ORF), thus in the information encoded by the gene. Additionally, non-synonymous mutations change the amino acid residue in the primary sequence of the protein and are the type of mutation that has typically been used in cancer immunotherapy, i.e., neoepitope vaccines. Although synonymous mutations do not change the primary sequence of the protein, they can alter the splicing process in the mRNA, which can lead to rejoining of exons. On the other hand, the sequences of RNA molecules can also be modified by enzymes such as ADARs, which convert adenosine to inosine in the mRNA. In addition, RNA molecules can be methylated by enzymes such as METTL3, methylation modifies the translation of RNAs, including non-coding RNAs such as circRNA. Furthermore, translation of the 5 ́ UTR and 3 ́ UTR regions, as well as of non-coding RNAs and different ORFs, generates a diversity of neoepitopes in tumour cells. Finally, the immunoproteasome containing subunits other than the constitutive proteosome generates a new repertoire of epitopes. Additionally, the absence of proteosome activity modifies the epitopes present on MHC class I molecules, mainly represented by epitopes from the signal peptides of the proteins. 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"paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "208" "paginaFinal" => "214" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estudio de la campaña de prevención y control del brote de hepatitis A en hombres que tienen sexo con hombres en Sevilla (2016-2018)" ] ] "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" => 1577 "Ancho" => 3389 "Tamanyo" => 357052 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Incidence of HA and vaccination by epidemiological week in the province of Seville, together with key moments of the prevention campaign (2016–2018).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "María Concepción Galdeano Osuna, María Baca Fuentes, Beatriz Jiménez Navajo, Miguel Porras-Povedano" "autores" => array:4 [ 0 => array:2 [ "nombre" => "María Concepción" "apellidos" => "Galdeano Osuna" ] 1 => array:2 [ "nombre" => "María" "apellidos" => "Baca Fuentes" ] 2 => array:2 [ "nombre" => "Beatriz" "apellidos" => "Jiménez Navajo" ] 3 => array:2 [ "nombre" => "Miguel" "apellidos" => "Porras-Povedano" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1576988722000413" "doi" => "10.1016/j.vacun.2022.04.004" "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/S1576988722000413?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146022000759?idApp=UINPBA00004N" "url" => "/24451460/0000002300000003/v3_202302191852/S2445146022000759/v3_202302191852/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Preliminary data on messenger RNA (mRNA) vaccines against respiratory syncytial virus" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "215" "paginaFinal" => "221" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Jordi Reina, María Fernández-Billón" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Jordi" "apellidos" => "Reina" "email" => array:1 [ 0 => "jorge.reina@ssib.esy" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cr0005" ] ] ] 1 => array:2 [ "nombre" => "María" "apellidos" => "Fernández-Billón" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Virología, Servicio de Microbiología, Hospital Universitario Son Espases, Facultad de Medicina, Universitat Illes Balears, Palma de Mallorca, Spain" "identificador" => "af0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cr0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Datos preliminares de las vacunas de ARN mensajero (ARNm) frente al virus respiratorio sincitial" ] ] "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" => 1354 "Ancho" => 1634 "Tamanyo" => 252867 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Schematic structure of the RSV F-glycoprotein in its pre- and post-fusion active forms with the antigenic areas of each (modified from Graham et al.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a>).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Epidemiology</span><p id="p0005" class="elsevierStylePara elsevierViewall">Respiratory syncytial virus (RSV) was discovered in 1955, designated as chimpanzee coryza 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 preferentially in epidemic form in the winter months. Although it can affect the entire population, its pathological impact is much greater in children (<<span class="elsevierStyleHsp" style=""></span>5 years) and in the older population (><span class="elsevierStyleHsp" style=""></span>65 years).<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a> It is thus estimated to be responsible for 22% of acute respiratory infections (ARI) in the paediatric population. In a 2015 global study, RSV was estimated to cause 33.1 million ARIs per year, leading to about 3.2 million hospitalisations and about 59 000 hospital deaths in children under 5 years of age. In addition, in children under 6 months of age, RSV causes about 1.4 million hospitalisations and about 27 300 deaths annually.<a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a> In the older population, RSV is responsible for about 17 000 deaths per year due to pneumonia or its complications,<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> although it actually affects only 2% of the world's population.<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">In the paediatric population, the peak of hospitalisation is between 2 and 3 months, although the risk of severe infection continues until the age of 5 years. It is estimated that by the age of 3 years almost the entire population has been infected with RSV, with reinfections occurring annually or every 3–5 years,<a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a> suggesting an immune response that is unable to protect for long periods of time. Given that the aim of RSV vaccination is to prevent severe infection and its consequences, the target populations to be vaccinated would be children under 2 years of age (preferably <<span class="elsevierStyleHsp" style=""></span>6 months), pregnant women to transmit immunity to the newborn and the elderly population.<a class="elsevierStyleCrossRefs" href="#bb0030"><span class="elsevierStyleSup">6–8</span></a></p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Molecular characteristics of RSV</span><p id="p0015" class="elsevierStylePara elsevierViewall">RSV is an enveloped virus with an unsegmented single-stranded negative RNA genome (15 200 nucleotides) containing 10 genes and encoding 11 distinct proteins; it belongs to the family Pneumoviridae and the genus Orthopneumovirus. Four proteins are found in the virus envelope: the matrix protein (M), the small hydrophobic protein (SH, small hydrophobic), and 2 glycoproteins designated F (fusion) and G (attachment glycoprotein).<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">Glycoproteins F and G are directly involved in the process of infectivity and development of respiratory disease. Thus, glycoprotein G is responsible for the attachment of the virus to the epithelial cell, while F participates in the entry of the virus into the cell, through its fusion with the cytoplasmic membrane; this protein is also responsible for the fusion of the infected cells, giving rise to the formation of the syncytia, typical of this infection, and which give the virus its name.<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">In addition to their functions and due to their external position in RSV, they are the immunodominant glycoproteins that induce neutralising antibodies in the infected host. Three types of epitopes have been identified in glycoprotein G: (a) conserved, detectable in all strains; (b) group-specific, expressed only in the same antigenic group; and (c) species-specific, present only in specific strains within the same antigenic group and located in the hypervariable C-terminal region. The F-glycoprotein is derived from an inactive precursor form containing 3 hydrophobic peptides: (a) signal peptide in the N-terminal region; (b) the transmembrane region, which links F to the cell membrane and the viral envelope; and (c) the fusion peptide, which inserts into the cell membrane and determines the fusion process between them.<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a></p><p id="p0030" class="elsevierStylePara elsevierViewall">There are 2 known subgroups within RSV, the so-called A and B, which tend to co-circulate seasonally or alternatively. The antigenic difference between the 2 groups is determined by the sequence of glycoprotein G (only 35% homology between A and B strains). Therefore, some antibodies directed against G-glycoprotein G are only subtype specific, whereas most antibodies directed against F-glycoprotein have neutralising activity against both antigenic groups A and B, as they have 90% identity in their amino acid sequences.<a class="elsevierStyleCrossRefs" href="#bb0045"><span class="elsevierStyleSup">9–11</span></a></p><p id="p0035" class="elsevierStylePara elsevierViewall">Most vaccines in development use F-glycoprotein as the antigenic element; however, there are 2 presentations of F-glycoprotein, the so-called pre-fusion, inactive trimeric precursor F<span class="elsevierStyleInf">0</span>, (pre-F) and the post-fusion (post-F) formed, after enzymatic hydrolysis, by the F<span class="elsevierStyleInf">1</span> and F<span class="elsevierStyleInf">2</span>. subunit. In the pre-F form, an antigenic site called “site zero (Φ)” has been described, which seems to be the most powerful in inducing neutralising antibodies.<a class="elsevierStyleCrossRefs" href="#bb0060"><span class="elsevierStyleSup">12–14</span></a> The post-F form, although more stable and easier to produce than the pre-F form, is discouraged as an antigen because of its lower immune response, especially in neutralising antibodies, and it is therefore recommended that the pre-F form be used in preference for vaccines.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a></p><p id="p0040" class="elsevierStylePara elsevierViewall">RSV has multiple mechanisms to evade host immunity, which explains why it is a very ubiquitous virus and consecutively re-infects people; the genetic and antigenic variations described are much less frequent than those observed in other RNA viruses.<a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0065"><span class="elsevierStyleSup">13</span></a> Three mechanisms of evasion have been recognised in this virus, including anatomical, conformational evasion of neutralising antibodies, and direct modulation of immune functions. All of them should be taken into account in the process of developing a future vaccine.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a></p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Target populations</span><p id="p0045" class="elsevierStylePara elsevierViewall">RSV is a good vaccine candidate because as a virus it has shown genetic and antigenic stability, most infections are self-limiting and the only natural reservoir is humans.<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a> However, the disastrous experience of the first formalin-inactivated vaccine in 1966, which not only failed to produce protective antibody levels and protection against RSV infection, but also resulted in vaccinated individuals developing a much more severe disease than unvaccinated individuals. With deaths among those vaccinated, it led to the cessation of this vaccination and greatly delayed efforts to develop new effective and especially safe vaccines.<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a> (<a class="elsevierStyleCrossRefs" href="#f0005">Figs. 1 and 2</a>).</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0050" class="elsevierStylePara elsevierViewall">As mentioned above and according to epidemiological data, there are clearly 3 target populations that require different approaches to RSV vaccination. These are: naive children <<span class="elsevierStyleHsp" style=""></span>4–6 months, children ><span class="elsevierStyleHsp" style=""></span>6 months, and adults >65 years (<a class="elsevierStyleCrossRef" href="#f0015">Fig. 3</a>).</p><elsevierMultimedia ident="f0015"></elsevierMultimedia><p id="p0055" class="elsevierStylePara elsevierViewall">Generally speaking, infants aged 4–6 months have a still immature and developing immune system, characterised by low interferon expression, predominance of regulatory T cells with tolerogenic reactivity and a limited B cell repertoire. This results in a poor response to exogenous antigens, interfering with the natural process of antigenic presentation and the formation of highly efficient mature antibodies. Despite this, this age group is considered the most at risk and the priority for vaccination.<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a> In this age group, the use of monoclonal antibodies is currently the most appropriate choice.<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a></p><p id="p0060" class="elsevierStylePara elsevierViewall">A vaccine approach for this age group would be vaccination during the gestational process, so that antibodies formed in an adult could be transmitted to the newborn in the first months of life. Active transplacental transfer begins at approximately 28–30 weeks of gestation; therefore, this would be the appropriate time for the immunisation process. However, the optimal timing, second or third trimester, and the durability and amount of antibodies formed is still not definitively known, but may be similar to that obtained with influenza or pertussis vaccination. In these vaccinated pregnant women, subsequent breastfeeding may provide a significant amount of IgA that could have a protective effect.<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a></p><p id="p0065" class="elsevierStylePara elsevierViewall">Vaccination of pregnant women may be questionable if its sole purpose is to protect the newborn and not the mother. The actual impact of RSV on pregnant women and its complications is currently unknown, although 1 study has estimated the attack rate during the second or third trimester to be approximately 10%–13%, suggesting that vaccination may also benefit the mother.<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a></p><p id="p0070" class="elsevierStylePara elsevierViewall">Although the highest incidence of RSV ARI occurs in the first 3–4 months of life, the virus continues to infect all other age groups with varying clinical impact. Thus, more than 50% of hospitalisations due to acute RSV infection occur in children ><span class="elsevierStyleHsp" style=""></span>6 months, with the 6–24 month age group being the most affected by the virus. Therefore, the population between 6 months and 5 years of age would constitute a target group whose objective would be to reduce the circulation of the virus and its collateral effect on children and the elderly population.<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">The third vaccination target group would be the elderly population aged 65 years and older. In this group, it is estimated that in the United States of America, 3%–10% of ARI are caused by RSV, which would represent about 250 000 admissions and 14 000 deaths per year. Immunosenescence and underlying diseases would favour predisposition to respiratory infections, including RSV.<a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a></p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Messenger RNA vaccines</span><p id="p0080" class="elsevierStylePara elsevierViewall">The advent of nucleic acid (RNA and DNA) technology used in SARS-CoV-2 vaccines raises the prospect of its future application against other respiratory viruses such as RSV. mRNA vaccines offer a number of advantages over other types of vaccines, such as: (a) a very favourable safety profile (RNA is a non-infectious molecule, non-integratable into the cell genome, and is rapidly degraded by cytoplasmic RNAs); (b) a highly controllable antigen production process with high antigenic identity, as it is produced in a manner similar to the viral replication process in natural infection by the human cell itself; (c) rapid and scalable production, requiring little time for initial production and/or subsequent re-actualisation; and (d) does not require the use of cell cultures that could alter the antigenicity of the final protein.<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">For use as vaccines, a conventional, non-replicative, cellular-like mRNA has been developed. In this molecule, the genetic sequence of the protein (antigen) to be expressed is flanked at each of its 5′ and 3′ ends by an untranslated region (UTR) sequence. In addition, like all mRNAs, it has at the 5′ end the sequence known as cap (m7G-ppp-N-5′) and at the 3′ end a sequence of adenines of variable length (polyA). Two types of these vaccines have been developed, unmodified (natural) mRNA and modified mRNA; in the latter, the uridine nucleoside has been replaced by 1-methyl-seudouridine, which stabilises the molecule. The advantages of mRNA are that it is a simple, small molecule (about 2–3 kb) and because it encodes a single protein, the immune response is highly specific. However, the expression of this mRNA (antigen production) is limited and transient in nature, requiring the administration of high doses to obtain good vaccine efficacy.<a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p><p id="p0090" class="elsevierStylePara elsevierViewall">The fragility and rapid physiological degradation of mRNA molecules has made it necessary to protect them so that they can be administered in mammals. The best solution to this problem has been to embed them within a complex lipid structure of about 80 nm, similar to RSV itself, forming what are called lipid nanoparticles (LNPs).<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a></p><p id="p0095" class="elsevierStylePara elsevierViewall">Historically, in 2013 Geall et al.<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a> reported immunogenicity and protection of a group of mice against RSV disease after 2 intramuscular doses of a naked mRNA self-amplifiable vaccine. However, vaccine cost-effectiveness studies showed that naked mRNA, without protection against RNAsas, could not be used routinely and had to be protected by a nanolipid structure.</p><p id="p0100" class="elsevierStylePara elsevierViewall">Subsequently, Espeseth et al.<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a> evaluated the ability to induce immune responses of an NPL-mRNA vaccine with different forms of F protein presentation, such as complete, monomeric, trimeric, stabilised pre-F, and unstabilised pre-F (<a class="elsevierStyleCrossRef" href="#f0020">Fig. 4</a>). The pre-F can be stabilised by introducing mutations in the disulfide bridge of the structure (design of disulfide, DS) or by filling mutations (cavity-filling, Cav1). All these mutations introduce covalent bonds that prevent the structural rearrangements that determine the transition from pre-F to functional F.<a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">24</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a> Each was administered at an mRNA concentration of 10 μg, with a booster dose at 3 weeks. Studies in mice with the pre-F form showed, for all protein forms, a robust antibody immune response comparable to that obtained with the reference protein DS-Cav1 and far superior to it in the cellular response in CD4<span class="elsevierStyleHsp" style=""></span>+ and CD8<span class="elsevierStyleHsp" style=""></span>+ cells.<a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a></p><elsevierMultimedia ident="f0020"></elsevierMultimedia><p id="p0105" class="elsevierStylePara elsevierViewall">Comparison between the quality of the humoral immune response has shown that, although the original and stabilised pre-F form induce a similar immune response, the stabilised pre-F has shown a higher affinity and antigenic specificity. This process seems to be due to the fact that most of the neutralising antibodies induced are directed against the “zero site (Φ)” of the F protein. Since this site is the predominant site in the natural human RSV response, it is preferable to select an antigen containing the stabilising mutations that maintain and protect this epitope. In addition, mice immunised with the NPL-mRNA-pre-F vaccine did not develop infection following inoculation with the experimental infective dose of both RSV-A and RSV-B. Initial safety data seem to indicate no local or systemic inflammatory responses in mice that would contradict its use.</p><p id="p0110" class="elsevierStylePara elsevierViewall">For their part, Aliprantis et al.<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a>, reported the first study of phase 1 on healthy young human adults (aged between 18 and 49 years, part A) and older adults (aged 60–79 years, part B) to assess the safety and immunogenicity of the NPL-mRNA-177 vaccine (Protocol mRNA-1777-P101, V171) consisting of the pre-F protein stabilised with the mutations of the DS-Cav1 molecule versus placebo. In part A, a study was performed at doses of 25, 100, and 200 μg and in part B at 25, 200, and 300 μg, respectively. The NPLs consisted of cholesterol, DSPC, MC3, and PEG2000-DMG.</p><p id="p0115" class="elsevierStylePara elsevierViewall">The results obtained show, in both juveniles and adults, a significant increase in neutralising antibody levels against pre-F, as well as a potent induction of preferentially CD4<span class="elsevierStyleHsp" style=""></span>+ cell-mediated immunity. Due to the absence of a correlate of immunological protection in adults, it is difficult to establish whether the level of immunity obtained in this vaccinated population will be sufficient to protect them from RSV infection or disease. However, elevated levels of neutralising antibodies to both RSV-A and RSV-B seem to indicate a real capacity for protection, even in the long term.<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a></p><p id="p0120" class="elsevierStylePara elsevierViewall">Safety analyses indicate few adverse responses, except for local manifestations at the puncture site. Even the highest dose (300 μg) is tolerated by the majority of people studied. Therefore, it is concluded that the NPL-mRNA-177 vaccine increases the immune response against RSV pre-F, with no adverse effects that would preclude the initiation of a study in later clinical phases.<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a></p><p id="p0125" class="elsevierStylePara elsevierViewall">These preliminary data confirm the safety and immunogenicity of NPL-mRNA vaccines based on the RSV pre-F protein.<a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">27</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0140"><span class="elsevierStyleSup">28</span></a> Phase 2 trials appear to have been initiated and preliminary results are awaited. The proven efficacy of mRNA technology for the development of vaccines against different viruses opens the door to its study in those that affect the human population.</p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Funding</span><p id="p0130" class="elsevierStylePara elsevierViewall">This review article did not receive any public or prívate funding.</p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Conflict of interests</span><p id="p0135" class="elsevierStylePara elsevierViewall">Dr. Jordi Reina forms part of the Editorial Board of the journal “Vacunas”.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1851315" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1609762" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1851316" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1609761" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "s0005" "titulo" => "Epidemiology" ] 5 => array:2 [ "identificador" => "s0010" "titulo" => "Molecular characteristics of RSV" ] 6 => array:2 [ "identificador" => "s0015" "titulo" => "Target populations" ] 7 => array:2 [ "identificador" => "s0020" "titulo" => "Messenger RNA vaccines" ] 8 => array:2 [ "identificador" => "s0025" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "s0030" "titulo" => "Conflict of interests" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1609762" "palabras" => array:4 [ 0 => "Respiratory syncytial virus" 1 => "Messenger RNA" 2 => "Nanoparticle vaccines" 3 => "Vaccine efficacy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1609761" "palabras" => array:4 [ 0 => "Virus respiratorio sincitial" 1 => "ARN mensajero" 2 => "Vacunas de nanopartículas" 3 => "Eficacia vacunal" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">The respiratory syncytial virus (RSV) is the main cause of acute respiratory infections that preferably affect children <<span class="elsevierStyleHsp" style=""></span>5 years of age. However, it also has a high epidemiological impact on those ><span class="elsevierStyleHsp" style=""></span>65 years. Despite being a virus with an RNA genome, it has high genetic and antigenic stability (only subgroups A and B are known) and the only reservoir is the human being, which makes it an ideal candidate for the development of a vaccine. Most of the vaccines in development use glycoprotein F in its pre-fusion form (pre-F) as antigen, since it induces a higher rate of neutralising antibodies and cellular immunity. Messenger RNA (mRNA) vaccines are very effective, which is why they have recently been designed against RSV. Several NPL-mRNA (nanoparticle) type vaccines have shown safety and immunogenicity in humans. The rates of neutralising antibodies obtained are well above other vaccines and cellular immunity is preferable for the CD4<span class="elsevierStyleHsp" style=""></span>+ type. Adverse effects are few and local even at high doses. Preliminary data confirm the safety and immunogenicity of NPL-mRNA type vaccines based on RSV pre-F protein.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">El virus respiratorio sincitial (VRS) es el principal causante de las infecciones respiratorias agudas que afectan preferentemente a los < 5 años. Sin embargo, también posee un elevado impacto epidemiológico en los > 65 años. A pesar de ser un virus con un genoma ARN presenta una elevada estabilidad genética y antigénica (solo se conocen los subgrupos A y B) y el único reservorio es el ser humano, lo que lo hace un candidato ideal para la elaboración de una vacuna. La mayoría de las vacunas en desarrollo utilizan como antígeno la glicoproteína F en su forma pre-fusión (preF), ya que induce una mayor tasa de anticuerpos neutralizantes e inmunidad celular. Las vacunas de ARN mensajero (ARNm) se han mostrado muy eficaces, por ello recientemente se han diseñado frente al VRS. Varias vacunas del tipo NPL-ARNm (nanopartículas) han mostrado seguridad e inmunogenicidad en el ser humano. Las tasas de anticuerpos neutralizantes obtenidas están muy por encima de otras vacunas y la inmunidad celular es preferentemente de tipo CD4+. Los efectos adversos son escasos y locales, incluso a dosis elevadas. Los datos preliminares confirman la seguridad e inmunogenicidad de las vacunas de tipo NPL-ARNm basadas en la proteína preF del VRS.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="np4005">Please cite this article as: Reina J, Fernández-Billón M. Datos preliminares de las vacunas de ARN mensajero (ARNm) frente al virus respiratorio sincitial. Vacunas. 2022. <span class="elsevierStyleInterRef" id="ir3005" href="https://doi.org/10.1016/j.vacun.2022.04.001">https://doi.org/10.1016/j.vacun.2022.04.001</span></p>" ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "f0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1482 "Ancho" => 2165 "Tamanyo" => 248630 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Schematic structure of respiratory syncytial virus and its main proteins (modified from Beugeling et al.<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</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" => 1354 "Ancho" => 1634 "Tamanyo" => 252867 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Schematic structure of the RSV F-glycoprotein in its pre- and post-fusion active forms with the antigenic areas of each (modified from Graham et al.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</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" => 979 "Ancho" => 2175 "Tamanyo" => 199073 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Target groups and candidate populations for RSV vaccination. Each period may have its own most appropriate vaccine type, but the NPL-mRNA vaccine could be used in any of them (modified from Mejias et al.<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a>).</p>" ] ] 3 => array:8 [ "identificador" => "f0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1366 "Ancho" => 2175 "Tamanyo" => 76947 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0020" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Schematic structure of the wild-type RSV F protein (wtRSVF) and the form stabilised by insertion mutations (DS-Cav1). The black dots correspond to the amino acid changes and the area between the arrows to the new disulphide bridge created with them.</p> <p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">HRA: heptad repeats type A; HRB: heptad repeats type B; FP: fusion peptide; PS: signal peptide; PT: transmembrane peptide (modified from Espeseth et al.<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a>).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:28 [ 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. 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Review article
Preliminary data on messenger RNA (mRNA) vaccines against respiratory syncytial virus
Datos preliminares de las vacunas de ARN mensajero (ARNm) frente al virus respiratorio sincitial
Unidad de Virología, Servicio de Microbiología, Hospital Universitario Son Espases, Facultad de Medicina, Universitat Illes Balears, Palma de Mallorca, Spain