Current situation and future perspectives of vaccines against respiratory syncytial virus

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"cabecera" => "Review article" "titulo" => "Current situation and future perspectives of vaccines against respiratory syncytial virus" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "150" "paginaFinal" => "157" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Jordi Reina, Elisa Gónzalez de Herrero" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Jordi" "apellidos" => "Reina" "email" => array:1 [ 0 => "jorge.reina@ssib.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cr0005" ] ] ] 1 => array:2 [ "nombre" => "Elisa" "apellidos" => "Gónzalez de Herrero" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidad de Virología, Servicio de Microbiología, Hospital Universitario Son Espases, Facultad de Medicina de la 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" => "Situación actual y perspectivas de futuro de las vacunas 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" => 2012 "Ancho" => 2372 "Tamanyo" => 432335 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Schematic structure of 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">7</a>)." ] ] ] "textoCompleto" => "EpidemiologyRespiratory syncytial virus (RSV) was discovered in 1955, designated as chimpanzeecoryzaagent and associated with bronchiolitis in children in 1957.<a class="elsevierStyleCrossRef" href="#bb0005">1</a>,<a class="elsevierStyleCrossRef" href="#bb0010">2</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 (<5 years) and the elderly (>65 years) s).<a class="elsevierStyleCrossRef" href="#bb0015">3</a> Thus, it is estimated to be responsible for 22% of acute respiratory infections (ARI) in the paediatric population. A 2015 global study estimated that RSV caused 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">4</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">5</a> Although it actually affects only 2% of the world's population.<a class="elsevierStyleCrossRef" href="#bb0030">6</a>,<a class="elsevierStyleCrossRef" href="#bb0035">7</a>In the paediatric population, the peak of hospitalisation is between 2–3 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">4</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 <6 months) and pregnant women, in order to transmit immunity to the newborn and the frail elderly population.<a class="elsevierStyleCrossRefs" href="#bb0030">6–8</a>Molecular characteristics of RSVRSV is an enveloped virus with a single-stranded, negative, unsegmented 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, smallhydrophobic) and two glycoproteins designated F (fusion) and G (attachmentglycoprotein)<a class="elsevierStyleCrossRef" href="#bb0045">9</a> (<a class="elsevierStyleCrossRef" href="#f0005">Fig. 1</a>).<elsevierMultimedia ident="f0005"></elsevierMultimedia>Glycoproteins F and G are directly involved in the process of infectivity and development of respiratory disease. Thus, glycoprotein G is responsible for the binding 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 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">9</a>In addition to their functions and due to their external position in RSV, it is 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 that contains three hydrophobic peptides: a) signal peptide in the N-terminal region; b) the transmembrane region, which links F to the cell membrane and 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">3</a>,<a class="elsevierStyleCrossRef" href="#bb0045">9</a>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">9–11</a>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 F0, (pre-F) and the post-fusion (post-F) formed, after enzymatic hydrolysis, by the F1 and F2 subunit. In the pre-F form, an antigenic zone called “zero site (Φ)” has been described, which seems to be the most powerful in inducing neutralising antibodies<a class="elsevierStyleCrossRefs" href="#bb0060">12–14</a> (<a class="elsevierStyleCrossRef" href="#f0010">Fig. 2</a>). The post-F form, although more stable and easier to produce than the pre-F, is not recommended as an antigen because of its lower immune response, especially in neutralising antibodies, and therefore it is recommended to use the pre-F form for vaccines.<a class="elsevierStyleCrossRef" href="#bb0035">7</a>,<a class="elsevierStyleCrossRef" href="#bb0040">8</a><elsevierMultimedia ident="f0010"></elsevierMultimedia>Target populationsRSV 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">9</a>,<a class="elsevierStyleCrossRef" href="#bb0055">11</a> However, the disastrous experience of the first formalin-inactivated vaccine in 1966, which not only failed to produce protective antibody levels or protection against RSV infection, but also caused vaccinated individuals to develop a much more severe disease than unvaccinated individuals, with deaths among those vaccinated, led to the cessation of this vaccination and greatly delayed efforts to develop new effective and especially safe vaccines.<a class="elsevierStyleCrossRef" href="#bb0075">15</a>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 aged <4–6 months, children >6 months and those >65 years. In general terms, children 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">11</a>,<a class="elsevierStyleCrossRef" href="#bb0080">16</a> (<a class="elsevierStyleCrossRef" href="#t0005">Table 1</a>). In this age group, the use of monoclonal antibodies is currently the most appropriate choice.<a class="elsevierStyleCrossRef" href="#bb0050">10</a>,<a class="elsevierStyleCrossRef" href="#bb0055">11</a><elsevierMultimedia ident="t0005"></elsevierMultimedia>A vaccination 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 (<a class="elsevierStyleCrossRef" href="#t0010">Table 2</a>). However, the optimal time is the second or third trimester, and the durability and quantity of antibodies formed is not yet definitively known, but could be similar to that obtained with vaccination against influenza or pertussis. In these vaccinated pregnant women, subsequent breastfeeding could provide a significant amount of IgA that could have a protective effect.<a class="elsevierStyleCrossRef" href="#bb0040">8</a>,<a class="elsevierStyleCrossRef" href="#bb0055">11</a><elsevierMultimedia ident="t0010"></elsevierMultimedia>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 one 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">17</a>Although the highest incidence of RSV ARI occurs in the first 3–4 months of life, the virus continues to infect at other ages with varying clinical impact. Thus, more than 50% of hospitalisations due to acute RSV infection occur in children >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, the objective of which would be to reduce the circulation of the virus and its collateral effect on children and the elderly.<a class="elsevierStyleCrossRef" href="#bb0050">10</a>,<a class="elsevierStyleCrossRef" href="#bb0055">11</a>The third vaccination target group would be the frail elderly population aged 65 years and older. In this group, it is estimated that 3%–10% of ARI are caused by RSV, which would represent some 250,000 admissions and 14,000 deaths per year (<a class="elsevierStyleCrossRef" href="#t0015">Table 3</a>). Immunosenescence and underlying diseases would favour predisposition to respiratory infections, including RSV.<a class="elsevierStyleCrossRef" href="#bb0090">18</a><elsevierMultimedia ident="t0015"></elsevierMultimedia>There is currently a wide range of vaccine platforms that will allow us to establish their usefulness in the near future in each of the risk groups. Most of these new vaccines are still in the experimental animal phase or Phase I/II in humans, although some of them show promising results.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0100">20</a>Particulate vaccinesThis type of vaccine consists of self-assembled synthetic nanoparticles containing the viral antigen; as they lack the genome, they are safe and non-replicative. Three RSV vaccines based on this technology are currently under advanced study.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0100">20</a>The RSV F vaccine is composed of F proteins with the post-F conformation and stabilised with polysorbate 80 and can be associated with aluminium as an adjuvant or without it. It is being evaluated in pregnant women, pre-school children (2–6 years) and those over 60 years of age. In all these groups and in Phase I trials, this vaccine has been shown to be well tolerated and to induce a strong immune response.<a class="elsevierStyleCrossRef" href="#bb0105">21</a>,<a class="elsevierStyleCrossRef" href="#bb0110">22</a>The ResVax vaccine, which contains the pre-F protein, is designed for pregnant women and has aluminium phosphate as an adjuvant. It aims to protect the newborn against RSV through the antibodies generated in the mother. In a Phase II study, 50 healthy pregnant women in the third trimester were tested for their ability to efficiently produce antibodies. This vaccine is part of the PREARE project, a multicentre Phase III trial, randomised versus placebo, which aims to test vaccine efficacy against lower respiratory tract disease (LRTI) in children aged 90–180 days.<a class="elsevierStyleCrossRef" href="#bb0115">23</a> 4363 pregnant women were studied and given an intramuscular dose of the vaccine (120 μg of protein F adsorbed with 0.4 mg of aluminium) between 28 and 36 weeks. Overall, the ResVax vaccine did not significantly prevent LRTI but it did reduce upper respiratory tract disease (URTI) by 44%. However, it showed 39.4% efficacy in reducing LRTI, 58.8% efficacy in reducing RSV-related hypoxaemia in children under 3 months of age, and a lower incidence of pneumonia (49.4%) in those vaccinated. ResVax is therefore considered the first RSV vaccine to show efficacy in a Phase III clinical trial.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0100">20</a>In the 60+ population, ResVax was not able to demonstrate protective efficacy in a Phase III trial (RESOLVE trial, 2015). It studied 11,850 adults who received a single intramuscular dose of 135 μg without adjuvant. The vaccine did not reduce the incidence of moderate or severe LRTI and overall RSV-associated respiratory symptoms. However, it did reduce hospitalisations due to COPD exacerbations by 61%. Another Phase II trial was conducted in 2017 in this age group; the objective was to evaluate the safety and immunogenicity of one or two doses of ResVax with or without adjuvants (aluminium phosphate or Matrix-M1). It was observed that the 2 adjuvants increased the intensity, duration and quality of the immune response against the F protein relative to the unadjuvanted vaccine. This study seems to indicate the future need for the use of some form of adjuvant in the population aged >60 years.<a class="elsevierStyleCrossRef" href="#bb0050">10</a>,<a class="elsevierStyleCrossRef" href="#bb0055">11</a>,<a class="elsevierStyleCrossRef" href="#bb0100">20</a>The SynGEM vaccine contains the pre-F protein that is bound to bacterial particles (BP) derived from Lactococcuslactis. The vaccine is prepared by treating the bacteria with acid, washing it and mixing it with the F protein, resulting in a dead bacterial particle, to which the antigen is bound. In this way, the BP acts both as an immunostimulator and as an antigenic carrier.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0120">24</a> It is a nasally administered vaccine and BP enhances antigenic presentation at the mucosal level of the respiratory tract. In a Phase I trial, 48 people received two doses (350 μg of Pre-F and 5 mg of BP) separated by 28 days. Specific oropharyngeal mucosal IgA and systemic IgG antibodies were detected and persisted for 6 months. However, neutralising antibodies (specific to the zero site (Φ) of the F protein) were not detected. Therefore, the need to optimise the vaccine content was established, which was not realised due to the bankruptcy of the manufacturing company.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0100">20</a>Subunit vaccinesThese vaccines are made up of RSV protein fragments or subunits; they are usually poorly immunogenic and therefore require second doses or adjuvants. These types of vaccines basically induce a CD4 T-cell response with the potential risk of causing vaccine-enhanced disease, especially in seronegative children. They have therefore only been studied in pregnant women and older people who presumably already have immunological evidence of previous RSV infection.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0125">25</a>,<a class="elsevierStyleCrossRef" href="#bb0130">26</a>The VRC-RSVRGP084–00-VP vaccine contains the DS-Cav1 protein which is a variant of the F protein that has been stabilised in its pre-F conformation by protein engineering. Preliminary results with a single 50 μg dose of Phase I show that it is able to increase pre-neutralising antibodies to RSV by 7–15-fold.<a class="elsevierStyleCrossRef" href="#bb0135">27</a>RSV-pre-F vaccine is being studied in adults in 2 Phase I/II with and without adjuvant. The efficacy shown was 86.7% for symptomatic infection, neutralising antibody titres increased with the second dose and remained elevated for long periods of time.<a class="elsevierStyleCrossRef" href="#bb0140">28</a> A Phase IIb study was also initiated in healthy pregnant women to assess the safety, tolerability and immunogenicity of pre-F in this group and to determine the characteristics of the antibodies transferred placentally to their children.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0125">25</a>Also using the pre-F protein (between 45 and 135 μg) and the adjuvant aluminium hydroxide or MF59 or without adjuvant, GSK3888550A for pregnant women and GSK3844766A for older adults<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0100">20</a> are at an advanced stage of evaluation. However, studies and results have yet to be published, preliminary data seem to indicate little additive effect of adjuvant, which may indicate that without adjuvant, the level of immune saturation is achieved.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>The DPX-RSV vaccine is based on the ectodomain part of the RSV SH protein (She) and conjugated to a lipid base (DepoVax) which confers stability and immunogenicity. The Phase I trial has shown safety and a sustained IgG response of at least one year's duration. The G protein-derived subunit vaccine (BARS13) has entered a Phase I trial that has not been completed.<a class="elsevierStyleCrossRef" href="#bb0145">29</a>Vector vaccinesVector vaccines use a non-replicating viral vector to incorporate the genetic information of the antigen to be immunised; they are considered chimeric or recombinant vaccines and are completely safe as they do not incorporate the complete genome of the virus. One of the possible drawbacks is that pre-existing antivector antibodies (against some adenovirus serotypes) may reduce vaccine efficacy.<a class="elsevierStyleCrossRef" href="#bb0050">10</a>,<a class="elsevierStyleCrossRef" href="#bb0055">11</a>,<a class="elsevierStyleCrossRef" href="#bb0145">29</a>,<a class="elsevierStyleCrossRef" href="#bb0100">20</a>The MVA-BN-RSV vaccine is based on the modified non-replicative vaccinia Ankara virus, previously used against smallpox. This vaccine incorporates the external RSV F and G proteins and 2 internal proteins (N and M2). A Phase I trial has shown that it induces a strong humoral and cellular response.<a class="elsevierStyleCrossRef" href="#bb0150">30</a> A subsequent Phase II trial to assess safety and immunogenicity in 420 adults over 55 years of age showed that it was well tolerated and induced persistent immunity for at least 6 months with the possibility of a second dose at 12 months. Based on these data, a Phase III trial in those over 55 years of age is planned.<a class="elsevierStyleCrossRef" href="#bb0150">30</a>The PanAd3-RSV and MVA-RSV vaccines incorporate the F, N and M2 proteins into a non-replicative simian defective adenovirus (PanAd3) or MVA virus. They have different routes of administration, PanAd3 is intramuscular or intranasal and MVA is exclusively intramuscular. Early trials have shown that both are well tolerated and induce specific immunity despite prior RSV immunity.<a class="elsevierStyleCrossRef" href="#bb0155">31</a>The VXA-RSV-F vaccine uses adenovirus serotype 5 as a non-replicating vector and encodes the F protein; this vaccine is orally administered and specific for adults. Preclinical data in mice show a strong and sustained immune response in mice and therefore a Phase I trial has been initiated for which results are not available.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>Using the adenoviral vector, a vaccine expressing the pre-F protein (Ad26.RSV.Pre-F) has been developed. In a Phase II study in adults, the co-administration of the influenza vaccine and this new RSV vaccine was studied, with an acceptable safety profile and absence of immune interference between them.<a class="elsevierStyleCrossRef" href="#bb0160">32</a>Other vector vaccines under study include ChAd155-RSV, which encodes RSV F, N and M2–1 proteins, and those using parainfluenza virus as a vector (PIV3), in an attempt to obtain immunity against both viruses. The PIV3-RSV vaccine has been tested in seronegative children and only 50% of them showed an immune response to RSV and 100% to PIV3. The low immunogenicity against RSV is likely to be due to the low antigenic expression of the pre-F protein in the vaccine production process.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0100">20</a>Attenuated vaccinesAttenuated vaccines are defined as those containing an altered or modified virus in order to reduce its pathogenic capacity as much as possible, while maintaining its immunological response capacity. They can be obtained by classical methods (low-temperature/cold-adapted or by chemical modifications) or by reverse genetics techniques that hinder viral replication. These attenuated vaccines have many advantages, such as: a) ability to replicate in the respiratory tract despite the presence of maternal antibodies; b) ability to induce humoral and cellular immune responses; and c) the possibility of being administered nasally, which is much better tolerated by the infant population. There are many attenuated vaccines under study in Phase I, but none have moved on to Phase II, due to the higher safety requirements. To facilitate their recommendation, the RSV genome is being modified to eliminate its M2–2 regulatory system, thereby increasing transcription and antigenic expression, but drastically decreasing the replication capacity of RSV.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0100">20</a>,<a class="elsevierStyleCrossRef" href="#bb0165">33</a>,<a class="elsevierStyleCrossRef" href="#bb0170">34</a>Two candidates (RSV MEDI ΔM2–2 and RSV LID ΔM2–2) have been clinically evaluated and shown to induce an RSV neutralising antibody response. Both induce a strong neutralising antibody response, however, the LID ΔM2–2 has been found to be more effective. Attenuated vaccines, despite their efficacy and safety, appear to be the main candidates for population-based vaccination programmes in the paediatric population for the time being.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0175">35</a>RNA-messenger vaccinesThe 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 provide 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 RNAases); (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 processing and/or subsequent re-actualisation; and d) does not require the use of cell cultures that could alter the antigenicity of the final protein.Historically, in 2013 Geall et al.<a class="elsevierStyleCrossRef" href="#bb0180">36</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.Subsequently, Espeseth et al.<a class="elsevierStyleCrossRef" href="#bb0185">37</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 and stabilised and unstabilised pre-F. The pre-F can be stabilised by a nanolipid structure. Pre-F can be stabilised by introducing mutations in the disulphide bridge of the structure, all of which introduce covalent bonds that prevent the structural rearrangements that determine the transition from pre-F to functional F.<a class="elsevierStyleCrossRef" href="#bb0190">38</a>,<a class="elsevierStyleCrossRef" href="#bb0195">39</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+ and CD8 + cells.<a class="elsevierStyleCrossRef" href="#bb0200">40</a>Aliprantis et al.<a class="elsevierStyleCrossRef" href="#bb0130">26</a> reported the first Phase 1 human study in young (18–49 years, part A) and older (60–79 years, part B) healthy adults to evaluate 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.The results obtained show, in both young people and adults, a significant increase in neutralising antibody levels against pre-F, as well as a potent induction of preferentially CD4+ 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="#bb0205">41</a>The epidemiological impact of annual epidemics of RSV, which affect the extremes of life, determines the need to establish a prevention strategy. Vaccines are one of the best tools in this field and must be part of this strategy. Multiple vaccine platforms are currently being studied, based on the pre-F protein, although the use of long-lived monoclonal antibodies in the first year of life should be considered.<a class="elsevierStyleCrossRef" href="#bb0210">42</a> In the paediatric population, beyond this period, attenuated vaccines are likely to play a relevant role, as they expose the immune system to the whole virus particle and induce a broad-spectrum neutralising antibody response. In the population over 65 years of age, there is a clear need to use a subunit vaccine with an immune-stimulating adjuvant or mRNA vaccines. In pregnant women, a vaccination programme will probably not be implemented, as monoclonal antibodies administered at birth would cover this need.The future of RSV infection and disease prevention in the human population will be based on the use of monoclonal antibodies and age-appropriate vaccines.FundingThis review article has not been funded by any public or prívate entity." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1894872" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1639550" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1894873" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1639551" "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" => "Particulate vaccines" ] 8 => array:2 [ "identificador" => "s0025" "titulo" => "Subunit vaccines" ] 9 => array:2 [ "identificador" => "s0030" "titulo" => "Vector vaccines" ] 10 => array:2 [ "identificador" => "s0035" "titulo" => "Attenuated vaccines" ] 11 => array:2 [ "identificador" => "s0040" "titulo" => "RNA-messenger vaccines" ] 12 => array:2 [ "identificador" => "s0045" "titulo" => "Funding" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1639550" "palabras" => array:3 [ 0 => "Respiratory Syncytial Virus" 1 => "Vaccines" 2 => "Risk groups" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1639551" "palabras" => array:3 [ 0 => "Virus respiratorio sincitial" 1 => "Vacunas" 2 => "Grupos de riesgo" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The Respiratory Syncytial Virus (RSV) is the cause of acute respiratory pathologies (bronchiolitis and pneumonia) that occurs preferably as epidemic in the winter months. RSV is a good vaccine candidate since as a virus it has shown genetic and antigenic stability, most infections are self-limited and the only natural reservoir is humans. According to epidemiological data, there are three target populations that require different approaches for the RSV vaccine: naive children <4–6 months, children >6 months, and >65 years. Multiple vaccine platforms based on the preF protein are currently being studied, although the use of long-lived monoclonal antibodies must be considered in the first year of life. In the child population, beyond this period, attenuated vaccines probably play a relevant role, since they expose the complete viral particle to the immune system and induce a broad-spectrum neutralising antibody response. In the population > 65 years of age, the need to use a subunit vaccine with an adjuvant that stimulates the immune response or mRNA vaccines is evident. The future in the prevention of RSV infection and disease in the human population will be based on the use of monoclonal antibodies and vaccines adapted to each age group." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El Vvirus respiratorio sincitial (VRS) es el causante de patologías respiratorias agudas (bronquiolitis y neumonías) que se presenta preferentemente de forma epidémica en los meses invernales. El VRS es un buen candidato vacunal ya que como virus ha mostrado una estabilidad genética y antigénica, la mayoría de las infecciones son autolimitadas y el único reservorio natural es el ser humano. De acuerdo con los datos epidemiológicos existen tres poblaciones diana que requieren de aproximaciones diferentes para la vacuna frente al VRS: los niños naive de <4–6 meses, los niños >6 meses y los >65 años. En estos momentos se están estudiando múltiples plataformas vacunales, basadas en la proteína preF, aunque hay que considerar la utilización de los anticuerpos monoclonales de vida prolongada en el primer año de vida. En la población infantil, mas allá de este período, probablemente las vacunas atenuadas tengan un papel relevante, ya que exponen al sistema inmune la partícula vírica completa e inducen una respuesta de anticuerpos neutralizantes de amplio espectro. En la población de >65 años, es evidente la necesidad de utilizar una vacuna de subunidades con un adyuvante que estimule la respuesta inmune o las vacunas de ARNm. El futuro en la prevención de la infección y enfermedad por VRS en la población humana, se basará en la utilización de anticuerpos monoclonales y vacunadas adaptadas a cada grupo de edad." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Reina J, de Herrero EG. Situación actual y perspectivas de futuro de las vacunas frente al virus respiratorio sincitial. Vacunas. 2022. https://doi.org/10.1016/j.vacun.2022.12.005" ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "f0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1171 "Ancho" => 1711 "Tamanyo" => 169754 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Schematic structure of respiratory syncytial virus and its main proteins (modified from Beugeling et al.<a class="elsevierStyleCrossRef" href="#bb0015">3</a>)." ] ] 1 => array:8 [ "identificador" => "f0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2012 "Ancho" => 2372 "Tamanyo" => 432335 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Schematic structure of 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">7</a>)." ] ] 2 => array:8 [ "identificador" => "t0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Adapted from Biagi et al.<a class="elsevierStyleCrossRef" href="#bb0030">6</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Company \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Novavax \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Particulates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SynGEM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mucosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Particulates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ad26.RSV.preF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Janssen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral vector \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ChAd155-RSV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GSK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral vector \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEDI-534 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Astra-Zeneca \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral vector \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SeVRSV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral vector \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV MEDI ΔM2–2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV LID ΔM2–2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV cps2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV LID cp ΔM2–2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV LID ΔM2–21030s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV D46/NS2/NΔM2–2-HindIII \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV ΔNS2 Δ1313 I1314L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV 6120/F1/G2/ΔNS1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV 6120/ΔNS2/1030 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV 276 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV D46 cpΔM2–2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MEDI-559 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Astra-Zeneca \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MV-012-968 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Meissa Vaccines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Attenuated virus \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rBCG-N-hRSV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">University of Chile \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chimera \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3167211.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Main vaccines under development against respiratory syncytial virus in the paediatric population." ] ] 3 => array:8 [ "identificador" => "t0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Adapted from Biagi et al.<a class="elsevierStyleCrossRef" href="#bb0030">6</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Company \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ResVax \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Novavax \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Particulates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VRC-RSVRGP084–00-VP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIAID \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subunits \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV-F vaccine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pfizer \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subunits \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GSK3888550A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GSK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subunits \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3167210.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Main vaccines under development against respiratory syncytial virus in the pregnant population." ] ] 4 => array:8 [ "identificador" => "t0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Adapted from Biagi et al.<a class="elsevierStyleCrossRef" href="#bb0030">6</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Company \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Novavax \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Particulates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SynGEM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mucosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Particulates \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RSV vaccine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pfizer \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subunits \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GSK3844766A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GSK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subunits \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DPX-RSV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dalhousie University \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subunits \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BARS13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vaccine Laborat \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subunits \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MVA-BN RSV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bavarian Nordic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral vector \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VXA-RSVf oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vaxart \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral vector \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ad26.RSV.preF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Janssen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral vector \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PanAd3-RSV y MVA-RSV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ReiThera \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral vector \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3167212.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Major respiratory syncytial virus vaccines in development in the adult population." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:42 [ 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:6 [ "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" ] ] ] ] ] ] ] ] 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:6 [ "tituloSerie" => "Expert Rev Vaccines" "fecha" => "2019" "volumen" => "18" "paginaInicial" => "935" "paginaFinal" => "950" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31446807" "web" => "Medline" ] ] ] ] ] ] ] ] 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" => "Respiratory syncytial virus infection in elderly and high-risk asults" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.R. Falsey" 1 => "P.A. Hennessey" 2 => "M.A. Formica" 3 => "C. Cox" 4 => "E.E. 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Poletti" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/vaccines8040672" "Revista" => array:3 [ "tituloSerie" => "Vaccines" "fecha" => "2020" "itemHostRev" => array:3 [ "pii" => "S0924857915002435" "estado" => "S300" "issn" => "09248579" ] ] ] ] ] ] ] 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" => "The respiratory syncytial virus vaccine lanscape: lessons from the graveyard and promising candidates" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N.I. Mazur" 1 => "D. Higgins" 2 => "M.C. Nunes" 3 => "J.A. Melero" 4 => "A.C. Langedijk" 5 => "N. Horsley" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1473-3099(18)30292-5" "Revista" => array:7 [ "tituloSerie" => "Lancet Infect Dis" "fecha" => "2018" "volumen" => "18" "numero" => "10" "paginaInicial" => "e295" "paginaFinal" => "e311" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29914800" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bb0045" "etiqueta" => "9." "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" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bb0050" "etiqueta" => "10." "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. 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Review article

Current situation and future perspectives of vaccines against respiratory syncytial virus

Situación actual y perspectivas de futuro de las vacunas frente al virus respiratorio sincitial

Jordi Reina

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jorge.reina@ssib.es

Corresponding author.

, Elisa Gónzalez de Herrero

Unidad de Virología, Servicio de Microbiología, Hospital Universitario Son Espases, Facultad de Medicina de la Universitat Illes Balears, Palma de Mallorca, Spain

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          "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Schematic structure of RSV F-glycoprotein in its pre- and post-fusion active forms with the antigenic areas of each &#40;modified from Graham et al&#46;<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a>&#41;&#46;</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 &#40;RSV&#41; was discovered in 1955&#44; designated as chimpanzeecoryzaagent and associated with bronchiolitis in children in 1957&#46;<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0010"><span class="elsevierStyleSup">2</span></a> It causes acute respiratory illnesses &#40;bronchiolitis and pneumonias&#41; that occur preferentially in epidemic form in the winter months&#46; Although it can affect the entire population&#44; its pathological impact is much greater in children &#40;&#60;5&#8239;years&#41; and the elderly &#40;&#62;65&#8239;years&#41; s&#41;&#46;<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a> Thus&#44; it is estimated to be responsible for 22&#37; of acute respiratory infections &#40;ARI&#41; in the paediatric population&#46; A 2015 global study estimated that RSV caused 33&#46;1 million ARIs per year&#44; leading to about 3&#46;2 million hospitalisations and about 59&#44;000 hospital deaths in children under 5&#8239;years of age&#46; In addition&#44; in children under 6&#8239;months of age&#44; RSV causes about 1&#46;4 million hospitalisations and about 27&#44;300 deaths annually&#46;<a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a> In the older population&#44; RSV is responsible for about 17&#44;000 deaths per year due to pneumonia or its complications&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> Although it actually affects only 2&#37; of the world&#39;s population&#46;<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">In the paediatric population&#44; the peak of hospitalisation is between 2&#8211;3&#8239;months&#44; although the risk of severe infection continues until the age of 5&#8239;years&#46; It is estimated that by the age of 3&#8239;years almost the entire population has been infected with RSV&#44; with reinfections occurring annually or every 3&#8211;5&#8239;years&#44;<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&#46; Given that the aim of RSV vaccination is to prevent severe infection and its consequences&#44; the target populations to be vaccinated would be children under 2&#8239;years of age &#40;preferably &#60;<span class="elsevierStyleHsp" style=""></span>6&#8239;months&#41; and pregnant women&#44; in order to transmit immunity to the newborn and the frail elderly population&#46;<a class="elsevierStyleCrossRefs" href="#bb0030"><span class="elsevierStyleSup">6&#8211;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 a single-stranded&#44; negative&#44; unsegmented RNA genome &#40;15&#44;200 nucleotides&#41; containing 10 genes and encoding 11 distinct proteins&#59; it belongs to the family Pneumoviridae and the genus Orthopneumovirus&#46; Four proteins are found in the virus envelope&#58; the matrix protein &#40;M&#41;&#44; the small hydrophobic protein &#40;SH&#44; smallhydrophobic&#41; and two glycoproteins designated F &#40;fusion&#41; and G &#40;attachmentglycoprotein&#41;<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a> &#40;<a class="elsevierStyleCrossRef" href="#f0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0020" class="elsevierStylePara elsevierViewall">Glycoproteins F and G are directly involved in the process of infectivity and development of respiratory disease&#46; Thus&#44; glycoprotein G is responsible for the binding of the virus to the epithelial cell&#44; while F participates in the entry of the virus into the cell&#44; through its fusion with the cytoplasmic membrane&#46; This protein is also responsible for the fusion of infected cells&#44; giving rise to the formation of the syncytia&#44; typical of this infection and which give the virus its name&#46;<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&#44; it is the immunodominant glycoproteins that induce neutralising antibodies in the infected host&#46; Three types of epitopes have been identified in glycoprotein G&#58; a&#41; conserved&#44; detectable in all strains&#59; b&#41; group-specific&#44; expressed only in the same antigenic group&#59; and c&#41; species-specific&#44; present only in specific strains within the same antigenic group and located in the hypervariable C-terminal region&#46; The F glycoprotein is derived from an inactive precursor form that contains three hydrophobic peptides&#58; a&#41; signal peptide in the N-terminal region&#59; b&#41; the transmembrane region&#44; which links F to the cell membrane and viral envelope&#59; and c&#41; the fusion peptide&#44; which inserts into the cell membrane and determines the fusion process between them&#46;<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</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&#44; the so-called A and B&#44; which tend to co-circulate seasonally or alternatively&#46; The antigenic difference between the 2 groups is determined by the sequence of glycoprotein G &#40;only 35&#37; homology between A and B strains&#41;&#46; Therefore&#44; some antibodies directed against G-glycoprotein G are only subtype specific&#44; whereas most antibodies directed against F-glycoprotein have neutralising activity against both antigenic groups A and B as they have 90&#37; identity in their amino acid sequences&#46;<a class="elsevierStyleCrossRefs" href="#bb0045"><span class="elsevierStyleSup">9&#8211;11</span></a></p><p id="p0035" class="elsevierStylePara elsevierViewall">Most vaccines in development use F-glycoprotein as the antigenic element&#46; However&#44; there are 2 presentations of F-glycoprotein&#44; the so-called pre-fusion&#44; inactive trimeric precursor F0&#44; &#40;pre-F&#41; and the post-fusion &#40;post-F&#41; formed&#44; after enzymatic hydrolysis&#44; by the F<span class="elsevierStyleInf">1</span> and F<span class="elsevierStyleInf">2</span> subunit&#46; In the pre-F form&#44; an antigenic zone called &#8220;zero site &#40;&#934;&#41;&#8221; has been described&#44; which seems to be the most powerful in inducing neutralising antibodies<a class="elsevierStyleCrossRefs" href="#bb0060"><span class="elsevierStyleSup">12&#8211;14</span></a> &#40;<a class="elsevierStyleCrossRef" href="#f0010">Fig&#46; 2</a>&#41;&#46; The post-F form&#44; although more stable and easier to produce than the pre-F&#44; is not recommended as an antigen because of its lower immune response&#44; especially in neutralising antibodies&#44; and therefore it is recommended to use the pre-F form for vaccines&#46;<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="f0010"></elsevierMultimedia></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Target populations</span><p id="p0040" class="elsevierStylePara elsevierViewall">RSV is a good vaccine candidate because as a virus it has shown genetic and antigenic stability&#44; most infections are self-limiting and the only natural reservoir is humans&#46;<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a> However&#44; the disastrous experience of the first formalin-inactivated vaccine in 1966&#44; which not only failed to produce protective antibody levels or protection against RSV infection&#44; but also caused vaccinated individuals to develop a much more severe disease than unvaccinated individuals&#44; with deaths among those vaccinated&#44; led to the cessation of this vaccination and greatly delayed efforts to develop new effective and especially safe vaccines&#46;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a></p><p id="p0045" class="elsevierStylePara elsevierViewall">As mentioned above&#44; and according to epidemiological data&#44; there are clearly 3 target populations that require different approaches to RSV vaccination&#46; These are&#58; naive children aged &#60;<span class="elsevierStyleHsp" style=""></span>4&#8211;6&#8239;months&#44; children &#62;<span class="elsevierStyleHsp" style=""></span>6&#8239;months and those &#62;<span class="elsevierStyleHsp" style=""></span>65&#8239;years&#46; In general terms&#44; children aged 4&#8211;6&#8239;months have a still immature and developing immune system characterised by low interferon expression&#44; predominance of regulatory T-cells with tolerogenic reactivity and a limited B-cell repertoire&#46; This results in a poor response to exogenous antigens&#44; interfering with the natural process of antigenic presentation and the formation of highly efficient mature antibodies&#46; Despite this&#44; 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">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a> &#40;<a class="elsevierStyleCrossRef" href="#t0005">Table 1</a>&#41;&#46; In this age group&#44; the use of monoclonal antibodies is currently the most appropriate choice&#46;<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="t0005"></elsevierMultimedia><p id="p0050" class="elsevierStylePara elsevierViewall">A vaccination approach for this age group would be vaccination during the gestational process&#44; so that antibodies formed in an adult could be transmitted to the newborn in the first months of life&#46; Active transplacental transfer begins at approximately 28&#8211;30&#8239;weeks of gestation&#59; therefore&#44; this would be the appropriate time for the immunisation process &#40;<a class="elsevierStyleCrossRef" href="#t0010">Table 2</a>&#41;&#46; However&#44; the optimal time is the second or third trimester&#44; and the durability and quantity of antibodies formed is not yet definitively known&#44; but could be similar to that obtained with vaccination against influenza or pertussis&#46; In these vaccinated pregnant women&#44; subsequent breastfeeding could provide a significant amount of IgA that could have a protective effect&#46;<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="t0010"></elsevierMultimedia><p id="p0055" class="elsevierStylePara elsevierViewall">Vaccination of pregnant women may be questionable if its sole purpose is to protect the newborn and not the mother&#46; The actual impact of RSV on pregnant women and its complications is currently unknown&#44; although one study has estimated the attack rate during the second or third trimester to be approximately 10&#37;&#8211;13&#37;&#44; suggesting that vaccination may also benefit the mother&#46;<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a></p><p id="p0060" class="elsevierStylePara elsevierViewall">Although the highest incidence of RSV ARI occurs in the first 3&#8211;4&#8239;months of life&#44; the virus continues to infect at other ages with varying clinical impact&#46; Thus&#44; more than 50&#37; of hospitalisations due to acute RSV infection occur in children &#62;<span class="elsevierStyleHsp" style=""></span>6&#8239;months&#44; with the 6&#8211;24&#8239;month age group being the most affected by the virus&#46; Therefore&#44; the population between 6&#8239;months and 5&#8239;years of age would constitute a target group&#44; the objective of which would be to reduce the circulation of the virus and its collateral effect on children and the elderly&#46;<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a></p><p id="p0065" class="elsevierStylePara elsevierViewall">The third vaccination target group would be the frail elderly population aged 65&#8239;years and older&#46; In this group&#44; it is estimated that 3&#37;&#8211;10&#37; of ARI are caused by RSV&#44; which would represent some 250&#44;000 admissions and 14&#44;000 deaths per year &#40;<a class="elsevierStyleCrossRef" href="#t0015">Table 3</a>&#41;&#46; Immunosenescence and underlying diseases would favour predisposition to respiratory infections&#44; including RSV&#46;<a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a></p><elsevierMultimedia ident="t0015"></elsevierMultimedia><p id="p0070" class="elsevierStylePara elsevierViewall">There is currently a wide range of vaccine platforms that will allow us to establish their usefulness in the near future in each of the risk groups&#46; Most of these new vaccines are still in the experimental animal phase or Phase I&#47;II in humans&#44; although some of them show promising results&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Particulate vaccines</span><p id="p0075" class="elsevierStylePara elsevierViewall">This type of vaccine consists of self-assembled synthetic nanoparticles containing the viral antigen&#59; as they lack the genome&#44; they are safe and non-replicative&#46; Three RSV vaccines based on this technology are currently under advanced study&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">The RSV F vaccine is composed of F proteins with the post-F conformation and stabilised with polysorbate 80 and can be associated with aluminium as an adjuvant or without it&#46; It is being evaluated in pregnant women&#44; pre-school children &#40;2&#8211;6&#8239;years&#41; and those over 60&#8239;years of age&#46; In all these groups and in Phase I trials&#44; this vaccine has been shown to be well tolerated and to induce a strong immune response&#46;<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">The ResVax vaccine&#44; which contains the pre-F protein&#44; is designed for pregnant women and has aluminium phosphate as an adjuvant&#46; It aims to protect the newborn against RSV through the antibodies generated in the mother&#46; In a Phase II study&#44; 50 healthy pregnant women in the third trimester were tested for their ability to efficiently produce antibodies&#46; This vaccine is part of the PREARE project&#44; a multicentre Phase III trial&#44; randomised versus placebo&#44; which aims to test vaccine efficacy against lower respiratory tract disease &#40;LRTI&#41; in children aged 90&#8211;180&#8239;days&#46;<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a> 4363 pregnant women were studied and given an intramuscular dose of the vaccine &#40;120&#8239;&#956;g of protein F adsorbed with 0&#46;4&#8239;mg of aluminium&#41; between 28 and 36&#8239;weeks&#46; Overall&#44; the ResVax vaccine did not significantly prevent LRTI but it did reduce upper respiratory tract disease &#40;URTI&#41; by 44&#37;&#46; However&#44; it showed 39&#46;4&#37; efficacy in reducing LRTI&#44; 58&#46;8&#37; efficacy in reducing RSV-related hypoxaemia in children under 3&#8239;months of age&#44; and a lower incidence of pneumonia &#40;49&#46;4&#37;&#41; in those vaccinated&#46; ResVax is therefore considered the first RSV vaccine to show efficacy in a Phase III clinical trial&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p><p id="p0090" class="elsevierStylePara elsevierViewall">In the 60<span class="elsevierStyleHsp" style=""></span>&#43; population&#44; ResVax was not able to demonstrate protective efficacy in a Phase III trial &#40;RESOLVE trial&#44; 2015&#41;&#46; It studied 11&#44;850 adults who received a single intramuscular dose of 135&#8239;&#956;g without adjuvant&#46; The vaccine did not reduce the incidence of moderate or severe LRTI and overall RSV-associated respiratory symptoms&#46; However&#44; it did reduce hospitalisations due to COPD exacerbations by 61&#37;&#46; Another Phase II trial was conducted in 2017 in this age group&#59; the objective was to evaluate the safety and immunogenicity of one or two doses of ResVax with or without adjuvants &#40;aluminium phosphate or Matrix-M1&#41;&#46; It was observed that the 2 adjuvants increased the intensity&#44; duration and quality of the immune response against the F protein relative to the unadjuvanted vaccine&#46; This study seems to indicate the future need for the use of some form of adjuvant in the population aged &#62;<span class="elsevierStyleHsp" style=""></span>60&#8239;years&#46;<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p><p id="p0095" class="elsevierStylePara elsevierViewall">The SynGEM vaccine contains the pre-F protein that is bound to bacterial particles &#40;BP&#41; derived from Lactococcuslactis&#46; The vaccine is prepared by treating the bacteria with acid&#44; washing it and mixing it with the F protein&#44; resulting in a dead bacterial particle&#44; to which the antigen is bound&#46; In this way&#44; the BP acts both as an immunostimulator and as an antigenic carrier&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">24</span></a> It is a nasally administered vaccine and BP enhances antigenic presentation at the mucosal level of the respiratory tract&#46; In a Phase I trial&#44; 48 people received two doses &#40;350&#8239;&#956;g of Pre-F and 5&#8239;mg of BP&#41; separated by 28&#8239;days&#46; Specific oropharyngeal mucosal IgA and systemic IgG antibodies were detected and persisted for 6&#8239;months&#46; However&#44; neutralising antibodies &#40;specific to the zero site &#40;&#934;&#41; of the F protein&#41; were not detected&#46; Therefore&#44; the need to optimise the vaccine content was established&#44; which was not realised due to the bankruptcy of the manufacturing company&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Subunit vaccines</span><p id="p0100" class="elsevierStylePara elsevierViewall">These vaccines are made up of RSV protein fragments or subunits&#59; they are usually poorly immunogenic and therefore require second doses or adjuvants&#46; These types of vaccines basically induce a CD4 T-cell response with the potential risk of causing vaccine-enhanced disease&#44; especially in seronegative children&#46; They have therefore only been studied in pregnant women and older people who presumably already have immunological evidence of previous RSV infection&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a></p><p id="p0105" class="elsevierStylePara elsevierViewall">The VRC-RSVRGP084&#8211;00-VP vaccine contains the DS-Cav1 protein which is a variant of the F protein that has been stabilised in its pre-F conformation by protein engineering&#46; Preliminary results with a single 50&#8239;&#956;g dose of Phase I show that it is able to increase pre-neutralising antibodies to RSV by 7&#8211;15-fold&#46;<a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">27</span></a></p><p id="p0110" class="elsevierStylePara elsevierViewall">RSV-pre-F vaccine is being studied in adults in 2 Phase I&#47;II with and without adjuvant&#46; The efficacy shown was 86&#46;7&#37; for symptomatic infection&#44; neutralising antibody titres increased with the second dose and remained elevated for long periods of time&#46;<a class="elsevierStyleCrossRef" href="#bb0140"><span class="elsevierStyleSup">28</span></a> A Phase IIb study was also initiated in healthy pregnant women to assess the safety&#44; tolerability and immunogenicity of pre-F in this group and to determine the characteristics of the antibodies transferred placentally to their children&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a></p><p id="p0115" class="elsevierStylePara elsevierViewall">Also using the pre-F protein &#40;between 45 and 135&#8239;&#956;g&#41; and the adjuvant aluminium hydroxide or MF59 or without adjuvant&#44; GSK3888550A for pregnant women and GSK3844766A for older adults<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a> are at an advanced stage of evaluation&#46; However&#44; studies and results have yet to be published&#44; preliminary data seem to indicate little additive effect of adjuvant&#44; which may indicate that without adjuvant&#44; the level of immune saturation is achieved&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a></p><p id="p0120" class="elsevierStylePara elsevierViewall">The DPX-RSV vaccine is based on the ectodomain part of the RSV SH protein &#40;She&#41; and conjugated to a lipid base &#40;DepoVax&#41; which confers stability and immunogenicity&#46; The Phase I trial has shown safety and a sustained IgG response of at least one year&#39;s duration&#46; The G protein-derived subunit vaccine &#40;BARS13&#41; has entered a Phase I trial that has not been completed&#46;<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a></p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Vector vaccines</span><p id="p0125" class="elsevierStylePara elsevierViewall">Vector vaccines use a non-replicating viral vector to incorporate the genetic information of the antigen to be immunised&#59; they are considered chimeric or recombinant vaccines and are completely safe as they do not incorporate the complete genome of the virus&#46; One of the possible drawbacks is that pre-existing antivector antibodies &#40;against some adenovirus serotypes&#41; may reduce vaccine efficacy&#46;<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p><p id="p0130" class="elsevierStylePara elsevierViewall">The MVA-BN-RSV vaccine is based on the modified non-replicative vaccinia Ankara virus&#44; previously used against smallpox&#46; This vaccine incorporates the external RSV F and G proteins and 2 internal proteins &#40;N and M2&#41;&#46; A Phase I trial has shown that it induces a strong humoral and cellular response&#46;<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a> A subsequent Phase II trial to assess safety and immunogenicity in 420 adults over 55&#8239;years of age showed that it was well tolerated and induced persistent immunity for at least 6&#8239;months with the possibility of a second dose at 12&#8239;months&#46; Based on these data&#44; a Phase III trial in those over 55&#8239;years of age is planned&#46;<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a></p><p id="p0135" class="elsevierStylePara elsevierViewall">The PanAd3-RSV and MVA-RSV vaccines incorporate the F&#44; N and M2 proteins into a non-replicative simian defective adenovirus &#40;PanAd3&#41; or MVA virus&#46; They have different routes of administration&#44; PanAd3 is intramuscular or intranasal and MVA is exclusively intramuscular&#46; Early trials have shown that both are well tolerated and induce specific immunity despite prior RSV immunity&#46;<a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a></p><p id="p0140" class="elsevierStylePara elsevierViewall">The VXA-RSV-F vaccine uses adenovirus serotype 5 as a non-replicating vector and encodes the F protein&#59; this vaccine is orally administered and specific for adults&#46; Preclinical data in mice show a strong and sustained immune response in mice and therefore a Phase I trial has been initiated for which results are not available&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a></p><p id="p0145" class="elsevierStylePara elsevierViewall">Using the adenoviral vector&#44; a vaccine expressing the pre-F protein &#40;Ad26&#46;RSV&#46;Pre-F&#41; has been developed&#46; In a Phase II study in adults&#44; the co-administration of the influenza vaccine and this new RSV vaccine was studied&#44; with an acceptable safety profile and absence of immune interference between them&#46;<a class="elsevierStyleCrossRef" href="#bb0160"><span class="elsevierStyleSup">32</span></a></p><p id="p0150" class="elsevierStylePara elsevierViewall">Other vector vaccines under study include ChAd155-RSV&#44; which encodes RSV F&#44; N and M2&#8211;1 proteins&#44; and those using parainfluenza virus as a vector &#40;PIV3&#41;&#44; in an attempt to obtain immunity against both viruses&#46; The PIV3-RSV vaccine has been tested in seronegative children and only 50&#37; of them showed an immune response to RSV and 100&#37; to PIV3&#46; The low immunogenicity against RSV is likely to be due to the low antigenic expression of the pre-F protein in the vaccine production process&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Attenuated vaccines</span><p id="p0155" class="elsevierStylePara elsevierViewall">Attenuated vaccines are defined as those containing an altered or modified virus in order to reduce its pathogenic capacity as much as possible&#44; while maintaining its immunological response capacity&#46; They can be obtained by classical methods &#40;low-temperature&#47;cold-adapted or by chemical modifications&#41; or by reverse genetics techniques that hinder viral replication&#46; These attenuated vaccines have many advantages&#44; such as&#58; a&#41; ability to replicate in the respiratory tract despite the presence of maternal antibodies&#59; b&#41; ability to induce humoral and cellular immune responses&#59; and c&#41; the possibility of being administered nasally&#44; which is much better tolerated by the infant population&#46; There are many attenuated vaccines under study in Phase I&#44; but none have moved on to Phase II&#44; due to the higher safety requirements&#46; To facilitate their recommendation&#44; the RSV genome is being modified to eliminate its M2&#8211;2 regulatory system&#44; thereby increasing transcription and antigenic expression&#44; but drastically decreasing the replication capacity of RSV&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0165"><span class="elsevierStyleSup">33</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0170"><span class="elsevierStyleSup">34</span></a></p><p id="p0160" class="elsevierStylePara elsevierViewall">Two candidates &#40;RSV MEDI &#916;M2&#8211;2 and RSV LID &#916;M2&#8211;2&#41; have been clinically evaluated and shown to induce an RSV neutralising antibody response&#46; Both induce a strong neutralising antibody response&#44; however&#44; the LID &#916;M2&#8211;2 has been found to be more effective&#46; Attenuated vaccines&#44; despite their efficacy and safety&#44; appear to be the main candidates for population-based vaccination programmes in the paediatric population for the time being&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0175"><span class="elsevierStyleSup">35</span></a></p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">RNA-messenger vaccines</span><p id="p0165" class="elsevierStylePara elsevierViewall">The advent of nucleic acid &#40;RNA and DNA&#41; technology used in SARS-CoV-2 vaccines raises the prospect of its future application against other respiratory viruses such as RSV&#46; mRNA vaccines provide a number of advantages over other types of vaccines&#44; such as&#58; &#40;a&#41; a very favourable safety profile &#40;RNA is a non-infectious molecule&#44; non-integratable into the cell genome and is rapidly degraded by cytoplasmic RNAases&#41;&#59; &#40;b&#41; a highly controllable antigen production process with high antigenic identity&#44; as it is produced in a manner similar to the viral replication process in natural infection by the human cell itself&#59; c&#41; rapid and scalable production&#44; requiring little time for initial processing and&#47;or subsequent re-actualisation&#59; and d&#41; does not require the use of cell cultures that could alter the antigenicity of the final protein&#46;</p><p id="p0170" class="elsevierStylePara elsevierViewall">Historically&#44; in 2013 Geall et al&#46;<a class="elsevierStyleCrossRef" href="#bb0180"><span class="elsevierStyleSup">36</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&#46; However&#44; vaccine cost-effectiveness studies showed that naked mRNA&#44; without protection against RNAsas&#44; could not be used routinely and had to be protected by a nanolipid structure&#46;</p><p id="p0175" class="elsevierStylePara elsevierViewall">Subsequently&#44; Espeseth et al&#46;<a class="elsevierStyleCrossRef" href="#bb0185"><span class="elsevierStyleSup">37</span></a> evaluated the ability to induce immune responses of an NPL-mRNA vaccine with different forms of F-protein presentation&#44; such as complete&#44; monomeric&#44; trimeric and stabilised and unstabilised pre-F&#46; The pre-F can be stabilised by a nanolipid structure&#46; Pre-F can be stabilised by introducing mutations in the disulphide bridge of the structure&#44; all of which introduce covalent bonds that prevent the structural rearrangements that determine the transition from pre-F to functional F&#46;<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0195"><span class="elsevierStyleSup">39</span></a> Each was administered at an mRNA concentration of 10&#8239;&#956;g&#44; with a booster dose at 3&#8239;weeks&#46; Studies in mice with the pre-F form showed&#44; for all protein forms&#44; 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>&#43; and CD8&#8239;&#43;&#8239;cells&#46;<a class="elsevierStyleCrossRef" href="#bb0200"><span class="elsevierStyleSup">40</span></a></p><p id="p0180" class="elsevierStylePara elsevierViewall">Aliprantis et al&#46;<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a> reported the first Phase 1 human study in young &#40;18&#8211;49&#8239;years&#44; part A&#41; and older &#40;60&#8211;79&#8239;years&#44; part B&#41; healthy adults to evaluate the safety and immunogenicity of the NPL-mRNA-177 vaccine &#40;Protocol mRNA-1777-P101&#44; V171&#41; consisting of the pre-F protein stabilised with the mutations of the DS-Cav1 molecule versus placebo&#46; In part A&#44; a study was performed at doses of 25&#44; 100 and 200&#8239;&#956;g and in part B at 25&#44; 200 and 300&#8239;&#956;g respectively&#46; The NPLs consisted of cholesterol&#44; DSPC&#44; MC3 and PEG2000-DMG&#46;</p><p id="p0185" class="elsevierStylePara elsevierViewall">The results obtained show&#44; in both young people and adults&#44; a significant increase in neutralising antibody levels against pre-F&#44; as well as a potent induction of preferentially CD4<span class="elsevierStyleHsp" style=""></span>&#43; cell-mediated immunity&#46; Due to the absence of a correlate of immunological protection in adults&#44; 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&#46; However&#44; elevated levels of neutralising antibodies to both RSV-A and RSV-B seem to indicate a real capacity for protection&#44; even in the long term&#46;<a class="elsevierStyleCrossRef" href="#bb0205"><span class="elsevierStyleSup">41</span></a></p><p id="p0190" class="elsevierStylePara elsevierViewall">The epidemiological impact of annual epidemics of RSV&#44; which affect the extremes of life&#44; determines the need to establish a prevention strategy&#46; Vaccines are one of the best tools in this field and must be part of this strategy&#46; Multiple vaccine platforms are currently being studied&#44; based on the pre-F protein&#44; although the use of long-lived monoclonal antibodies in the first year of life should be considered&#46;<a class="elsevierStyleCrossRef" href="#bb0210"><span class="elsevierStyleSup">42</span></a> In the paediatric population&#44; beyond this period&#44; attenuated vaccines are likely to play a relevant role&#44; as they expose the immune system to the whole virus particle and induce a broad-spectrum neutralising antibody response&#46; In the population over 65&#8239;years of age&#44; there is a clear need to use a subunit vaccine with an immune-stimulating adjuvant or mRNA vaccines&#46; In pregnant women&#44; a vaccination programme will probably not be implemented&#44; as monoclonal antibodies administered at birth would cover this need&#46;</p><p id="p0195" class="elsevierStylePara elsevierViewall">The future of RSV infection and disease prevention in the human population will be based on the use of monoclonal antibodies and age-appropriate vaccines&#46;</p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Funding</span><p id="p0200" class="elsevierStylePara elsevierViewall">This review article has not been funded by any public or pr&#237;vate entity&#46;</p></span></span>"
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        "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">The Respiratory Syncytial Virus &#40;RSV&#41; is the cause of acute respiratory pathologies &#40;bronchiolitis and pneumonia&#41; that occurs preferably as epidemic in the winter months&#46; RSV is a good vaccine candidate since as a virus it has shown genetic and antigenic stability&#44; most infections are self-limited and the only natural reservoir is humans&#46; According to epidemiological data&#44; there are three target populations that require different approaches for the RSV vaccine&#58; naive children &#60;<span class="elsevierStyleHsp" style=""></span>4&#8211;6&#8239;months&#44; children &#62;<span class="elsevierStyleHsp" style=""></span>6&#8239;months&#44; and&#8239;&#62;65&#8239;years&#46; Multiple vaccine platforms based on the preF protein are currently being studied&#44; although the use of long-lived monoclonal antibodies must be considered in the first year of life&#46; In the child population&#44; beyond this period&#44; attenuated vaccines probably play a relevant role&#44; since they expose the complete viral particle to the immune system and induce a broad-spectrum neutralising antibody response&#46; In the population&#8239;&#62;&#8239;65&#8239;years of age&#44; the need to use a subunit vaccine with an adjuvant that stimulates the immune response or mRNA vaccines is evident&#46; The future in the prevention of RSV infection and disease in the human population will be based on the use of monoclonal antibodies and vaccines adapted to each age group&#46;</p></span>"
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        "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0050" class="elsevierStyleSimplePara elsevierViewall">El Vvirus respiratorio sincitial &#40;VRS&#41; es el causante de patolog&#237;as respiratorias agudas &#40;bronquiolitis y neumon&#237;as&#41; que se presenta preferentemente de forma epid&#233;mica en los meses invernales&#46; El VRS es un buen candidato vacunal ya que como virus ha mostrado una estabilidad gen&#233;tica y antig&#233;nica&#44; la mayor&#237;a de las infecciones son autolimitadas y el &#250;nico reservorio natural es el ser humano&#46; De acuerdo con los datos epidemiol&#243;gicos existen tres poblaciones diana que requieren de aproximaciones diferentes para la vacuna frente al VRS&#58; los ni&#241;os naive de &#60;<span class="elsevierStyleHsp" style=""></span>4&#8211;6 meses&#44; los ni&#241;os &#62;<span class="elsevierStyleHsp" style=""></span>6 meses y los &#62;<span class="elsevierStyleHsp" style=""></span>65 a&#241;os&#46; En estos momentos se est&#225;n estudiando m&#250;ltiples plataformas vacunales&#44; basadas en la prote&#237;na preF&#44; aunque hay que considerar la utilizaci&#243;n de los anticuerpos monoclonales de vida prolongada en el primer a&#241;o de vida&#46; En la poblaci&#243;n infantil&#44; mas all&#225; de este per&#237;odo&#44; probablemente las vacunas atenuadas tengan un papel relevante&#44; ya que exponen al sistema inmune la part&#237;cula v&#237;rica completa e inducen una respuesta de anticuerpos neutralizantes de amplio espectro&#46; En la poblaci&#243;n de &#62;<span class="elsevierStyleHsp" style=""></span>65 a&#241;os&#44; es evidente la necesidad de utilizar una vacuna de subunidades con un adyuvante que estimule la respuesta inmune o las vacunas de ARNm&#46; El futuro en la prevenci&#243;n de la infecci&#243;n y enfermedad por VRS en la poblaci&#243;n humana&#44; se basar&#225; en la utilizaci&#243;n de anticuerpos monoclonales y vacunadas adaptadas a cada grupo de edad&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="np4005">Please cite this article as&#58; Reina J&#44; de Herrero EG&#46; Situaci&#243;n actual y perspectivas de futuro de las vacunas frente al virus respiratorio sincitial&#46; Vacunas&#46; 2022&#46; <span class="elsevierStyleInterRef" id="ir3005" href="https://doi.org/10.1016/j.vacun.2022.12.005">https&#58;&#47;&#47;doi&#46;org&#47;10&#46;1016&#47;j&#46;vacun&#46;2022&#46;12&#46;005</span></p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Company&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV F</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">Novavax&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">Particulates&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SynGEM</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Particulates&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Ad26&#46;RSV&#46;preF</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">Janssen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral vector&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">ChAd155-RSV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">GSK&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">Viral vector&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MEDI-534</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Astra-Zeneca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral vector&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SeVRSV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral vector&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV MEDI &#916;M2&#8211;2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV LID &#916;M2&#8211;2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV cps2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV LID cp &#916;M2&#8211;2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV LID &#916;M2&#8211;21030s</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV D46&#47;NS2&#47;N&#916;M2&#8211;2-HindIII</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV &#916;NS2 &#916;1313 I1314L</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV 6120&#47;F1&#47;G2&#47;&#916;NS1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV 6120&#47;&#916;NS2&#47;1030</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV 276</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV D46 cp&#916;M2&#8211;2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MEDI-559</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Astra-Zeneca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MV-012-968</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Meissa Vaccines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Attenuated virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">rBCG-N-hRSV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">University of Chile&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chimera&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab3167211.png"
              ]
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          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Main vaccines under development against respiratory syncytial virus in the paediatric population&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "t0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "al0020"
            "detalle" => "Table "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Adapted from Biagi et al&#46;<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Company&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ResVax</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Novavax&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Particulates&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">VRC-RSVRGP084&#8211;00-VP</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NIAID&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subunits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV-F vaccine</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pfizer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subunits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">GSK3888550A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GSK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subunits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              ]
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        "descripcion" => array:1 [
          "en" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Main vaccines under development against respiratory syncytial virus in the pregnant population&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "t0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "al0025"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">Adapted from Biagi et al&#46;<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a></p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Company&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV F</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Novavax&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Particulates&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">SynGEM</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mucosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Particulates&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">RSV vaccine</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pfizer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subunits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">GSK3844766A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GSK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subunits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">DPX-RSV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dalhousie University&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subunits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BARS13</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vaccine Laborat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subunits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MVA-BN RSV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bavarian Nordic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral vector&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">VXA-RSVf oral</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vaxart&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral vector&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Ad26&#46;RSV&#46;preF</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Janssen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral vector&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">PanAd3-RSV y MVA-RSV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ReiThera&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral vector&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">Major respiratory syncytial virus vaccines in development in the adult population&#46;</p>"
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        0 => array:2 [
          "identificador" => "bs0005"
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            0 => array:3 [
              "identificador" => "bb0005"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent &#40;CCA&#41;&#46; I&#46; Isolation properties and characterization"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Chanock"
                            1 => "B&#46; Roizman"
                            2 => "R&#46; Myers"
                          ]
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                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1093/oxfordjournals.aje.a119901"
                      "Revista" => array:6 [
                        "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"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent &#40;CCA&#41;&#46; II&#46; Epidemiologic aspects of infection in infants and young children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46; Chanock"
                            1 => "L&#46; Finberg"
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                    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"
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                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&#46; Beugeling"
                            1 => "J&#46; De Zee"
                            2 => "H&#46;J&#46; Woerdenbarg"
                            3 => "H&#46;W&#46; Frijlink"
                            4 => "J&#46;C&#46; Wilschut"
                            5 => "W&#46;L&#46; Hinrichs"
                          ]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/14760584.2019.1657013"
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                        "tituloSerie" => "Expert Rev Vaccines"
                        "fecha" => "2019"
                        "volumen" => "18"
                        "paginaInicial" => "935"
                        "paginaFinal" => "950"
                        "link" => array:1 [
                          0 => array:2 [
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Global&#44; regional and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in Young children in 2015&#58; a systematic review and modelling study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Shi"
                            1 => "D&#46;A&#46; McAllister"
                            2 => "K&#46;L&#46; O&#180;Brien"
                            3 => "E&#46;A&#46; Simoes"
                            4 => "A&#46; Shabir"
                            5 => "T&#46; Shi"
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                      "doi" => "10.1016/S0140-6736(17)30938"
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                      "titulo" => "Respiratory syncytial virus infection in elderly and high-risk asults"
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                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46;R&#46; Falsey"
                            1 => "P&#46;A&#46; Hennessey"
                            2 => "M&#46;A&#46; Formica"
                            3 => "C&#46; Cox"
                            4 => "E&#46;E&#46; Walsh"
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                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa043951"
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                        "tituloSerie" => "N Engl J Med"
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                      "titulo" => "Current state and challenges in developing respiratory syncytial virus vaccines"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Biagi"
                            1 => "A&#46; Dondi"
                            2 => "S&#46; Scarpini"
                            3 => "A&#46; Rocca"
                            4 => "S&#46; Vandini"
                            5 => "G&#46; Poletti"
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                    0 => array:2 [
                      "doi" => "10.3390/vaccines8040672"
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                          "etal" => false
                          "autores" => array:1 [
                            0 => "B&#46;S&#46; Graham"
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                      "doi" => "10.1016/j.coviro.2017.03.012"
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                        "tituloSerie" => "Curr Opin Virol"
                        "fecha" => "2017"
                        "volumen" => "23"
                        "paginaInicial" => "107"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28525878"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The respiratory syncytial virus vaccine lanscape&#58; lessons from the graveyard and promising candidates"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46;I&#46; Mazur"
                            1 => "D&#46; Higgins"
                            2 => "M&#46;C&#46; Nunes"
                            3 => "J&#46;A&#46; Melero"
                            4 => "A&#46;C&#46; Langedijk"
                            5 => "N&#46; Horsley"
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                      "doi" => "10.1016/S1473-3099(18)30292-5"
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                        "tituloSerie" => "Lancet Infect Dis"
                        "fecha" => "2018"
                        "volumen" => "18"
                        "numero" => "10"
                        "paginaInicial" => "e295"
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                      "titulo" => "Paramyxociridae&#58; the viruses and their replication"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46;K&#46; Plemper"
                            1 => "R&#46;A&#46; Lamb"
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Article information

ISSN: 24451460
Original language: English

DOI:10.1016/j.vacune.2023.03.002

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