Mucosal anti-infections vaccines: Beyond conventional vaccines

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Reprogramación epigenética en células de la inmunidad innata al estimular la inmunidad entrenada. 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"Review Article" "titulo" => "Mucosal anti-infections vaccines: Beyond conventional vaccines" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "49" "paginaFinal" => "55" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Silvia Sánchez Ramón, Mario Manzanares, Gloria Candelas" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Silvia" "apellidos" => "Sánchez Ramón" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Mario" "apellidos" => "Manzanares" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:4 [ "nombre" => "Gloria" "apellidos" => "Candelas" "email" => array:1 [ 0 => "gloria.candelas@salud.madrid.org" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Inmunología, Hospital Clínico San Carlos, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Reumatología, Hospital Clínico San Carlos, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Vacunas antiinfecciosas de mucosas en la profilaxis de infecciones recurrentes: más allá de las vacunas convencionales" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1159 "Ancho" => 2167 "Tamanyo" => 175683 ] ] "descripcion" => array:1 [ "en" => "Trained immunity. Epigenetic reprogramming in innate immunity cells on stimulating the trained immunity. Once pathogen 1 had been recognised by a receptor, the monocytes experienced an epigenetic reprogramming (mainly through mutilations in the DNA) and metabolic changes, so that they were prepared to respond more robustly to a secondary non specific stimulation (pathogens 1, 2 and 3)." ] ] ] "textoCompleto" => "The post-antibiotic era and the current challenge in the prevention of recurrent infections in autoimmune diseasesAccording to the World Health Organisation, resistance to antibiotics is the main focus of attention in public health and the search for alternatives in prophylaxis to recurrent infections is urgent.<a class="elsevierStyleCrossRefs" href="#bib0265">1–3</a> Antibiotics are the keystone therapy for infectious diseases, they are effective against most bacterial, fungal and parasitic pathogens, but there is a growing problem of multi-resistance, and only a small number of drugs are effective against virus. One example is that despite the major reduction in respiratory and invasive diseases from Streptococcus pneumoniae (pneumococcal disease), due to the extended use of antibiotics and the introduction of new conjugated parenteral vaccines it is still a significant cause of morbimortality in humans.<a class="elsevierStyleCrossRefs" href="#bib0280">4,5</a> In this context of what has been called “the post-antibiotic era” there is a clear need for new alternative treatments for infectious diseases. Antibiotics will remain the main means of combating the pathogenic microorganisms, but alterative drugs to replace them or be used as adjuvant therapy to antibiotics may be efficacious in preventing these infections.Under natural conditions, most bacteria do not live as individual cells, but as pseudomulticellular organisms which carry out commonly coordinated behaviour patterns through intercellular molecular signals in a process known as “Quorum sensing” (QS). This increases the capacity of the bacteria to adapt through absorption and incorporation, using the recombination of new genetic material of the bacterial community surrounding it.<a class="elsevierStyleCrossRef" href="#bib0290">6</a> This multicellular coordination of bacterial attacks maximises the opportunities for establishing infection and allowing the bacteria to spread.<a class="elsevierStyleCrossRef" href="#bib0295">7</a> Approximately 65% of the agents which cause human infections form biofilms which support chronic infections.<a class="elsevierStyleCrossRef" href="#bib0295">7</a> The main benefit for the bacteria in forming these biofilms is that they are physically protected and possess between 10 and 1000 times more resistance than a single bacteria.<a class="elsevierStyleCrossRef" href="#bib0295">7</a> Today biofilms present a major challenge to antibiotic efficacy.One particular case is patients with recurrent bacterial infections who require almost continuous treatment with antibiotics, leading to an increased risk of antibiotic resistance. Furthermore, these patients frequently present with secondary dysbiosis due to repeated doses of antibiotics,<a class="elsevierStyleCrossRef" href="#bib0300">8</a> which in turn may lead to a fungal superinfection. It is particularly in the context of recurrent infections that mucosal polybacterial vaccines could be a good alternative to wide-ranging antibiotics used for preventative ends. These vaccines are used as immunomodulators to prevent infections in immunocompetent patients, but their use in immunocompromised patients is increasingly greater.Infection is one of the main causes of mobimortality in patients with systemic autoimmune diseases (SAD). Predisposition to infection in patients with SAD is associated with an anomalous response of the innate and underlying adaptive immune system to the actual disease and secondary to immunomodulators and immunosuppressants. Glucocorticoids may reduce the response of innate and adaptive immunity, inducing susceptibility to bacterial infections by streptococci, Staphylococcus aureus, gram negative bacilli, and diseases caused by fungi such as Candida and Aspergillus spp. Other immunosuppressant treatments may damage adaptive immunity inducing infections caused by virus (especially the herpes virus, such as herpes zoster, cytomegalovirus or Ebstein-Baar vurs), bacteria (Legionella spp., Listeria monocytogenes and Salmonella tiphy), Mycobacterium tuberculosis and fungi (Candida, Aspergillus, Histoplasma capsulatum and Cryptococcus) and Pneumocystis jirovecii. Moreover, B cell compromise with reduction in the production of immunoglobulins is associated with recurrent infections by encapsulated germs (Streptococcus pneumoniae, Haemophilus influenzae, meningococcus).In the Spanish registry of adverse events of biological therapies (BIOBADASER) a higher rate of infections has been found in patients with rheumatoid arthritis (RA) who receive anti-TNF<a class="elsevierStyleCrossRef" href="#bib0305">9</a>; similar data are continuing to be confirmed in different reports, where the frequency of the infections and infestations amount to 23.9% of all adverse events recorded in patients with biologic therapy.There are several possible explanations for a higher risk of infection in patients with RA. Recent evidence suggest that patients with RA have immunological changes which involve the majority of T cells circulating from an early stage during the course of the disease.<a class="elsevierStyleCrossRef" href="#bib0310">10</a> As a result, the capacity of the immune system to respond to new antigenic stimuli may be compromised. Alternatively, therapy with glucocorticoids and other immunosuppressants may also predispose patients with RA to the development of sepsis.<a class="elsevierStyleCrossRefs" href="#bib0315">11,12</a> Other factors which may play a part in the risk of infection in patients with RA are factors relating to the disease (immobility, joint surgery), extra-articular RA manifestations (Felty syndrome, rheumatoid pulmonary disease) and comorbidities (diabetes mellitus).The infections are usually located in the upper and lower respiratory tract, the skin and the genital and urinary tract. They are normally due to the Staphylococcus aureus and to gram negative bacteria. Equally, a higher frequency of herpes zoster has been reported and cases of opportunistic infections as well, such as listeriosis, widespread aspergilosis and other infrequent infections found in Spain, such as histoplasmosis and coccidioidomycosis, although rates were low. A higher rate of infections was also described with the other biologic agents.As a result of the above, adjuvant or alternative therapeutic strategies to antibiotics are increasingly urgent, such as the immunisation of these patients with vaccines to prevent primary and recurrent infections, to reduce the repeated use of antibiotics, along with the appearance of resistance and of severe infectious diseases. In doing so, hospitalisations from these events will consequently drop.This review covers the most up-to-date information on the mechanisms of action of mucosal polybacterial immunomodulators, also known as mucosal anti-infective vaccines.At the threshold: mucosal immunity, a new paradigm of trained immunityMucus membranes make up a very large surface area of our body, approximately 200 times greater than the area covered by the skin.<a class="elsevierStyleCrossRef" href="#bib0325">13</a> The mucous membranes are the main entry route for infectious and environmental agents. As a result mucosal infections are one of the main causes of morbimortality in the world, with infants and the elderly being the most susceptible to them and no effective vaccines available in most cases. The mucosa-associated lymphoid tissue (MALT) encompasses a complex network of highly specialised and compartimentalised components of innate and adaptive immunity.<a class="elsevierStyleCrossRefs" href="#bib0325">13,14</a> It includes a nasopharangeal-associated lymphoid tissue (NALT), bronchial-associated lymphoid tissue (BALT), mucosa gastrointestinal-associated lymphoid tissue (GALT), urinary genital tract and a exocrine gland tissues.<a class="elsevierStyleCrossRefs" href="#bib0335">15,16</a> The dendritic cells (DC) are activated on recognizing common structures in the pathogenic microorganisms highly preserved throughout the evolution by pattern recognition receptors (PRR) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). DC antigen uptake may be carried out directly and indirectly.<a class="elsevierStyleCrossRef" href="#bib0345">17</a> Indirect route is, for example, through uptake by M cells Microfold), by calciform cells, by neonatal Fc receptors (FcRn) and through apoptosis.<a class="elsevierStyleCrossRef" href="#bib0345">17</a> M cells are specialised cells which capture antigens and enteric bacteria through the epithelial surface for uptake and processing by the DD and macrophages, which will initiate the effector immune response.<a class="elsevierStyleCrossRef" href="#bib0350">18</a> The DC may also directly capture antigens from the lumen by extending their dendrites.<a class="elsevierStyleCrossRef" href="#bib0350">18</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Trained immunityClinical and epidemiological evidence extracted from studies with standard vaccines highlighted a reduction of infant mortality in individuals vaccinated against measles and tuberculosis during their first year of life due to infection, compared with those who were not vaccinated.<a class="elsevierStyleCrossRef" href="#bib0355">19</a> These results cannot be explained by a specific protection to these diseases, but due to a wide spectrum of protection, more in keeping with innate immunity, in what is called trained immunity.<a class="elsevierStyleCrossRefs" href="#bib0360">20,21</a> Trained immunity refers to the fact there are cells—for example monocyte/macrophage or natural killer (NK) cells, among others—capable of generating an intensified response to a second infection by the same micro organism and by a different (crossover protection) separate from the adaptive response (lymphocyte T and B), although it also increases the adaptive response.<a class="elsevierStyleCrossRefs" href="#bib0370">22–26</a> Studies from 50 years ago had already reported that infections confer antibacterial properties acquired through specific pathogenic bacteria and also others which are non-related.<a class="elsevierStyleCrossRef" href="#bib0370">22</a> The mechanisms which measure this trained immunity include epigenetic and transcriptional reprogramming of cells of the innate immunity, including modifications in the histones and the DNA which may support the transcription of proinflammatory cytokines,<a class="elsevierStyleCrossRef" href="#bib0375">23</a> a contribution of microRNAs, together with metabolic changes (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0395">27</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Application of trained immunity as mucosal anti-infective vaccinesMucosal anti-infective vaccines are complete inactive combinations of bacteria or fungi or bacterial lysates which stimulate the immune system through PRRs common to several germs, which according to many studies reduce the number of re-infections by the same pathogens and by other pathogens than the contents in the vaccines (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The underlying mechanisms to this collateral benefit may mostly be due to the “trained immunity” rather than any specific one, which it has also been seen contributes to the protector effect.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Unlike conventional vaccines administered parenterally, mucosal vaccines act directly on specific tissues where the pathogens start or spread infections. An immunological equilibrium exists on mucosal surfaces maintained by comensal flora. The induction of innate responses could lead to CD activation, macrophages, epithelial cells and NK cells, whilst stimulation from adaptive immunity would lead to the production of specific antibodies and B and T memory cells. Appropriately formulated mucosal vaccines stimulate the two components of the immune system, making them promising tools for therapeutic prevention and prophylaxis of infections.<a class="elsevierStyleCrossRefs" href="#bib0400">28–30</a> Anti-body responses in mucous membranes, principally secretory IgA, stimulated by these vaccines, inhibit a critical step in the microbial infectious pathogenesis, the adhesion of the micro organism to the epithelial cells of the mucous membrane, conferring better protection against colonisation and invasion than parenteral vaccines.<a class="elsevierStyleCrossRef" href="#bib0415">31</a> The mucous membrane IgG mark the opsonization and internalisation of pathogens which have crossed over the epithelial barrier through phagocytosis. This leads to activation of the phagocytes and elimination of the pathogens or the presentation of antigens derived from them, encouraging the differentiation of multiple subtypes of T effector lymphocytes, such as lymphocytes Th17, lymphocytes Tγδ and lymphocytes T CD8+cytotoxics (CTL), for the destruction of the pathogen.<a class="elsevierStyleCrossRef" href="#bib0420">32</a> The tissue-resident memory T cells (TRM) may respond quickly to a pathogen-local re-infection, regardless of T lymphocyte recruitment from the blood. When the TRM CD8+ are activated they release IFN-γ, which amplifies and complements the innate immune response activation creating an antiviral microenvironment in the mucous membrane. The induction of TRM lymphocytes is currently a challenge for vaccination strategies, and mucosal vaccines may be an effective route for persistently generating TRM lymphocytes.<a class="elsevierStyleCrossRef" href="#bib0425">33</a>Administration through mucous membranes induces tolerance, which is an added benefit in SAD treatment. Sublingual vaccines for allergenic immunotherapy have been used for one hundred years and recent studies suggest that sublingual immunotherapy may improve induction of systemic tolerance. In accordance with the current model of underlying immune mechanisms, the allergen is captured by the tolerogenic plasmacytoid CD of the tonsils which later emigrate to the cervical lymphatic nodules and induce a response of the Treg lymphocytes.<a class="elsevierStyleCrossRef" href="#bib0430">34</a> Biopsies of oral epithelium have shown that there is a larger amount of Treg cells in patients treated with sublingual immunotherapy than in patients treated with placebo.<a class="elsevierStyleCrossRef" href="#bib0435">35</a> This model in allergy would be transferable to that which occurs in patients with SAD, although specific studies are required to prove this.Anti-infective vaccines in autoimmune diseasesAutoimmune diseases are a key objective for the development of these drugs.<a class="elsevierStyleCrossRef" href="#bib0440">36</a> The induction of secretion of specific sIgA has many regulatory mechanisms which may also promote a low T lymphocyte mucosal and systemic response capacity, through a modulating effect of the differentiation of Treg lymphocytes.<a class="elsevierStyleCrossRef" href="#bib0445">37</a>Experimental modelsIntranasal and sublingual mucosal administration of antigens may induce deep suppression of cellular immunity, as has been shown by the reduction of delayed hypersensitivity reactions, low levels of T cell proliferation and high levels of immunosuppressant cytokine secretion.<a class="elsevierStyleCrossRefs" href="#bib0430">34,38,39</a> A recent study demonstrated that the oral vaccine with an attenuated vaccine of Salmonella would induce specific Treg cells to the antigen I of the colonisation factor (CFA/I) of the fimbrias, whilst simultaneously protecting against experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis.<a class="elsevierStyleCrossRef" href="#bib0460">40</a> In this study, oral vaccination compared with an irrelevant antigen would induce Treg cells which could control autoimmunity and a concomitant anti-infectious effect. Another study in EAE has proven this dual effect against a respiratory tract bacterial infection through the production of the anti-inflammatory cytokine IL-10 which would eliminate the migration of auto-reactive T cells from the central nervous system.<a class="elsevierStyleCrossRef" href="#bib0465">41</a> Similar studies in the experimental model of arthritis induced by collagen in DBA/1 mice suggest that the induction of a bystander immunity against the bacteria could potentially control autoimmune or inflammatory processes.<a class="elsevierStyleCrossRefs" href="#bib0440">36,38</a> This immunomodulating effect of some bacteria could be exploited to improve a new concept of bacterial mucosal vaccines as a therapeutic innovation to boost immunological tolerance (cross-over tolerance) and homeostasis within the context of autoimmune diseases.Clinical trialsOne prospective observational clinical trial evaluated the clinical and immunological effects of treatment with sublingual vaccines of bacterial combinations in antigen specific responses to bacteria which were responsible for respiratory tract infections.<a class="elsevierStyleCrossRef" href="#bib0470">42</a> Daily immunisation with a polyvalent bacterial sublingual preparation for a period of 6 months was studied in a cohort of 17 patients with recurrent respiratory infections (RRI). The number of respiratory infections in immunised patients significantly dropped compared with the previous year. There was also a clear reduction in the severity and duration of the infectious respiratory events. The immunological results demonstrated a considerable increase in the prolipherative frequency and capacity of specific T CD4+ lymphocytes in blood compared with bacterial antigen contents in the vaccine, after 6 months of treatment. Furthermore, an increase in the prolipherative capacity of the specific T CD4+ and CD8+ lymphoctyes of influenza virus antigens after 6 months of treatment was observed (not contained in the vaccine), which may suggest that the bacterial preparation had stimulated the T lymphocytes non specifically in vivo to the influenza virus, which led to a more powerful response. The case of one of the patients described in this study is interesting. The patient had suffered 12 episodes of oral herpes the previous year and only reported 3 episodes after immunisation with the bacterial preparation, suggesting a non specific in vivo effect which enhanced the antiviral response (trained immunity). In another prospective observational study with 669 women with recurrent urinary tract infections (RUTI) efficacy was compared between a prophylactic treatment with antibiotics (Septrin) and the bacterial sublingual preparation, where 100% of patients experienced a new infection the following year versus less than 10% in the group treated with the bacterial preparation. An interesting finding in this study was that the patients who had previously had infections with bacteria which were not included in the vaccine did not develop reinfections, suggesting that a horizontal or cross protection could be attributed to a strengthening of the innate trained immunity.<a class="elsevierStyleCrossRefs" href="#bib0475">43–45</a>In one prospective observational study performed by our group 50 patients with inflammatory diseases (RA [43.18%], systemic erythematous lupus [22.72%] and mixed connective tissue disease [6.81%]) under treatment with DMARD biologics and/or non biologics and glucocorticoids mostly at low doses, who presented with recurrent urinary and/or respiratory infections, were treated with two different polybacterial sublingual preparations depending on the type of infection (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The vaccines were administered in cycles of 3 months per year and the clinical response was recorded after 6 months and after 1 year. Paired comparison of the number of infectious events in both groups demonstrated a considerable reduction in the rate of repetitive urinary tract infections (RUTI) of 5.57±8.41 compared with 1.0±1.28 (P<.05) and in the rate of repeated respiratory tract infections (RRTI) of 4.1±1.98 compared with .95±1.52 (P<.05) in the previous year to the year after the vaccine, as well as a considerable reduction in the use of antibiotics 6 months after the vaccine (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Six of the 38 patients treated with the vaccine for RUTI who presented simultaneously with respiratory infections improved significantly not just from their urinary infection but also from the respiratory infection, suggesting an innate cross-over protection.<a class="elsevierStyleCrossRefs" href="#bib0490">46,47</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Advantages and drawbacks of mucosal vaccinesTherapeutic interventions with mucosal anti-infective vaccines have different advantages to standard parenteral vaccines: (a) their effects are directly felt in the infection site of the mucous membrane and they may prevent infection and colonisation by pathogens; (b) immunisation in mucous membranes may lead to the secretion of antibodies in other more distant mucous membranes and also systemically<a class="elsevierStyleCrossRef" href="#bib0310">10</a>; (c) administration does not require medical professionals and they may be used in mass vaccines and disease prevention campaigns, (d) they are painless and simple to administer. Also, bearing in mind that gram positive bacteria stimulate the production of IL-12 and that gram negative bacteria stimulate the production of IL-10 by monocytes, the combination of gram positive and gram negative bacteria in anti-infective vaccines of mucous membranes appears to carry a synergic immunological response which could be greater depending on the pathology involved.<a class="elsevierStyleCrossRef" href="#bib0500">48</a> Differences in the induction of immunity response were observed depending on the administration route, with sublingual being the most advantageous (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Lastly, there was a huge potential for development taking advantage of these trained immunity characteristics, which would be exploitable and improbable through tools such as reverse vaccinology for the development of adjuvants to standard vaccines. Notwithstanding, -unlike parenteral vaccines, these vaccines require repetitive stimulus and the duration of active treatment may be long and requires patient adherence to it.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>To sum up, therapeutic intervention with polybacterial preparations of mucosal administration with inactivated complete bacteria or with bacterial lysates stimulate the innate and adaptive immunity which is present in the mucous membranes<a class="elsevierStyleCrossRef" href="#bib0505">49</a> and offers greater clinical benefits, with its effect being attributed to the following mechanisms: (a) complete bacteria are presented to the immune system in the most natural way, maximising their entire potential as immunogens,<a class="elsevierStyleCrossRefs" href="#bib0485">45,50,51</a> and (b) the complete bacteria stimulate different immune mechanisms, which have been confirmed as highly important for a complete cellular activation, such as phagocytosis.<a class="elsevierStyleCrossRef" href="#bib0520">52</a> A change of design in the outcome of these vaccines is required, based on a clinical benefit effect rather than on the specific antigen itself.Immunodeficiencies secondary to immunosuppressant therapy (organ transplant, rheumatological disorders, oncology, and organ specific autoimmune diseases), chronic metabolic diseases (diabetes) or chronic infections (HIV) are situations which also lead to recurrent infections. The use of polybacterial vaccines in actively immunosuppressed patients for preserving a transplanted organ, or for keeping an autoimmune disease under control is a genuine clinical challenge due to the high risk of infections and the subsequent impact on morbimortality.ConclusionsTreatment with polybacterial drugs or mucosal anti-infective vaccines which enhance the innate trained immunity as the main objective in the prevention of recurrent infections is an innovative therapeutic strategy with promising results. New prospective studies and randomised clinical trials are required to assess their efficacy and optimise current preparations. Also, since the purpose of these drugs is a broad spectrum protection, the primary objectives of efficacy must be designed in keeping with clinical response.FinancingThis research study did not receive any specific finance from public sector agencies, the trade sector or any non profit-making entities.Conflict of interestsThe authors have no conflict of interests to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1308066" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1207720" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1308065" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1207721" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "The post-antibiotic era and the current challenge in the prevention of recurrent infections in autoimmune diseases" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "At the threshold: mucosal immunity, a new paradigm of trained immunity" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Trained immunity" ] ] ] 6 => array:2 [ "identificador" => "sec0020" "titulo" => "Application of trained immunity as mucosal anti-infective vaccines" ] 7 => array:3 [ "identificador" => "sec0025" "titulo" => "Anti-infective vaccines in autoimmune diseases" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Experimental models" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Clinical trials" ] ] ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Advantages and drawbacks of mucosal vaccines" ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0050" "titulo" => "Financing" ] 11 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of interests" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-05-18" "fechaAceptado" => "2018-10-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1207720" "palabras" => array:3 [ 0 => "Mucosal vaccines" 1 => "Recurrent infections" 2 => "Trained immunity" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1207721" "palabras" => array:3 [ 0 => "Vacunas de mucosas" 1 => "Infecciones de repetición" 2 => "Inmunidad entrenada" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "An urgent search is currently underway for alternatives to antibiotics to prevent infections, due to the accelerated evolution and increase in antibiotic resistance. This problem is more serious for patients with recurrent infections, since they have to use many cycles of antibiotics per year, so the risk for antibiotic resistance is higher and can be life-threatening. In recent years, the use of prophylactic vaccines via the mucosal route for these patients with recurrent infections has been demonstrated as a potentially beneficial and safe alternative to prevent infections. The new knowledge about mucosal immunity and trained immunity, a form of innate immunity memory that can enhance the response to different infectious threads, has made it easier to extend its use. The application of the new concepts of trained immunity may explain the simultaneous pro-tolerogenic and boosting effect or effects of these drugs on diverse immune cells for different infections. In this review, we describe the immunomodulatory mechanisms of mucosal polybacterial vaccines and their connection with trained immunity and its utility in the prevention of recurrent infections in immunosuppressed patients." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Existe una búsqueda urgente de alternativas a los antibióticos para prevenir infecciones, debido al aumento acelerado de la resistencia a los antibióticos. Esto es más grave para los pacientes con infecciones recurrentes que tienen que ser tratados con varios ciclos de antibióticos al año, lo que incrementa el riesgo de resistencia a los antibióticos, que puede ser potencialmente mortal. En los últimos años se ha demostrado que el uso de vacunas profilácticas por vía mucosa para estos pacientes es una alternativa potencialmente beneficiosa y segura para prevenir infecciones. El nuevo conocimiento sobre la inmunidad de las mucosas y la inmunidad entrenada, una forma de memoria de la inmunidad innata que puede mejorar la respuesta a diferentes amenazas por infecciones, ha hecho más fácil expandir su utilización. La aplicación clínica de la inmunidad entrenada de estos fármacos podría explicar sus efectos simultáneos pro-tolerogénicos y potenciadores en diversas células inmunitarias para diferentes infecciones. En esta revisión describimos los mecanismos inmunomoduladores de las vacunas polibacterianas de la mucosa, su conexión con la inmunidad entrenada y su utilidad en la prevención de infecciones recurrentes en pacientes inmunocomprometidos." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Sánchez Ramón S, Manzanares M, Candelas G. Vacunas antiinfecciosas de mucosas en la profilaxis de infecciones recurrentes: más allá de las vacunas convencionales. Reumatol Clin. 2020;16:49–55." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1153 "Ancho" => 2169 "Tamanyo" => 169923 ] ] "descripcion" => array:1 [ "en" => "As they are stimulated with an antigen, the dentritic cells induce different responses in the mucosal tissues. One of the most important responses is the differentiation of T lymphocytes into different subtypes, which in turn depends on what type of dentritic cells stimulates this differentiation. The figure includes the previously mentioned DC subtypes which induce differentiation of T lymphocytes in the mucous membranes (such as DC CX3CR1+, CD103+ and CD103+ CD11b+) and those which induce a stimulation of T lymphocytes so that they produce cytokines (an action carried out by the DC CCR2+ CD103− which leads to the production of IL17 by T lymphocytes)." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1159 "Ancho" => 2167 "Tamanyo" => 175683 ] ] "descripcion" => array:1 [ "en" => "Trained immunity. Epigenetic reprogramming in innate immunity cells on stimulating the trained immunity. Once pathogen 1 had been recognised by a receptor, the monocytes experienced an epigenetic reprogramming (mainly through mutilations in the DNA) and metabolic changes, so that they were prepared to respond more robustly to a secondary non specific stimulation (pathogens 1, 2 and 3)." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 565 "Ancho" => 1460 "Tamanyo" => 33976 ] ] "descripcion" => array:1 [ "en" => "Infectious events (mean) the year prior to the vaccine and at one year follow-up." ] ] 3 => array:9 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Sources: Benn et al.,<a class="elsevierStyleCrossRef" href="#bib0355">19</a> Jensen et al.<a class="elsevierStyleCrossRef" href="#bib0360">20</a> and Netea et al.<a class="elsevierStyleCrossRef" href="#bib0365">21</a>" "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PAMP \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Microorganism \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PRR \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lipoproteins \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Endobacteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR1, TLR22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peptidoglycans \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Parasites \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Zimosan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fungi \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lipoarabinomannan \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"> \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Porins \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"> \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GPI-mucins \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"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dectin 1/2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phospholipomannans Lipopeptideostriacil β-glycans \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"> \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lipopeptidosdiacil \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"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR2/TLR1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lipoteicoic acid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Micoplasma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR2/TLR6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diaminopimelic acid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gram negative bacteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NOD1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Muropeptides \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gram positive and gram negative bacteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NOD2, NALP1 Y NALP3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Envelope glycoproteins \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Virus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Glycoinositol phosophylipids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Protozoans \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mannans \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Candida \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HSP70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Host \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lipopolysaccharides</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gram negative bacteria \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 " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR4, DC-SIGN, CD14, CR3 and CR4</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gram positive and gram negative bacteria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CpG ODN without mehylation (ssDNA)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Great majority of bacteria \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 " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR9, DHX9, DHX36</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fungi, protozoans \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">dsDNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Virus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DA1, IFI16, STING, AIM2, DDX4, MRE11, cGAS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Flagelline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mobile bacteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">dsDNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Virus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR3, helicase RIG-1, MDA5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ssDNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Virus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR7, TLR8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23rRNA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bacteria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carbohydrates</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Virus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type C lectins, mannose receptors</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fungi \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Micobacteria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Profilin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Protozoans \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR11 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2241438.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Innate repertoire of pattern recognition receptors (PRR) which combine with pathogen associated molecular patterns (PAMP) and damage associated molecular patterns (DAMP)." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VSP for IRTR \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VSP for RUTI \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Staphylococcus spp. 30% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">K. pneumoniae 25% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S. pneumoniae 60% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">E. coli 25% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">K. pneumoniae 4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">E. faecalis 25% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">M. catarrhalis 3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P. vulgaris 25% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">H. influenzae 3% \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2241440.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Composition of polybacterial vaccines." ] ] 5 => array:9 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: adapted from Alecsandru et al.<a class="elsevierStyleCrossRef" href="#bib0470">42</a>" "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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"> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sublingual route \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Nasal route \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Oral route \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Upper respiratory tract \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lower respiratory tract \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ a +++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stomach \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+/+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+/+++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intestine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colon \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rectum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Genital tract \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blood \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+++ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2241439.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Comparison of anatomical dissemination of sIgA depending on the immunisation routes." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:52 [ 0 => array:3 [ "identificador" => "bib0265" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Organization WH. Worlwide country situation analysis: response to antimicrobial resistance. Available from: <a target="_blank" href="http://www.who.int/drugresistance/documents/situationanalysis/en/2015/2015">http://www.who.int/drugresistance/documents/situationanalysis/en/2015/2015</a> [accessed March 2016]." ] ] ] 1 => array:3 [ "identificador" => "bib0270" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Organization WH. Antimicrobial resistance: global report on surveillance 2014. Available from: <a target="_blank" href="http://www.who.int/drugresistance/documents/surveillancereport/en/2014">http://www.who.int/drugresistance/documents/surveillancereport/en/2014</a> [accessed March 2016]." ] ] ] 2 => array:3 [ "identificador" => "bib0275" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Fórum WE. Global risks 2015. Available from: <a target="_blank" href="http://reports.weforum.org/global-risks-2015/2015">http://reports.weforum.org/global-risks-2015/2015</a> [accessed March 2016]." ] ] ] 3 => array:3 [ "identificador" => "bib0280" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The impact of pneumococcal conjugate vaccines on carriage of and disease caused by Streptococcus pneumoniae serotypes 6C and 6D in southern Israel" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "N. Porat" 1 => "R. Benisty" 2 => "N. Givon-Lavi" 3 => "R. Trefler" 4 => "R. Dagan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.vaccine.2016.04.043" "Revista" => array:6 [ "tituloSerie" => "Vaccine" "fecha" => "2016" "volumen" => "34" "paginaInicial" => "2806" "paginaFinal" => "2812" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27113163" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0285" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A review of pneumococcal vaccines: current polysaccharide vaccine recommendations and future protein antigens" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C.C. Daniels" 1 => "P.D. Rogers" 2 => "C.M. Shelton" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5863/1551-6776-21.1.27" "Revista" => array:6 [ "tituloSerie" => "J Pediatr Pharmacol Ther" "fecha" => "2016" "volumen" => "21" "paginaInicial" => "27" "paginaFinal" => "35" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26997927" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0290" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Coordinated bacteriocin expression and competence in Streptococcus pneumoniae contributes to genetic adaptation through neighbor predation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "W.Y. Wholey" 1 => "T.J. Kochan" 2 => "D.N. Storck" 3 => "S. Dawid" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.ppat.1005413" "Revista" => array:5 [ "tituloSerie" => "PLoS Pathog" "fecha" => "2016" "volumen" => "12" "paginaInicial" => "e1005413" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26840124" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0295" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recent advances in novel antibacterial development" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A.J. Martín-Rodríguez" 1 => "H. Quezada" 2 => "G. Becerril" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Front Clin Drug Res Anti-Infect" "fecha" => "2016" "volumen" => "2" "paginaInicial" => "59" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0300" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vaccination strategies to promote mucosal antibody responses" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K. Chen" 1 => "A. 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Mucosal anti-infections vaccines: Beyond conventional vaccines

Vacunas antiinfecciosas de mucosas en la profilaxis de infecciones recurrentes: más allá de las vacunas convencionales

Silvia Sánchez Ramóna, Mario Manzanaresa, Gloria Candelasb,

Corresponding author

gloria.candelas@salud.madrid.org

Corresponding author.

a Servicio de Inmunología, Hospital Clínico San Carlos, Madrid, Spain

b Servicio de Reumatología, Hospital Clínico San Carlos, Madrid, Spain

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due to the extended use of antibiotics and the introduction of new conjugated parenteral vaccines it is still a significant cause of morbimortality in humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">4&#44;5</span></a> In this context of what has been called &#8220;the post-antibiotic era&#8221; there is a clear need for new alternative treatments for infectious diseases&#46; Antibiotics will remain the main means of combating the pathogenic microorganisms&#44; but alterative drugs to replace them or be used as adjuvant therapy to antibiotics may be efficacious in preventing these infections&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Under natural conditions&#44; most bacteria do not live as individual cells&#44; but as pseudomulticellular organisms which carry out commonly coordinated behaviour patterns through intercellular molecular signals in a process known as &#8220;Quorum sensing&#8221; &#40;QS&#41;&#46; This increases the capacity of the bacteria to adapt through absorption and incorporation&#44; using the recombination of new genetic material of the bacterial community surrounding it&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">6</span></a> This multicellular coordination of bacterial attacks maximises the opportunities for establishing infection and allowing the bacteria to spread&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">7</span></a> Approximately 65&#37; of the agents which cause human infections form biofilms which support chronic infections&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">7</span></a> The main benefit for the bacteria in forming these biofilms is that they are physically protected and possess between 10 and 1000 times more resistance than a single bacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">7</span></a> Today biofilms present a major challenge to antibiotic efficacy&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">One particular case is patients with recurrent bacterial infections who require almost continuous treatment with antibiotics&#44; leading to an increased risk of antibiotic resistance&#46; Furthermore&#44; these patients frequently present with secondary dysbiosis due to repeated doses of antibiotics&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">8</span></a> which in turn may lead to a fungal superinfection&#46; It is particularly in the context of recurrent infections that mucosal polybacterial vaccines could be a good alternative to wide-ranging antibiotics used for preventative ends&#46; These vaccines are used as immunomodulators to prevent infections in immunocompetent patients&#44; but their use in immunocompromised patients is increasingly greater&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Infection is one of the main causes of mobimortality in patients with systemic autoimmune diseases &#40;SAD&#41;&#46; Predisposition to infection in patients with SAD is associated with an anomalous response of the innate and underlying adaptive immune system to the actual disease and secondary to immunomodulators and immunosuppressants&#46; Glucocorticoids may reduce the response of innate and adaptive immunity&#44; inducing susceptibility to bacterial infections by streptococci&#44; <span class="elsevierStyleItalic">Staphylococcus aureus</span>&#44; gram negative bacilli&#44; and diseases caused by fungi such as <span class="elsevierStyleItalic">Candida</span> and <span class="elsevierStyleItalic">Aspergillus</span> spp&#46; Other immunosuppressant treatments may damage adaptive immunity inducing infections caused by virus &#40;especially the herpes virus&#44; such as herpes zoster&#44; cytomegalovirus or Ebstein-Baar vurs&#41;&#44; bacteria &#40;<span class="elsevierStyleItalic">Legionella</span> spp&#46;&#44; <span class="elsevierStyleItalic">Listeria monocytogenes</span> and <span class="elsevierStyleItalic">Salmonella tiphy</span>&#41;&#44; <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> and fungi &#40;<span class="elsevierStyleItalic">Candida</span>&#44; <span class="elsevierStyleItalic">Aspergillus</span>&#44; <span class="elsevierStyleItalic">Histoplasma capsulatum</span> and <span class="elsevierStyleItalic">Cryptococcus</span>&#41; and <span class="elsevierStyleItalic">Pneumocystis jirovecii</span>&#46; Moreover&#44; B cell compromise with reduction in the production of immunoglobulins is associated with recurrent infections by encapsulated germs &#40;<span class="elsevierStyleItalic">Streptococcus pneumoniae&#44; Haemophilus influenzae</span>&#44; meningococcus&#41;&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In the Spanish registry of adverse events of biological therapies &#40;BIOBADASER&#41; a higher rate of infections has been found in patients with rheumatoid arthritis &#40;RA&#41; who receive anti-TNF<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">9</span></a>&#59; similar data are continuing to be confirmed in different reports&#44; where the frequency of the infections and infestations amount to 23&#46;9&#37; of all adverse events recorded in patients with biologic therapy&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">There are several possible explanations for a higher risk of infection in patients with RA&#46; Recent evidence suggest that patients with RA have immunological changes which involve the majority of T cells circulating from an early stage during the course of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">10</span></a> As a result&#44; the capacity of the immune system to respond to new antigenic stimuli may be compromised&#46; Alternatively&#44; therapy with glucocorticoids and other immunosuppressants may also predispose patients with RA to the development of sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">11&#44;12</span></a> Other factors which may play a part in the risk of infection in patients with RA are factors relating to the disease &#40;immobility&#44; joint surgery&#41;&#44; extra-articular RA manifestations &#40;Felty syndrome&#44; rheumatoid pulmonary disease&#41; and comorbidities &#40;diabetes mellitus&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The infections are usually located in the upper and lower respiratory tract&#44; the skin and the genital and urinary tract&#46; They are normally due to the <span class="elsevierStyleItalic">Staphylococcus aureus</span> and to gram negative bacteria&#46; Equally&#44; a higher frequency of herpes zoster has been reported and cases of opportunistic infections as well&#44; such as listeriosis&#44; widespread aspergilosis and other infrequent infections found in Spain&#44; such as histoplasmosis and coccidioidomycosis&#44; although rates were low&#46; A higher rate of infections was also described with the other biologic agents&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">As a result of the above&#44; adjuvant or alternative therapeutic strategies to antibiotics are increasingly urgent&#44; such as the immunisation of these patients with vaccines to prevent primary and recurrent infections&#44; to reduce the repeated use of antibiotics&#44; along with the appearance of resistance and of severe infectious diseases&#46; In doing so&#44; hospitalisations from these events will consequently drop&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">This review covers the most up-to-date information on the mechanisms of action of mucosal polybacterial immunomodulators&#44; also known as mucosal anti-infective vaccines&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">At the threshold&#58; mucosal immunity&#44; a new paradigm of trained immunity</span><p id="par0050" class="elsevierStylePara elsevierViewall">Mucus membranes make up a very large surface area of our body&#44; approximately 200 times greater than the area covered by the skin&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">13</span></a> The mucous membranes are the main entry route for infectious and environmental agents&#46; As a result mucosal infections are one of the main causes of morbimortality in the world&#44; with infants and the elderly being the most susceptible to them and no effective vaccines available in most cases&#46; The mucosa-associated lymphoid tissue &#40;MALT&#41; encompasses a complex network of highly specialised and compartimentalised components of innate and adaptive immunity&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">13&#44;14</span></a> It includes a nasopharangeal-associated lymphoid tissue &#40;NALT&#41;&#44; bronchial-associated lymphoid tissue &#40;BALT&#41;&#44; mucosa gastrointestinal-associated lymphoid tissue &#40;GALT&#41;&#44; urinary genital tract and a exocrine gland tissues&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">15&#44;16</span></a> The dendritic cells &#40;DC&#41; are activated on recognizing common structures in the pathogenic microorganisms highly preserved throughout the evolution by pattern recognition receptors &#40;PRR&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; DC antigen uptake may be carried out directly and indirectly&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">17</span></a> Indirect route is&#44; for example&#44; through uptake by M cells Microfold&#41;&#44; by calciform cells&#44; by neonatal Fc receptors &#40;FcRn&#41; and through apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">17</span></a> M cells are specialised cells which capture antigens and enteric bacteria through the epithelial surface for uptake and processing by the DD and macrophages&#44; which will initiate the effector immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">18</span></a> The DC may also directly capture antigens from the lumen by extending their dendrites&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">18</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Trained immunity</span><p id="par0055" class="elsevierStylePara elsevierViewall">Clinical and epidemiological evidence extracted from studies with standard vaccines highlighted a reduction of infant mortality in individuals vaccinated against measles and tuberculosis during their first year of life due to infection&#44; compared with those who were not vaccinated&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">19</span></a> These results cannot be explained by a specific protection to these diseases&#44; but due to a wide spectrum of protection&#44; more in keeping with innate immunity&#44; in what is called trained immunity&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">20&#44;21</span></a> Trained immunity refers to the fact there are cells&#8212;for example monocyte&#47;macrophage or natural killer &#40;NK&#41; cells&#44; among others&#8212;capable of generating an intensified response to a second infection by the same micro organism and by a different &#40;crossover protection&#41; separate from the adaptive response &#40;lymphocyte T and B&#41;&#44; although it also increases the adaptive response&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">22&#8211;26</span></a> Studies from 50 years ago had already reported that infections confer antibacterial properties acquired through specific pathogenic bacteria and also others which are non-related&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">22</span></a> The mechanisms which measure this trained immunity include epigenetic and transcriptional reprogramming of cells of the innate immunity&#44; including modifications in the histones and the DNA which may support the transcription of proinflammatory cytokines&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">23</span></a> a contribution of microRNAs&#44; together with metabolic changes &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">27</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Application of trained immunity as mucosal anti-infective vaccines</span><p id="par0060" class="elsevierStylePara elsevierViewall">Mucosal anti-infective vaccines are complete inactive combinations of bacteria or fungi or bacterial lysates which stimulate the immune system through PRRs common to several germs&#44; which according to many studies reduce the number of re-infections by the same pathogens and by other pathogens than the contents in the vaccines &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The underlying mechanisms to this collateral benefit may mostly be due to the &#8220;trained immunity&#8221; rather than any specific one&#44; which it has also been seen contributes to the protector effect&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Unlike conventional vaccines administered parenterally&#44; mucosal vaccines act directly on specific tissues where the pathogens start or spread infections&#46; An immunological equilibrium exists on mucosal surfaces maintained by comensal flora&#46; The induction of innate responses could lead to CD activation&#44; macrophages&#44; epithelial cells and NK cells&#44; whilst stimulation from adaptive immunity would lead to the production of specific antibodies and B and T memory cells&#46; Appropriately formulated mucosal vaccines stimulate the two components of the immune system&#44; making them promising tools for therapeutic prevention and prophylaxis of infections&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">28&#8211;30</span></a> Anti-body responses in mucous membranes&#44; principally secretory IgA&#44; stimulated by these vaccines&#44; inhibit a critical step in the microbial infectious pathogenesis&#44; the adhesion of the micro organism to the epithelial cells of the mucous membrane&#44; conferring better protection against colonisation and invasion than parenteral vaccines&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">31</span></a> The mucous membrane IgG mark the opsonization and internalisation of pathogens which have crossed over the epithelial barrier through phagocytosis&#46; This leads to activation of the phagocytes and elimination of the pathogens or the presentation of antigens derived from them&#44; encouraging the differentiation of multiple subtypes of T effector lymphocytes&#44; such as lymphocytes Th17&#44; lymphocytes T&#947;&#948; and lymphocytes T CD8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cytotoxics &#40;CTL&#41;&#44; for the destruction of the pathogen&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">32</span></a> The tissue-resident memory T cells &#40;TRM&#41; may respond quickly to a pathogen-local re-infection&#44; regardless of T lymphocyte recruitment from the blood&#46; When the TRM CD8&#43; are activated they release IFN-&#947;&#44; which amplifies and complements the innate immune response activation creating an antiviral microenvironment in the mucous membrane&#46; The induction of TRM lymphocytes is currently a challenge for vaccination strategies&#44; and mucosal vaccines may be an effective route for persistently generating TRM lymphocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">33</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Administration through mucous membranes induces tolerance&#44; which is an added benefit in SAD treatment&#46; Sublingual vaccines for allergenic immunotherapy have been used for one hundred years and recent studies suggest that sublingual immunotherapy may improve induction of systemic tolerance&#46; In accordance with the current model of underlying immune mechanisms&#44; the allergen is captured by the tolerogenic plasmacytoid CD of the tonsils which later emigrate to the cervical lymphatic nodules and induce a response of the Treg lymphocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">34</span></a> Biopsies of oral epithelium have shown that there is a larger amount of Treg cells in patients treated with sublingual immunotherapy than in patients treated with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">35</span></a> This model in allergy would be transferable to that which occurs in patients with SAD&#44; although specific studies are required to prove this&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Anti-infective vaccines in autoimmune diseases</span><p id="par0075" class="elsevierStylePara elsevierViewall">Autoimmune diseases are a key objective for the development of these drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">36</span></a> The induction of secretion of specific sIgA has many regulatory mechanisms which may also promote a low T lymphocyte mucosal and systemic response capacity&#44; through a modulating effect of the differentiation of Treg lymphocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">37</span></a></p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Experimental models</span><p id="par0080" class="elsevierStylePara elsevierViewall">Intranasal and sublingual mucosal administration of antigens may induce deep suppression of cellular immunity&#44; as has been shown by the reduction of delayed hypersensitivity reactions&#44; low levels of T cell proliferation and high levels of immunosuppressant cytokine secretion&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">34&#44;38&#44;39</span></a> A recent study demonstrated that the oral vaccine with an attenuated vaccine of <span class="elsevierStyleItalic">Salmonella</span> would induce specific Treg cells to the antigen I of the colonisation factor &#40;CFA&#47;I&#41; of the fimbrias&#44; whilst simultaneously protecting against experimental autoimmune encephalomyelitis &#40;EAE&#41;&#44; a murine model of multiple sclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">40</span></a> In this study&#44; oral vaccination compared with an irrelevant antigen would induce Treg cells which could control autoimmunity and a concomitant anti-infectious effect&#46; Another study in EAE has proven this dual effect against a respiratory tract bacterial infection through the production of the anti-inflammatory cytokine IL-10 which would eliminate the migration of auto-reactive T cells from the central nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">41</span></a> Similar studies in the experimental model of arthritis induced by collagen in DBA&#47;1 mice suggest that the induction of a bystander immunity against the bacteria could potentially control autoimmune or inflammatory processes&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">36&#44;38</span></a> This immunomodulating effect of some bacteria could be exploited to improve a new concept of bacterial mucosal vaccines as a therapeutic innovation to boost immunological tolerance &#40;cross-over tolerance&#41; and homeostasis within the context of autoimmune diseases&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Clinical trials</span><p id="par0085" class="elsevierStylePara elsevierViewall">One prospective observational clinical trial evaluated the clinical and immunological effects of treatment with sublingual vaccines of bacterial combinations in antigen specific responses to bacteria which were responsible for respiratory tract infections&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">42</span></a> Daily immunisation with a polyvalent bacterial sublingual preparation for a period of 6 months was studied in a cohort of 17 patients with recurrent respiratory infections &#40;RRI&#41;&#46; The number of respiratory infections in immunised patients significantly dropped compared with the previous year&#46; There was also a clear reduction in the severity and duration of the infectious respiratory events&#46; The immunological results demonstrated a considerable increase in the prolipherative frequency and capacity of specific T CD4&#43; lymphocytes in blood compared with bacterial antigen contents in the vaccine&#44; after 6 months of treatment&#46; Furthermore&#44; an increase in the prolipherative capacity of the specific T CD4&#43; and CD8&#43; lymphoctyes of influenza virus antigens after 6 months of treatment was observed &#40;not contained in the vaccine&#41;&#44; which may suggest that the bacterial preparation had stimulated the T lymphocytes non specifically <span class="elsevierStyleItalic">in vivo</span> to the influenza virus&#44; which led to a more powerful response&#46; The case of one of the patients described in this study is interesting&#46; The patient had suffered 12 episodes of oral herpes the previous year and only reported 3 episodes after immunisation with the bacterial preparation&#44; suggesting a non specific <span class="elsevierStyleItalic">in vivo</span> effect which enhanced the antiviral response &#40;trained immunity&#41;&#46; In another prospective observational study with 669 women with recurrent urinary tract infections &#40;RUTI&#41; efficacy was compared between a prophylactic treatment with antibiotics &#40;Septrin&#41; and the bacterial sublingual preparation&#44; where 100&#37; of patients experienced a new infection the following year <span class="elsevierStyleItalic">versus</span> less than 10&#37; in the group treated with the bacterial preparation&#46; An interesting finding in this study was that the patients who had previously had infections with bacteria which were not included in the vaccine did not develop reinfections&#44; suggesting that a horizontal or cross protection could be attributed to a strengthening of the innate trained immunity&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">43&#8211;45</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In one prospective observational study performed by our group 50 patients with inflammatory diseases &#40;RA &#91;43&#46;18&#37;&#93;&#44; systemic erythematous lupus &#91;22&#46;72&#37;&#93; and mixed connective tissue disease &#91;6&#46;81&#37;&#93;&#41; under treatment with DMARD biologics and&#47;or non biologics and glucocorticoids mostly at low doses&#44; who presented with recurrent urinary and&#47;or respiratory infections&#44; were treated with two different polybacterial sublingual preparations depending on the type of infection &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The vaccines were administered in cycles of 3 months per year and the clinical response was recorded after 6 months and after 1 year&#46; Paired comparison of the number of infectious events in both groups demonstrated a considerable reduction in the rate of repetitive urinary tract infections &#40;RUTI&#41; of 5&#46;57<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;41 compared with 1&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;28 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; and in the rate of repeated respiratory tract infections &#40;RRTI&#41; of 4&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;98 compared with &#46;95<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;52 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; in the previous year to the year after the vaccine&#44; as well as a considerable reduction in the use of antibiotics 6 months after the vaccine &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Six of the 38 patients treated with the vaccine for RUTI who presented simultaneously with respiratory infections improved significantly not just from their urinary infection but also from the respiratory infection&#44; suggesting an innate cross-over protection&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">46&#44;47</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Advantages and drawbacks of mucosal vaccines</span><p id="par0095" class="elsevierStylePara elsevierViewall">Therapeutic interventions with mucosal anti-infective vaccines have different advantages to standard parenteral vaccines&#58; &#40;a&#41; their effects are directly felt in the infection site of the mucous membrane and they may prevent infection and colonisation by pathogens&#59; &#40;b&#41; immunisation in mucous membranes may lead to the secretion of antibodies in other more distant mucous membranes and also systemically<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">10</span></a>&#59; &#40;c&#41; administration does not require medical professionals and they may be used in mass vaccines and disease prevention campaigns&#44; &#40;d&#41; they are painless and simple to administer&#46; Also&#44; bearing in mind that gram positive bacteria stimulate the production of IL-12 and that gram negative bacteria stimulate the production of IL-10 by monocytes&#44; the combination of gram positive and gram negative bacteria in anti-infective vaccines of mucous membranes appears to carry a synergic immunological response which could be greater depending on the pathology involved&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">48</span></a> Differences in the induction of immunity response were observed depending on the administration route&#44; with sublingual being the most advantageous &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Lastly&#44; there was a huge potential for development taking advantage of these trained immunity characteristics&#44; which would be exploitable and improbable through tools such as reverse vaccinology for the development of adjuvants to standard vaccines&#46; Notwithstanding&#44; -unlike parenteral vaccines&#44; these vaccines require repetitive stimulus and the duration of active treatment may be long and requires patient adherence to it&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">To sum up&#44; therapeutic intervention with polybacterial preparations of mucosal administration with inactivated complete bacteria or with bacterial lysates stimulate the innate and adaptive immunity which is present in the mucous membranes<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">49</span></a> and offers greater clinical benefits&#44; with its effect being attributed to the following mechanisms&#58; &#40;a&#41; complete bacteria are presented to the immune system in the most natural way&#44; maximising their entire potential as immunogens&#44;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">45&#44;50&#44;51</span></a> and &#40;b&#41; the complete bacteria stimulate different immune mechanisms&#44; which have been confirmed as highly important for a complete cellular activation&#44; such as phagocytosis&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">52</span></a> A change of design in the outcome of these vaccines is required&#44; based on a clinical benefit effect rather than on the specific antigen itself&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Immunodeficiencies secondary to immunosuppressant therapy &#40;organ transplant&#44; rheumatological disorders&#44; oncology&#44; and organ specific autoimmune diseases&#41;&#44; chronic metabolic diseases &#40;diabetes&#41; or chronic infections &#40;HIV&#41; are situations which also lead to recurrent infections&#46; The use of polybacterial vaccines in actively immunosuppressed patients for preserving a transplanted organ&#44; or for keeping an autoimmune disease under control is a genuine clinical challenge due to the high risk of infections and the subsequent impact on morbimortality&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0110" class="elsevierStylePara elsevierViewall">Treatment with polybacterial drugs or mucosal anti-infective vaccines which enhance the innate trained immunity as the main objective in the prevention of recurrent infections is an innovative therapeutic strategy with promising results&#46; New prospective studies and randomised clinical trials are required to assess their efficacy and optimise current preparations&#46; Also&#44; since the purpose of these drugs is a broad spectrum protection&#44; the primary objectives of efficacy must be designed in keeping with clinical response&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Financing</span><p id="par0115" class="elsevierStylePara elsevierViewall">This research study did not receive any specific finance from public sector agencies&#44; the trade sector or any non profit-making entities&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of interests</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare&#46;</p></span></span>"
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          "titulo" => "The post-antibiotic era and the current challenge in the prevention of recurrent infections in autoimmune diseases"
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          "titulo" => "At the threshold&#58; mucosal immunity&#44; a new paradigm of trained immunity"
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              "identificador" => "sec0015"
              "titulo" => "Trained immunity"
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          "identificador" => "sec0020"
          "titulo" => "Application of trained immunity as mucosal anti-infective vaccines"
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          "titulo" => "Anti-infective vaccines in autoimmune diseases"
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          "identificador" => "sec0040"
          "titulo" => "Advantages and drawbacks of mucosal vaccines"
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          "titulo" => "Conclusions"
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          "titulo" => "Financing"
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    "fechaRecibido" => "2018-05-18"
    "fechaAceptado" => "2018-10-10"
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            0 => "Mucosal vaccines"
            1 => "Recurrent infections"
            2 => "Trained immunity"
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:3 [
            0 => "Vacunas de mucosas"
            1 => "Infecciones de repetici&#243;n"
            2 => "Inmunidad entrenada"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">An urgent search is currently underway for alternatives to antibiotics to prevent infections&#44; due to the accelerated evolution and increase in antibiotic resistance&#46; This problem is more serious for patients with recurrent infections&#44; since they have to use many cycles of antibiotics per year&#44; so the risk for antibiotic resistance is higher and can be life-threatening&#46; In recent years&#44; the use of prophylactic vaccines <span class="elsevierStyleItalic">via</span> the mucosal route for these patients with recurrent infections has been demonstrated as a potentially beneficial and safe alternative to prevent infections&#46; The new knowledge about mucosal immunity and trained immunity&#44; a form of innate immunity memory that can enhance the response to different infectious threads&#44; has made it easier to extend its use&#46; The application of the new concepts of trained immunity may explain the simultaneous pro-tolerogenic and boosting effect or effects of these drugs on diverse immune cells for different infections&#46; In this review&#44; we describe the immunomodulatory mechanisms of mucosal polybacterial vaccines and their connection with trained immunity and its utility in the prevention of recurrent infections in immunosuppressed patients&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Existe una b&#250;squeda urgente de alternativas a los antibi&#243;ticos para prevenir infecciones&#44; debido al aumento acelerado de la resistencia a los antibi&#243;ticos&#46; Esto es m&#225;s grave para los pacientes con infecciones recurrentes que tienen que ser tratados con varios ciclos de antibi&#243;ticos al a&#241;o&#44; lo que incrementa el riesgo de resistencia a los antibi&#243;ticos&#44; que puede ser potencialmente mortal&#46; En los &#250;ltimos a&#241;os se ha demostrado que el uso de vacunas profil&#225;cticas por v&#237;a mucosa para estos pacientes es una alternativa potencialmente beneficiosa y segura para prevenir infecciones&#46; El nuevo conocimiento sobre la inmunidad de las mucosas y la inmunidad entrenada&#44; una forma de memoria de la inmunidad innata que puede mejorar la respuesta a diferentes amenazas por infecciones&#44; ha hecho m&#225;s f&#225;cil expandir su utilizaci&#243;n&#46; La aplicaci&#243;n cl&#237;nica de la inmunidad entrenada de estos f&#225;rmacos podr&#237;a explicar sus efectos simult&#225;neos pro-tolerog&#233;nicos y potenciadores en diversas c&#233;lulas inmunitarias para diferentes infecciones&#46; En esta revisi&#243;n describimos los mecanismos inmunomoduladores de las vacunas polibacterianas de la mucosa&#44; su conexi&#243;n con la inmunidad entrenada y su utilidad en la prevenci&#243;n de infecciones recurrentes en pacientes inmunocomprometidos&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; S&#225;nchez Ram&#243;n S&#44; Manzanares M&#44; Candelas G&#46; Vacunas antiinfecciosas de mucosas en la profilaxis de infecciones recurrentes&#58; m&#225;s all&#225; de las vacunas convencionales&#46; Reumatol Clin&#46; 2020&#59;16&#58;49&#8211;55&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">As they are stimulated with an antigen&#44; the dentritic cells induce different responses in the mucosal tissues&#46; One of the most important responses is the differentiation of T lymphocytes into different subtypes&#44; which in turn depends on what type of dentritic cells stimulates this differentiation&#46; The figure includes the previously mentioned DC subtypes which induce differentiation of T lymphocytes in the mucous membranes &#40;such as DC CX3CR1&#43;&#44; CD103&#43; and CD103&#43; CD11b&#43;&#41; and those which induce a stimulation of T lymphocytes so that they produce cytokines &#40;an action carried out by the DC CCR2&#43; CD103&#8722; which leads to the production of IL17 by T lymphocytes&#41;&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Trained immunity&#46; Epigenetic reprogramming in innate immunity cells on stimulating the trained immunity&#46; Once pathogen 1 had been recognised by a receptor&#44; the monocytes experienced an epigenetic reprogramming &#40;mainly through mutilations in the DNA&#41; and metabolic changes&#44; so that they were prepared to respond more robustly to a secondary non specific stimulation &#40;pathogens 1&#44; 2 and 3&#41;&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Infectious events &#40;mean&#41; the year prior to the vaccine and at one year follow-up&#46;</p>"
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PAMP&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Microorganism&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PRR&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lipoproteins&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Endobacteria&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR1&#44; TLR22&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Peptidoglycans&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Parasites&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">&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Zimosan&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fungi&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">&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lipoarabinomannan&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">&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">&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Porins&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">&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">&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GPI-mucins&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">&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dectin 1&#47;2&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phospholipomannans Lipopeptideostriacil &#946;-glycans&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">&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">&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lipopeptidosdiacil&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">&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR2&#47;TLR1&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lipoteicoic acid&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Micoplasma&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR2&#47;TLR6&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diaminopimelic acid&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gram negative bacteria&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NOD1&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Muropeptides&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gram positive and gram negative bacteria&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NOD2&#44; NALP1 Y NALP3&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Envelope glycoproteins&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virus&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR4&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glycoinositol phosophylipids&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Protozoans&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">&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mannans&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Candida&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">&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HSP70&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Host&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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lipopolysaccharides</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gram negative bacteria&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR4&#44; DC-SIGN&#44; CD14&#44; CR3 and CR4</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gram positive and gram negative bacteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CpG ODN without mehylation &#40;ssDNA&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Great majority of bacteria&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  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR9&#44; DHX9&#44; DHX36</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fungi&#44; protozoans&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">dsDNA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virus&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DA1&#44; IFI16&#44; STING&#44; AIM2&#44; DDX4&#44; MRE11&#44; cGAS&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Flagelline&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mobile bacteria&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR5&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">dsDNA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virus&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR3&#44; helicase RIG-1&#44; MDA5&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ssDNA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virus&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR7&#44; TLR8&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23rRNA&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bacteria&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carbohydrates</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Virus&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  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type C lectins&#44; mannose receptors</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fungi&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Micobacteria&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Profilin&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Protozoans&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TLR11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Innate repertoire of pattern recognition receptors &#40;PRR&#41; which combine with pathogen associated molecular patterns &#40;PAMP&#41; and damage associated molecular patterns &#40;DAMP&#41;&#46;</p>"
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            0 => array:2 [
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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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VSP for IRTR&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VSP for RUTI&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Staphylococcus</span> spp&#46; 30&#37;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">K&#46; pneumoniae</span> 25&#37;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">S&#46; pneumoniae</span> 60&#37;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">E&#46; coli</span> 25&#37;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">K&#46; pneumoniae</span> 4&#37;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">E&#46; faecalis</span> 25&#37;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">M&#46; catarrhalis</span> 3&#37;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">P&#46; vulgaris</span> 25&#37;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">H&#46; influenzae</span> 3&#37;&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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Composition of polybacterial vaccines&#46;</p>"
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                  <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
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sublingual route&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Upper respiratory tract&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="left" valign="\n
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                  \t\t\t\t">&#43;&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower respiratory tract&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43; a &#43;&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stomach&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#47;&#43;&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#47;&#43;&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intestine&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Colon&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rectum&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Genital tract&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blood&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#43;&#43;&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Comparison of anatomical dissemination of sIgA depending on the immunisation routes&#46;</p>"
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      ]
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
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            0 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "1"
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                0 => array:1 [
                  "referenciaCompleta" => "Organization WH&#46; Worlwide country situation analysis&#58; response to antimicrobial resistance&#46; Available from&#58; <a target="_blank" href="http://www.who.int/drugresistance/documents/situationanalysis/en/2015/2015">http&#58;&#47;&#47;www&#46;who&#46;int&#47;drugresistance&#47;documents&#47;situationanalysis&#47;en&#47;2015&#47;2015</a> &#91;accessed March 2016&#93;&#46;"
                ]
              ]
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            1 => array:3 [
              "identificador" => "bib0270"
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Article information

ISSN: 21735743
Original language: English

DOI:10.1016/j.reumae.2018.10.020

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Year/Month	Html	Pdf	Total

2024 November	10	3	13
2024 October	78	36	114
2024 September	62	24	86
2024 August	63	35	98
2024 July	51	29	80
2024 June	82	35	117
2024 May	72	36	108
2024 April	48	23	71
2024 March	45	29	74
2024 February	32	24	56
2024 January	30	22	52
2023 December	37	21	58
2023 November	29	26	55
2023 October	36	29	65
2023 September	134	37	171
2023 August	41	20	61
2023 July	37	22	59
2023 June	42	25	67
2023 May	38	30	68
2023 April	28	10	38
2023 March	57	29	86
2023 February	45	25	70
2023 January	34	12	46
2022 December	63	36	99
2022 November	55	39	94
2022 October	64	45	109
2022 September	34	28	62
2022 August	27	37	64
2022 July	34	37	71
2022 June	40	38	78
2022 May	35	47	82
2022 April	30	40	70
2022 March	32	43	75
2022 February	50	26	76
2022 January	89	40	129
2021 December	55	34	89
2021 November	46	58	104
2021 October	65	50	115
2021 September	33	41	74
2021 August	34	45	79
2021 July	27	26	53
2021 June	72	33	105
2021 May	39	38	77
2021 April	117	92	209
2021 March	51	47	98
2021 February	46	20	66
2021 January	44	19	63
2020 December	50	20	70
2020 November	32	15	47
2020 October	32	14	46
2020 September	36	30	66
2020 August	24	19	43
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