The role of “original antigenic sin” on influenza vaccine response

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Tisler, N. Nikitina, E. Yusuf" "autores" => array:3 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Tisler" ] 1 => array:2 [ "nombre" => "N." "apellidos" => "Nikitina" ] 2 => array:2 [ "nombre" => "E." 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Adapted from Krammer.<a class="elsevierStyleCrossRef" href="#bb0125">25</a>" ] ] ] "textoCompleto" => "IntroductionThe human influenza virus was first isolated by Wilson Smith in 1933 from embryonated eggs inoculated with human respiratory secretions.<a class="elsevierStyleCrossRef" href="#bb0005">1</a> Following the start of the first widespread vaccinations a decade later, a number of phenomena were observed that were not initially explained. By 1930, it was already apparent that influenza strains varied antigenically over time. By the mid-1940s, it was observed that these variations were sufficiently intense to evade the protection obtained after an initial vaccination. As early as 1947, students vaccinated against influenza A (H1N1) (Rhodes strain) were seen to have lower antibody titres than unvaccinated students, but higher antibody titres against the previously vaccinated PR8 influenza strain; i.e., the new vaccine stimulated the response against the first vaccine strain to the detriment of the new strain.<a class="elsevierStyleCrossRef" href="#bb0010">2</a>We should be cognizant of the fact that protection against influenza viruses takes place fundamentally by means of the neutralising antibodies that are generated by the immune system. Humans respond to influenza infection by producing open-ended memory cells and neutralising antibodies. However, the hallmark of the influenza viruses is their ability to evolve constantly and their antigenic variation, which often means that variants are not neutralised by pre-existing antibodies because, while they maintain shared epitopes, they have unique epitopes that allow them to escape the immune system. When a host is exposed to a new influenza antigenic variant, the following phenomena are necessary for successful protection to develop: (a) activation of memory B cells that recognise the shared epitopes and (b) activation of naive B cells that recognise the novel epitopes. In repeated infections, the second response is not induced with the same intensity as the first, making it difficult to eliminate the first response.<a class="elsevierStyleCrossRef" href="#bb0015">3</a>,<a class="elsevierStyleCrossRef" href="#bb0020">4</a>In the early 1950s, it was observed that individuals were more likely to maintain high antibody titres to influenza strains to which they had been exposed during childhood, even if they had not recirculated, than to those that were circulating at the time.<a class="elsevierStyleCrossRef" href="#bb0025">5</a>,<a class="elsevierStyleCrossRef" href="#bb0030">6</a> In 1956, an increase in the immune response against previous influenza strains was detected after a new contact with the influenza virus in addition to a significant increase in antibodies against the first strains, [even] higher than that obtained against the new vaccine strains.<a class="elsevierStyleCrossRef" href="#bb0035">7</a>Davenport et al.<a class="elsevierStyleCrossRef" href="#bb0030">6</a> demonstrated that prior exposure to an influenza antigen had a suppressive effect on the magnitude and quality of the response to a new strain and that the vaccine response was age-dependent. These studies indicated that an eariler exposure affected only the specificity of the immune response, but did not affect overall protection against the virus. Some studies confirmed that pre-existing antibodies are partially protective and reduce susceptibility and the chance of developing immunity to new strains.<a class="elsevierStyleCrossRef" href="#bb0030">6</a>,<a class="elsevierStyleCrossRef" href="#bb0040">8</a>The original antigenic sinIn 1960, Thomas Francis, studying the response to revaccination against influenza, confirmed that people who were revaccinated had a lower antibody immune response than those who had not been previously vaccinated.<a class="elsevierStyleCrossRef" href="#bb0045">9</a> This, together with all the preceding data, reinforced his hypothesis that «the first dominant influenza antigen» is repeatedly stimulated throughout a person’s life, even though it becomes secondary or minor in subsequent strains. This phenomenon was given the elegant name «the original antigenic sin» (OAS) based on the theological doctrine of the original sin in humans as described by St. Augustine: «the deliberate sin of the first man is the cause of original sin.» Francis was referring to the process that determined that, following a second exposure to a different antigenic strain of the same influenza virus, the immune system responded with antibodies having less lower strength and specificity. According to this author: «Antibodies originating in childhood are largely a response to the dominant antigen of the influenza virus causing the first infection in life. The immunological fingerprint established by the original influenza virus infection will determine the antibody response thereafter.» By analogy, it is named after the theological concept of original sin, so that a person will carry the sin of their first influenza exposure for the rest of their life.<a class="elsevierStyleCrossRef" href="#bb0045">9</a> Thus, the OAS is based on the induction of a more robust or intense immune response to the initial influenza antigen (antigenic imprint) compared to the immune response induced by a subsequent new vaccine (antigen). Vaccine-induced antibodies bind to the novel exogenous influenza virus more weakly than those from the original, albeit antigenically distinct, strain.<a class="elsevierStyleCrossRef" href="#bb0045">9</a>,<a class="elsevierStyleCrossRef" href="#bb0050">10</a>This phenomenon, later to be denominated «Hoskins’ paradox, negative interference, or antigenic interaction,» means that, in a new vaccination with antigenically different strains of the same virus, the immune system responds basically with the antibodies already present, due to «immunological laziness,» and with the new ones induced by the new vaccine to a lesser degree, thereby dereasing the protective efficacy against the latter.<a class="elsevierStyleCrossRefs" href="#bb0055">11–13</a> Thus, the immunological fingerprint left by the very first contact with the virus will determine the future response to it, as it will be trapped by the first immune response<a class="elsevierStyleCrossRef" href="#bb0045">9</a> (<a class="elsevierStyleCrossRef" href="#f0005">Fig. 1</a>). The OAS could somehow «freeze and hierarchise» the repertoire of the immune response to an ever-changing virus, always favouring the first antigenic contact<a class="elsevierStyleCrossRef" href="#bb0070">14</a>.<elsevierMultimedia ident="f0005"></elsevierMultimedia>In 1966, St. Fazekas et al.<a class="elsevierStyleCrossRef" href="#bb0075">15</a>,<a class="elsevierStyleCrossRef" href="#bb0080">16</a> reported that the secondary response of rabbits revaccinated against influenza was «inadequate,» inasmuch as the antibodies in this second dose reacted with greater intensity and affinity to the first antigen than to the second antigen. It appeared that this study indicated that prior exposure to an influenza antigen affected the specificity of the immune response, but this did not appear to affect overall immune protection against the influenza virus. This suppressive effect was evident in the 2009 influenza pandemic with the A (H1N1) pdm09 strain. People with immunity to the same 1918 strain responded with higher antibody intensity to the new pandemic strain than those born from 1957 onward.<a class="elsevierStyleCrossRef" href="#bb0085">17</a>,<a class="elsevierStyleCrossRef" href="#bb0090">18</a>Smith et al.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>,<a class="elsevierStyleCrossRef" href="#bb0100">20</a> put forth the hypothesis of «antigenic distance» in 1999 according to which the differences in vaccine efficacy were due to relative antigenic relatedness to previous vaccine strains, current vaccine strains, and circulating epidemic strains. In their model, when the past and current vaccine strains are similar, the current vaccine gives an intense response that cross-reacts preferentially with the previous vaccine strain; however, the response against the current vaccine strains will be lower because it is an already known antigen. If there is little antigenic difference between current and past vaccine strains, hardly any strong immune response is induced. When the antigenic distance between these three types of strains is very close, the predictive vaccine efficacy is that it will be very strong. However, if the antigenic distance between past and present vaccine strains is very close, but very distant from circulating strains, the efficacy will be doubtful.<a class="elsevierStyleCrossRefs" href="#bb0095">19–21</a>The OAS argues that the immune response to the first influenza strain, its antigens, and corresponding epitopes that occurred in infancy (most children are infected by an influenza strain before the age of 3 years) will permanently determine the antibody response to new circulating or vaccine strains, such that antibodies that recognise conserved antigens are enhanced by exposure to related strains and often at the expense of responses to new antigens. Despite growing older or acquiring antibodies to other influenza strains, the levels of the original antibodies remain high throughout a person’s lifetime; that is to say that there is a stronger response to the first antigenic contact than to subsequent contacts unless the latter are similar to the original ones. The first influenza infection in childhood «marks or imprints» the immune system forever, giving rise to lifelong immune responses specifically directed against the epitopes that «marked or imprinted» the first influenza virus (<a class="elsevierStyleCrossRef" href="#t0005">Table 1</a>). This early marking, or immunological memory orientation, provides protection against contemporary strains, while vaccine mismatch results in a negative interaction in prior immunity.<a class="elsevierStyleCrossRefs" href="#bb0110">22–24</a><elsevierMultimedia ident="t0005"></elsevierMultimedia>Adapted from Zhang et al.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>Immunological memoryImmune memory never acts as a «bad guy», but on the contrary, it is the power of immune memory that keeps us safe from reinfections by the same virus, as long as neutralising immunity is induced after an initial exposure or vaccination. The problem of the OAS arises after exposure to a closely related virus with a similar but not identical panel of antigens. We must remember that the OAS cannot occur without the involvement of germinal centres, where memory B cells survive with a high recognition affinity for the first antigenic contact, far superior to naive B cells that may be stimulated on second or new contact with a lower antigenic strain. Therefore, the response of memory B cells and cytotoxic T cells<a class="elsevierStyleCrossRef" href="#bb0125">25</a>,<a class="elsevierStyleCrossRef" href="#bb0130">26</a> to a related yet antigenically distant virus may not only be ineffective, but may also lead to a diminished response of naive B cells capable of producing neutralising antibodies.<a class="elsevierStyleCrossRefs" href="#bb0125">25–28</a> Thus, the OAS is a double-edged sword for immune memory; it can either allow full protection against a variant of a known virus or create an obstacle to obtaining immunity against it.<a class="elsevierStyleCrossRef" href="#bb0040">8</a>,<a class="elsevierStyleCrossRef" href="#bb0055">11</a>,<a class="elsevierStyleCrossRef" href="#bb0115">23</a>During a subsequent infection or vaccination, the immune system uses the «initial imprinting» memory by modifying the B cell clonotypes and adapting them to the new antigen. Repeated vaccination may allow the development of different rounds of «refinement, shaping, and narrowing» of the protection induced by the initial imprint. The hierarchy of immune preference or immunodominance may depend on the order of infection or exposure with a different response between the first and subsequent antigenic exposures (<a class="elsevierStyleCrossRef" href="#f0010">Fig. 2</a>). By looking at the history of influenza virus circulation through the lens and trail of imprinting, assumptions can be made about the virus that imprinted on an individual by cross-referencing their year of birth with the predominant influenza strain and epitope signature circulating at the time<a class="elsevierStyleCrossRefs" href="#bb0140">28–30</a>.<elsevierMultimedia ident="f0010"></elsevierMultimedia>Krammer<a class="elsevierStyleCrossRef" href="#bb0125">25</a> has proposed different types of OAS performance, not always as harmful (sinful), in relation to the low affinity of the immune response to new influenza antigenic variants and the intense response to earlier strains. Thus, the «back-boosting» model describes the increase in antibody titre to historical influenza strains that occurs after influenza vaccination. This model, which is also known as «antigenic seniority,» might account for the lower immune response after revaccination. It establishes the existence of a dominant antibody response, as a consequence of repeated exposures to the same antigens, rather than the existence of an immune imprint against the first viral antigen.<a class="elsevierStyleCrossRef" href="#bb0155">31</a> Thus, childhood strains would occupy an older (more senior) antigenic position in the immune system repertoire and each new influenza strain would occupy a more recent position in the induction of an immune response.<a class="elsevierStyleCrossRef" href="#bb0160">32</a>,<a class="elsevierStyleCrossRef" href="#bb0165">33</a> Over time, immune responses accumulate, leading to elevated antibody titres to the childhood strains. In this model, each new antigenic strain occupies a place in the immune hierarchy. Antibodies to influenza viruses first encountered in life increase over time as a result of repeated exposure. In these cases, the response to new strains is generally not affected.The model of «head-epitope-specific imprinting» is based on the fact that when two antigenically different influenza strains have a common haemagglutinin head epitope, this initially acts as the dominant one and produces an intense memory response after a second exposure, thereby affecting the process of antigenic head immunodominance. This is the case with the H1 epitope K133 of the haemagglutinin head. This epitope is primed during the first exposure to any influenza virus and determines an intense recall response after a second exposure.<a class="elsevierStyleCrossRef" href="#bb0125">25</a>,<a class="elsevierStyleCrossRef" href="#bb0155">31</a>On the other hand, the «antigen masking» model has been postulated to explain low vaccine efficacy, based on the observation that the effectiveness of some vaccines is sometimes better in unvaccinated individuals than in those who have already been vaccinated (<a class="elsevierStyleCrossRef" href="#f0015">Fig. 3</a>). This phenomenon might be caused by the existence of pre-existing circulating antibodies that mask new vaccine antigens, not allowing them to bind to B-cell receptors and thus, their activation process.<a class="elsevierStyleCrossRefs" href="#bb0170">34–36</a><elsevierMultimedia ident="f0015"></elsevierMultimedia>The amount of influenza antigen available to naive B cells is higher during the initial exposure because of high viral replication. Subsequent responses would decrease the amount of influenza antigen available to new B cells exposed to a second antigenically similar strain. A great deal of specific antibody is produced during the first exposure and less in the second.<a class="elsevierStyleCrossRef" href="#bb0060">12</a>,<a class="elsevierStyleCrossRef" href="#bb0125">25</a> Naïve B cells reactive to the epitopes of a new strain must compete with memory B cells from the first (memory) infection/exposure. Memory B cells are more efficient at presenting the influenza antigen than naive B cells. Thus, the OAS differentiates between current and past immunological memory, to the benefit of the former.<a class="elsevierStyleCrossRefs" href="#bb0175">35–37</a>The preventive efficacy of vaccines relies on the induction by an antigen of efficient production of memory B and T cells, in addition to the production of specific antibodies. In viruses with the ability to vary antigenically, the OAS could be a problem, in that secondary responses would be much less protective than the original ones. The immune response to vaccines is almost always directed against the immunodominant epitopes, regardless of the possible antigenic variation of the viruses.<a class="elsevierStyleCrossRef" href="#bb0190">38</a>,<a class="elsevierStyleCrossRef" href="#bb0195">39</a> In general, this phenomenon is not terribly important, as the immune system responds with antibodies that cross-react to these possible variants. However, the OAS can sometimes be a major problem in terms of vaccine development, due to the induction of suboptimal or non-cross-reactive immune responses. This phenomenon has been described in the seasonal influenza vaccination strategy, which sometimes fails to produce antibodies that cross-react with new antigenic variants. Thus the «blind spots» caused by the OAS could be responsible for the increased severity of the different influenza epidemics, as they do not induce an effective immune response.<a class="elsevierStyleCrossRef" href="#bb0055">11</a>,<a class="elsevierStyleCrossRef" href="#bb0085">17</a>Original antigenic sin and the efficacy of the flu vaccineThe OAS theory has recently re-emerged as a possible explanation for the low efficacy of certain vaccines, differences in vaccine efficacy across age groups over time, as well as for the decrease in efficacy in repeated vaccinations. Both immunological and epidemiological research lend credibility to this hypothesis.<a class="elsevierStyleCrossRef" href="#bb0015">3</a>,<a class="elsevierStyleCrossRef" href="#bb0020">4</a>,<a class="elsevierStyleCrossRef" href="#bb0085">17</a> Thus, although all age groups respond to the vaccine strain, the quality or cross-reactivity of their response depends on their presumed historical infection. Adults and children today still exhibit different patterns of cross-reactivity following influenza vaccination.<a class="elsevierStyleCrossRef" href="#bb0025">5</a>,<a class="elsevierStyleCrossRef" href="#bb0170">34</a>,<a class="elsevierStyleCrossRef" href="#bb0190">38</a> Likewise, there is strong evidence in humans and animal models that memory B cells, presumably specific for conserved influenza epitopes, are reactivated upon subsequent influenza exposures.<a class="elsevierStyleCrossRef" href="#bb0075">15</a>,<a class="elsevierStyleCrossRef" href="#bb0080">16</a>,<a class="elsevierStyleCrossRef" href="#bb0140">28</a> One implication is that age cohorts differ against which antigens they developed protective antibodies and these antigens are partially determined by past exposures. As the virus mutates its epitopes, different lymphocyte subpopulations, defined directly by their antibody specificities and indirectly by their historical exposure, may lose protection over time.<a class="elsevierStyleCrossRef" href="#bb0015">3</a>,<a class="elsevierStyleCrossRef" href="#bb0125">25</a>Ranjeva et al.<a class="elsevierStyleCrossRef" href="#bb0200">40</a> have suggested that protection against influenza viruses has different origins in children and adults. In children, the detection of neutralising inhibitory antibodies (HI) is a good correlate of protection. In adults, the time since the first infection is much more important as a correlate of protection than the current levels of HI antibodies, as successive infections scarcely change the titre of these antibodies. This may be because children tend to produce antibodies directed against the haemagglutinin head, whereas adults produce antibodies directed against other antigenic sites.<a class="elsevierStyleCrossRef" href="#bb0200">40</a>,<a class="elsevierStyleCrossRef" href="#bb0205">41</a> In contrast, in people who have not been previously vaccinated, or if the previous vaccine strain has minimal cross-reactivity with the current vaccine strain, the response and effectiveness of the current vaccine (even if it does not closely match the circulating strain) will be much higher. This negative interference between vaccines arises from the reactivation of memory responses that are conserved between vaccine strains awaiting responses to the new antigen.<a class="elsevierStyleCrossRef" href="#bb0160">32</a>,<a class="elsevierStyleCrossRef" href="#bb0165">33</a>Ndifon<a class="elsevierStyleCrossRef" href="#bb0210">42</a> has postulated that the OAS is a logical consequence of Treg (cross-reacting T regulatory lymphocytes) cell-mediated immunosuppression induced by the first influenza antigen. Treg cells would decrease the amount of the second antigen that dendritic cells are able to bind to their cell surface, thereby preventing the activation of naive B- and T lymphocytes with specificity against this new antigen.<a class="elsevierStyleCrossRef" href="#bb0215">43</a>,<a class="elsevierStyleCrossRef" href="#bb0220">44</a> Moreover, because lymphocytes previously activated by the first antigen are much more sensitive to it compared to naïve ones, their reactivation by the second antigen would be affected much less by Treg cells.Several methods have been proposed to avoid or circumvent the OAS phenomenon with vaccines. Thus, different antigenic serotypes could be included in the same vaccine; in this way, the first contact with the vaccine would induce an initial response against all of them, as proposed by Francis in 1960:<a class="elsevierStyleCrossRef" href="#bb0045">9</a>,<a class="elsevierStyleCrossRef" href="#bb0050">10</a> «Deficiencies in children’s immunity to influenza must be eliminated by providing them early in life with the antigenic stimuli necessary to cope with current and future strains. Subsequent natural exposures will then serve to enhance the broad immunity established by the initial vaccination. In this way, the OAS of natural infection could be replaced by an initial blessing of the immunity induced by it (original antigenic benefit)».<a class="elsevierStyleCrossRef" href="#bb0190">38</a>,<a class="elsevierStyleCrossRef" href="#bb0225">45</a> Also, increasing the antigenic dose (high-load vaccines) presented to naïve lymphocytes could diminish the effect of OAS. This would be because the high antigen load would keep lymphocyte activation much less sensitive to the suppressive role of Treg cells on effector T cells.<a class="elsevierStyleCrossRef" href="#bb0215">43</a>,<a class="elsevierStyleCrossRef" href="#bb0220">44</a>Alternatively, the vaccine may be capable of inducing direct activation of dendritic cells by specific adjuvants in the first immunisation. With this initial stimulation, the possibility of generating B- and T cells that cross-react to multiple viral subtypes would be increased; this process would diminish the effect of the OAS, but would not completely eliminate it.<a class="elsevierStyleCrossRef" href="#bb0015">3</a>,<a class="elsevierStyleCrossRef" href="#bb0135">27</a> One could also attempt to stimulate the dendritic cells in the revaccination process to produce a new response to the secondary serotypes. Perhaps the best strategy would be the use of recombinant (DNA/RNA) vaccines, in which a single recombinant viral vector includes the different influenza subtypes with minimal impact on previous immunity.<a class="elsevierStyleCrossRef" href="#bb0055">11</a>,<a class="elsevierStyleCrossRef" href="#bb0060">12</a>Although knowledge of OAS has progressed enormously since 1960, many questions remain unanswered. One of the aspects not yet clarified is how different types of antigenic exposure (natural infection, inactivated vaccine, attenuated vaccine, or other types of vaccines) are able to create this immune imprint, which will subsequently induce this negative interference. We also do not know how certain types of exposures are capable of modifying or reprogramming the pre-existing immune hierarchy. These concepts have profound implications when considering the design of a new influenza vaccine, so that the OAS response may be desirable in some cases (when it stimulates the response against conserved epitopes), but collateral in other situations (when it is directed against novel neutralising epitopes or minor variant strains).<a class="elsevierStyleCrossRef" href="#bb0085">17</a>,<a class="elsevierStyleCrossRef" href="#bb0120">24</a>ConclusionIt can be concluded that the OAS is: (a) a universal phenomenon that reflects the way the immune system acts in both animals and humans;<a class="elsevierStyleCrossRef" href="#bb0120">24</a> (b) it is based on the behaviour of B cells stimulated by a lower antigenic load that has little impact on naïve cells;<a class="elsevierStyleCrossRef" href="#bb0075">15</a>,<a class="elsevierStyleCrossRef" href="#bb0080">16</a> and (c) it is exacerbated by the process of revaccination with low amounts of immunogens, as memory B cells sequester the immunogen, hindering the activation of naïve cells, despite the fact that the latter have a higher affinity of their antibodies against the immunogen.<a class="elsevierStyleCrossRef" href="#bb0150">30</a> Despite the persistent connotation of «sin» as a negative attribute, it seems clear that OAS responses will never be entirely good or bad, but will depend on the previous immune status. Nonetheless, it does appear to be clear and well established that the «first flu is forever,»<a class="elsevierStyleCrossRef" href="#bb0230">46</a> as it will shape the way in which our immune system will respond to other influenza strains throughout the rest of our lives. However, Morens et al.<a class="elsevierStyleCrossRef" href="#bb0235">47</a> ask: Is the original antigenic sin really a sin from which our immune system needs to be saved or is it an epidemiological blessing in disguise? Despite the time that has elapsed since its description, we still have much to learn from this type of immune response that seems to directly affect the efficacy of influenza revaccations.FundingThis article review has not received any funding from any public or private organisation.Conflict of interestsDr. Jordi Reina states that he is a member of the Editorial Board of the Vaccines Journal and that he has not participated in the manuscript review process." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1716234" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1516890" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1716233" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1516891" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "s0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "s0010" "titulo" => "The original antigenic sin" ] 6 => array:2 [ "identificador" => "s0015" "titulo" => "Immunological memory" ] 7 => array:2 [ "identificador" => "s0020" "titulo" => "Original antigenic sin and the efficacy of the flu vaccine" ] 8 => array:2 [ "identificador" => "s0025" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "s0030" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "s0035" "titulo" => "Conflict of interests" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1516890" "palabras" => array:4 [ 0 => "Flu" 1 => "Original antigenic sin" 2 => "Vaccination" 3 => "Immune response" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1516891" "palabras" => array:4 [ 0 => "Gripe" 1 => "Pecado antigénico original" 2 => "Vacunación" 3 => "Respuesta inmune" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "In 1960 Thomas Francis, studying the response to revaccination against influenza, confirmed that those revaccinated had a lower antibody immune response than those who had not been previously vaccinated. This data reinforced his hypothesis according to which the first dominant influenza antigen is repeatedly stimulated throughout people's lives, despite the fact that it becomes secondary or less in later strains.He gave this phenomenon the name of "original antigenic sin" (OAS). Antibodies originating in childhood are largely a response to the dominant antigen of the influenza virus that causes the first infection of life. The immunological footprint established by the original influenza virus infection will determine the antibody response from that moment on. This phenomenon, also called Hoskins paradox, negative interference or antigenic interaction, determines that in a new vaccination with antigenically different influenza strains of the same virus, the immune system responds basically with the antibodies already present, due to immunological laziness, and to a lesser extent with the new induced by the new vaccine, reducing the protective efficacy against this second.For all this and despite the persistent connotation of "sin" as a negative attribute, it seems clear that the responses of the PAO will never be totally good or bad but will depend on the previous immune situation. But it does seem clear and proven that "the first flu is forever" as it will mark the way in which our immune system will respond to other flu strains throughout the rest of our lives." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "En 1960 Thomas Francis, estudiando la respuesta a la revacunación frente a la gripe, confirmó que los revacunados presentaban una menor respuesta inmune de anticuerpos que los que no se habían vacunado previamente. Este dato reforzó su hipótesis según la cual el primer antígeno gripal dominante se estimula repetidamente a lo largo de la vida de las personas, a pesar de que éste se convierta en secundario o menor en las cepas posteriores.A este fenómeno le dio el nombre de “pecado antigénico original” (original antigenic sin) (PAO). Los anticuerpos originados en la infancia son en gran medida una respuesta al antígeno dominante del virus gripal que causa la primera infección de la vida. La huella inmunológica establecida por la infección del virus gripal original determinará la respuesta de anticuerpos a partir de ese momento.Este fenómeno, también denominado paradoja de Hoskins, interferencia negativa o interacción antigénica, determina que, en una nueva vacunación con cepas gripales antigénicamente distintas del mismo virus, el sistema inmune responde básicamente con los anticuerpos ya presentes, por pereza inmunológica y en menor medida con los nuevos inducidos por la nueva vacuna, disminuyendo la eficacia protectora frente a esta segunda. Por todo ello, y a pesar de la persistente connotación de “pecado” como un atributo negativo, parece evidente que las respuestas del PAO nunca serán totalmente buenas o malas, sino que dependerán de la situación inmune previa. Pero sí parece evidente y constatado que “la primera gripe es para siempre” (first flu s forever) ya que marcará la forma mediante la cual nuestro sistema inmune responderá a lo largo del resto de nuestra vida a otras cepas gripales." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Reina J, Iglesias C. El papel del «pecado antigénico original» en la respuesta a la vacunación frente a la gripe. Vacunas. 2022. https://doi.org/10.1016/j.vacun.2021.11.001" ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "f0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1947 "Ancho" => 2961 "Tamanyo" => 340301 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Response of the immune system against different influenza subtypes due to the original antigenic sin induced by the first virus (modified from Vatti et al.<a class="elsevierStyleCrossRef" href="#bb0055">11</a>)." ] ] 1 => array:8 [ "identificador" => "f0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2402 "Ancho" => 2979 "Tamanyo" => 309246 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "The effect of the original antigenic sin on the humoral immune system response after vaccination and revaccination with different influenza subtypes." ] ] 2 => array:8 [ "identificador" => "f0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1708 "Ancho" => 2711 "Tamanyo" => 173122 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Schematic of the original antigenic sin based on antigen masking. Adapted from Krammer.<a class="elsevierStyleCrossRef" href="#bb0125">25</a>" ] ] 3 => array:8 [ "identificador" => "t0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0020" "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=""><tbody title="tbody"><tr title="table-row"><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">Original antigenic sin \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 " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Describes the peculiar way in which the humoral immune system responds after sequential exposure to antigenically related influenza viruses. \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 " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antigenic imprint \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 " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Describes the observation that an initial exposure to an influenza virus determines an immunological imprint that will establish future responses to other antigenically similar strains. \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 " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Previous reinforcement \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 " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Describes the low immune response to new antigenic variants due to the strong response to the initial ones. \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 " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative interference \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 " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Describes the hypothesis that specific antibodies to the original/ primary influenza strain negatively interfere with the immune response to subsequent influenza strains. \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 " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antigenic antiquity \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 " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Describes a variation of the OAS that establishes the hierarchical nature of the immune response to new influenza strains without attributing the negative concept to it. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2913578.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Definitions used in the immune response to influenza viruses." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:47 [ 0 => array:3 [ "identificador" => "bb0005" "etiqueta" => "1." 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Epstein" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.aak9816" "Revista" => array:6 [ "tituloSerie" => "Science" "fecha" => "2016" "volumen" => "354" "paginaInicial" => "706" "paginaFinal" => "707" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27846592" "web" => "Medline" ] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bb0235" "etiqueta" => "47." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The wages of original antigenic sin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D.M. Morens" 1 => "D.S. Burke" 2 => "S.B. Halstead" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3201/eid1606.100453" "Revista" => array:5 [ "tituloSerie" => "Emerg Infect Dis" "fecha" => "2010" "volumen" => "6" "paginaInicial" => "1023" "paginaFinal" => "1024" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/24451460/0000002300000001/v1_202205211410/S2445146022000103/v1_202205211410/en/main.assets" "Apartado" => array:4 [ "identificador" => "75009" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Review article" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/24451460/0000002300000001/v1_202205211410/S2445146022000103/v1_202205211410/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146022000103?idApp=UINPBA00004N"]

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Review article

The role of “original antigenic sin” on influenza vaccine response

El papel del «pecado antigénico original» en la respuesta a la vacunación frente a la gripe

Jordi Reina

Corresponding author

jorge.reina@ssib.es

Corresponding author.

, Carla Iglesias

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

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">The human influenza virus was first isolated by Wilson Smith in 1933 from embryonated eggs inoculated with human respiratory secretions&#46;<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a> Following the start of the first widespread vaccinations a decade later&#44; a number of phenomena were observed that were not initially explained&#46; By 1930&#44; it was already apparent that influenza strains varied antigenically over time&#46; By the mid-1940s&#44; it was observed that these variations were sufficiently intense to evade the protection obtained after an initial vaccination&#46; As early as 1947&#44; students vaccinated against influenza A &#40;H1N1&#41; &#40;Rhodes strain&#41; were seen to have lower antibody titres than unvaccinated students&#44; but higher antibody titres against the previously vaccinated PR8 influenza strain&#59; i&#46;e&#46;&#44; the new vaccine stimulated the response against the first vaccine strain to the detriment of the new strain&#46;<a class="elsevierStyleCrossRef" href="#bb0010"><span class="elsevierStyleSup">2</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">We should be cognizant of the fact that protection against influenza viruses takes place fundamentally by means of the neutralising antibodies that are generated by the immune system&#46; Humans respond to influenza infection by producing open-ended memory cells and neutralising antibodies&#46; However&#44; the hallmark of the influenza viruses is their ability to evolve constantly and their antigenic variation&#44; which often means that variants are not neutralised by pre-existing antibodies because&#44; while they maintain shared epitopes&#44; they have unique epitopes that allow them to escape the immune system&#46; When a host is exposed to a new influenza antigenic variant&#44; the following phenomena are necessary for successful protection to develop&#58; &#40;a&#41; activation of memory B cells that recognise the shared epitopes and &#40;b&#41; activation of naive B cells that recognise the novel epitopes&#46; In repeated infections&#44; the second response is not induced with the same intensity as the first&#44; making it difficult to eliminate the first response&#46;<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">In the early 1950s&#44; it was observed that individuals were more likely to maintain high antibody titres to influenza strains to which they had been exposed during childhood&#44; even if they had not recirculated&#44; than to those that were circulating at the time&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a> In 1956&#44; an increase in the immune response against previous influenza strains was detected after a new contact with the influenza virus in addition to a significant increase in antibodies against the first strains&#44; &#91;even&#93; higher than that obtained against the new vaccine strains&#46;<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">Davenport et al&#46;<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a> demonstrated that prior exposure to an influenza antigen had a suppressive effect on the magnitude and quality of the response to a new strain and that the vaccine response was age-dependent&#46; These studies indicated that an eariler exposure affected only the specificity of the immune response&#44; but did not affect overall protection against the virus&#46; Some studies confirmed that pre-existing antibodies are partially protective and reduce susceptibility and the chance of developing immunity to new strains&#46;<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a></p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">The original antigenic sin</span><p id="p0025" class="elsevierStylePara elsevierViewall">In 1960&#44; Thomas Francis&#44; studying the response to revaccination against influenza&#44; confirmed that people who were revaccinated had a lower antibody immune response than those who had not been previously vaccinated&#46;<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a> This&#44; together with all the preceding data&#44; reinforced his hypothesis that &#171;the first dominant influenza antigen&#187; is repeatedly stimulated throughout a person&#8217;s life&#44; even though it becomes secondary or minor in subsequent strains&#46; This phenomenon was given the elegant name &#171;<span class="elsevierStyleItalic">the original antigenic sin</span>&#187; &#40;OAS&#41; based on the theological doctrine of the original sin in humans as described by St&#46; Augustine&#58; &#171;<span class="elsevierStyleItalic">the deliberate sin of the first man is the cause of original sin</span>&#46;&#187; Francis was referring to the process that determined that&#44; following a second exposure to a different antigenic strain of the same influenza virus&#44; the immune system responded with antibodies having less lower strength and specificity&#46; According to this author&#58; &#171;Antibodies originating in childhood are largely a response to the dominant antigen of the influenza virus causing the first infection in life&#46; The immunological fingerprint established by the original influenza virus infection will determine the antibody response thereafter&#46;&#187; By analogy&#44; it is named after the theological concept of original sin&#44; so that a person will carry the sin of their first influenza exposure for the rest of their life&#46;<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a> Thus&#44; the OAS is based on the induction of a more robust or intense immune response to the initial influenza antigen &#40;antigenic imprint&#41; compared to the immune response induced by a subsequent new vaccine &#40;antigen&#41;&#46; Vaccine-induced antibodies bind to the novel exogenous influenza virus more weakly than those from the original&#44; albeit antigenically distinct&#44; strain&#46;<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a></p><p id="p0030" class="elsevierStylePara elsevierViewall">This phenomenon&#44; later to be denominated &#171;Hoskins&#8217; paradox&#44; negative interference&#44; or antigenic interaction&#44;&#187; means that&#44; in a new vaccination with antigenically different strains of the same virus&#44; the immune system responds basically with the antibodies already present&#44; due to &#171;immunological laziness&#44;&#187; and with the new ones induced by the new vaccine to a lesser degree&#44; thereby dereasing the protective efficacy against the latter&#46;<a class="elsevierStyleCrossRefs" href="#bb0055"><span class="elsevierStyleSup">11&#8211;13</span></a> Thus&#44; the immunological fingerprint left by the very first contact with the virus will determine the future response to it&#44; as it will be trapped by the first immune response<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a> &#40;<a class="elsevierStyleCrossRef" href="#f0005">Fig&#46; 1</a>&#41;&#46; The OAS could somehow &#171;freeze and hierarchise&#187; the repertoire of the immune response to an ever-changing virus&#44; always favouring the first antigenic contact<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">14</span></a>&#46;</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0035" class="elsevierStylePara elsevierViewall">In 1966&#44; St&#46; Fazekas et al&#46;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a> reported that the secondary response of rabbits revaccinated against influenza was &#171;inadequate&#44;&#187; inasmuch as the antibodies in this second dose reacted with greater intensity and affinity to the first antigen than to the second antigen&#46; It appeared that this study indicated that prior exposure to an influenza antigen affected the specificity of the immune response&#44; but this did not appear to affect overall immune protection against the influenza virus&#46; This suppressive effect was evident in the 2009 influenza pandemic with the A &#40;H1N1&#41; pdm09 strain&#46; People with immunity to the same 1918 strain responded with higher antibody intensity to the new pandemic strain than those born from 1957 onward&#46;<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a></p><p id="p0040" class="elsevierStylePara elsevierViewall">Smith et al&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a> put forth the hypothesis of &#171;antigenic distance&#187; in 1999 according to which the differences in vaccine efficacy were due to relative antigenic relatedness to previous vaccine strains&#44; current vaccine strains&#44; and circulating epidemic strains&#46; In their model&#44; when the past and current vaccine strains are similar&#44; the current vaccine gives an intense response that cross-reacts preferentially with the previous vaccine strain&#59; however&#44; the response against the current vaccine strains will be lower because it is an already known antigen&#46; If there is little antigenic difference between current and past vaccine strains&#44; hardly any strong immune response is induced&#46; When the antigenic distance between these three types of strains is very close&#44; the predictive vaccine efficacy is that it will be very strong&#46; However&#44; if the antigenic distance between past and present vaccine strains is very close&#44; but very distant from circulating strains&#44; the efficacy will be doubtful&#46;<a class="elsevierStyleCrossRefs" href="#bb0095"><span class="elsevierStyleSup">19&#8211;21</span></a></p><p id="p0045" class="elsevierStylePara elsevierViewall">The OAS argues that the immune response to the first influenza strain&#44; its antigens&#44; and corresponding epitopes that occurred in infancy &#40;most children are infected by an influenza strain before the age of 3 years&#41; will permanently determine the antibody response to new circulating or vaccine strains&#44; such that antibodies that recognise conserved antigens are enhanced by exposure to related strains and often at the expense of responses to new antigens&#46; Despite growing older or acquiring antibodies to other influenza strains&#44; the levels of the original antibodies remain high throughout a person&#8217;s lifetime&#59; that is to say that there is a stronger response to the first antigenic contact than to subsequent contacts unless the latter are similar to the original ones&#46; The first influenza infection in childhood &#171;marks or imprints&#187; the immune system forever&#44; giving rise to lifelong immune responses specifically directed against the epitopes that &#171;marked or imprinted&#187; the first influenza virus &#40;<a class="elsevierStyleCrossRef" href="#t0005">Table 1</a>&#41;&#46; This early marking&#44; or immunological memory orientation&#44; provides protection against contemporary strains&#44; while vaccine mismatch results in a negative interaction in prior immunity&#46;<a class="elsevierStyleCrossRefs" href="#bb0110"><span class="elsevierStyleSup">22&#8211;24</span></a></p><elsevierMultimedia ident="t0005"></elsevierMultimedia><p id="p0050" class="elsevierStylePara elsevierViewall">Adapted from Zhang et al&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a></p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Immunological memory</span><p id="p0055" class="elsevierStylePara elsevierViewall">Immune memory never acts as a &#171;bad guy&#187;&#44; but on the contrary&#44; it is the power of immune memory that keeps us safe from reinfections by the same virus&#44; as long as neutralising immunity is induced after an initial exposure or vaccination&#46; The problem of the OAS arises after exposure to a closely related virus with a similar but not identical panel of antigens&#46; We must remember that the OAS cannot occur without the involvement of germinal centres&#44; where memory B cells survive with a high recognition affinity for the first antigenic contact&#44; far superior to naive B cells that may be stimulated on second or new contact with a lower antigenic strain&#46; Therefore&#44; the response of memory B cells and cytotoxic T cells<a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a> to a related yet antigenically distant virus may not only be ineffective&#44; but may also lead to a diminished response of naive B cells capable of producing neutralising antibodies&#46;<a class="elsevierStyleCrossRefs" href="#bb0125"><span class="elsevierStyleSup">25&#8211;28</span></a> Thus&#44; the OAS is a double-edged sword for immune memory&#59; it can either allow full protection against a variant of a known virus or create an obstacle to obtaining immunity against it&#46;<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a></p><p id="p0060" class="elsevierStylePara elsevierViewall">During a subsequent infection or vaccination&#44; the immune system uses the &#171;initial imprinting&#187; memory by modifying the B cell clonotypes and adapting them to the new antigen&#46; Repeated vaccination may allow the development of different rounds of &#171;refinement&#44; shaping&#44; and narrowing&#187; of the protection induced by the initial imprint&#46; The hierarchy of immune preference or immunodominance may depend on the order of infection or exposure with a different response between the first and subsequent antigenic exposures &#40;<a class="elsevierStyleCrossRef" href="#f0010">Fig&#46; 2</a>&#41;&#46; By looking at the history of influenza virus circulation through the lens and trail of imprinting&#44; assumptions can be made about the virus that imprinted on an individual by cross-referencing their year of birth with the predominant influenza strain and epitope signature circulating at the time<a class="elsevierStyleCrossRefs" href="#bb0140"><span class="elsevierStyleSup">28&#8211;30</span></a>&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0065" class="elsevierStylePara elsevierViewall">Krammer<a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a> has proposed different types of OAS performance&#44; not always as harmful &#40;sinful&#41;&#44; in relation to the low affinity of the immune response to new influenza antigenic variants and the intense response to earlier strains&#46; Thus&#44; the &#171;back-boosting&#187; model describes the increase in antibody titre to historical influenza strains that occurs after influenza vaccination&#46; This model&#44; which is also known as &#171;antigenic seniority&#44;&#187; might account for the lower immune response after revaccination&#46; It establishes the existence of a dominant antibody response&#44; as a consequence of repeated exposures to the same antigens&#44; rather than the existence of an immune imprint against the first viral antigen&#46;<a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a> Thus&#44; childhood strains would occupy an older &#40;more senior&#41; antigenic position in the immune system repertoire and each new influenza strain would occupy a more recent position in the induction of an immune response&#46;<a class="elsevierStyleCrossRef" href="#bb0160"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0165"><span class="elsevierStyleSup">33</span></a> Over time&#44; immune responses accumulate&#44; leading to elevated antibody titres to the childhood strains&#46; In this model&#44; each new antigenic strain occupies a place in the immune hierarchy&#46; Antibodies to influenza viruses first encountered in life increase over time as a result of repeated exposure&#46; In these cases&#44; the response to new strains is generally not affected&#46;</p><p id="p0070" class="elsevierStylePara elsevierViewall">The model of &#171;head-epitope-specific imprinting&#187; is based on the fact that when two antigenically different influenza strains have a common haemagglutinin head epitope&#44; this initially acts as the dominant one and produces an intense memory response after a second exposure&#44; thereby affecting the process of antigenic head immunodominance&#46; This is the case with the H1 epitope K133 of the haemagglutinin head&#46; This epitope is primed during the first exposure to any influenza virus and determines an intense recall response after a second exposure&#46;<a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">On the other hand&#44; the &#171;antigen masking&#187; model has been postulated to explain low vaccine efficacy&#44; based on the observation that the effectiveness of some vaccines is sometimes better in unvaccinated individuals than in those who have already been vaccinated &#40;<a class="elsevierStyleCrossRef" href="#f0015">Fig&#46; 3</a>&#41;&#46; This phenomenon might be caused by the existence of pre-existing circulating antibodies that mask new vaccine antigens&#44; not allowing them to bind to B-cell receptors and thus&#44; their activation process&#46;<a class="elsevierStyleCrossRefs" href="#bb0170"><span class="elsevierStyleSup">34&#8211;36</span></a></p><elsevierMultimedia ident="f0015"></elsevierMultimedia><p id="p0080" class="elsevierStylePara elsevierViewall">The amount of influenza antigen available to naive B cells is higher during the initial exposure because of high viral replication&#46; Subsequent responses would decrease the amount of influenza antigen available to new B cells exposed to a second antigenically similar strain&#46; A great deal of specific antibody is produced during the first exposure and less in the second&#46;<a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a> Na&#239;ve B cells reactive to the epitopes of a new strain must compete with memory B cells from the first &#40;memory&#41; infection&#47;exposure&#46; Memory B cells are more efficient at presenting the influenza antigen than naive B cells&#46; Thus&#44; the OAS differentiates between current and past immunological memory&#44; to the benefit of the former&#46;<a class="elsevierStyleCrossRefs" href="#bb0175"><span class="elsevierStyleSup">35&#8211;37</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">The preventive efficacy of vaccines relies on the induction by an antigen of efficient production of memory B and T cells&#44; in addition to the production of specific antibodies&#46; In viruses with the ability to vary antigenically&#44; the OAS could be a problem&#44; in that secondary responses would be much less protective than the original ones&#46; The immune response to vaccines is almost always directed against the immunodominant epitopes&#44; regardless of the possible antigenic variation of the viruses&#46;<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0195"><span class="elsevierStyleSup">39</span></a> In general&#44; this phenomenon is not terribly important&#44; as the immune system responds with antibodies that cross-react to these possible variants&#46; However&#44; the OAS can sometimes be a major problem in terms of vaccine development&#44; due to the induction of suboptimal or non-cross-reactive immune responses&#46; This phenomenon has been described in the seasonal influenza vaccination strategy&#44; which sometimes fails to produce antibodies that cross-react with new antigenic variants&#46; Thus the &#171;blind spots&#187; caused by the OAS could be responsible for the increased severity of the different influenza epidemics&#44; as they do not induce an effective immune response&#46;<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a></p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Original antigenic sin and the efficacy of the flu vaccine</span><p id="p0090" class="elsevierStylePara elsevierViewall">The OAS theory has recently re-emerged as a possible explanation for the low efficacy of certain vaccines&#44; differences in vaccine efficacy across age groups over time&#44; as well as for the decrease in efficacy in repeated vaccinations&#46; Both immunological and epidemiological research lend credibility to this hypothesis&#46;<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a> Thus&#44; although all age groups respond to the vaccine strain&#44; the quality or cross-reactivity of their response depends on their presumed historical infection&#46; Adults and children today still exhibit different patterns of cross-reactivity following influenza vaccination&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0170"><span class="elsevierStyleSup">34</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a> Likewise&#44; there is strong evidence in humans and animal models that memory B cells&#44; presumably specific for conserved influenza epitopes&#44; are reactivated upon subsequent influenza exposures&#46;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0140"><span class="elsevierStyleSup">28</span></a> One implication is that age cohorts differ against which antigens they developed protective antibodies and these antigens are partially determined by past exposures&#46; As the virus mutates its epitopes&#44; different lymphocyte subpopulations&#44; defined directly by their antibody specificities and indirectly by their historical exposure&#44; may lose protection over time&#46;<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a></p><p id="p0095" class="elsevierStylePara elsevierViewall">Ranjeva et al&#46;<a class="elsevierStyleCrossRef" href="#bb0200"><span class="elsevierStyleSup">40</span></a> have suggested that protection against influenza viruses has different origins in children and adults&#46; In children&#44; the detection of neutralising inhibitory antibodies &#40;HI&#41; is a good correlate of protection&#46; In adults&#44; the time since the first infection is much more important as a correlate of protection than the current levels of HI antibodies&#44; as successive infections scarcely change the titre of these antibodies&#46; This may be because children tend to produce antibodies directed against the haemagglutinin head&#44; whereas adults produce antibodies directed against other antigenic sites&#46;<a class="elsevierStyleCrossRef" href="#bb0200"><span class="elsevierStyleSup">40</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0205"><span class="elsevierStyleSup">41</span></a> In contrast&#44; in people who have not been previously vaccinated&#44; or if the previous vaccine strain has minimal cross-reactivity with the current vaccine strain&#44; the response and effectiveness of the current vaccine &#40;even if it does not closely match the circulating strain&#41; will be much higher&#46; This negative interference between vaccines arises from the reactivation of memory responses that are conserved between vaccine strains awaiting responses to the new antigen&#46;<a class="elsevierStyleCrossRef" href="#bb0160"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0165"><span class="elsevierStyleSup">33</span></a></p><p id="p0100" class="elsevierStylePara elsevierViewall">Ndifon<a class="elsevierStyleCrossRef" href="#bb0210"><span class="elsevierStyleSup">42</span></a> has postulated that the OAS is a logical consequence of Treg &#40;cross-reacting T regulatory lymphocytes&#41; cell-mediated immunosuppression induced by the first influenza antigen&#46; Treg cells would decrease the amount of the second antigen that dendritic cells are able to bind to their cell surface&#44; thereby preventing the activation of naive B- and T lymphocytes with specificity against this new antigen&#46;<a class="elsevierStyleCrossRef" href="#bb0215"><span class="elsevierStyleSup">43</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0220"><span class="elsevierStyleSup">44</span></a> Moreover&#44; because lymphocytes previously activated by the first antigen are much more sensitive to it compared to na&#239;ve ones&#44; their reactivation by the second antigen would be affected much less by Treg cells&#46;</p><p id="p0105" class="elsevierStylePara elsevierViewall">Several methods have been proposed to avoid or circumvent the OAS phenomenon with vaccines&#46; Thus&#44; different antigenic serotypes could be included in the same vaccine&#59; in this way&#44; the first contact with the vaccine would induce an initial response against all of them&#44; as proposed by Francis in 1960&#58;<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a> &#171;Deficiencies in children&#8217;s immunity to influenza must be eliminated by providing them early in life with the antigenic stimuli necessary to cope with current and future strains&#46; Subsequent natural exposures will then serve to enhance the broad immunity established by the initial vaccination&#46; In this way&#44; the OAS of natural infection could be replaced by an initial blessing of the immunity induced by it &#40;original antigenic benefit&#41;&#187;&#46;<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0225"><span class="elsevierStyleSup">45</span></a> Also&#44; increasing the antigenic dose &#40;high-load vaccines&#41; presented to na&#239;ve lymphocytes could diminish the effect of OAS&#46; This would be because the high antigen load would keep lymphocyte activation much less sensitive to the suppressive role of Treg cells on effector T cells&#46;<a class="elsevierStyleCrossRef" href="#bb0215"><span class="elsevierStyleSup">43</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0220"><span class="elsevierStyleSup">44</span></a></p><p id="p0110" class="elsevierStylePara elsevierViewall">Alternatively&#44; the vaccine may be capable of inducing direct activation of dendritic cells by specific adjuvants in the first immunisation&#46; With this initial stimulation&#44; the possibility of generating B- and T cells that cross-react to multiple viral subtypes would be increased&#59; this process would diminish the effect of the OAS&#44; but would not completely eliminate it&#46;<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">27</span></a> One could also attempt to stimulate the dendritic cells in the revaccination process to produce a new response to the secondary serotypes&#46; Perhaps the best strategy would be the use of recombinant &#40;DNA&#47;RNA&#41; vaccines&#44; in which a single recombinant viral vector includes the different influenza subtypes with minimal impact on previous immunity&#46;<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a></p><p id="p0115" class="elsevierStylePara elsevierViewall">Although knowledge of OAS has progressed enormously since 1960&#44; many questions remain unanswered&#46; One of the aspects not yet clarified is how different types of antigenic exposure &#40;natural infection&#44; inactivated vaccine&#44; attenuated vaccine&#44; or other types of vaccines&#41; are able to create this immune imprint&#44; which will subsequently induce this negative interference&#46; We also do not know how certain types of exposures are capable of modifying or reprogramming the pre-existing immune hierarchy&#46; These concepts have profound implications when considering the design of a new influenza vaccine&#44; so that the OAS response may be desirable in some cases &#40;when it stimulates the response against conserved epitopes&#41;&#44; but collateral in other situations &#40;when it is directed against novel neutralising epitopes or minor variant strains&#41;&#46;<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Conclusion</span><p id="p0120" class="elsevierStylePara elsevierViewall">It can be concluded that the OAS is&#58; &#40;a&#41; a universal phenomenon that reflects the way the immune system acts in both animals and humans&#59;<a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">24</span></a> &#40;b&#41; it is based on the behaviour of B cells stimulated by a lower antigenic load that has little impact on na&#239;ve cells&#59;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a> and &#40;c&#41; it is exacerbated by the process of revaccination with low amounts of immunogens&#44; as memory B cells sequester the immunogen&#44; hindering the activation of na&#239;ve cells&#44; despite the fact that the latter have a higher affinity of their antibodies against the immunogen&#46;<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a> Despite the persistent connotation of &#171;sin&#187; as a negative attribute&#44; it seems clear that OAS responses will never be entirely good or bad&#44; but will depend on the previous immune status&#46; Nonetheless&#44; it does appear to be clear and well established that the &#171;first flu is forever&#44;&#187;<a class="elsevierStyleCrossRef" href="#bb0230"><span class="elsevierStyleSup">46</span></a> as it will shape the way in which our immune system will respond to other influenza strains throughout the rest of our lives&#46; However&#44; Morens et al&#46;<a class="elsevierStyleCrossRef" href="#bb0235"><span class="elsevierStyleSup">47</span></a> ask&#58; Is the original antigenic sin really a sin from which our immune system needs to be saved or is it an epidemiological blessing in disguise&#63; Despite the time that has elapsed since its description&#44; we still have much to learn from this type of immune response that seems to directly affect the efficacy of influenza revaccations&#46;</p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Funding</span><p id="p0125" class="elsevierStylePara elsevierViewall">This article review has not received any funding from any public or private organisation&#46;</p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Conflict of interests</span><p id="p0130" class="elsevierStylePara elsevierViewall">Dr&#46; Jordi Reina states that he is a member of the Editorial Board of the Vaccines Journal and that he has not participated in the manuscript review process&#46;</p></span></span>"
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          "titulo" => "Introduction"
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        5 => array:2 [
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          "titulo" => "The original antigenic sin"
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          "titulo" => "Immunological memory"
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          "identificador" => "s0020"
          "titulo" => "Original antigenic sin and the efficacy of the flu vaccine"
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          "titulo" => "Conclusion"
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          "titulo" => "Funding"
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          "titulo" => "Conflict of interests"
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          "titulo" => "References"
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          "palabras" => array:4 [
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            1 => "Original antigenic sin"
            2 => "Vaccination"
            3 => "Immune response"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:4 [
            0 => "Gripe"
            1 => "Pecado antig&#233;nico original"
            2 => "Vacunaci&#243;n"
            3 => "Respuesta inmune"
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        "titulo" => "Abstract"
        "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">In 1960 Thomas Francis&#44; studying the response to revaccination against influenza&#44; confirmed that those revaccinated had a lower antibody immune response than those who had not been previously vaccinated&#46; This data reinforced his hypothesis according to which the first dominant influenza antigen is repeatedly stimulated throughout people&#39;s lives&#44; despite the fact that it becomes secondary or less in later strains&#46;</p><p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">He gave this phenomenon the name of &#34;original antigenic sin&#34; &#40;OAS&#41;&#46; Antibodies originating in childhood are largely a response to the dominant antigen of the influenza virus that causes the first infection of life&#46; The immunological footprint established by the original influenza virus infection will determine the antibody response from that moment on&#46; This phenomenon&#44; also called Hoskins paradox&#44; negative interference or antigenic interaction&#44; determines that in a new vaccination with antigenically different influenza strains of the same virus&#44; the immune system responds basically with the antibodies already present&#44; due to immunological laziness&#44; and to a lesser extent with the new induced by the new vaccine&#44; reducing the protective efficacy against this second&#46;</p><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">For all this and despite the persistent connotation of &#34;sin&#34; as a negative attribute&#44; it seems clear that the responses of the PAO will never be totally good or bad but will depend on the previous immune situation&#46; But it does seem clear and proven that &#34;the first flu is forever&#34; as it will mark the way in which our immune system will respond to other flu strains throughout the rest of our lives&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">En 1960 Thomas Francis&#44; estudiando la respuesta a la revacunaci&#243;n frente a la gripe&#44; confirm&#243; que los revacunados presentaban una menor respuesta inmune de anticuerpos que los que no se hab&#237;an vacunado previamente&#46; Este dato reforz&#243; su hip&#243;tesis seg&#250;n la cual el primer ant&#237;geno gripal dominante se estimula repetidamente a lo largo de la vida de las personas&#44; a pesar de que &#233;ste se convierta en secundario o menor en las cepas posteriores&#46;</p><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">A este fen&#243;meno le dio el nombre de &#8220;pecado antig&#233;nico original&#8221; &#40;<span class="elsevierStyleItalic">original antigenic sin</span>&#41; &#40;PAO&#41;&#46; Los anticuerpos originados en la infancia son en gran medida una respuesta al ant&#237;geno dominante del virus gripal que causa la primera infecci&#243;n de la vida&#46; La huella inmunol&#243;gica establecida por la infecci&#243;n del virus gripal original determinar&#225; la respuesta de anticuerpos a partir de ese momento&#46;</p><p id="sp0050" class="elsevierStyleSimplePara elsevierViewall">Este fen&#243;meno&#44; tambi&#233;n denominado paradoja de Hoskins&#44; interferencia negativa o interacci&#243;n antig&#233;nica&#44; determina que&#44; en una nueva vacunaci&#243;n con cepas gripales antig&#233;nicamente distintas del mismo virus&#44; el sistema inmune responde b&#225;sicamente con los anticuerpos ya presentes&#44; por pereza inmunol&#243;gica y en menor medida con los nuevos inducidos por la nueva vacuna&#44; disminuyendo la eficacia protectora frente a esta segunda&#46; Por todo ello&#44; y a pesar de la persistente connotaci&#243;n de &#8220;pecado&#8221; como un atributo negativo&#44; parece evidente que las respuestas del PAO nunca ser&#225;n totalmente buenas o malas&#44; sino que depender&#225;n de la situaci&#243;n inmune previa&#46; Pero s&#237; parece evidente y constatado que &#8220;la primera gripe es para siempre&#8221; &#40;<span class="elsevierStyleItalic">first flu s forever</span>&#41; ya que marcar&#225; la forma mediante la cual nuestro sistema inmune responder&#225; a lo largo del resto de nuestra vida a otras cepas gripales&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="np0050">Please cite this article as&#58; Reina J&#44; Iglesias C&#46; El papel del &#171;pecado antig&#233;nico original&#187; en la respuesta a la vacunaci&#243;n frente a la gripe&#46; Vacunas&#46; 2022&#46; <span class="elsevierStyleInterRef" id="ir2015" href="https://doi.org/10.1016/j.vacun.2021.11.001">https&#58;&#47;&#47;doi&#46;org&#47;10&#46;1016&#47;j&#46;vacun&#46;2021&#46;11&#46;001</span></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Original antigenic sin</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">Describes the peculiar way in which the humoral immune system responds after sequential exposure to antigenically related influenza viruses&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Antigenic imprint</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">Describes the observation that an initial exposure to an influenza virus determines an immunological imprint that will establish future responses to other antigenically similar strains&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Previous reinforcement</span>&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  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Describes the low immune response to new antigenic variants due to the strong response to the initial ones&#46;&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  " align="" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Negative interference</span>&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  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Describes the hypothesis that specific antibodies to the original&#47; primary influenza strain negatively interfere with the immune response to subsequent influenza strains&#46;&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  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Antigenic antiquity</span>&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  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Describes a variation of the OAS that establishes the hierarchical nature of the immune response to new influenza strains without attributing the negative concept to it&#46;&nbsp;\t\t\t\t\t\t\n
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                      "titulo" => "Wilson Smith&#44; 1897-1965"
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                          "autores" => array:1 [
                            0 => "D&#46;G&#46; Evans"
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                      "doi" => "10.1098/rsbm.1966.0023"
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                        "tituloSerie" => "Biogr Mem Fellows R Soc"
                        "fecha" => "1966"
                        "volumen" => "12"
                        "paginaInicial" => "478"
                        "paginaFinal" => "487"
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                      "titulo" => "Experience with vaccination against influenza in the spring of 1947&#58; a preliminary report"
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                        0 => array:2 [
                          "etal" => false
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                            0 => "T&#46; Francis"
                            1 => "J&#46;E&#46; Salk"
                            2 => "J&#46;J&#46; Quilligan"
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                      "doi" => "10.2105/ajph.37.8.1013"
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                        "tituloSerie" => "Am J Public Health Nations Health"
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                        "volumen" => "37"
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Article information

ISSN: 24451460
Original language: English

DOI:10.1016/j.vacune.2022.02.001

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