Simultaneous formulation of chemical and genetic adjuvants could result in finding an efficient H5 influenza DNA vaccine

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"apellidos" => "Rabella" ] 28 => array:2 [ "nombre" => "M." "apellidos" => "del Cuerpo" ] 29 => array:2 [ "nombre" => "A." "apellidos" => "Moreno-Docón" ] 30 => array:2 [ "nombre" => "A." "apellidos" => "Navascués" ] 31 => array:2 [ "nombre" => "S." "apellidos" => "Pérez-Castro" ] 32 => array:2 [ "nombre" => "M.P." "apellidos" => "Romero" ] 33 => array:2 [ "nombre" => "M." "apellidos" => "Aranzamendi" ] 34 => array:2 [ "nombre" => "A." "apellidos" => "Martínez-Sapiña" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1576988720300728?idApp=UINPBA00004N" "url" => "/15769887/0000002200000001/v2_202106031157/S1576988720300728/v2_202106031157/es/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Review article" "titulo" => "Simultaneous formulation of chemical and genetic adjuvants could result in finding an efficient H5 influenza DNA vaccine" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "39" "paginaFinal" => "46" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M. Ghaemi, S-E. Tabtabaeizadeh" "autores" => array:2 [ 0 => array:4 [ "nombre" => "M." "apellidos" => "Ghaemi" "email" => array:1 [ 0 => "m.ghaemi@shirazu.ac.ir" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "S-E." "apellidos" => "Tabtabaeizadeh" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Mashhad, Iran" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La formulación simultánea de adyuvantes químicos y genéticos podría conducir al hallazgo de una vacuna de ADN eficaz frente a la gripe H5" ] ] "textoCompleto" => "IntroductionDNA vaccine, as a third generation vaccine, appeared as a new approach to solve some of the perennial problems, such as the lack of immunogenicity or the reversion of pathogenicity, which had been associated with conventional vaccines. The initial enthusiasm for the DNA vaccine decreased gradually because, first, it could not meet some of the expectations and, secondly, it could not be used commonly for the immunization of humans or animals due to the limitations in plasmid delivery and its lack of immunogenicity. In November 2017, a breakthrough occurred in the field of DNA vaccines. The USDA gave its first conditional approval to a DNA vaccine for chickens, which was a DNA vaccine against the highly pathogenic H5 influenza virus.<a class="elsevierStyleCrossRef" href="#bib0200">1</a> This was the first veterinary DNA vaccine approved for influenza and among the first DNA vaccines authorized in the US for food-producing animals. Some of the DNA vaccines licensed for veterinary applications are against the following agents and disorders: West Nile Virus for horses in 2005,<a class="elsevierStyleCrossRef" href="#bib0205">2</a> infectious hematopoietic necrosis virus for salmon in 2005,<a class="elsevierStyleCrossRef" href="#bib0210">3</a> and melanoma cancer for dogs approved conditionally in 2007 and with full licensure in 2010.<a class="elsevierStyleCrossRef" href="#bib0215">4</a> Growth hormone-releasing factor, encoded by a plasmid DNA for pigs, was approved in 2007 for application in gene delivery.<a class="elsevierStyleCrossRef" href="#bib0220">5</a> This recently approved H5 influenza DNA vaccine is significant because of its target species, which is chicken, and its target agent, which is the H5 influenza virus. As the chicken is the most industrialized poultry affected by the influenza virus, this vaccine can greatly help the poultry industries and the governments to combat the H5 influenza virus worldwide. Also, because the H5 subtype is one of the deadliest zoonotic influenza subtypes and a potential danger for public health,<a class="elsevierStyleCrossRef" href="#bib0225">6</a> this vaccine can be considered as a step forward to develop an H5 influenza DNA vaccine for human immunization. As, finding an efficient H5 influenza DNA vaccine is still challenging, we aimed to review the articles which have reported the effects of an adjuvant on the H5 influenza DNA vaccines.H5 influenza virusInfluenza virus is one of the most important disease agents worldwide circulating between birds, animals and human. In 1918, the influenza pandemic, in what is still one of the deadliest disease outbreaks in recorded history, infected 500 million people around the world and 50–100 million people, which was equal to 3–5% of the world's population at the time, died because of the virus.<a class="elsevierStyleCrossRef" href="#bib0230">7</a> During the H5 influenza virus panzootic, which started in 2004, many warned that we might encounter another influenza pandemic because the H5 influenza virus could infect humans with more than 50% mortality rate. Since 2003, and as of 15 February 2019, 860 laboratory-confirmed cases of human infection, including 454 deaths, with the H5N1 influenza virus have been reported from 16 Asian countries.<a class="elsevierStyleCrossRef" href="#bib0225">6</a>Also, Influenza virus has been caused severe effects on the poultry industry in different countries. For example, in the last world organization for animal health (OIE) report of total poultry losses due to H5 influenza outbreaks, approximately 122 million birds were killed or died from January 2013 to August 2018 (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The influenza virus constantly evolves by mutation and re-assortment with the emergence of new subtypes and can evade the host immune system.<a class="elsevierStyleCrossRef" href="#bib0235">8</a> Therefore, to be protective, the influenza vaccine must be adapted to the new evolved subtypes. Currently, an inactivated vaccine, prepared from the egg-propagated virus, is commonly used for immunization against the influenza virus.<a class="elsevierStyleCrossRef" href="#bib0240">9</a> Nevertheless, it is clear that contemporary influenza vaccines should be more flexible and universal, and, in particular, they need to be produced faster in case of a new influenza outbreak. Such required features can be found in DNA vaccines, which can be developed rapidly according to the new subtypes of influenza viral genes.DNA vaccineThe characteristics of DNA vaccines make them a suitable vaccine candidate for different evolving disease agents. A DNA vaccine is usually an efficient eukaryotic expression plasmid, which contains the gene of a candidate antigen(s). After the DNA vaccine plasmids are inoculated, the plasmid can transfect the cells of the inoculation site. They must enter the cells and be expressed efficiently so the target antigen can be produced and propagated. If the DNA vaccine plasmids coding for appropriate target antigen cannot enter the nucleus of the cells, due to the lack of the immunogenic protein production, DNA vaccine will not elicit a sufficient immune response.<a class="elsevierStyleCrossRef" href="#bib0245">10</a> DNA vaccine development is generally based on the synthesis of the nucleic acid for codon-optimized genes or possibly the cloning of an appropriate gene from a pathogen into the expression plasmid.<a class="elsevierStyleCrossRef" href="#bib0250">11</a> The DNA vaccine has different features that make it a highly efficient vaccine type for influenza control. While the inactivated influenza vaccines mostly induce antibody production to protect the body effectively, the DNA vaccines can efficiently elicit both humoral and cell-mediated immune responses. To produce DNA vaccines, unlike what is involved in the process of killed influenza vaccine production, there is no need to grow live viruses, and if a pandemic influenza emerges, the DNA vaccine production can quickly be scaled up. A DNA vaccine is also extremely stable at room temperature and that obviates the cold chain which is needed for most of the other vaccines. Additionally, a DNA plasmid is generally produced in bacterial culture which simplifies the purification process compared with that for viral culture using cell cultures or chicken embryos, potentially containing infectious pathogens. Thus, this process of production taking place in bacterial culture improves the safety of the DNA vaccine considerably.<a class="elsevierStyleCrossRef" href="#bib0255">12</a> On the other hand, the use of DNA vaccine has some concerns which are based mainly on safety issues. One of the safety issues concerning DNA vaccination in livestock and poultry eaten by humans could be potential transfection of the plasmid containing an antibiotic resistance gene to alimentary tract bacteria, persisting in them and subsequently spreading antibiotic resistance genes to other bacteria.<a class="elsevierStyleCrossRef" href="#bib0260">13</a> Another safety issue could be the potential for plasmid DNA in food to transfect human cells and integrate into their genome at sites that can activate oncogenes which may lead to cellular oncogenic transformation.<a class="elsevierStyleCrossRef" href="#bib0265">14</a> A third consideration could be that inoculation of significant quantities of plasmid DNA might induce anti-DNA antibodies which have been associated with auto-immune disease in humans.<a class="elsevierStyleCrossRef" href="#bib0270">15</a>Different strategies and modifications, including different adjuvants, conserved and/or optimized antigen sequences, expression under a strong eukaryotic promoter, the inclusion of transcriptional enhancers such as Intron A, different delivery methods or devices, DNA quantity, and DNA booster repeat, have been tested since the DNA vaccine emerged.<a class="elsevierStyleCrossRef" href="#bib0275">16</a> Improvement in both the expression level of an antigen and the efficiency of transfection are essential for enhancing the efficacy of DNA immunization. The efficiency of transfection can be mainly improved by electroporation and the application of adjuvants. Since the electroporation is not applied easily in the poultry field, the use of effective adjuvant can improve the vaccine efficacy to a great extent. Developing potent and safe adjuvants to produce vaccines which are capable of inducing protective and long-lasting immunity has become an expanding field in vaccine development.<a class="elsevierStyleCrossRef" href="#bib0280">17</a> As it was pointed out previously, the conditionally approved H5 influenza DNA vaccine contained a patented adjuvant named ENABL@, which seems to be the main factor behind the success of this vaccine.<a class="elsevierStyleCrossRef" href="#bib0285">18</a>In this review, published reports of various adjuvants used with H5 influenza DNA vaccines were considered and comparative evaluations were conducted on their results and conclusions.Material and methodsThe articles reviewed in this paper were retrieved from the PubMed database. The search was conducted without any time limit and keywords were Influenza ‘AND’ DNA vaccine ‘AND’ adjuvant. Also, some data were collected from the WHO and OIE websites.ResultsEighteen studies which had used different types of adjuvants in the H5 influenza DNA vaccines were reviewed. The adjuvants used in the studies could be generally divided into two types: ‘genetic adjuvants’ and ‘chemical adjuvants’.Genetic adjuvantsGenetic adjuvants are expression vectors which encode active biological proteins such as cell ligand, cytokine, and adhesion protein.<a class="elsevierStyleCrossRef" href="#bib0290">19</a> Genetic adjuvants can improve and modulate the immune response of a DNA vaccine in two general ways: (1) through plasmids encoding cytokines or other immunoreactive proteins co-administered with the main antigen-coding plasmid<a class="elsevierStyleCrossRef" href="#bib0295">20</a>; (2) through the main immunogenic gene fused with DNA sequence coding for a peptide ligand which can bind to the cell surface receptors of the antigen-presenting cells (APCs). Thereby after expression, the antigen would be targeted to the APCs via the interaction between the ligand fused to the antigen and the receptors on the APCs.<a class="elsevierStyleCrossRef" href="#bib0300">21</a> In the first type of the genetic adjuvants, cytokines are produced in a similar manner as the main antigen encoded by the DNA vaccine. For example, Lim and colleagues (2015) co-administered chicken cytokines IL-15 and IL-18 plasmids with the H5 DNA plasmid that significantly enhanced the chickens’ immune responses. The co-administration of the IL-15 encoding plasmid significantly enhanced the HI titer in immunized specific-pathogen-free (SPF) chickens. The co-administration of either IL-15 or IL-18 plasmids also increased the CD4+ T cell population but had no impact on modulating the CD8+ T cell population.<a class="elsevierStyleCrossRef" href="#bib0305">22</a>In one study, a plasmid coding a protein (MDA5) that is capable of detecting replication of positive and negative sense RNA viruses and then induce type 1 interferon gene transcription was used as a genetic adjuvant. In this study, the influenza infection was mimicked by the DNA vaccine to stimulate the innate immune system. To this end, Liniger and colleagues (2012) co-administered a plasmid encoding 483 N-terminal amino acids of the melanoma differentiation-associated gene 5 product (chMDA5) with the HA plasmid to the chickens. The ChMDA5 co-expression induced approximately 10-fold higher HA-specific antibody responses compared to the HA expression alone. The ChMDA5 co-expression enhanced protection against a lethal H5N1 challenge infection in chickens.<a class="elsevierStyleCrossRef" href="#bib0310">23</a> In a similar study, the genetic adjuvant effects of a plasmid encoding X-linked inhibitor of apoptosis (XIAP), as a modulator of apoptosis and a stimulator of inflammatory signaling, were explored on the immunogenicity of an influenza H5 DNA vaccine in mice by Tabatabaeizadeh et al. (2015). Finally, it was concluded that the co-expression of an anti-apoptotic molecular adjuvant with a pro-apoptotic antigen could prolong the duration of antigen expression and enhance the immune response.<a class="elsevierStyleCrossRef" href="#bib0315">24</a> CD40 was another immunoreactive molecule which was used as a molecular adjuvant. It was co-administered as a separate plasmid with the H5-coding sequence to the mice in 2014. The results showed that CD40, as a molecular adjuvant, could significantly enhance the production of anti-HA antibodies and increase the levels of the Th2 cytokines, including IL-4 and IL-6.<a class="elsevierStyleCrossRef" href="#bib0320">25</a>In the second type of genetic adjuvants, the gene of a main antigen is fused with the immunoreactive genes. Thus, the antigen and the immunoreactive genes are expressed as an integrated protein. For example, in two studies in 2010, these were shown that the fusion of the Mycobacterial DNA binding protein 1 (MDP1) gene of Mycobacterium bovis<a class="elsevierStyleCrossRef" href="#bib0325">26</a> and the early secreted antigenic target 6 kDa (ESAT-6) gene of Mycobacterium tuberculosis<a class="elsevierStyleCrossRef" href="#bib0330">27</a> with the encoding H5 gene induced a significantly higher antibody response in chickens than that induced by the H5 encoding plasmid alone. The MDP1 is a major cellular protein produced by the Mycobacterium bovis. This protein has both nucleic acid binding activity and macro-molecular bio-synthesis inhibitory properties, which together play a key role in modulating bacterial growth. The Mycobacterium tuberculosis ESAT-6 is a 95-amino acid protein which has been shown to play a major role in the virulence and immunogenicity caused by Mycobacterium tuberculosis. Studies have shown that Esat-6 elicits both antibody response in human and non-human primates and cell-mediated immunity, which results in the secretion of IFN-γ by T cells.<a class="elsevierStyleCrossRef" href="#bib0330">27</a>HSP70 was the other mycobacterial gene that was fused with the H5 gene. HSP70 molecules act as an antigen carrier and are capable of promoting the antigen presentation of the chaperoned peptides through interactions with receptors on the APCs. Rasoli and colleagues (2010) showed that H5+HSP70 DNA vaccine produced a higher HI antibody titer in chickens than did the simple H5 DNA vaccine.<a class="elsevierStyleCrossRef" href="#bib0335">28</a> The other gene which was fused with the H5 gene to create the H5 DNA vaccine was CD154 (CD40 ligand). CD154 targets the H5 antigen to the APCs, including B cells, macrophages, and dendritic cells (DCs). In a study in 2010, it was concluded that CD40-targeting significantly enhanced the humoral response and conferred partial protection against the genetically distant and highly pathogenic influenza in ducks.<a class="elsevierStyleCrossRef" href="#bib0340">29</a>Chemical adjuvantsThe effects of different chemical adjuvants, as carriers or immunomodulators, on H5 DNA vaccine immunogens have been investigated. Vaxfectin@, Lipofectamin@, and Lipofectin@ are among the industrialized liposomal adjuvants that can carry the DNA vaccine and improve its transfection.<a class="elsevierStyleCrossRefs" href="#bib0345">30–32</a> Also, the cationic derivatives of the polyprenols (PTAI) were tested with the help of neutral lipids, such as DOPE (1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine), DC-cholesterol [{3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl] cholesterol} hydrochloride], or DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) in chickens.<a class="elsevierStyleCrossRef" href="#bib0345">30</a> Cationic lipids, as DNA vehicles, are able to interact spontaneously with negatively charged nucleic acid forming lipoplexes (lipid–nucleic acid complexes). Non-specific interactions with the surface of the cellular membrane stimulate the uptake of the lipoplexes by the cells via endocytosis while the presence of helper lipids, such as DOPE, DC, or DOPC, modifies the properties of the lipoplexes and facilitates DNA release from endosomes. Stachyra and colleagues (2014) found that the mixture of PTAI and a helper lipid could induce a strong humoral response to the antigen encoded by the DNA vaccine plasmid. The results of the animal immunization added evidence to the claim that PTAI compositions, especially the mixtures of PTAI and DOPE and DC-cholesterol, could work as an effective carrier of DNA vaccine, comparable to the commercially available lipid transfection reagents.<a class="elsevierStyleCrossRef" href="#bib0345">30</a> Another chemical adjuvant called silver nanoparticles (AgNP) with polyethylene glycol (PEG) was evaluated as a carrier in the oral vaccination of the H5 DNA vaccine in chickens. Jazayeri and colleagues (2012) showed that AgNP+H5 enhanced both pro-inflammatory and Th1-like cytokine expression.<a class="elsevierStyleCrossRef" href="#bib0360">33</a> The adjuvant effects of natural products, such as Nigella sativa oil, were also investigated by Mady et al. (2013). Nigella sativa oil was used as an immunostimulant adjuvant in an H5-based DNA vaccine, which induced a potent cell-mediated response in chickens.<a class="elsevierStyleCrossRef" href="#bib0365">34</a> As one of the phenyl analogs of alpha-galactosylceramide (alpha-GalCer), C34 was another chemical adjuvant that was examined by Hung et al. (2014). The adjuvant effects of C34 on the H5 DNA vaccine were assessed in mice and the results showed that the H5 DNA vaccine could not only enhance the humoral immune response and protect the mice against the virus challenge but also broaden the spectrum of neutralization against the pseudotyped HA viruses.<a class="elsevierStyleCrossRef" href="#bib0370">35</a>In recent studies, researchers have used both chemical and genetic adjuvants. For example, Redkiewicz and colleagues (2017) benefited from kB gene segment, that is recognized by cytoplasmic NF-kB (nuclear factor kappa light-chain enhance of activated B cells) and resulted in enhanced transcription and expression of downstream genes. They improved the H5 influenza DNA plasmid immunogenicity in chickens by using kB gene as a genetic adjuvant, plus Lipofectin@ as a chemical adjuvant.<a class="elsevierStyleCrossRef" href="#bib0375">36</a> Also, Bahadoran and colleagues (2017) combined an interferon regulatory factor 3 (IRF-3) gene with a H5 influenza DNA plasmid vaccine as a genetic adjuvant and a polyamidoamine (PAMAM) dendrimer conjugated with HIV-1 transactivator of transcription (TAT) peptide as a chemical adjuvant to enhance H5 influenza antibody responses. They reported that the IRF3 gene and TAT-PMAM compound together induced the immune response of the H5 DNA vaccine in mice more than did the other groups containing only the chemical or the genetic adjuvants.<a class="elsevierStyleCrossRef" href="#bib0380">37</a>Different types of genetic and/or chemical adjuvants used for the H5 influenza DNA vaccine are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>DiscussionIn this review, we summarized the previous research on the influenza H5 DNA vaccines co-administered with different genetic and/or chemical adjuvants. Although different assays, including ELISA, virus neutralization, ELISpot, flow cytometry, and cell proliferation, have been used to evaluate immunological responses in different H5 DNA vaccine studies, we only used the results from the Hemagglutination Inhibition (HI) assay to compare the immunogenicity of different DNA vaccines. The HI assay is a well-established test for measuring the antibody response against the hemagglutinin of the influenza virus and shows good correlation with the influenza virus neutralization tests.<a class="elsevierStyleCrossRef" href="#bib0385">38</a> This test was frequently used in almost all influenza vaccine studies while other immunological tests were performed only sporadically; thus, it can be stated that the latter groups of tests are not good candidates for comparing the studies on H5 DNA vaccines. Although, the correlation between HI tier and protection against lethal challenge is not straightforward (chickens with HI titer could die after challenge while chicken with negative HI titer survive), because the protection against challenge is a very critical index in determining of the efficacy of a vaccine, the result of these experiments were also summarized when available in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.Among the genetic adjuvants, the Esat-6 gene of Mycobacterium tuberculosis induced the highest humoral response against influenza H5. Overall, the highest HI titers (log2) in all experiments varied between 6 and 7, but the highest HI titer was induced by the H5+Esat-6 genes and its value was reported to be as high as 13, which is almost two times higher than that of the other studies. Given that the uncommonly high value reported for the HI titer in this experiment has not been repeated in any other studies, it is safe to consider this value an exceptional value. However, more research should be done to determine what exactly the adjuvant effects of the Esat-6 gene are on H5 DNA vaccines.After the Esat-6 gene, the chicken MDA5 gene induced the most potent humoral response. By employing the fact that innate immune activation leads to an adaptive immune response, Liniger and colleagues hypothesized that mimicking virus infection by the DNA vaccine might improve influenza vaccine-induced adaptive immune responses. Pattern-recognition receptors (PRRs) activation triggers an antiviral state interceded regularly by the induction of interferon type I (IFN type I) and the activation of other antiviral proteins. The PRRs that explicitly detect the intracellular viral RNA are the cytosolic RIG-I-like receptors (RLR), which contain the helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). An important point in this regard is that chickens lack RIG-I protein. Instead, they detect the viral dsRNA by the MDA5 factor. A group of researchers co-administered a plasmid encoding the N-terminal amino acids of chMDA5 with an H5 DNA vaccine plasmid to directly activate the RIG-I-like signaling pathway. The result showed that this strategy could significantly elevate the H5 antibody response (6.6 mean HI titer), leading to the protection of chickens against a lethal H5N1 influenza challenge.<a class="elsevierStyleCrossRef" href="#bib0350">31</a> After MDA5, CD154 gene induced the highest HI titer by targeting the H5 antigen to APCs,<a class="elsevierStyleCrossRef" href="#bib0345">30</a> but the mean HI titer of 6.5 was reached only after 4 or 5 DNA vaccine boosters which complicates its potential use for field vaccination programs.In other studies, the immunomodulators, such as cytokines, and immunostimulators, such as mycobacterial components, have been exploited as the genetic adjuvants (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). A comparison of the cytokines revealed that the co-administration of IL-15 plasmid with H5 plasmid induced two times more H5 specific antibody than did the co-administration of IL-18 plasmid with H5 plasmid (4 vs. 2.7 mean HI titer, respectively).<a class="elsevierStyleCrossRef" href="#bib0300">21</a> Although the co-administration of XIAP plasmid to inhibit the apoptosis of the H5 plasmid-transfected cells did not considerably elevate the humoral response (3 mean HI titer),<a class="elsevierStyleCrossRef" href="#bib0315">24</a> it induced more antibody than did the IL-18 plasmid. Plasmids encoding genes of Mycobacterium spp. and the IL-15 plasmids elicited the same HI titer value, but it must be noted that the mycobacterial genetic adjuvants were administered three times (two boosters) while the IL-15 genetic adjuvant was administered only once (one booster).Both silver nanoparticle (AgNP) and Lipofectin® were potent chemical adjuvants for the H5 DNA vaccine in inducing a humoral response in chickens. The advantages of AgNP that made it applicable to the poultry industry were the oral route of administration and reaching of the highest HI titer without any booster.<a class="elsevierStyleCrossRef" href="#bib0360">33</a> Lipofectin® was the most potent adjuvant among IM administered DNA vaccines in chickens. This DNA carrier was originally used as a commercial transfection reagent and was then tested as the DNA vaccine adjuvant, but it appears that it is too expensive to be an affordable DNA vaccine adjuvant in the poultry industry. The adjuvant effects of cationic derivatives of polyprenols (PTAI) on the induction of H5-specific antibody were comparable with those of the commercialized carriers of the DNA vaccine, such as Vaxfectin®, Lipofectamin®, and Lipofectin®. However, they may be applicable for human H5 DNA vaccine, as shown in a clinical trial by Smith and colleagues.<a class="elsevierStyleCrossRef" href="#bib0355">32</a>Different factors, including the viral strain of hemagglutinin gene, the plasmid type, the dose and route of administration, the intervals, the number of boosters, the host species, and the day of sampling post-vaccination, could affect the immunogenicity of a DNA vaccine. Although these factors varied in different studies, in the present review, we tried to compare the highest mean of HI titers induced by these adjuvants. The mean of the highest HI titers elicited by all genetic adjuvants and chemical adjuvants was 5.45 and 5, respectively, which shows that the two types of adjuvants were not significantly different. Due to the fact that the means of the highest HI titers elicited by the genetic and chemical adjuvants were close to each other, it can be observed that one adjuvant type could not be preferred to the other type. So, the use of both genetic and chemical adjuvants may synergistically improve the immunogenicity of the H5 DNA vaccine. For example, Stachyra et al. (2014) used Lipofectin® as a chemical adjuvant and reached to 5.6 mean HI titer after 42 days. While, Redkiewicz et al. (2017) applied both genetic (kB gene) and chemical adjuvants (Lipofectin®) in the H5 DNA vaccine and reached to the same HI titer one week earlier (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).As there has been no publications of results at this time of the H5 DNA vaccine containing ENABL adjuvant, this adjuvant was not included in the review. However, recent commercialisation of the H5 DNA/ENABL vaccines requires some comment on its nature. ENABL® is a patented adjuvant technology that features a unique lipid/polymer matrix for more efficient vaccine delivery. The use of this technology can result in the higher level absorption of the vaccine plasmid into the target cells, leading to a greater immune response. ENABL® also gives the potential for reduction in the number of vaccine doses or even to induce an immune response after a single dose. Other benefits of ENABL® include improved safety with the injection site reactions and less risk of carcass condemnation. Due to its unique lipid/polymer matrix, ENABL®, compared to its counterparts, has a greater loading capacity that allows for higher antigen-to-adjuvant ratios and greater potential for development of multivalent vaccines.<a class="elsevierStyleCrossRef" href="#bib0285">18</a>ConclusionDNA vaccines can be one of the front-line tools in the fight against the current and emerging animal diseases because it can be developed far faster than conventional vaccines. Finding an effective and safe adjuvant could be the key to success in the DNA vaccine field, as it was shown in the recently licensed H5 influenza DNA vaccine for chickens contained ENABL® adjuvant. As the manufacturer claims this new adjuvant, ENABL®, is a safe and effective adjuvant, it is advisable that independent researchers evaluate its efficiency experimentally to elucidate its strengths and weaknesses. By comparing the results of different studies on the DNA vaccine adjuvants, it could be concluded that the formulation of an H5 DNA vaccine with both Lipofectin® as the most potent chemical adjuvant and Esat-6 gene of Mycobacterium tuberculosis as the best genetic adjuvant would potentially produce the optimized DNA vaccine against H5 influenza virus for chickens. Also, PTAI could be formulated in a H5 influenza DNA vaccine instead of Lipofectin® to make the adjuvant more affordable. Additionally, it seems that AgNP could be a potent candidate adjuvant for oral H5 influenza DNA vaccine. Finally, more research is needed to find optimum adjuvants for DNA vaccine use in routine vaccination programs.FundingThis research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.Conflict of interestNone." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1519860" "titulo" => "Abstract" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Results" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1378172" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1519859" "titulo" => "Resumen" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Resultados" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1378173" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "H5 influenza virus" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "DNA vaccine" ] ] ] 5 => array:2 [ "identificador" => "sec0020" "titulo" => "Material and methods" ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Genetic adjuvants" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Chemical adjuvants" ] ] ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-05-26" "fechaAceptado" => "2020-09-30" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1378172" "palabras" => array:5 [ 0 => "Genetic adjuvant" 1 => "Chemical adjuvant" 2 => "DNA vaccine" 3 => "H5 subtype" 4 => "Influenza virus" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1378173" "palabras" => array:5 [ 0 => "Adyuvante genético" 1 => "Adyuvante químico" 2 => "Vacuna de ADN" 3 => "Subtipo H5" 4 => "Virus de la gripe" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectivesThe H5 influenza virus constantly evolves by mutation and re-assortment and results in the emergence of new subtypes. The DNA vaccine may be an ideal candidate vaccine for influenza virus because it can be developed rapidly in response to the new subtypes of influenza viral genes. As, finding an efficient H5 influenza DNA vaccine is still challenging, we aimed to review the articles which have reported the effects of an adjuvant on the H5 influenza DNA vaccines. ResultsDifferent types of adjuvants have been co-administered with the H5 influenza DNA vaccines. These adjuvants are generally divided into two types: ‘genetic adjuvants’ and ‘chemical adjuvants’. Among the genetic adjuvants, the Esat-6 gene of Mycobacterium tuberculosis was found to induce the highest humoral response. Both Lipofectin® and silver nanoparticle (AgNP) were potent chemical adjuvants for DNA vaccine in chickens via IM and oral administration routes, respectively. ConclusionIt could be concluded that the formulation of an H5 DNA vaccine with both Lipofectin® as the most potent chemical adjuvant and Esat-6 gene of Mycobacterium tuberculosis as the best genetic adjuvant is proposed for chicken immunization against H5 influenza virus. Also, the cationic derivatives of the polyprenols (PTAI) can be formulated in DNA vaccine instead of Lipofectin® to make the adjuvant more affordable. Additionally, it seems that AgNP could be a potent candidate adjuvant for the oral H5 influenza DNA vaccine. Finally, more research is needed to find better adjuvants to include DNA vaccines as an applied vaccine type." "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Results" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivosEl virus de la gripe H5 está en constante evolución por mutación y recombinación, lo cual origina la aparición de nuevos subtipos. La vacuna de ADN podría ser una candidata ideal como vacuna frente al virus de la gripe, ya que puede desarrollarse rápidamente como respuesta a los nuevos subtipos de los genes virales de gripe. Como encontrar una vacuna de ADN eficaz frente a la gripe H5 es aún difícil, nuestro objetivo fue revisar los artículos que han reportado los efectos de un adyuvante en las vacunas de ADN frente a la gripe H5. ResultadosSe han co-administrado diferentes tipos de adyuvantes junto con las vacunas de ADN frente a la gripe H5. Dichos adyuvantes se dividen por lo general en 2 tipos: «adyuvantes genéticos» y «adyuvantes químicos». Entre los adyuvantes genéticos, se encontró que el gen Esat-6 de Mycobacterium tuberculosis inducía la mayor respuesta humoral. Tanto Lipofectin® como las nanopartículas de plata (AgNP) fueron adyuvantes químicos potentes para la vacuna de ADN en pollos, a través de las vías IM y de administración oral, respectivamente. ConclusiónPodría concluirse que se propone la formulación de una vacuna de ADN frente a la gripe H5 con Lipofectin®, como adyuvante químico más potente, y el gen Esat-6 de Mycobacterium tuberculosis como el mejor adyuvante genético para inmunización de pollos frente al virus de la gripe H5. También podrían formularse en la vacuna de ADN los derivados catiónicos de los poliprenoles (PTAI) en lugar de Lipofectin® para hacer que el adyuvante fuera más asequible. Además, parece que AgNP podría ser un potente candidato a adyuvante para la vacuna oral de ADN frente a la gripe H5. Por último, se necesita más investigación para encontrar mejores adyuvantes a incluir en vacunas de ADN como tipo de vacuna aplicada." "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0020" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0025" "titulo" => "Resultados" ] 2 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusión" ] ] ] ] "multimedia" => array:2 [ 0 => array:9 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Data source: OIE website.<a class="elsevierStyleCrossRef" href="#bib0390">39</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">Region \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Poultry losses \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">Africa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8,291,669 \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">America \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28,224,324 \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">Asia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71,326,121 \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">Europe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14,260,122 \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">Oceania \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">490,000 \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">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">122,592,236 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2610061.png" ] ] ] ] "descripcion" => array:1 [ "en" => "The losses, including animals killed or disposed of, due to the H5 influenza outbreaks in domestic birds by region from January 2013 to August 2018. There is no report for total poultry losses due to H5 influenza outbreaks in domestic birds after August 2018." ] ] 1 => 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:2 [ "leyenda" => "Abbreviations: DPV: days post first vaccination; AgNP: silver nanoparticles; C34: phenyl analogs of alpha-galactosylceramide; PTAI: cationic derivatives of polyprenols; iNKT: invariant natural killer T; M.: Mycobacterium." "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">Gene/chemical name \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Role \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Protective efficacy \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Administration (type/booster times) \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene source/tested organism \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Highest mean HI/DPV \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reference \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" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Genetic adjuvants</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">IL-15 \t\t\t\t\t\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">Immuno-modulator (Cytokine) \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/one \t\t\t\t\t\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">Chicken/Chicken \t\t\t\t\t\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">4/35 \t\t\t\t\t\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">Lim et al., 2012 \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">IL-18 \t\t\t\t\t\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">Immuno-modulator (Cytokine) \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/one \t\t\t\t\t\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">Chicken/Chicken \t\t\t\t\t\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">2.7/35 \t\t\t\t\t\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">Lim et al., 2012 \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">MDA5 \t\t\t\t\t\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">Mimicking virus infection \t\t\t\t\t\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">83% \t\t\t\t\t\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">IM/one \t\t\t\t\t\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">Chicken/Chicken \t\t\t\t\t\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">6.6/43 \t\t\t\t\t\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">Liniger et al., 2012 \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">XIAP \t\t\t\t\t\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">Inhibition of apoptosis \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/one \t\t\t\t\t\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">Mouse/Mouse \t\t\t\t\t\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">3/35 \t\t\t\t\t\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">Tabatabaeizadeh et al., 2015 \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">MDP-1 \t\t\t\t\t\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">Immuno-stimulator \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/two \t\t\t\t\t\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">M. bovis/Chicken \t\t\t\t\t\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">3.7/35 \t\t\t\t\t\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">Jalilian et al., 2010 \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">Esat-6 \t\t\t\t\t\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">Immuno-stimulator \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/two \t\t\t\t\t\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">M. tuberculosis/Chicken \t\t\t\t\t\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">13/42 \t\t\t\t\t\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">Oveissi et al., 2010 \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">CD154 \t\t\t\t\t\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">Antigen targeting \t\t\t\t\t\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">100% \t\t\t\t\t\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">IM/four or five \t\t\t\t\t\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">Duck/Duck \t\t\t\t\t\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">6.5/140 \t\t\t\t\t\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">Yao et al., 2010 \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">CD40 \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/two \t\t\t\t\t\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">Mouse/Mouse \t\t\t\t\t\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">NA \t\t\t\t\t\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">Chen et al., 2014 \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">Antigen targeting \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/two \t\t\t\t\t\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">M. tuberculosis/Chicken \t\t\t\t\t\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">4.1/35 \t\t\t\t\t\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">Rasoli et al., 2010 \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 " colspan="7" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chemical adjuvants</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">AgNP \t\t\t\t\t\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">DNA vaccine carrier \t\t\t\t\t\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">NA \t\t\t\t\t\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">Oral/none \t\t\t\t\t\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">Chicken \t\t\t\t\t\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">5.6/35 \t\t\t\t\t\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">Jazayeri et al., 2012 \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">Nigella sativa \t\t\t\t\t\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">Immunostimulant \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/none \t\t\t\t\t\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">Chicken \t\t\t\t\t\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">NA \t\t\t\t\t\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">Mady et al., 2013 \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">C34 \t\t\t\t\t\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">Activates iNKT cells \t\t\t\t\t\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">85% \t\t\t\t\t\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">IM+EP/none \t\t\t\t\t\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">Mouse \t\t\t\t\t\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">NA \t\t\t\t\t\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">Hung et al., 2014 \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">PTAI \t\t\t\t\t\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">Liposomal carrier \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/one \t\t\t\t\t\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">Chicken \t\t\t\t\t\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">4/28 \t\t\t\t\t\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">Stachyra et al., 2017 \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">Vaxfectin \t\t\t\t\t\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">Liposomal carrier \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/one \t\t\t\t\t\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">Human \t\t\t\t\t\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">5.8/56 \t\t\t\t\t\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">Smith et al., 2010 \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">Lipofectamine \t\t\t\t\t\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">Liposomal carrier \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/none \t\t\t\t\t\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">Chicken \t\t\t\t\t\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">4/28 \t\t\t\t\t\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">Mady et al., 2013 \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">Lipofectin \t\t\t\t\t\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">Liposomal carrier \t\t\t\t\t\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">100% \t\t\t\t\t\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">IM/one \t\t\t\t\t\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">Chicken \t\t\t\t\t\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">5.6/42 \t\t\t\t\t\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">Stachyra et al., 2014 \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 " colspan="7" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Both adjuvants</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">κB/Lipofectin \t\t\t\t\t\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">Targeting DNA vaccine to the cell nucleus \t\t\t\t\t\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">NA \t\t\t\t\t\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">IM/one \t\t\t\t\t\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">Chicken \t\t\t\t\t\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">5.5/35 \t\t\t\t\t\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">Redkiewicz et al., 2017 \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">IRF3/PMAM-TAT \t\t\t\t\t\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">Improved gene delivery \t\t\t\t\t\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">NA \t\t\t\t\t\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">ID/one \t\t\t\t\t\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">Mouse/Mouse \t\t\t\t\t\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">3.1/35 \t\t\t\t\t\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">Bahadoran et al., 2017 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2610060.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Different adjuvants used for H5 influenza DNA vaccine." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:39 [ 0 => array:3 [ "identificador" => "bib0200" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "AgriLabs. First DNA vaccine licensed for chickens. PR newswire: Cision. <a target="_blank" href="https://www.prnewswire.com/news-releases/first-dna-vaccine-licensed-for-chickens-300554855.html">https://www.prnewswire.com/news-releases/first-dna-vaccine-licensed-for-chickens-300554855.html</a>." ] ] ] 1 => array:3 [ "identificador" => "bib0205" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immunologic responses to West Nile virus in vaccinated and clinically affected horses" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.H. Davidson" 1 => "J.L. Traub-Dargatz" 2 => "R.M. Rodeheaver" 3 => "E.N. Ostlund" 4 => "D.D. Pedersen" 5 => "R.G. 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Review article

Simultaneous formulation of chemical and genetic adjuvants could result in finding an efficient H5 influenza DNA vaccine

La formulación simultánea de adyuvantes químicos y genéticos podría conducir al hallazgo de una vacuna de ADN eficaz frente a la gripe H5

M. Ghaemia,

Corresponding author

m.ghaemi@shirazu.ac.ir

Corresponding author.

, S-E. Tabtabaeizadehb

a Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

b Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Mashhad, Iran

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        "autoresLista" => "M&#46; Ghaemi, S-E&#46; Tabtabaeizadeh"
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          0 => array:4 [
            "nombre" => "M&#46;"
            "apellidos" => "Ghaemi"
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              0 => "m.ghaemi@shirazu.ac.ir"
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        "afiliaciones" => array:2 [
          0 => array:3 [
            "entidad" => "Department of Pathobiology&#44; School of Veterinary Medicine&#44; Shiraz University&#44; Shiraz&#44; Iran"
            "etiqueta" => "a"
            "identificador" => "aff0005"
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          1 => array:3 [
            "entidad" => "Razi Vaccine and Serum Research Institute&#44; Agricultural Research&#44; Education and Extension Organization &#40;AREEO&#41;&#44; Mashhad&#44; Iran"
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            "identificador" => "aff0010"
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    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "La formulaci&#243;n simult&#225;nea de adyuvantes qu&#237;micos y gen&#233;ticos podr&#237;a conducir al hallazgo de una vacuna de ADN eficaz frente a la gripe H5"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">DNA vaccine&#44; as a third generation vaccine&#44; appeared as a new approach to solve some of the perennial problems&#44; such as the lack of immunogenicity or the reversion of pathogenicity&#44; which had been associated with conventional vaccines&#46; The initial enthusiasm for the DNA vaccine decreased gradually because&#44; first&#44; it could not meet some of the expectations and&#44; secondly&#44; it could not be used commonly for the immunization of humans or animals due to the limitations in plasmid delivery and its lack of immunogenicity&#46; In November 2017&#44; a breakthrough occurred in the field of DNA vaccines&#46; The USDA gave its first conditional approval to a DNA vaccine for chickens&#44; which was a DNA vaccine against the highly pathogenic H5 influenza virus&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">1</span></a> This was the first veterinary DNA vaccine approved for influenza and among the first DNA vaccines authorized in the US for food-producing animals&#46; Some of the DNA vaccines licensed for veterinary applications are against the following agents and disorders&#58; West Nile Virus for horses in 2005&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">2</span></a> infectious hematopoietic necrosis virus for salmon in 2005&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">3</span></a> and melanoma cancer for dogs approved conditionally in 2007 and with full licensure in 2010&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">4</span></a> Growth hormone-releasing factor&#44; encoded by a plasmid DNA for pigs&#44; was approved in 2007 for application in gene delivery&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a> This recently approved H5 influenza DNA vaccine is significant because of its target species&#44; which is chicken&#44; and its target agent&#44; which is the H5 influenza virus&#46; As the chicken is the most industrialized poultry affected by the influenza virus&#44; this vaccine can greatly help the poultry industries and the governments to combat the H5 influenza virus worldwide&#46; Also&#44; because the H5 subtype is one of the deadliest zoonotic influenza subtypes and a potential danger for public health&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a> this vaccine can be considered as a step forward to develop an H5 influenza DNA vaccine for human immunization&#46; As&#44; finding an efficient H5 influenza DNA vaccine is still challenging&#44; we aimed to review the articles which have reported the effects of an adjuvant on the H5 influenza DNA vaccines&#46;</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">H5 influenza virus</span><p id="par0010" class="elsevierStylePara elsevierViewall">Influenza virus is one of the most important disease agents worldwide circulating between birds&#44; animals and human&#46; In 1918&#44; the influenza pandemic&#44; in what is still one of the deadliest disease outbreaks in recorded history&#44; infected 500 million people around the world and 50&#8211;100 million people&#44; which was equal to 3&#8211;5&#37; of the world&#39;s population at the time&#44; died because of the virus&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">7</span></a> During the H5 influenza virus panzootic&#44; which started in 2004&#44; many warned that we might encounter another influenza pandemic because the H5 influenza virus could infect humans with more than 50&#37; mortality rate&#46; Since 2003&#44; and as of 15 February 2019&#44; 860 laboratory-confirmed cases of human infection&#44; including 454 deaths&#44; with the H5N1 influenza virus have been reported from 16 Asian countries&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Also&#44; Influenza virus has been caused severe effects on the poultry industry in different countries&#46; For example&#44; in the last world organization for animal health &#40;OIE&#41; report of total poultry losses due to H5 influenza outbreaks&#44; approximately 122 million birds were killed or died from January 2013 to August 2018 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The influenza virus constantly evolves by mutation and re-assortment with the emergence of new subtypes and can evade the host immune system&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> Therefore&#44; to be protective&#44; the influenza vaccine must be adapted to the new evolved subtypes&#46; Currently&#44; an inactivated vaccine&#44; prepared from the egg-propagated virus&#44; is commonly used for immunization against the influenza virus&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> Nevertheless&#44; it is clear that contemporary influenza vaccines should be more flexible and universal&#44; and&#44; in particular&#44; they need to be produced faster in case of a new influenza outbreak&#46; Such required features can be found in DNA vaccines&#44; which can be developed rapidly according to the new subtypes of influenza viral genes&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">DNA vaccine</span><p id="par0025" class="elsevierStylePara elsevierViewall">The characteristics of DNA vaccines make them a suitable vaccine candidate for different evolving disease agents&#46; A DNA vaccine is usually an efficient eukaryotic expression plasmid&#44; which contains the gene of a candidate antigen&#40;s&#41;&#46; After the DNA vaccine plasmids are inoculated&#44; the plasmid can transfect the cells of the inoculation site&#46; They must enter the cells and be expressed efficiently so the target antigen can be produced and propagated&#46; If the DNA vaccine plasmids coding for appropriate target antigen cannot enter the nucleus of the cells&#44; due to the lack of the immunogenic protein production&#44; DNA vaccine will not elicit a sufficient immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">10</span></a> DNA vaccine development is generally based on the synthesis of the nucleic acid for codon-optimized genes or possibly the cloning of an appropriate gene from a pathogen into the expression plasmid&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">11</span></a> The DNA vaccine has different features that make it a highly efficient vaccine type for influenza control&#46; While the inactivated influenza vaccines mostly induce antibody production to protect the body effectively&#44; the DNA vaccines can efficiently elicit both humoral and cell-mediated immune responses&#46; To produce DNA vaccines&#44; unlike what is involved in the process of killed influenza vaccine production&#44; there is no need to grow live viruses&#44; and if a pandemic influenza emerges&#44; the DNA vaccine production can quickly be scaled up&#46; A DNA vaccine is also extremely stable at room temperature and that obviates the cold chain which is needed for most of the other vaccines&#46; Additionally&#44; a DNA plasmid is generally produced in bacterial culture which simplifies the purification process compared with that for viral culture using cell cultures or chicken embryos&#44; potentially containing infectious pathogens&#46; Thus&#44; this process of production taking place in bacterial culture improves the safety of the DNA vaccine considerably&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">12</span></a> On the other hand&#44; the use of DNA vaccine has some concerns which are based mainly on safety issues&#46; One of the safety issues concerning DNA vaccination in livestock and poultry eaten by humans could be potential transfection of the plasmid containing an antibiotic resistance gene to alimentary tract bacteria&#44; persisting in them and subsequently spreading antibiotic resistance genes to other bacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">13</span></a> Another safety issue could be the potential for plasmid DNA in food to transfect human cells and integrate into their genome at sites that can activate oncogenes which may lead to cellular oncogenic transformation&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">14</span></a> A third consideration could be that inoculation of significant quantities of plasmid DNA might induce anti-DNA antibodies which have been associated with auto-immune disease in humans&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">15</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Different strategies and modifications&#44; including different adjuvants&#44; conserved and&#47;or optimized antigen sequences&#44; expression under a strong eukaryotic promoter&#44; the inclusion of transcriptional enhancers such as Intron A&#44; different delivery methods or devices&#44; DNA quantity&#44; and DNA booster repeat&#44; have been tested since the DNA vaccine emerged&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">16</span></a> Improvement in both the expression level of an antigen and the efficiency of transfection are essential for enhancing the efficacy of DNA immunization&#46; The efficiency of transfection can be mainly improved by electroporation and the application of adjuvants&#46; Since the electroporation is not applied easily in the poultry field&#44; the use of effective adjuvant can improve the vaccine efficacy to a great extent&#46; Developing potent and safe adjuvants to produce vaccines which are capable of inducing protective and long-lasting immunity has become an expanding field in vaccine development&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">17</span></a> As it was pointed out previously&#44; the conditionally approved H5 influenza DNA vaccine contained a patented adjuvant named ENABL&#64;&#44; which seems to be the main factor behind the success of this vaccine&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">18</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In this review&#44; published reports of various adjuvants used with H5 influenza DNA vaccines were considered and comparative evaluations were conducted on their results and conclusions&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><p id="par0040" class="elsevierStylePara elsevierViewall">The articles reviewed in this paper were retrieved from the PubMed database&#46; The search was conducted without any time limit and keywords were Influenza &#8216;AND&#8217; DNA vaccine &#8216;AND&#8217; adjuvant&#46; Also&#44; some data were collected from the WHO and OIE websites&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0045" class="elsevierStylePara elsevierViewall">Eighteen studies which had used different types of adjuvants in the H5 influenza DNA vaccines were reviewed&#46; The adjuvants used in the studies could be generally divided into two types&#58; &#8216;genetic adjuvants&#8217; and &#8216;chemical adjuvants&#8217;&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Genetic adjuvants</span><p id="par0050" class="elsevierStylePara elsevierViewall">Genetic adjuvants are expression vectors which encode active biological proteins such as cell ligand&#44; cytokine&#44; and adhesion protein&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">19</span></a> Genetic adjuvants can improve and modulate the immune response of a DNA vaccine in two general ways&#58; &#40;1&#41; through plasmids encoding cytokines or other immunoreactive proteins co-administered with the main antigen-coding plasmid<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">20</span></a>&#59; &#40;2&#41; through the main immunogenic gene fused with DNA sequence coding for a peptide ligand which can bind to the cell surface receptors of the antigen-presenting cells &#40;APCs&#41;&#46; Thereby after expression&#44; the antigen would be targeted to the APCs via the interaction between the ligand fused to the antigen and the receptors on the APCs&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">21</span></a> In the first type of the genetic adjuvants&#44; cytokines are produced in a similar manner as the main antigen encoded by the DNA vaccine&#46; For example&#44; Lim and colleagues &#40;2015&#41; co-administered chicken cytokines IL-15 and IL-18 plasmids with the H5 DNA plasmid that significantly enhanced the chickens&#8217; immune responses&#46; The co-administration of the IL-15 encoding plasmid significantly enhanced the HI titer in immunized specific-pathogen-free &#40;SPF&#41; chickens&#46; The co-administration of either IL-15 or IL-18 plasmids also increased the CD4<span class="elsevierStyleSup">&#43;</span> T cell population but had no impact on modulating the CD8<span class="elsevierStyleSup">&#43;</span> T cell population&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">22</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In one study&#44; a plasmid coding a protein &#40;MDA5&#41; that is capable of detecting replication of positive and negative sense RNA viruses and then induce type 1 interferon gene transcription was used as a genetic adjuvant&#46; In this study&#44; the influenza infection was mimicked by the DNA vaccine to stimulate the innate immune system&#46; To this end&#44; Liniger and colleagues &#40;2012&#41; co-administered a plasmid encoding 483 N-terminal amino acids of the melanoma differentiation-associated gene 5 product &#40;chMDA5&#41; with the HA plasmid to the chickens&#46; The ChMDA5 co-expression induced approximately 10-fold higher HA-specific antibody responses compared to the HA expression alone&#46; The ChMDA5 co-expression enhanced protection against a lethal H5N1 challenge infection in chickens&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">23</span></a> In a similar study&#44; the genetic adjuvant effects of a plasmid encoding X-linked inhibitor of apoptosis &#40;XIAP&#41;&#44; as a modulator of apoptosis and a stimulator of inflammatory signaling&#44; were explored on the immunogenicity of an influenza H5 DNA vaccine in mice by Tabatabaeizadeh et al&#46; &#40;2015&#41;&#46; Finally&#44; it was concluded that the co-expression of an anti-apoptotic molecular adjuvant with a pro-apoptotic antigen could prolong the duration of antigen expression and enhance the immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">24</span></a> CD40 was another immunoreactive molecule which was used as a molecular adjuvant&#46; It was co-administered as a separate plasmid with the H5-coding sequence to the mice in 2014&#46; The results showed that CD40&#44; as a molecular adjuvant&#44; could significantly enhance the production of anti-HA antibodies and increase the levels of the Th2 cytokines&#44; including IL-4 and IL-6&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">25</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In the second type of genetic adjuvants&#44; the gene of a main antigen is fused with the immunoreactive genes&#46; Thus&#44; the antigen and the immunoreactive genes are expressed as an integrated protein&#46; For example&#44; in two studies in 2010&#44; these were shown that the fusion of the Mycobacterial DNA binding protein 1 &#40;<span class="elsevierStyleItalic">MDP1</span>&#41; gene of <span class="elsevierStyleItalic">Mycobacterium bovis</span><a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">26</span></a> and the early secreted antigenic target 6 kDa &#40;<span class="elsevierStyleItalic">ESAT-6</span>&#41; gene of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span><a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">27</span></a> with the encoding <span class="elsevierStyleItalic">H5</span> gene induced a significantly higher antibody response in chickens than that induced by the H5 encoding plasmid alone&#46; The MDP1 is a major cellular protein produced by the <span class="elsevierStyleItalic">Mycobacterium bovis</span>&#46; This protein has both nucleic acid binding activity and macro-molecular bio-synthesis inhibitory properties&#44; which together play a key role in modulating bacterial growth&#46; The <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> ESAT-6 is a 95-amino acid protein which has been shown to play a major role in the virulence and immunogenicity caused by <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span>&#46; Studies have shown that Esat-6 elicits both antibody response in human and non-human primates and cell-mediated immunity&#44; which results in the secretion of IFN-&#947; by T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">27</span></a><span class="elsevierStyleItalic">HSP70</span> was the other mycobacterial gene that was fused with the <span class="elsevierStyleItalic">H5</span> gene&#46; HSP70 molecules act as an antigen carrier and are capable of promoting the antigen presentation of the chaperoned peptides through interactions with receptors on the APCs&#46; Rasoli and colleagues &#40;2010&#41; showed that H5<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HSP70 DNA vaccine produced a higher HI antibody titer in chickens than did the simple H5 DNA vaccine&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">28</span></a> The other gene which was fused with the H5 gene to create the H5 DNA vaccine was <span class="elsevierStyleItalic">CD154</span> &#40;CD40 ligand&#41;&#46; CD154 targets the H5 antigen to the APCs&#44; including B cells&#44; macrophages&#44; and dendritic cells &#40;DCs&#41;&#46; In a study in 2010&#44; it was concluded that CD40-targeting significantly enhanced the humoral response and conferred partial protection against the genetically distant and highly pathogenic influenza in ducks&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Chemical adjuvants</span><p id="par0065" class="elsevierStylePara elsevierViewall">The effects of different chemical adjuvants&#44; as carriers or immunomodulators&#44; on H5 DNA vaccine immunogens have been investigated&#46; Vaxfectin&#64;&#44; Lipofectamin&#64;&#44; and Lipofectin&#64; are among the industrialized liposomal adjuvants that can carry the DNA vaccine and improve its transfection&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">30&#8211;32</span></a> Also&#44; the cationic derivatives of the polyprenols &#40;PTAI&#41; were tested with the help of neutral lipids&#44; such as DOPE &#40;1&#44;2-dioleoyl-sn-glycero-3-phosphatidylethanolamine&#41;&#44; DC-cholesterol &#91;&#123;3&#946;-&#91;N-&#40;N&#8242;&#44;N&#8242;-dimethylaminoethane&#41;-carbamoyl&#93; cholesterol&#125; hydrochloride&#93;&#44; or DOPC &#40;1&#44;2-dioleoyl-sn-glycero-3-phosphatidylcholine&#41; in chickens&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">30</span></a> Cationic lipids&#44; as DNA vehicles&#44; are able to interact spontaneously with negatively charged nucleic acid forming lipoplexes &#40;lipid&#8211;nucleic acid complexes&#41;&#46; Non-specific interactions with the surface of the cellular membrane stimulate the uptake of the lipoplexes by the cells via endocytosis while the presence of helper lipids&#44; such as DOPE&#44; DC&#44; or DOPC&#44; modifies the properties of the lipoplexes and facilitates DNA release from endosomes&#46; Stachyra and colleagues &#40;2014&#41; found that the mixture of PTAI and a helper lipid could induce a strong humoral response to the antigen encoded by the DNA vaccine plasmid&#46; The results of the animal immunization added evidence to the claim that PTAI compositions&#44; especially the mixtures of PTAI and DOPE and DC-cholesterol&#44; could work as an effective carrier of DNA vaccine&#44; comparable to the commercially available lipid transfection reagents&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">30</span></a> Another chemical adjuvant called silver nanoparticles &#40;AgNP&#41; with polyethylene glycol &#40;PEG&#41; was evaluated as a carrier in the oral vaccination of the H5 DNA vaccine in chickens&#46; Jazayeri and colleagues &#40;2012&#41; showed that AgNP<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>H5 enhanced both pro-inflammatory and Th1-like cytokine expression&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">33</span></a> The adjuvant effects of natural products&#44; such as <span class="elsevierStyleItalic">Nigella sativa</span> oil&#44; were also investigated by Mady et al&#46; &#40;2013&#41;&#46; <span class="elsevierStyleItalic">Nigella sativa</span> oil was used as an immunostimulant adjuvant in an H5-based DNA vaccine&#44; which induced a potent cell-mediated response in chickens&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">34</span></a> As one of the phenyl analogs of alpha-galactosylceramide &#40;alpha-GalCer&#41;&#44; C34 was another chemical adjuvant that was examined by Hung et al&#46; &#40;2014&#41;&#46; The adjuvant effects of C34 on the H5 DNA vaccine were assessed in mice and the results showed that the H5 DNA vaccine could not only enhance the humoral immune response and protect the mice against the virus challenge but also broaden the spectrum of neutralization against the pseudotyped HA viruses&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">35</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In recent studies&#44; researchers have used both chemical and genetic adjuvants&#46; For example&#44; Redkiewicz and colleagues &#40;2017&#41; benefited from <span class="elsevierStyleItalic">kB</span> gene segment&#44; that is recognized by cytoplasmic NF-kB &#40;nuclear factor kappa light-chain enhance of activated B cells&#41; and resulted in enhanced transcription and expression of downstream genes&#46; They improved the H5 influenza DNA plasmid immunogenicity in chickens by using <span class="elsevierStyleItalic">kB</span> gene as a genetic adjuvant&#44; plus Lipofectin&#64; as a chemical adjuvant&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">36</span></a> Also&#44; Bahadoran and colleagues &#40;2017&#41; combined an interferon regulatory factor 3 &#40;<span class="elsevierStyleItalic">IRF-3</span>&#41; gene with a H5 influenza DNA plasmid vaccine as a genetic adjuvant and a polyamidoamine &#40;PAMAM&#41; dendrimer conjugated with HIV-1 transactivator of transcription &#40;TAT&#41; peptide as a chemical adjuvant to enhance H5 influenza antibody responses&#46; They reported that the <span class="elsevierStyleItalic">IRF3</span> gene and TAT-PMAM compound together induced the immune response of the H5 DNA vaccine in mice more than did the other groups containing only the chemical or the genetic adjuvants&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">37</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Different types of genetic and&#47;or chemical adjuvants used for the H5 influenza DNA vaccine are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">In this review&#44; we summarized the previous research on the influenza H5 DNA vaccines co-administered with different genetic and&#47;or chemical adjuvants&#46; Although different assays&#44; including ELISA&#44; virus neutralization&#44; ELISpot&#44; flow cytometry&#44; and cell proliferation&#44; have been used to evaluate immunological responses in different H5 DNA vaccine studies&#44; we only used the results from the Hemagglutination Inhibition &#40;HI&#41; assay to compare the immunogenicity of different DNA vaccines&#46; The HI assay is a well-established test for measuring the antibody response against the hemagglutinin of the influenza virus and shows good correlation with the influenza virus neutralization tests&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">38</span></a> This test was frequently used in almost all influenza vaccine studies while other immunological tests were performed only sporadically&#59; thus&#44; it can be stated that the latter groups of tests are not good candidates for comparing the studies on H5 DNA vaccines&#46; Although&#44; the correlation between HI tier and protection against lethal challenge is not straightforward &#40;chickens with HI titer could die after challenge while chicken with negative HI titer survive&#41;&#44; because the protection against challenge is a very critical index in determining of the efficacy of a vaccine&#44; the result of these experiments were also summarized when available in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Among the genetic adjuvants&#44; the <span class="elsevierStyleItalic">Esat-6</span> gene of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> induced the highest humoral response against influenza H5&#46; Overall&#44; the highest HI titers &#40;log<span class="elsevierStyleInf">2</span>&#41; in all experiments varied between 6 and 7&#44; but the highest HI titer was induced by the <span class="elsevierStyleItalic">H5</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Esat-6</span> genes and its value was reported to be as high as 13&#44; which is almost two times higher than that of the other studies&#46; Given that the uncommonly high value reported for the HI titer in this experiment has not been repeated in any other studies&#44; it is safe to consider this value an exceptional value&#46; However&#44; more research should be done to determine what exactly the adjuvant effects of the <span class="elsevierStyleItalic">Esat-6</span> gene are on H5 DNA vaccines&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">After the <span class="elsevierStyleItalic">Esat-6</span> gene&#44; the chicken <span class="elsevierStyleItalic">MDA5</span> gene induced the most potent humoral response&#46; By employing the fact that innate immune activation leads to an adaptive immune response&#44; Liniger and colleagues hypothesized that mimicking virus infection by the DNA vaccine might improve influenza vaccine-induced adaptive immune responses&#46; Pattern-recognition receptors &#40;PRRs&#41; activation triggers an antiviral state interceded regularly by the induction of interferon type I &#40;IFN type I&#41; and the activation of other antiviral proteins&#46; The PRRs that explicitly detect the intracellular viral RNA are the cytosolic RIG-I-like receptors &#40;RLR&#41;&#44; which contain the helicases retinoic acid-inducible gene I &#40;RIG-I&#41; and melanoma differentiation-associated gene 5 &#40;MDA5&#41;&#46; An important point in this regard is that chickens lack RIG-I protein&#46; Instead&#44; they detect the viral dsRNA by the MDA5 factor&#46; A group of researchers co-administered a plasmid encoding the N-terminal amino acids of chMDA5 with an H5 DNA vaccine plasmid to directly activate the RIG-I-like signaling pathway&#46; The result showed that this strategy could significantly elevate the H5 antibody response &#40;6&#46;6 mean HI titer&#41;&#44; leading to the protection of chickens against a lethal H5N1 influenza challenge&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">31</span></a> After MDA5&#44; <span class="elsevierStyleItalic">CD154</span> gene induced the highest HI titer by targeting the H5 antigen to APCs&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">30</span></a> but the mean HI titer of 6&#46;5 was reached only after 4 or 5 DNA vaccine boosters which complicates its potential use for field vaccination programs&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In other studies&#44; the immunomodulators&#44; such as cytokines&#44; and immunostimulators&#44; such as mycobacterial components&#44; have been exploited as the genetic adjuvants &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; A comparison of the cytokines revealed that the co-administration of IL-15 plasmid with H5 plasmid induced two times more H5 specific antibody than did the co-administration of IL-18 plasmid with H5 plasmid &#40;4 vs&#46; 2&#46;7 mean HI titer&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">21</span></a> Although the co-administration of XIAP plasmid to inhibit the apoptosis of the H5 plasmid-transfected cells did not considerably elevate the humoral response &#40;3 mean HI titer&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">24</span></a> it induced more antibody than did the IL-18 plasmid&#46; Plasmids encoding genes of <span class="elsevierStyleItalic">Mycobacterium</span> spp&#46; and the IL-15 plasmids elicited the same HI titer value&#44; but it must be noted that the mycobacterial genetic adjuvants were administered three times &#40;two boosters&#41; while the IL-15 genetic adjuvant was administered only once &#40;one booster&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Both silver nanoparticle &#40;AgNP&#41; and Lipofectin&#174; were potent chemical adjuvants for the H5 DNA vaccine in inducing a humoral response in chickens&#46; The advantages of AgNP that made it applicable to the poultry industry were the oral route of administration and reaching of the highest HI titer without any booster&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">33</span></a> Lipofectin&#174; was the most potent adjuvant among IM administered DNA vaccines in chickens&#46; This DNA carrier was originally used as a commercial transfection reagent and was then tested as the DNA vaccine adjuvant&#44; but it appears that it is too expensive to be an affordable DNA vaccine adjuvant in the poultry industry&#46; The adjuvant effects of cationic derivatives of polyprenols &#40;PTAI&#41; on the induction of H5-specific antibody were comparable with those of the commercialized carriers of the DNA vaccine&#44; such as Vaxfectin&#174;&#44; Lipofectamin&#174;&#44; and Lipofectin&#174;&#46; However&#44; they may be applicable for human H5 DNA vaccine&#44; as shown in a clinical trial by Smith and colleagues&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Different factors&#44; including the viral strain of hemagglutinin gene&#44; the plasmid type&#44; the dose and route of administration&#44; the intervals&#44; the number of boosters&#44; the host species&#44; and the day of sampling post-vaccination&#44; could affect the immunogenicity of a DNA vaccine&#46; Although these factors varied in different studies&#44; in the present review&#44; we tried to compare the highest mean of HI titers induced by these adjuvants&#46; The mean of the highest HI titers elicited by all genetic adjuvants and chemical adjuvants was 5&#46;45 and 5&#44; respectively&#44; which shows that the two types of adjuvants were not significantly different&#46; Due to the fact that the means of the highest HI titers elicited by the genetic and chemical adjuvants were close to each other&#44; it can be observed that one adjuvant type could not be preferred to the other type&#46; So&#44; the use of both genetic and chemical adjuvants may synergistically improve the immunogenicity of the H5 DNA vaccine&#46; For example&#44; Stachyra et al&#46; &#40;2014&#41; used Lipofectin&#174; as a chemical adjuvant and reached to 5&#46;6 mean HI titer after 42 days&#46; While&#44; Redkiewicz et al&#46; &#40;2017&#41; applied both genetic &#40;<span class="elsevierStyleItalic">kB</span> gene&#41; and chemical adjuvants &#40;Lipofectin&#174;&#41; in the H5 DNA vaccine and reached to the same HI titer one week earlier &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">As there has been no publications of results at this time of the H5 DNA vaccine containing ENABL adjuvant&#44; this adjuvant was not included in the review&#46; However&#44; recent commercialisation of the H5 DNA&#47;ENABL vaccines requires some comment on its nature&#46; ENABL&#174; is a patented adjuvant technology that features a unique lipid&#47;polymer matrix for more efficient vaccine delivery&#46; The use of this technology can result in the higher level absorption of the vaccine plasmid into the target cells&#44; leading to a greater immune response&#46; ENABL&#174; also gives the potential for reduction in the number of vaccine doses or even to induce an immune response after a single dose&#46; Other benefits of ENABL&#174; include improved safety with the injection site reactions and less risk of carcass condemnation&#46; Due to its unique lipid&#47;polymer matrix&#44; ENABL&#174;&#44; compared to its counterparts&#44; has a greater loading capacity that allows for higher antigen-to-adjuvant ratios and greater potential for development of multivalent vaccines&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusion</span><p id="par0115" class="elsevierStylePara elsevierViewall">DNA vaccines can be one of the front-line tools in the fight against the current and emerging animal diseases because it can be developed far faster than conventional vaccines&#46; Finding an effective and safe adjuvant could be the key to success in the DNA vaccine field&#44; as it was shown in the recently licensed H5 influenza DNA vaccine for chickens contained ENABL&#174; adjuvant&#46; As the manufacturer claims this new adjuvant&#44; ENABL&#174;&#44; is a safe and effective adjuvant&#44; it is advisable that independent researchers evaluate its efficiency experimentally to elucidate its strengths and weaknesses&#46; By comparing the results of different studies on the DNA vaccine adjuvants&#44; it could be concluded that the formulation of an H5 DNA vaccine with both Lipofectin&#174; as the most potent chemical adjuvant and <span class="elsevierStyleItalic">Esat-6</span> gene of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> as the best genetic adjuvant would potentially produce the optimized DNA vaccine against H5 influenza virus for chickens&#46; Also&#44; PTAI could be formulated in a H5 influenza DNA vaccine instead of Lipofectin&#174; to make the adjuvant more affordable&#46; Additionally&#44; it seems that AgNP could be a potent candidate adjuvant for oral H5 influenza DNA vaccine&#46; Finally&#44; more research is needed to find optimum adjuvants for DNA vaccine use in routine vaccination programs&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Funding</span><p id="par0120" class="elsevierStylePara elsevierViewall">This research did not receive any grant from funding agencies in the public&#44; commercial&#44; or not-for-profit sectors&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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        0 => array:3 [
          "identificador" => "xres1519860"
          "titulo" => "Abstract"
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            0 => array:2 [
              "identificador" => "abst0005"
              "titulo" => "Objectives"
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            1 => array:2 [
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              "titulo" => "Results"
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          "titulo" => "Resumen"
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          "titulo" => "Palabras clave"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0010"
              "titulo" => "H5 influenza virus"
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            1 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "DNA vaccine"
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        5 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Material and methods"
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          "titulo" => "Results"
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            0 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Genetic adjuvants"
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              "identificador" => "sec0035"
              "titulo" => "Chemical adjuvants"
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          "titulo" => "Discussion"
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        8 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conclusion"
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          "identificador" => "sec0050"
          "titulo" => "Funding"
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          "identificador" => "sec0055"
          "titulo" => "Conflict of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2020-05-26"
    "fechaAceptado" => "2020-09-30"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1378172"
          "palabras" => array:5 [
            0 => "Genetic adjuvant"
            1 => "Chemical adjuvant"
            2 => "DNA vaccine"
            3 => "H5 subtype"
            4 => "Influenza virus"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:5 [
            0 => "Adyuvante gen&#233;tico"
            1 => "Adyuvante qu&#237;mico"
            2 => "Vacuna de ADN"
            3 => "Subtipo H5"
            4 => "Virus de la gripe"
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    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The H5 influenza virus constantly evolves by mutation and re-assortment and results in the emergence of new subtypes&#46; The DNA vaccine may be an ideal candidate vaccine for influenza virus because it can be developed rapidly in response to the new subtypes of influenza viral genes&#46; As&#44; finding an efficient H5 influenza DNA vaccine is still challenging&#44; we aimed to review the articles which have reported the effects of an adjuvant on the H5 influenza DNA vaccines&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Results</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Different types of adjuvants have been co-administered with the H5 influenza DNA vaccines&#46; These adjuvants are generally divided into two types&#58; &#8216;genetic adjuvants&#8217; and &#8216;chemical adjuvants&#8217;&#46; Among the genetic adjuvants&#44; the <span class="elsevierStyleItalic">Esat-6</span> gene of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> was found to induce the highest humoral response&#46; Both Lipofectin&#174; and silver nanoparticle &#40;AgNP&#41; were potent chemical adjuvants for DNA vaccine in chickens via IM and oral administration routes&#44; respectively&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusion</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">It could be concluded that the formulation of an H5 DNA vaccine with both Lipofectin&#174; as the most potent chemical adjuvant and <span class="elsevierStyleItalic">Esat-6</span> gene of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> as the best genetic adjuvant is proposed for chicken immunization against H5 influenza virus&#46; Also&#44; the cationic derivatives of the polyprenols &#40;PTAI&#41; can be formulated in DNA vaccine instead of Lipofectin&#174; to make the adjuvant more affordable&#46; Additionally&#44; it seems that AgNP could be a potent candidate adjuvant for the oral H5 influenza DNA vaccine&#46; Finally&#44; more research is needed to find better adjuvants to include DNA vaccines as an applied vaccine type&#46;</p></span>"
        "secciones" => array:3 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Results"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Conclusion"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Objetivos</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">El virus de la gripe H5 est&#225; en constante evoluci&#243;n por mutaci&#243;n y recombinaci&#243;n&#44; lo cual origina la aparici&#243;n de nuevos subtipos&#46; La vacuna de ADN podr&#237;a ser una candidata ideal como vacuna frente al virus de la gripe&#44; ya que puede desarrollarse r&#225;pidamente como respuesta a los nuevos subtipos de los genes virales de gripe&#46; Como encontrar una vacuna de ADN eficaz frente a la gripe H5 es a&#250;n dif&#237;cil&#44; nuestro objetivo fue revisar los art&#237;culos que han reportado los efectos de un adyuvante en las vacunas de ADN frente a la gripe H5&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Resultados</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Se han co-administrado diferentes tipos de adyuvantes junto con las vacunas de ADN frente a la gripe H5&#46; Dichos adyuvantes se dividen por lo general en 2 tipos&#58; &#171;adyuvantes gen&#233;ticos&#187; y &#171;adyuvantes qu&#237;micos&#187;&#46; Entre los adyuvantes gen&#233;ticos&#44; se encontr&#243; que el gen <span class="elsevierStyleItalic">Esat-6</span> de <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> induc&#237;a la mayor respuesta humoral&#46; Tanto Lipofectin&#174; como las nanopart&#237;culas de plata &#40;AgNP&#41; fueron adyuvantes qu&#237;micos potentes para la vacuna de ADN en pollos&#44; a trav&#233;s de las v&#237;as IM y de administraci&#243;n oral&#44; respectivamente&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusi&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Podr&#237;a concluirse que se propone la formulaci&#243;n de una vacuna de ADN frente a la gripe H5 con Lipofectin&#174;&#44; como adyuvante qu&#237;mico m&#225;s potente&#44; y el gen <span class="elsevierStyleItalic">Esat-6</span> de <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> como el mejor adyuvante gen&#233;tico para inmunizaci&#243;n de pollos frente al virus de la gripe H5&#46; Tambi&#233;n podr&#237;an formularse en la vacuna de ADN los derivados cati&#243;nicos de los poliprenoles &#40;PTAI&#41; en lugar de Lipofectin&#174; para hacer que el adyuvante fuera m&#225;s asequible&#46; Adem&#225;s&#44; parece que AgNP podr&#237;a ser un potente candidato a adyuvante para la vacuna oral de ADN frente a la gripe H5&#46; Por &#250;ltimo&#44; se necesita m&#225;s investigaci&#243;n para encontrar mejores adyuvantes a incluir en vacunas de ADN como tipo de vacuna aplicada&#46;</p></span>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Region&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Poultry losses&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Africa&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">8&#44;291&#44;669&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">America&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="char" valign="\n
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                  \t\t\t\t">28&#44;224&#44;324&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Asia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71&#44;326&#44;121&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
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                  \t\t\t\t">Europe&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">14&#44;260&#44;122&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Oceania&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">490&#44;000&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Total&nbsp;\t\t\t\t\t\t\n
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">The losses&#44; including animals killed or disposed of&#44; due to the H5 influenza outbreaks in domestic birds by region from January 2013 to August 2018&#46; There is no report for total poultry losses due to H5 influenza outbreaks in domestic birds after August 2018&#46;</p>"
        ]
      ]
      1 => 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:2 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; DPV&#58; days post first vaccination&#59; AgNP&#58; silver nanoparticles&#59; C34&#58; phenyl analogs of alpha-galactosylceramide&#59; PTAI&#58; cationic derivatives of polyprenols&#59; iNKT&#58; invariant natural killer T&#59; M&#46;&#58; <span class="elsevierStyleItalic">Mycobacterium&#46;</span></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene&#47;chemical name&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Role&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="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Protective efficacy&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="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Administration &#40;type&#47;booster times&#41;&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="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene source&#47;tested organism&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="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Highest mean HI&#47;DPV&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="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reference&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" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Genetic adjuvants</span></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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">IL-15</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Immuno-modulator &#40;Cytokine&#41;&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">NA&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">IM&#47;one&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">Chicken&#47;Chicken&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">4&#47;35&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">Lim et al&#46;&#44; 2012&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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">IL-18</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Immuno-modulator &#40;Cytokine&#41;&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">NA&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">IM&#47;one&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">Chicken&#47;Chicken&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">2&#46;7&#47;35&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">Lim et al&#46;&#44; 2012&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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">MDA5</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mimicking virus infection&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">83&#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">IM&#47;one&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">Chicken&#47;Chicken&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">6&#46;6&#47;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">Liniger et al&#46;&#44; 2012&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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">XIAP</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibition of apoptosis&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">NA&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">IM&#47;one&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">Mouse&#47;Mouse&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">3&#47;35&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">Tabatabaeizadeh et al&#46;&#44; 2015&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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">MDP-1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Immuno-stimulator&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">NA&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">IM&#47;two&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">M&#46; bovis</span>&#47;Chicken&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">3&#46;7&#47;35&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">Jalilian et al&#46;&#44; 2010&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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Esat-6</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Immuno-stimulator&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">NA&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">IM&#47;two&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">M&#46; tuberculosis</span>&#47;Chicken&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">13&#47;42&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">Oveissi et al&#46;&#44; 2010&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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CD154</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antigen targeting&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">100&#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">IM&#47;four or five&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">Duck&#47;Duck&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">6&#46;5&#47;140&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">Yao et al&#46;&#44; 2010&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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CD40</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&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">NA&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">IM&#47;two&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">Mouse&#47;Mouse&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">NA&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">Chen et al&#46;&#44; 2014&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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">HSP70</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antigen targeting&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">NA&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">IM&#47;two&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">M&#46; tuberculosis</span>&#47;Chicken&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">4&#46;1&#47;35&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">Rasoli et al&#46;&#44; 2010&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  " colspan="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Chemical adjuvants</span></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="elsevierStyleHsp" style=""></span>AgNP&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">DNA vaccine carrier&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">NA&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">Oral&#47;none&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">Chicken&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">5&#46;6&#47;35&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">Jazayeri et al&#46;&#44; 2012&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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Nigella sativa</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Immunostimulant&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">NA&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">IM&#47;none&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">Chicken&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">NA&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">Mady et al&#46;&#44; 2013&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="elsevierStyleHsp" style=""></span>C34&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">Activates iNKT cells&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">85&#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">IM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>EP&#47;none&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">Mouse&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">NA&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">Hung et al&#46;&#44; 2014&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="elsevierStyleHsp" style=""></span>PTAI&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">Liposomal carrier&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">NA&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">IM&#47;one&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">Chicken&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">4&#47;28&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">Stachyra et al&#46;&#44; 2017&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="elsevierStyleHsp" style=""></span>Vaxfectin&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">Liposomal carrier&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">NA&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">IM&#47;one&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">Human&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">5&#46;8&#47;56&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">Smith et al&#46;&#44; 2010&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="elsevierStyleHsp" style=""></span>Lipofectamine&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">Liposomal carrier&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">NA&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">IM&#47;none&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">Chicken&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">4&#47;28&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">Mady et al&#46;&#44; 2013&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="elsevierStyleHsp" style=""></span>Lipofectin&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">Liposomal carrier&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">100&#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">IM&#47;one&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">Chicken&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">5&#46;6&#47;42&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">Stachyra et al&#46;&#44; 2014&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  " colspan="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Both adjuvants</span></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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#954;B</span>&#47;Lipofectin&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">Targeting DNA vaccine to the cell nucleus&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">NA&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">IM&#47;one&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">Chicken&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">5&#46;5&#47;35&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">Redkiewicz et al&#46;&#44; 2017&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="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">IRF3</span>&#47;PMAM-TAT&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">Improved gene delivery&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">NA&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">ID&#47;one&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">Mouse&#47;Mouse&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">3&#46;1&#47;35&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">Bahadoran et al&#46;&#44; 2017&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 15769887
Original language: English

DOI:10.1016/j.vacun.2020.09.010

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