Influence of HLA-G polymorphism in antibody response to hepatitis B vaccination during the first year of life

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A) SDS-PAGE at 10% acrylamide. B) Western Blotting with anti-His antibody. Cellular lysates of E. coli SHuffle® T7 with: lane 1: pET-28a (C-); lanes 2-4: pETHPV16L1myc-His. PM, Broad Range Protein Molecular Weight Marker (Promega, U.S.A.). The arrows indicate the band corresponding to HPV-16 L1-His." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "S.M. Brito Molina, Y. Serrano Rivero, A. Falero Morejón, E. Pimienta Rodríguez, S. Rodríguez Salgueiro, O. Ancheta Niebla, K. Marro Domínguez" "autores" => array:7 [ 0 => array:2 [ "nombre" => "S.M." "apellidos" => "Brito Molina" ] 1 => array:2 [ "nombre" => "Y." "apellidos" => "Serrano Rivero" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Falero Morejón" ] 3 => array:2 [ "nombre" => "E." "apellidos" => "Pimienta Rodríguez" ] 4 => array:2 [ "nombre" => "S." "apellidos" => "Rodríguez Salgueiro" ] 5 => array:2 [ "nombre" => "O." "apellidos" => "Ancheta Niebla" ] 6 => array:2 [ "nombre" => "K." "apellidos" => "Marro Domínguez" ] ] ] ] "resumen" => array:1 [ 0 => array:3 [ "titulo" => "Highlights" "clase" => "author-highlights" "resumen" => "<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•HPV-16 L1-His protein represented ∼ 12% of total proteins.</li><li class="elsevierStyleListItem" id="lsti0010">•It was purified to a purity of ∼ 90% by means of Ni2+ ion affinity chromatography.</li><li class="elsevierStyleListItem" id="lsti0015">•9 mg de pentamers of cultured L1-His/L was obtained after renaturalisation.</li></ul>" ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1576988720300376" "doi" => "10.1016/j.vacun.2020.06.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1576988720300376?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146020300200?idApp=UINPBA00004N" "url" => "/24451460/0000002100000002/v1_202011280950/S2445146020300200/v1_202011280950/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S2445146020300236" "issn" => "24451460" "doi" => "10.1016/j.vacune.2020.10.006" "estado" => "S300" "fechaPublicacion" => "2020-07-01" "aid" => "155" "documento" => "simple-article" "crossmark" => 0 "subdocumento" => "edi" "cita" => "Vacunas. 2020;21:73-5" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "Editorial" "titulo" => "Collateral effects of Covid-19 pandemic emergency response on worldwide immunizations" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "73" "paginaFinal" => "75" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efectos colaterales de la respuesta de emergencia pandémica de Covid-19 en las inmunizaciones mundiales" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "N. Torner" "autores" => array:1 [ 0 => array:2 [ "nombre" => "N." "apellidos" => "Torner" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1576988720300352" "doi" => "10.1016/j.vacun.2020.07.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1576988720300352?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146020300236?idApp=UINPBA00004N" "url" => "/24451460/0000002100000002/v1_202011280950/S2445146020300236/v1_202011280950/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Influence of HLA-G polymorphism in antibody response to hepatitis B vaccination during the first year of life" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "76" "paginaFinal" => "81" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A.A. El Shahaway, A.A. Ahmed, M.A. Arafa, M.M. Malek" "autores" => array:4 [ 0 => array:4 [ "nombre" => "A.A." "apellidos" => "El Shahaway" "email" => array:1 [ 0 => "aliaabdelmonem@yahoo.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "A.A." "apellidos" => "Ahmed" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M.A." "apellidos" => "Arafa" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "M.M." "apellidos" => "Malek" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Medical Microbiology and Immunology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Pediatrics Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Influencia del polimorfismo HLA-G en la respuesta de anticuerpos a la vacuna frente a la hepatitis B durante el primer año de vida" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1500 "Ancho" => 1500 "Tamanyo" => 161269 ] ] "descripcion" => array:1 [ "en" => "“HLA-G 14bp polymorphism” on agarose gel. Lane 1 is negative control, lane 2 is HLA-G ins/del genotype, lane 3 is the HLA-G ins/ins genotype, lanes 4 is 100-bp DNA ladder and Lanes 5 is HLA-G del/del genotype." ] ] ] "textoCompleto" => "IntroductionHepatitis B (HB) as an acute and chronic communicable disease, is responsible for annual death rates ranging from 500,000 to 1.2 million death per year globally.<a class="elsevierStyleCrossRef" href="#bib0160">1</a> In 1992, Egypt has launched an enforced vaccination program against hepatitis B infection among infants with a coverage rate of about 95% using a yeast recombinant (10μg) vaccine, with a schedule of 2,4,6 months old in combination with other obligatory vaccines {diphtheria, tetanus, pertussis and oral polio (DTP-OPV)}.<a class="elsevierStyleCrossRef" href="#bib0165">2</a>The HBsAg in recombinant hepatitis B vaccines is presented by antigen-presenting cells (APC) to T helper cells (CD4) that recognize the major histocompatibility complex (MHC) class II molecules on the APC.<a class="elsevierStyleCrossRef" href="#bib0170">3</a> The CD4+ Th lymphocytes are essential for efficient execution of the majority of specific immune responses including antigen-activated B lymphocyte production of antibody and antigen-specific CTL effector function.<a class="elsevierStyleCrossRef" href="#bib0175">4</a> If hepatitis B surface antibody (HBsAb) level is over or equal to 10mIU/mL after primary hepatitis B immunization, the person is responders. While the person is non-responder if HBsAb is <10mIU/mL.<a class="elsevierStyleCrossRef" href="#bib0180">5</a>HLA-G is originally defined as being expressed selectively on cytotrophoblast cells at the maternal-fetal interface to act as a ligand for inhibitory receptors on uterine natural killer (NK) cells attributing to the maternal–fetal tolerance.<a class="elsevierStyleCrossRef" href="#bib0185">6</a> Importantly, HLA-G is characterized by little allelic polymorphisms compared to classical MHC class I genes. However, a 14-base pair (14-bp) Insertion/Deletion (ins/del) polymorphism (rs66554220) in the 3′ untranslated HLA-G gene has been associated with HLA-G mRNA stability as well as protein levels.<a class="elsevierStyleCrossRef" href="#bib0190">7</a> Several observations suggest that 14bp ins/ins and +3142G/G genotypes are associated with lower HLA-G production than 14bp ins/del, del/del, +3142C/G, and C/C genotypes.<a class="elsevierStyleCrossRef" href="#bib0195">8</a>HLA-G has been engaged in several physiological and pathological processes including pregnancy, autoimmunity, transplantation, infection, and cancer.<a class="elsevierStyleCrossRef" href="#bib0200">9</a> This molecule prevents the cytolytic action of T lymphocytes and NK cells, the proliferation, and differentiation of B lymphocytes and their immunoglobulin secretion. Moreover, it induces various types of regulatory T (Treg) cells that inhibit CD4 proliferation.<a class="elsevierStyleCrossRef" href="#bib0205">10</a> It has been noted that in Tunisian patients with chronic HBV there was a relation between HLA-G 14bp ins/del polymorphism and HBV infection. The 14-bp insertion allele seems to be linked with raised hepatitis B virus replication.<a class="elsevierStyleCrossRef" href="#bib0210">11</a> Possible associations between the immune response to hepatitis B vaccination and HLA-G 14bp polymorphism have not been explored to date. Considering this, the present study aimed to assess the humoral response to hepatitis B vaccination in the first year of life. We also aimed to assess the association between the antibody response to hepatitis B vaccination and the polymorphism in HLA-G 14bp.MethodologyThis comparative cross-sectional study was conducted on 93 infants. They had received their hepatitis B vaccine doses at 2, 4, and 6 months old according to the World Health Organization (WHO) immunization schedules in Egypt. This could be known from the individual vaccination record book. This study was done in the Medical Microbiology and Immunology, and Clinical Pathology Departments, Faculty of Medicine, Zagazig University, from January 2017 to December 2018. We excluded infants born to HBsAg positive mothers, and those with anti-HBc positive, thalassemia, dialysis, liver failure, received corticosteroids or anti HB immunoglobulin. All infants were subjected to the following: full medical history taking and general examination to check the attainment of the inclusion criteria.Measurement of the anti-HBs titerPlasma samples were collected and kept at −20°C. The antibodies to HBsAg (anti-HBs) titer was measured by ELSA (DiaPro, Milan, Italy) and following the manufacturer instructions. All samples were done in duplicate, the optical density was measured at 450nm as the primary wavelength and 630nm as the reference wavelength by ELISA reader “Stat Fax® 303 Plus” then the mean absorbance of each sample was calculated. Anti-HBs titers were expressed in mIU/mL and were calculated using a standard curve calibrated against the WHO reference preparation. Anti-HBs ≥10mIU/mL was considered as stated by international standards to be immune against HB infection.Genotyping of “HLA-G 14bp polymorphism” at exon 8 (3′UTR)Genomic DNA was obtained from EDTA-anticoagulated venous blood (1mL) using a GeneJet Whole Blood genomic DNA extraction kit (Thermo Fisher Scientific Inc., Waltham, MA, USA), following the manufacturer's guidance. Genotyping of “HLA-G 14-bp polymorphism” (rs371194629) was done as described by Alegre et al.<a class="elsevierStyleCrossRef" href="#bib0215">12</a> Briefly, 100ng of extracted DNA was amplified in a 25μL reaction, with an ultimate concentration of the reagents (iNtRON Biotechnology, Korea): “1× Reaction Buffer, 2.5mM of each dNTP, 1.5mM MgCl2, 2.5 U Taq Polymerase, and 10pmol of each primer (5′-GTG ATG GGC TGT TTA AAG TGT CACC-3′) and RHG4 (5′-GGA AGG AAT GCA GTT CAG CAT GA-3′) using a PCR cycler (Biometra).<a class="elsevierStyleCrossRef" href="#bib0220">13</a> PCR protocol was “initial denaturation at 95°C for 3min, then 35 PCR cycles of denaturation at 95°C for 60s, annealing at 64°C for 60s, and elongation at 72°C for 60s, ended by final elongation at 72°C for 10min”. The investigation of amplified PCR products was done in 3% agarose gel including ethidium bromide (0.5μg/mL) (Sigma, USA) for 40min and then visualized against UV light using a gel documentation system. The interpretation of the “HLA-G 14-bp polymorphism” was done by first and second authors. Depending on the deletion of the 14bp from exon 8, the amplified PCR products were either of 224 or 210bp, or both 224 and 210bp (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Statistical analysisThe sample was calculated to be 93 cases using open-Epi at CI 95% and the power of the study is 80%.<a class="elsevierStyleCrossRef" href="#bib0225">14</a> The data were examined by computer using Statistical Package of Social Services version 22 (SPSS). Quantitative variables were described as the mean±SD & median (range), and categorical qualitative variables were expressed as absolute frequencies (number) & relative frequencies (percentage). Suitable statistical tests of significance were used after checked for normality. The differences in genotype/allele frequencies between patients and controls were evaluated by chi-square (χ2) test (2×2 contingency table for alleles and 2×3 contingency table for genotypes). The results were considered statistically significant when the significant probability was less than 0.05 (P<0.05). P-value <0.001 was considered highly statistically significant.Ethical approvalsThe study was approved by “Institutional Review Board” (IRB) no 5295. The parents of the participated children provided their written informed consent. This research was carried out in agreement with the Statement of Helsinki.ResultsDemographic characteristics of the participantsThe current study involved 93 infants as study subjects, including 47 (50.5%) boys and 46 (49.5%) girls up to 1 year old, with a mean age of 9.86±1.76 months old. Overall, 82 (88.2%) were responders to hepatitis B vaccine (anti-HBs>10mIU/mL). While, 11 (11.8%) were non-responders (anti-HBs<10mIU/mL). The mean antibody titers for responders and non-responders were 77.65±27.14IU/mL and 4.45±2.38IU/mL, respectively. There was no statistically significant variance between responder and non-responder groups as regard age and sex, as shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Association between the polymorphism of HLA-G 14bp and the responsiveness to hepatitis B vaccineAllelic and genotypic frequencies of 14bp HLA-G polymorphism among responders and non-responders to hepatitis B vaccine are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. No Hardy-Weinberg equilibrium deviation was observed in the studied samples for the 14bp HLA-G polymorphism (χ2=0.477; p=0.505). The ins/ins genotype was more frequent in non-responder than responder group (45.5% vs 18.3%), with a statistically significant difference between responder and non-responder groups.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The 14-bp insertion allele was significantly more frequent in non-responder than responder group (63.6% vs. 37.8%, respectively; P=0.013). Therefore, the higher frequencies of 14bp insertion allele in non-responder as compared to responder group indicate that this allele is associated with an increased risk of failure to respond to hepatitis B vaccine (OR 3.72, 95% CI 1.32–10.6). Besides, the responder group was 62% more likely to experience the wild allele “14bp deletion allele”<a class="elsevierStyleCrossRef" href="#bib0230">15</a> than the 14bp insertion allele with statistical significance (P=0.018).<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> illustrates the distribution of the anti-HBs titer (IU/mL) according to the responder and non-responder genotypes, the anti-HBs titer was statistically lower among ins/ins genotype than del/del and heterozygous, with a statistically significant difference (P<0.001, p<0.05) respectively.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>DiscussionHBV vaccine is a major public health improvement that has limited the burden of HBV morbidity and mortality.<a class="elsevierStyleCrossRef" href="#bib0235">16</a> Anti-HBs antibodies are a marker of immunity and a titer ≥10IU/L indicates sero-protection if measured 1–3 months after completion of the primary vaccination series. In healthy babies, one dose of the vaccine provides 30–40% protection against HBV infection, 50–75% protection with two doses and >90% protection with three doses.<a class="elsevierStyleCrossRef" href="#bib0240">17</a> The vaccination failure is a problem that hinders the protection achieved by HBV vaccine, in which the anti-HBs titer is less than 10IU/L (anti-HBs<10 IU/L). Individuals with vaccination failure are not effectively protected from HBV and are vulnerable to HBV infection in areas where it is endemic.<a class="elsevierStyleCrossRef" href="#bib0245">18</a>In this paper, we evaluate the humoral response to vaccination against hepatitis B in vaccinated infants. We observed that 88.2% of vaccinated infants were protected against HBV infection (anti-HBs≥10mIU/mL). This was similar to the previous literature in Ghana and Iran where reported sero-protection levels were 87.9%, and 87% respectively.<a class="elsevierStyleCrossRefs" href="#bib0250">19,20</a>Besides, this study showed that the non-responders (anti-HBs<10mIU/mL) percentage was 11.8% of studied infants. Some authors obtained the same results.<a class="elsevierStyleCrossRefs" href="#bib0250">19–21</a> However, some literature reported slightly lower percents of non-responders.<a class="elsevierStyleCrossRefs" href="#bib0265">22,23</a> This variation is explained by the difference in HB vaccine preparations, incorrect injection of HB vaccine, distinctive vaccination schedules and genetic differences. Regarding gender, the results of this present research are like some authors who reported that the immunological response to hepatitis B did not differ in gender.<a class="elsevierStyleCrossRefs" href="#bib0275">24,25</a>Production of anti-HBs antibody is helper T cell dependent. The non-responders to vaccination against hepatitis B could be attributed to defect in the HBsAg molecule presentation by dendritic cells (DCs) to naïve CD4+ lymphocytes, specific T and/or B cell repertoires and Treg cells.<a class="elsevierStyleCrossRef" href="#bib0285">26</a> Numerous studies have reported that there is an association between vaccine responsiveness and several polymorphisms including alternates of the MHC and cytokine and cytokine receptor genes. In the association analysis, the HLA-G SNPs have been significantly related to IgM concentrations (p<0.001). HLA-G plays a vital role in the antigen presentation and immunotolerance.<a class="elsevierStyleCrossRef" href="#bib0290">27</a> HLA-G was regarded as a significant genetic prone factor for infection with viruses such as human immunodeficiency virus (HIV), human papillomavirus (HPV), human cytomegalovirus virus (HCMV)<a class="elsevierStyleCrossRef" href="#bib0200">9</a> and HBV.<a class="elsevierStyleCrossRef" href="#bib0295">28</a>This research is the first to explore the association during the first year of life between the polymorphism of HLA-G 14bp and the HBs antibody following vaccination. The 14-bp insertion allele was significantly associated with non-responder. Besides, the responder group was more likely to experience the wild type allele than the insertion type. Furthermore, the anti-HBs titer was statistically lower among ins/ins genotype than del/del and heterozygous in responder and non-responder groups.Possible associations between the antibody reaction to hepatitis B vaccination and HLA-G14bp polymorphism have not been explored to date. We could not find relevant information in field literature about HLA-G 3′UTR 14-bp ins/del polymorphism and antibody response to hepatitis B vaccination, so comparing our results with other studies was not possible but there are several reports on HLA-G 3′UTR 14-bp gene variants and viral diseases. Laaribi et al.,<a class="elsevierStyleCrossRef" href="#bib0210">11</a> reported that the ins/ins genotype was accompanied with 2.5 times increased vulnerability to elevated HBV replication compared with the del/del and heterozygous genotypes in Tunisian patients with chronic HBV. In a clinical trial of GMZ2 malaria vaccine, it was found that the low vaccine immunogenicity caused by an increase of sHLA-G level induced by GMZ2.<a class="elsevierStyleCrossRef" href="#bib0300">29</a>We hypothesized that the polymorphisms in HLA-G 14bp may affect the anti-HBs titer through immune inhibition and induction of tolerance. This is through two mechanisms. The first is through the generation of tolerogenic DCs that are characterized by decreased class II of MHC and costimulatory molecules expression on the cell surface. As DCs are antigen presenting cells required for the efficient priming of T lymphocytes, so tolerogenic DCs are failed to stimulate allogenic T cells.<a class="elsevierStyleCrossRef" href="#bib0305">30</a> The vital steps in the immune response to HBV vaccination are the activation and proliferation of T cells.<a class="elsevierStyleCrossRef" href="#bib0310">31</a>The second mechanism is by induction of Treg cells that modulate the immune response. Moreover, HLA-G can inhibit all steps in the immune response: differentiation, proliferation, cytolysis, cytokine secretion, and immunoglobulin production.<a class="elsevierStyleCrossRef" href="#bib0205">10</a> Further research is needed to verify our results and to clarify the exact mechanism.ConclusionThis paper has clearly shown that the ins/ins genotype was significantly associated with non-responsiveness to hepatitis B vaccination.FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Conflict of interestsAuthors have no conflict of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1423021" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1300926" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1423022" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1300925" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methodology" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Measurement of the anti-HBs titer" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Genotyping of “HLA-G 14 bp polymorphism” at exon 8 (3′UTR)" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Ethical approvals" ] 8 => array:3 [ "identificador" => "sec0035" "titulo" => "Results" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Demographic characteristics of the participants" ] ] ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 10 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusion" ] 11 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 12 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interests" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-01-10" "fechaAceptado" => "2020-07-31" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1300926" "palabras" => array:4 [ 0 => "Hepatitis B Vaccination" 1 => "Humoral immunity" 2 => "HLA-G 14bp in/del" 3 => "Infants" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1300925" "palabras" => array:4 [ 0 => "Vacunación contra la hepatitis B" 1 => "Inmunidad humoral" 2 => "HLA-G 14bp in / del" 3 => "Lactantes" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveThis research intended to evaluate the antibody response to vaccination against hepatitis B during the first year of life. We also aimed to assess the association between the antibody response to hepatitis B vaccination and the polymorphism in HLA-G 14bp. Material and methodsIn this comparative cross-sectional study, 93 infants that received the hepatitis B vaccine at 2, 4, and 6 months old according to the World Health Organization immunization schedules, were evaluated for their antibodies to HBsAg (anti-HBs) following vaccination. Their genomic DNA was extracted and examined for the polymorphism in HLA-G 14bp by PCR. ResultsAmong 93 vaccinated infants, 11 infants (11.8%) were non-responders to vaccination against hepatitis B (anti-HBs<10IU/mL). The mean antibody titers for responders and non-responders were 77.65±27.14IU/mL and 4.45±2.38IU/mL, respectively. The 14-bp insertion allele was associated with an increased risk of failure o respond to hepatitis B vaccination (OR 3.72, 95% CI 1.32–10.6). ConclusionThis study reported, for the first time, that ins/ins genotype may be a risk factor for non-responsiveness to hepatitis B vaccination." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivoEl objetivo de este estudio fue evaluar la respuesta de anticuerpos a la vacuna frente a la hepatitis B durante el primer año de vida. También tratamos de evaluar la asociación entre la respuesta de anticuerpos a la vacuna frente a la hepatitis B y el polimorfismo en HLA-G 14bp. Material y métodosEn este estudio transversal comparativo se evaluó el HBsAg (anti-HBS) de 93 niños que recibieron la vacuna contra la hepatitis B a los 2, 4 y 6 meses de edad, conforme a los programas de la Organización Mundial de la Salud, fueron evaluados por sus anticuerpos frente a HBsAg (anti-HBs) después de la vacunación. Se extrajo su ADN genómico. examinándose el polimorfismo en HLA-G 14bp mediante la prueba PCR. ResultadosEntre los 93 niños vacunados, 11 niños (11,8%) no respondieron a la vacuna frente a la hepatitis B (anti-HBs<10UI/mL). Los títulos de anticuerpos medios para respondedores y no respondedores fueron de 77,65±27,14 y 4,45±2,38UI/mL, respectivamente. El alelo 14bp inserción se asoció a un incremento del riesgo de fallo de respuesta a la vacuna frente a la hepatitis B (OR: 3,72; IC 95%: 1,32-10,6). ConclusiónEste estudio reportó, por vez primera, que el genotipo ins/ins puede constituir un factor de riesgo para la no respuesta a la vacuna frente a la hepatitis B." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1500 "Ancho" => 1500 "Tamanyo" => 161269 ] ] "descripcion" => array:1 [ "en" => "“HLA-G 14bp polymorphism” on agarose gel. Lane 1 is negative control, lane 2 is HLA-G ins/del genotype, lane 3 is the HLA-G ins/ins genotype, lanes 4 is 100-bp DNA ladder and Lanes 5 is HLA-G del/del genotype." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "SD: standard deviation." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-responders \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">Responders \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">P value \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="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age(month)</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">Mean±SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.82±1.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9.87±1.81 \t\t\t\t\t\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">0.650 \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="4" 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="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sex (N%)</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">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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 (54.5) \t\t\t\t\t\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">1.0 \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">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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 (45.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\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">Anti-HBs titer (IU/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.45±2.38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77.65±27.14 \t\t\t\t\t\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">0.000<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2440580.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "P<0.001 is highly statistically significant." ] ] ] "descripcion" => array:1 [ "en" => "Baseline characteristics of the participants." ] ] 2 => 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 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Responder group \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-responder group \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">OR \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P-value \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="8" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Genotypes†</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">del/del \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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">42.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.298 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.06–1.47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.14 \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">ins/ins \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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">18.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1–13.83 \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">0.04<a class="elsevierStyleCrossRef" href="#tbl2fn1">*</a> \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">Heterozygous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.89 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.2–3.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.87 \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="8" 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="8" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HLA-G 14 bp allele‡</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">14-bp deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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">36.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.09–0.76 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.013<a class="elsevierStyleCrossRef" href="#tbl2fn1">*</a> \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">14-bp insertion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63.6 \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">3.74 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.32–10.6 \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">0.013<a class="elsevierStyleCrossRef" href="#tbl2fn1">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2440578.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tbl2fn1" "etiqueta" => "*" "nota" => "P value <0.05 is significant. Genotype and allele distributions were compared through Chi-square test as following: Responder versus Non-responder (p=0.090†; p=0.018‡)." ] ] ] "descripcion" => array:1 [ "en" => "Association of HLA-G 14bp polymorphism with response to the HB vaccine." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "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">Anti-HBs titer \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">del/del \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">ins/ins \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">Heterozygous \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">P-value \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="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Responder</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">Median (range) \t\t\t\t\t\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">98 (66-133) \t\t\t\t\t\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">35 (21.4–55.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77 (34–112) \t\t\t\t\t\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"><0.0001<a class="elsevierStyleCrossRef" href="#tblfn0015">†</a> \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="5" 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="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-responder</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">Median (range) \t\t\t\t\t\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">7.5 (7–8) \t\t\t\t\t\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">2.3 (1–4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.75 (3–7.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.031<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2440579.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "†" "nota" => "P-value <0.001 highly statistically significant." ] 1 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "*" "nota" => "p value <0.05 is significant." ] ] ] "descripcion" => array:1 [ "en" => "Distribution of anti-HBs titer (IU/mL) according to genotypes in responder and non-responder groups." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:31 [ 0 => array:3 [ "identificador" => "bib0160" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "D. 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Influence of HLA-G polymorphism in antibody response to hepatitis B vaccination during the first year of life

Influencia del polimorfismo HLA-G en la respuesta de anticuerpos a la vacuna frente a la hepatitis B durante el primer año de vida

A.A. El Shahawaya,

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aliaabdelmonem@yahoo.com

Corresponding author.

, A.A. Ahmedb, M.A. Arafac, M.M. Maleka

a Medical Microbiology and Immunology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

b Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

c Pediatrics Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">&#8220;HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp polymorphism&#8221; on agarose gel&#46; Lane 1 is negative control&#44; lane 2 is HLA-G ins&#47;del genotype&#44; lane 3 is the HLA-G ins&#47;ins genotype&#44; lanes 4 is 100-bp DNA ladder and Lanes 5 is HLA-G del&#47;del genotype&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Hepatitis B &#40;HB&#41; as an acute and chronic communicable disease&#44; is responsible for annual death rates ranging from 500&#44;000 to 1&#46;2 million death per year globally&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">1</span></a> In 1992&#44; Egypt has launched an enforced vaccination program against hepatitis B infection among infants with a coverage rate of about 95&#37; using a yeast recombinant &#40;10<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; vaccine&#44; with a schedule of 2&#44;4&#44;6 months old in combination with other obligatory vaccines &#123;diphtheria&#44; tetanus&#44; pertussis and oral polio &#40;DTP-OPV&#41;&#125;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The HBsAg in recombinant hepatitis B vaccines is presented by antigen-presenting cells &#40;APC&#41; to T helper cells &#40;CD4&#41; that recognize the major histocompatibility complex &#40;MHC&#41; class II molecules on the APC&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">3</span></a> The CD4&#43; Th lymphocytes are essential for efficient execution of the majority of specific immune responses including antigen-activated B lymphocyte production of antibody and antigen-specific CTL effector function&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">4</span></a> If hepatitis B surface antibody &#40;HBsAb&#41; level is over or equal to 10<span class="elsevierStyleHsp" style=""></span>mIU&#47;mL after primary hepatitis B immunization&#44; the person is responders&#46; While the person is non-responder if HBsAb is &#60;10<span class="elsevierStyleHsp" style=""></span>mIU&#47;mL&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">HLA-G is originally defined as being expressed selectively on cytotrophoblast cells at the maternal-fetal interface to act as a ligand for inhibitory receptors on uterine natural killer &#40;NK&#41; cells attributing to the maternal&#8211;fetal tolerance&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">6</span></a> Importantly&#44; HLA-G is characterized by little allelic polymorphisms compared to classical MHC class I genes&#46; However&#44; a 14-base pair &#40;14-bp&#41; Insertion&#47;Deletion &#40;ins&#47;del&#41; polymorphism &#40;rs66554220&#41; in the 3&#8242; untranslated HLA-G gene has been associated with HLA-G mRNA stability as well as protein levels&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">7</span></a> Several observations suggest that 14<span class="elsevierStyleHsp" style=""></span>bp ins&#47;ins and &#43;3142G&#47;G genotypes are associated with lower HLA-G production than 14<span class="elsevierStyleHsp" style=""></span>bp ins&#47;del&#44; del&#47;del&#44; &#43;3142C&#47;G&#44; and C&#47;C genotypes&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">HLA-G has been engaged in several physiological and pathological processes including pregnancy&#44; autoimmunity&#44; transplantation&#44; infection&#44; and cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">9</span></a> This molecule prevents the cytolytic action of T lymphocytes and NK cells&#44; the proliferation&#44; and differentiation of B lymphocytes and their immunoglobulin secretion&#46; Moreover&#44; it induces various types of regulatory T &#40;Treg&#41; cells that inhibit CD4 proliferation&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">10</span></a> It has been noted that in Tunisian patients with chronic HBV there was a relation between HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp ins&#47;del polymorphism and HBV infection&#46; The 14-bp insertion allele seems to be linked with raised hepatitis B virus replication&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">11</span></a> Possible associations between the immune response to hepatitis B vaccination and HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp polymorphism have not been explored to date&#46; Considering this&#44; the present study aimed to assess the humoral response to hepatitis B vaccination in the first year of life&#46; We also aimed to assess the association between the antibody response to hepatitis B vaccination and the polymorphism in HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methodology</span><p id="par0025" class="elsevierStylePara elsevierViewall">This comparative cross-sectional study was conducted on 93 infants&#46; They had received their hepatitis B vaccine doses at 2&#44; 4&#44; and 6 months old according to the World Health Organization &#40;WHO&#41; immunization schedules in Egypt&#46; This could be known from the individual vaccination record book&#46; This study was done in the Medical Microbiology and Immunology&#44; and Clinical Pathology Departments&#44; Faculty of Medicine&#44; Zagazig University&#44; from January 2017 to December 2018&#46; We excluded infants born to HBsAg positive mothers&#44; and those with anti-HBc positive&#44; thalassemia&#44; dialysis&#44; liver failure&#44; received corticosteroids or anti HB immunoglobulin&#46; All infants were subjected to the following&#58; full medical history taking and general examination to check the attainment of the inclusion criteria&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Measurement of the anti-HBs titer</span><p id="par0030" class="elsevierStylePara elsevierViewall">Plasma samples were collected and kept at &#8722;20<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; The antibodies to HBsAg &#40;anti-HBs&#41; titer was measured by ELSA &#40;DiaPro&#44; Milan&#44; Italy&#41; and following the manufacturer instructions&#46; All samples were done in duplicate&#44; the optical density was measured at 450<span class="elsevierStyleHsp" style=""></span>nm as the primary wavelength and 630<span class="elsevierStyleHsp" style=""></span>nm as the reference wavelength by ELISA reader &#8220;Stat Fax&#174; 303 Plus&#8221; then the mean absorbance of each sample was calculated&#46; Anti-HBs titers were expressed in mIU&#47;mL and were calculated using a standard curve calibrated against the WHO reference preparation&#46; Anti-HBs &#8805;10<span class="elsevierStyleHsp" style=""></span>mIU&#47;mL was considered as stated by international standards to be immune against HB infection&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Genotyping of &#8220;HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp polymorphism&#8221; at exon 8 &#40;3&#8242;UTR&#41;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Genomic DNA was obtained from EDTA-anticoagulated venous blood &#40;1<span class="elsevierStyleHsp" style=""></span>mL&#41; using a GeneJet Whole Blood genomic DNA extraction kit &#40;Thermo Fisher Scientific Inc&#46;&#44; Waltham&#44; MA&#44; USA&#41;&#44; following the manufacturer&#39;s guidance&#46; 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then 35 PCR cycles of denaturation at 95<span class="elsevierStyleHsp" style=""></span>&#176;C for 60<span class="elsevierStyleHsp" style=""></span>s&#44; annealing at 64<span class="elsevierStyleHsp" style=""></span>&#176;C for 60<span class="elsevierStyleHsp" style=""></span>s&#44; and elongation at 72<span class="elsevierStyleHsp" style=""></span>&#176;C for 60<span class="elsevierStyleHsp" style=""></span>s&#44; ended by final elongation at 72<span class="elsevierStyleHsp" style=""></span>&#176;C for 10<span class="elsevierStyleHsp" style=""></span>min&#8221;&#46; The investigation of amplified PCR products was done in 3&#37; agarose gel including ethidium bromide &#40;0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#41; &#40;Sigma&#44; USA&#41; for 40<span class="elsevierStyleHsp" style=""></span>min and then visualized against UV light using a gel documentation system&#46; The interpretation of the &#8220;HLA-G 14-bp polymorphism&#8221; was done by first and second authors&#46; Depending on the deletion of the 14<span class="elsevierStyleHsp" style=""></span>bp from exon 8&#44; the amplified PCR products were either of 224 or 210<span class="elsevierStyleHsp" style=""></span>bp&#44; or both 224 and 210<span class="elsevierStyleHsp" style=""></span>bp &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">The sample was calculated to be 93 cases using open-Epi at CI 95&#37; and the power of the study is 80&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">14</span></a> The data were examined by computer using Statistical Package of Social Services version 22 &#40;SPSS&#41;&#46; Quantitative variables were described as the mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD &#38; median &#40;range&#41;&#44; and categorical qualitative variables were expressed as absolute frequencies &#40;number&#41; &#38; relative frequencies &#40;percentage&#41;&#46; Suitable statistical tests of significance were used after checked for normality&#46; The differences in genotype&#47;allele frequencies between patients and controls were evaluated by chi-square &#40;<span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span>&#41; test &#40;2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 contingency table for alleles and 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>3 contingency table for genotypes&#41;&#46; The results were considered statistically significant when the significant probability was less than 0&#46;05 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <span class="elsevierStyleItalic">P</span>-value &#60;0&#46;001 was considered highly statistically significant&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ethical approvals</span><p id="par0045" class="elsevierStylePara elsevierViewall">The study was approved by &#8220;Institutional Review Board&#8221; &#40;IRB&#41; no 5295&#46; The parents of the participated children provided their written informed consent&#46; This research was carried out in agreement with the Statement of Helsinki&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Demographic characteristics of the participants</span><p id="par0050" class="elsevierStylePara elsevierViewall">The current study involved 93 infants as study subjects&#44; including 47 &#40;50&#46;5&#37;&#41; boys and 46 &#40;49&#46;5&#37;&#41; girls up to 1 year old&#44; with a mean age of 9&#46;86<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;76 months old&#46; Overall&#44; 82 &#40;88&#46;2&#37;&#41; were responders to hepatitis B vaccine &#40;anti-HBs<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mIU&#47;mL&#41;&#46; While&#44; 11 &#40;11&#46;8&#37;&#41; were non-responders &#40;anti-HBs<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mIU&#47;mL&#41;&#46; The mean antibody titers for responders and non-responders were 77&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#46;14<span class="elsevierStyleHsp" style=""></span>IU&#47;mL and 4&#46;45<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;38<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#44; respectively&#46; There was no statistically significant variance between responder and non-responder groups as regard age and sex&#44; as shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Association between the polymorphism of HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp and the responsiveness to hepatitis B vaccine</p><p id="par0060" class="elsevierStylePara elsevierViewall">Allelic and genotypic frequencies of 14<span class="elsevierStyleHsp" style=""></span>bp HLA-G polymorphism among responders and non-responders to hepatitis B vaccine are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; No Hardy-Weinberg equilibrium deviation was observed in the studied samples for the 14<span class="elsevierStyleHsp" style=""></span>bp HLA-G polymorphism &#40;<span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;477&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;505&#41;&#46; The ins&#47;ins genotype was more frequent in non-responder than responder group &#40;45&#46;5&#37; vs 18&#46;3&#37;&#41;&#44; with a statistically significant difference between responder and non-responder groups&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">The 14-bp insertion allele was significantly more frequent in non-responder than responder group &#40;63&#46;6&#37; vs&#46; 37&#46;8&#37;&#44; respectively&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;013&#41;&#46; Therefore&#44; the higher frequencies of 14<span class="elsevierStyleHsp" style=""></span>bp insertion allele in non-responder as compared to responder group indicate that this allele is associated with an increased risk of failure to respond to hepatitis B vaccine &#40;OR 3&#46;72&#44; 95&#37; CI 1&#46;32&#8211;10&#46;6&#41;&#46; Besides&#44; the responder group was 62&#37; more likely to experience the wild allele &#8220;14<span class="elsevierStyleHsp" style=""></span>bp deletion allele&#8221;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">15</span></a> than the 14<span class="elsevierStyleHsp" style=""></span>bp insertion allele with statistical significance &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;018&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> illustrates the distribution of the anti-HBs titer &#40;IU&#47;mL&#41; according to the responder and non-responder genotypes&#44; the anti-HBs titer was statistically lower among ins&#47;ins genotype than del&#47;del and heterozygous&#44; with a statistically significant difference &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; respectively&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">HBV vaccine is a major public health improvement that has limited the burden of HBV morbidity and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">16</span></a> Anti-HBs antibodies are a marker of immunity and a titer &#8805;10<span class="elsevierStyleHsp" style=""></span>IU&#47;L indicates sero-protection if measured 1&#8211;3 months after completion of the primary vaccination series&#46; In healthy babies&#44; one dose of the vaccine provides 30&#8211;40&#37; protection against HBV infection&#44; 50&#8211;75&#37; protection with two doses and &#62;90&#37; protection with three doses&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">17</span></a> The vaccination failure is a problem that hinders the protection achieved by HBV vaccine&#44; in which the anti-HBs titer is less than 10<span class="elsevierStyleHsp" style=""></span>IU&#47;L &#40;anti-HBs<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10 IU&#47;L&#41;&#46; Individuals with vaccination failure are not effectively protected from HBV and are vulnerable to HBV infection in areas where it is endemic&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">18</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In this paper&#44; we evaluate the humoral response to vaccination against hepatitis B in vaccinated infants&#46; We observed that 88&#46;2&#37; of vaccinated infants were protected against HBV infection &#40;anti-HBs<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mIU&#47;mL&#41;&#46; This was similar to the previous literature in Ghana and Iran where reported sero-protection levels were 87&#46;9&#37;&#44; and 87&#37; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Besides&#44; this study showed that the non-responders &#40;anti-HBs<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mIU&#47;mL&#41; percentage was 11&#46;8&#37; of studied infants&#46; Some authors obtained the same results&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">19&#8211;21</span></a> However&#44; some literature reported slightly lower percents of non-responders&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">22&#44;23</span></a> This variation is explained by the difference in HB vaccine preparations&#44; incorrect injection of HB vaccine&#44; distinctive vaccination schedules and genetic differences&#46; Regarding gender&#44; the results of this present research are like some authors who reported that the immunological response to hepatitis B did not differ in gender&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">24&#44;25</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Production of anti-HBs antibody is helper T cell dependent&#46; The non-responders to vaccination against hepatitis B could be attributed to defect in the HBsAg molecule presentation by dendritic cells &#40;DCs&#41; to na&#239;ve CD4&#43; lymphocytes&#44; specific T and&#47;or B cell repertoires and Treg cells&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">26</span></a> Numerous studies have reported that there is an association between vaccine responsiveness and several polymorphisms including alternates of the MHC and cytokine and cytokine receptor genes&#46; In the association analysis&#44; the HLA-G SNPs have been significantly related to IgM concentrations &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; HLA-G plays a vital role in the antigen presentation and immunotolerance&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">27</span></a> HLA-G was regarded as a significant genetic prone factor for infection with viruses such as human immunodeficiency virus &#40;HIV&#41;&#44; human papillomavirus &#40;HPV&#41;&#44; human cytomegalovirus virus &#40;HCMV&#41;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">9</span></a> and HBV&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">28</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">This research is the first to explore the association during the first year of life between the polymorphism of HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp and the HBs antibody following vaccination&#46; The 14-bp insertion allele was significantly associated with non-responder&#46; Besides&#44; the responder group was more likely to experience the wild type allele than the insertion type&#46; Furthermore&#44; the anti-HBs titer was statistically lower among ins&#47;ins genotype than del&#47;del and heterozygous in responder and non-responder groups&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Possible associations between the antibody reaction to hepatitis B vaccination and HLA-G14<span class="elsevierStyleHsp" style=""></span>bp polymorphism have not been explored to date&#46; We could not find relevant information in field literature about HLA-G 3&#8242;UTR 14-bp ins&#47;del polymorphism and antibody response to hepatitis B vaccination&#44; so comparing our results with other studies was not possible but there are several reports on HLA-G 3&#8242;UTR 14-bp gene variants and viral diseases&#46; Laaribi et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">11</span></a> reported that the ins&#47;ins genotype was accompanied with 2&#46;5 times increased vulnerability to elevated HBV replication compared with the del&#47;del and heterozygous genotypes in Tunisian patients with chronic HBV&#46; In a clinical trial of GMZ2 malaria vaccine&#44; it was found that the low vaccine immunogenicity caused by an increase of sHLA-G level induced by GMZ2&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">29</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">We hypothesized that the polymorphisms in HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp may affect the anti-HBs titer through immune inhibition and induction of tolerance&#46; This is through two mechanisms&#46; The first is through the generation of tolerogenic DCs that are characterized by decreased class II of MHC and costimulatory molecules expression on the cell surface&#46; As DCs are antigen presenting cells required for the efficient priming of T lymphocytes&#44; so tolerogenic DCs are failed to stimulate allogenic T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">30</span></a> The vital steps in the immune response to HBV vaccination are the activation and proliferation of T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">31</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">The second mechanism is by induction of Treg cells that modulate the immune response&#46; Moreover&#44; HLA-G can inhibit all steps in the immune response&#58; differentiation&#44; proliferation&#44; cytolysis&#44; cytokine secretion&#44; and immunoglobulin production&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">10</span></a> Further research is needed to verify our results and to clarify the exact mechanism&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conclusion</span><p id="par0115" class="elsevierStylePara elsevierViewall">This paper has clearly shown that the ins&#47;ins genotype was significantly associated with non-responsiveness to hepatitis B vaccination&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Funding</span><p id="par0120" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public&#44; commercial&#44; or not-for-profit sectors&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interests</span><p id="par0125" class="elsevierStylePara elsevierViewall">Authors have no conflict of interest to declare&#46;</p></span></span>"
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              "titulo" => "Genotyping of &#8220;HLA-G 14 bp polymorphism&#8221; at exon 8 &#40;3&#8242;UTR&#41;"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">This research intended to evaluate the antibody response to vaccination against hepatitis B during the first year of life&#46; We also aimed to assess the association between the antibody response to hepatitis B vaccination and the polymorphism in HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">In this comparative cross-sectional study&#44; 93 infants that received the hepatitis B vaccine at 2&#44; 4&#44; and 6 months old according to the World Health Organization immunization schedules&#44; were evaluated for their antibodies to HBsAg &#40;anti-HBs&#41; following vaccination&#46; Their genomic DNA was extracted and examined for the polymorphism in HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp by PCR&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Among 93 vaccinated infants&#44; 11 infants &#40;11&#46;8&#37;&#41; were non-responders to vaccination against hepatitis B &#40;anti-HBs<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#41;&#46; The mean antibody titers for responders and non-responders were 77&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#46;14<span class="elsevierStyleHsp" style=""></span>IU&#47;mL and 4&#46;45<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;38<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#44; respectively&#46; The 14-bp insertion allele was associated with an increased risk of failure o respond to hepatitis B vaccination &#40;OR 3&#46;72&#44; 95&#37; CI 1&#46;32&#8211;10&#46;6&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This study reported&#44; for the first time&#44; that ins&#47;ins genotype may be a risk factor for non-responsiveness to hepatitis B vaccination&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este estudio fue evaluar la respuesta de anticuerpos a la vacuna frente a la hepatitis B durante el primer a&#241;o de vida&#46; Tambi&#233;n tratamos de evaluar la asociaci&#243;n entre la respuesta de anticuerpos a la vacuna frente a la hepatitis B y el polimorfismo en HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">En este estudio transversal comparativo se evalu&#243; el HBsAg &#40;anti-HBS&#41; de 93 ni&#241;os que recibieron la vacuna contra la hepatitis B a los 2&#44; 4 y 6 meses de edad&#44; conforme a los programas de la Organizaci&#243;n Mundial de la Salud&#44; fueron evaluados por sus anticuerpos frente a HBsAg &#40;anti-HBs&#41; despu&#233;s de la vacunaci&#243;n&#46; Se extrajo su ADN gen&#243;mico&#46; examin&#225;ndose el polimorfismo en HLA-G 14<span class="elsevierStyleHsp" style=""></span>bp mediante la prueba PCR&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Entre los 93 ni&#241;os vacunados&#44; 11 ni&#241;os &#40;11&#44;8&#37;&#41; no respondieron a la vacuna frente a la hepatitis B &#40;anti-HBs<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>UI&#47;mL&#41;&#46; Los t&#237;tulos de anticuerpos medios para respondedores y no respondedores fueron de 77&#44;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;14 y 4&#44;45<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;38<span class="elsevierStyleHsp" style=""></span>UI&#47;mL&#44; respectivamente&#46; El alelo 14<span class="elsevierStyleHsp" style=""></span>bp inserci&#243;n se asoci&#243; a un incremento del riesgo de fallo de respuesta a la vacuna frente a la hepatitis B &#40;OR&#58; 3&#44;72&#59; IC 95&#37;&#58; 1&#44;32-10&#44;6&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Este estudio report&#243;&#44; por vez primera&#44; que el genotipo ins&#47;ins puede constituir un factor de riesgo para la no respuesta a la vacuna frente a la hepatitis B&#46;</p></span>"
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      "titulo" => "References"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis B virus epidemiology&#44; disease burden&#44; treatment&#44; and current and emerging prevention and control measures"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "D&#46; Lavanchy"
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                    0 => array:2 [
                      "doi" => "10.1046/j.1365-2893.2003. 00487.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Viral Hepat"
                        "fecha" => "2004"
                        "volumen" => "11"
                        "paginaInicial" => "97"
                        "paginaFinal" => "107"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14996343"
                            "web" => "Medline"
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              "identificador" => "bib0165"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serum level of anti-hepatitis B surface antigen among newborns and fully vaccinated infants and children aged 6 to 11 years"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46;S&#46; Afifi"
                            1 => "M&#46;H&#46; Mahran"
                            2 => "Z&#46;N&#46; Said"
                            3 => "I&#46;I&#46; Salama"
                            4 => "H&#46; El Khayat"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Aust J Basic Appl Sci"
                        "fecha" => "2009"
                        "volumen" => "3"
                        "paginaInicial" => "3239"
                        "paginaFinal" => "3245"
                      ]
                    ]
                  ]
                ]
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            ]
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              "etiqueta" => "3"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lifelong protection against hepatitis B&#58; the role of vaccine immunogenicity in immune memory"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46; Banatvala"
                            1 => "P&#46; Van Damme"
                            2 => "S&#46; Oehen"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0264-410x (00)00224-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Vaccine"
                        "fecha" => "2000"
                        "volumen" => "19"
                        "paginaInicial" => "877"
                        "paginaFinal" => "885"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11115711"
                            "web" => "Medline"
                          ]
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                      ]
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              "etiqueta" => "4"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Basic concepts of immune response defense development"
                      "autores" => array:1 [
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                            0 => "K&#46;C&#46; McCullough"
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                    0 => array:2 [
                      "doi" => "10.1093/ilar.46.3.230"
                      "Revista" => array:6 [
                        "tituloSerie" => "ILAR J"
                        "fecha" => "2005"
                        "volumen" => "46"
                        "paginaInicial" => "230"
                        "paginaFinal" => "240"
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Article information

ISSN: 24451460
Original language: English

DOI:10.1016/j.vacune.2020.10.007

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