Establishment of competitive binding assay to detect and differentiate hepatitis E virus infection

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Captions: “+” – low risk of bias; “−” – high risk of bias; blank – unclear risk of bias." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Fernando C. Schacher, Sofia M. Giongo, Fernanda J.P. Teixeira, Ângelo Z. Mattos" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Fernando C." "apellidos" => "Schacher" ] 1 => array:2 [ "nombre" => "Sofia M." "apellidos" => "Giongo" ] 2 => array:2 [ "nombre" => "Fernanda J.P." "apellidos" => "Teixeira" ] 3 => array:2 [ "nombre" => "Ângelo Z." 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ALT: alanine aminotransferase, HEV RNA: hepatitis E virus ribonucleic acid." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Filiz Akyüz, Bilger Çavuş, Binnur Pınarbaşı, Mürvet Bozacı, Bülent Baran, Umit Akyuz, Ahmet Uyanıkoglu, Kadir Demir, Fatih Beşışık, Sadakat Özdil, Güngör Boztaş, Zeynel Mungan, Selim Badur, Sadi Yenen, Sabahattin Kaymakoglu" "autores" => array:15 [ 0 => array:2 [ "nombre" => "Filiz" "apellidos" => "Akyüz" ] 1 => array:2 [ "nombre" => "Bilger" "apellidos" => "Çavuş" ] 2 => array:2 [ "nombre" => "Binnur" "apellidos" => "Pınarbaşı" ] 3 => array:2 [ "nombre" => "Mürvet" "apellidos" => "Bozacı" ] 4 => array:2 [ "nombre" => "Bülent" "apellidos" => "Baran" ] 5 => array:2 [ "nombre" => "Umit" "apellidos" => "Akyuz" ] 6 => array:2 [ "nombre" => "Ahmet" "apellidos" => "Uyanıkoglu" ] 7 => array:2 [ "nombre" => "Kadir" "apellidos" => "Demir" ] 8 => array:2 [ "nombre" => "Fatih" "apellidos" => "Beşışık" ] 9 => array:2 [ "nombre" => "Sadakat" "apellidos" => "Özdil" ] 10 => array:2 [ "nombre" => "Güngör" "apellidos" => "Boztaş" ] 11 => array:2 [ "nombre" => "Zeynel" "apellidos" => "Mungan" ] 12 => array:2 [ "nombre" => "Selim" "apellidos" => "Badur" ] 13 => array:2 [ "nombre" => "Sadi" "apellidos" => "Yenen" ] 14 => array:2 [ "nombre" => "Sabahattin" "apellidos" => "Kaymakoglu" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119300596?idApp=UINPBA00004N" "url" => "/16652681/0000001800000004/v3_201908230828/S1665268119300596/v3_201908230828/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Establishment of competitive binding assay to detect and differentiate hepatitis E virus infection" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "590" "paginaFinal" => "594" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Jiyue Wen, Weizhuo Lu, Jihong Meng" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Jiyue" "apellidos" => "Wen" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "#" "identificador" => "fn0030" ] ] ] 1 => array:3 [ "nombre" => "Weizhuo" "apellidos" => "Lu" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "#" "identificador" => "fn0030" ] ] ] 2 => array:4 [ "nombre" => "Jihong" "apellidos" => "Meng" "email" => array:1 [ 0 => "jihongmengg@163.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Pharmacology, Anhui Medical University, Hefei, Anhui, China" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Microbiology and Immunology, Southeast University School of Medicine, Nanjing, China" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Medical Branch, Hefei Technology College, Hefei, Anhui, China" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author: Department of Microbiology and Immunology, Southeast University School of Medicine, Nanjing, China; Telephone number: 0086-0551-65161133." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1038 "Ancho" => 1557 "Tamanyo" => 87356 ] ] "descripcion" => array:1 [ "en" => "Binding of 2B1 to p166W01, 4C5 to p166Chn inhibited by human serum anti-HEVs against genotype 1 HEV. G1: anti-HEVs against genotype 1 HEV." ] ] ] "textoCompleto" => "1IntroductionHEV is a small, non-enveloped, positive-strand RNA virus known to causes hepatitis E (HE), which can lead to detrimental prognostics, like sever acute hepatitis, chronic infection in the organ transplanted and immunosuppressed patients, high mortality among pregnant women and live failure <a class="elsevierStyleCrossRefs" href="#bib0155">[1,2]</a>. The genomes of HEV strains consist of three overlapping open reading frames (ORFs), one of which is ORF2 that encodes the capsid protein of virus, C-terminal region of capsid protein has been localized as predominant immunogenic domain <a class="elsevierStyleCrossRefs" href="#bib0165">[3,4]</a>.HEV strains infecting humans are classified into four genotypes <a class="elsevierStyleCrossRef" href="#bib0175">[5]</a>, genotypes 1 and 2 are associated with large waterborne epidemic and isolated exclusively from humans, and these two genotypes HEV failed infect pigs in experimental studies, suggesting unlikely potential risk of zoonotic transmission to humans <a class="elsevierStyleCrossRef" href="#bib0180">[6]</a>. Whereas, genotype 3, 4 viruses are mainly responsible for sporadic cases, recognized as zoonotic pathogens. Because genotypes 3, 4 strains have been isolated both from humans and many wild and domestic animals, and have been found cross-species transmission from animals to humans <a class="elsevierStyleCrossRefs" href="#bib0185">[7–9]</a>. Therefore, genotypes 1–4 HEV strains are classified into human(H) (genotypes 1 and 2)and zoonosis (Z) (genotypes 3 and 4) groups according to theirs compatible hosts by some people <a class="elsevierStyleCrossRef" href="#bib0200">[10]</a>. So, the confirmation of source of HEV infection from genotypes 1, 2 or zoonotic genotypes 3, 4 is an essential part of hepatitis E (HE) diagnosis and epidemiological investigation. The diagnosis of HE is mainly based on the results of laboratory test, mainly containing the detection of stool virus RNA and serum antibodies. The most widely used method for HE diagnosis is ELISA for its rapid and convenient characteristics <a class="elsevierStyleCrossRef" href="#bib0205">[11]</a>. As we all known, Wantai assay (ELISA) for HEV IgG detection is one of the most commonly used commercial kits, and has the highest sensitivity and specificity <a class="elsevierStyleCrossRef" href="#bib0210">[12]</a>. But till now, there is no simply serodiagnostic approach can disclose the origin of HEV isolates from human or zoonosis, except for genetic sequencing.Previous study has reported that the recombinant protein p166 (452–617 aa of ORF2 protein) could model HEV conformational neutralizing epitope(s) <a class="elsevierStyleCrossRef" href="#bib0215">[13]</a>. In our previous study, we have found the different sensitivity between p166 proteins of different genotypes in detection of human serum anti-HEV antibodies after different genotypes HEV infection <a class="elsevierStyleCrossRefs" href="#bib0220">[14,15]</a>. Moreover, the immunogenicity difference has also been found between the HEV p179 vaccine derived from genotype 4 strains and p239 vaccine (Hecolin) from genotype 1 HEV, the immunogenicity difference may attribute to the genotype-specific epitope(s) assessed by mAbs <a class="elsevierStyleCrossRef" href="#bib0230">[16]</a>. Therefore, we tested the hypothesis in this study that whether the genotype-specific mAbs could be used to detect and differentiate the source of HEV infection, from human or zoonosis.2Materials and methods2.1Serum samplesFifty five human serum samples with high antibody level were collected from year 2001 to 2006 <a class="elsevierStyleCrossRef" href="#bib0220">[14]</a>. The year of collection, HEV genotypes and sample size are shown as below: Chad (2004, genotype 1, n=10), Hungary (2001–2006, genotype 3, n=9), and China (2005–2006, genotype 4, n=36). The Chad samples were first sent to the Centers for Disease Control and Prevention (CDC) in Atlanta in 2004, serum samples from Hungary were initially referred to the Regional Laboratory for Virology in Pécs, and those from China were referred to the Southeast University School of Medicine and the Second Hospital in Nanjing. Personal identifiers of all serum samples in this study were completely stripped of before being tested at Southeast University. Another eight serum samples were obtained from rhesus monkeys which have been inoculated intravenously with HEV strain W01 (genotype 1, <a href="ncbi-n:JX857689">JX857689</a>) or NJ703 (genotype 4, <a href="ncbi-n:AY789225">AY789225</a>). Viruses inoculation and sera sample collection were in the charge of GuangXi Center for Disease Prevention and Control <a class="elsevierStyleCrossRef" href="#bib0230">[16]</a>. All serum samples were stored at −80°C until further use. The procedures involving animals in this study were approved by the local committee of Animal Use and Protection.2.2Recombinant proteinsRecombinant plasmid containing p166 nucleotide sequence was constructed and expressed in E. coli according to previous study <a class="elsevierStyleCrossRef" href="#bib0235">[17]</a>. Four His-tagged p166 were respectively generated from W01 (genotype 1, <a href="ncbi-n:JX857689">JX857689</a>), Mexico-14 (genotype 2, <a href="ncbi-n:M74506">M74506</a>), US-1 (genotype 3, <a href="ncbi-n:AF060668">AF060668</a>) and China-9829 (genotype 4, <a href="ncbi-n:AY789225">AY789225</a>) strains, designated as p166W01, p166Mex, p166Us and p166Chn. And two GST-tagged proteins, p166Sar and p166Chn were respectively generated from the HEV Pakistani Sar-55 strain (genotype 1, <a href="ncbi-n:M80581">M80581</a>) and the China-9829 strain (genotype 4, <a href="ncbi-n:AY789225">AY789225</a>).2.3Generation of mAbs against p166Sar and p166ChnThe mAbs 2B1 and 4C5 were prepared as previously described <a class="elsevierStyleCrossRef" href="#bib0230">[16]</a>, produced by injecting 106 hybridoma cells into the peritoneal cavity of the BALB/c mice. 7–10 days later, ascites fluid was harvested, filtered, centrifuged, and then purified with protein G affinity column. The purified mAbs were stored at −80°C until further use. All experimental procedures were approved by the Ethics Review Committee of Anhui Medical University, which comply with the Guide for the Care and Use of laboratory Animals published by the US National Institutes of Health (NIH publication no. 85-23, revised 2011).2.4Labeling mAbs with horseradish peroxidase (HRP)Purified mAbs were dialyzed against 100mM Carbonate/Bicarbonate buffer (pH 9.3) at 4°C over night. And then, antibodies were labeled with HRP according to the manufacturer's instructions (KPL). Methods are briefly described as follows: 1.5mg of HRP and 0.5mg of mAb were added into HRP conjugation buffer at a final volume of 0.5ml. After gently stirring at room temperature for 1h, the mixture was left standing at room temperature for 15min. And then, 10μl of the reducing agent was added into the mixture. At last, the same volume of distilled glycerol was added into the mixture for storage and further use.2.5Competitive binding assay2.5.1Determination of antigens and mAbs titersThe titers of coated antigens and HRP-conjugated mAbs were determined by ELISA. Initially, HRP-conjugated mAbs of two-fold dilutions in 1% casein PBS, ranging from 1:400 to 1:25,600 were prepared and then added in wells, which pre-coated with serial two-fold dilutions (from 1:200 to 1:6400) of p166W01 or p166Chn antigen. After incubating at 37°C for 45min, the ELISA plate was washed for five times with PBS containing 0.5% Tween-20 (PBST). And then, TMB liquid substrate was added for color development, which was stopped by adding stop solution. Finally, the Optical Density (OD) of each well was read at 450nm, with a 630nm reference wavelength to determine the dilution of coated antigen and HRP-conjugated mAb that give an OD value reading of approximately 1.0.2.5.2Competitive binding assay <a class="elsevierStyleCrossRef" href="#bib0240">[18]</a>The p166W01 and p166Chn were used as coating antigens to establish the competitive binding assay, respectively. Anti-HEV sera of saturating concentration were used to assess the inhibition percentage of the binding of HRP-mAb to antigen. The procedure was similar to our previous study <a class="elsevierStyleCrossRef" href="#bib0245">[19]</a>, the p166W01 or p166Chn of optional dilution was used as the coating antigen respectively, the mixture of HRP-conjugated mAb at twice the optional dilution and anti-HEV serum of saturated concentration was added to antigen coated well. The OD value was read at 450nm, with a 630nm reference wavelength. The inhibition percentage was calculated by the following formula: 100×[1−(A450,630 of HRP-conjugated mAb and serum anti-HEV IgG)/(A450,630 of HRP-conjugated mAb)].3Results3.1Isolation and characterization of mAbs against p166Sar or p166ChnThe mAbs were purified using immobilized protein G, and the specificity of mAbs was identified by ELISA with 4 genotypes p166 antigens (p166W01, p166Mex, p166Us, p166Chn), respectively. The results of ELISA revealed that mAb 2B1 reacted only with p166W01 and p166Mex, but not with p166US or p166Chn; whereas, mAb 4C5 reacted only with p166US and p166Chn, but not with p166W01 or p166Mex, suggesting that 2B1 and 4C5 were genotypes-specific mAbs <a class="elsevierStyleCrossRef" href="#bib0230">[16]</a>.3.2Determination of antigens and mAbs dilutionp166W01 protein was used as coating antigen to establish the competitive binding assay of mAb 2B1 and serum anti-HEV IgG; p166Chn antigen was used to establish the competitive binding assay of mAb 4C5 and serum anti-HEV IgG. As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, the dilution of p166W01 was 1:400, HRP-conjugated 2B1 was 1:6400,the mean OD value was close to 1.0; whereas, the dilution of p166Chn was 1:800, HRP-conjugated 4C5 was 1:6400, the mean OD value was close to 1.0 (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>3.3Binding of mAbs to antigens inhibited by serum anti-HEV IgG of rhesus monkeysSera sample containing anti-HEV IgG were collected from rhesus monkeys challenged with genotype 1HEV strains (W01) or genotype 4 HEV strains (NJ703) <a class="elsevierStyleCrossRef" href="#bib0230">[16]</a>, used to evaluate the binding inhibition of mAb 2B1 to p166W01, mAb 4C5 to p166Chn. As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, both the binding of mAb 2B1 to p166W01 and mAb 4C5 to p166Chn could be inhibited by the serum anti-HEVs against genotype 1 or 4 HEV. But more high inhibition percentages were obtained from the binding of 2B1 to p166W01 inhibited by genotype 1 anti-HEV IgGs, from 25% to 61%. Whereas, the inhibition percentage of mAb 4C5 to p166Chn inhibited by genotype 1 anti-HEV IgG strain was not more than 26%. On the contrary, the binding of mAb 4C5 to p166Chn was inhibited more remarkably by the gentoype 4 anti-HEV IgG (from 60% to 70%) than that by the genotype 1 anti-HEV IgG (from 0% to 38%).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>3.4Binding of mAbs to antigens inhibited by anti-HEV IgG in human serum against genotype 1 HEVAnti-HEV IgG in human sera infected by genotype 1 strains were also used to further demonstrate the binding inhibition of mAbs to antigens. As shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>, the binding of 2B1 to p166W01 was inhibited remarkably by the genotype 1 anti-HEV IgG, the inhibition percentages were from 57% to 85%. Whereas, genotype 1 anti-HEV IgG could only partially inhibit the binding of mAb 4C5 to p166Chn, the inhibition percentages were not more than 66%.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>3.5Binding of mAbs to antigens inhibited by human serum anti-HEV IgG against genotype 3 HEVWe followed the same approach to investigate the inhibition percentage of mAbs to antigens by serum anti-HEV IgG against the genotype 3 HEV. As shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>, the binding of 4C5 to p166Chn antigen was inhibited more remarkably by genotype 3 anti-HEV IgG, the inhibition percentages were from 45% to 83%. Whereas, each of the same serum could only partially inhibit the binding of 2B1 to p166W01, the inhibition percentages were not more than 61%.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>3.6Binding of mAbs to antigens inhibited by human serum anti-HEV IgG against genotype 4 HEVThe serum samples were collected from human infected by genotype 4 HEV strains, the binding inhibition of mAbs to antigens inhibited by serum anti-HEV IgG was evaluated with same approach. The results were similar to previous descriptions, the binding of 4C5 to p166Chn antigen was inhibited more remarkably by genotype 4 anti-HEV IgG, the inhibition percentages were from 30% to 96%. Whereas, each of the same serum could only partially inhibit the binding of 2B1 to p166W01, the inhibition percentages were not more than 57% (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>4DiscussionHEV infection is an important public health concern not only in developing countries but also in developed ones. The ratio of infection-to-mortality of HEV is generally considered to be small, but this significantly increases in pregnant women, in infants under the age of 2 years, and in adults over the age of 56 years. Moreover, the outbreaks of HEV have been repeatedly reported in India, Nepal, Pakistan, Burma, Mexico, and China <a class="elsevierStyleCrossRef" href="#bib0250">[20]</a>, due to inadequate sanitary conditions. Although only one serotype has been recognized, HEV of genotypes 1, 2 still differed from genotypes 3, 4 in their antigenic and immunogenic characteristics <a class="elsevierStyleCrossRef" href="#bib0230">[16]</a>. Especially, genotypes 3, 4 HEV strains may be capable of infecting cross-species, from chicken to wild birds, and even from animals to human beings <a class="elsevierStyleCrossRefs" href="#bib0255">[21,22]</a>. High prevalence of HEV frequently displayed in Asia and Africa. The anti-HEV-positive rates have been found more than 30% in most Asia and Africa countries, suggesting a high rate of subclinical infection <a class="elsevierStyleCrossRefs" href="#bib0265">[23–26]</a>. The appearance of anti-HEV antibodies in serum is considered as an epidemiological marker of HEV exposure assessment in a population <a class="elsevierStyleCrossRef" href="#bib0180">[6]</a>. Anti-HEV IgG can be detected within two weeks and lasting for more than 10 years after the virus exposure, and can be used as an index of epidemiological investigation <a class="elsevierStyleCrossRef" href="#bib0285">[27]</a>.As aforementioned, genotypes 1, 2 HEV only infect humans while genotypes 3,4 HEV are zoonotic agents, the main reservoir of HEV3 and HEV4 is domestic pigs. While, genotypes 1, 2 HEV are believed to transmitted via contaminated water. Furthermore, both genotypes 3 and 4 HEV have been reported in chronic infection, however, neither genotype 1 nor genotype 2 HEV has been shown to associate with chronic HE so far <a class="elsevierStyleCrossRef" href="#bib0290">[28]</a>. In addition, previous studies have reported that HEV could transmit by blood transfusion in a number of countries <a class="elsevierStyleCrossRefs" href="#bib0295">[29,30]</a>. Therefore, HE diagnosis and epidemiological investigation, especially, confirmation the source of HEV from genotypes 1, 2 or 3, 4 are essential parts of prevention of HEV transmission.In present study, we sought to clarify whether the genotype-specific mAbs 2B1 and 4C5 could be used for HE diagnosis and disclosure the source of HEV from human or zoonosis by establishment of the competitive binding assay. The results of competitive binding assay indicated that both the binding of 2B1 to p166W01, 4C5 to p166Chn could be inhibited by the anti-HEV IgG in rhesus monkey sera against genotypes 1 or 4 strains. But the genotype 1 anti-HEV IgG could inhibit the binding of 2B1 to p166W01 more significantly than that of 4C5 to p166Chn. Whereas, genotype 4 anti-HEV IgG in rhesus monkey sera could block the binding of 4C5 to p166Chn more strongly than that of 2B1 to p166W01.We next tried to further confirm the differences of competitive inhibition of the binding of mAbs to antigens. Thirty seven human sera samples infected by genotypes 1, 3 or 4 HEV were collected and used to confirm the differently binding inhibition between 2B1 to p166W01 with 4C5 to p166Chn. The results revealed that genotype 1 anti-HEV IgG could inhibit the binding of 2B1 to p166W01 more remarkably than that of 4C5 to p166Chn. Whereas, serum anti-HEV IgG against the genotypes 3 or 4 HEV could inhibit the binding of 4C5 to p166Chn more significantly than that of 2B1 to p166W01. These findings indicated that the binding of genotype-specific mAbs to p166W01 or p166Chn antigen can be blocked at different degree by anti-HEV IgG against genotype 1, 3 or 4. This is the first study that demonstrates the genotype-specific mAbs 2B1 and 4C5 may be used for HE diagnosis and epidemiological investigation of HEV exposure from human or zoonosis by establishment of competitive binding assay. Despite major steps forward in demonstrating a promising approach for detection and differentiation the serum anti-HEV IgG using a competitive binding assay, following questions need to be solved, the clinical phenotype of HE continues to emerges; locally acquired zoonotic hepatitis E is recognized slowly in developed countries. Therefore, further studies are urgently needed to optimize the experimental conditions of competitive binding assay for future development.AbbreviationsHEhepatitis EHEVhepatitis E virusIgGimmunoglobulin GmAbsmonoclonal antibodiesHRPHorseradish peroxidaseODOptical DensityORFsopen reading framesPBSTPBS containing 0.5% Tween-20Ethical statementAll experimental procedures were approved by the Ethics Review Committee of Anhui Medical University, which comply with the Guide for the Care and Use of laboratory Animals published by the US National Institutes of Health (NIH publication no. 85-23, revised 2011).FundingThis study was supported by Grants for Scientific Research of BSKY (No. XJ201612) from Anhui Medical University and from Natural Science Foundation of Hefei Technology College (No. 201914KJA020)ContributionsParticipated in research design and experiments: Jiyue Wen, Weizhuo Lu.Contributed new reagents or analytical tools: Weizhuo Lu.Performed data analysis: Jiyue Wen.Contributed to writing of the manuscript: Jiyue Wen, Jihong Meng.Conflict of interestThe authors have no conflict of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1233314" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1145646" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Serum samples" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Recombinant proteins" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Generation of mAbs against p166Sar and p166Chn" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Labeling mAbs with horseradish peroxidase (HRP)" ] 4 => array:3 [ "identificador" => "sec0035" "titulo" => "Competitive binding assay" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Determination of antigens and mAbs titers" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Competitive binding assay [18]" ] ] ] ] ] 4 => array:3 [ "identificador" => "sec0050" "titulo" => "Results" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Isolation and characterization of mAbs against p166Sar or p166Chn" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Determination of antigens and mAbs dilution" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Binding of mAbs to antigens inhibited by serum anti-HEV IgG of rhesus monkeys" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Binding of mAbs to antigens inhibited by anti-HEV IgG in human serum against genotype 1 HEV" ] 4 => array:2 [ "identificador" => "sec0075" "titulo" => "Binding of mAbs to antigens inhibited by human serum anti-HEV IgG against genotype 3 HEV" ] 5 => array:2 [ "identificador" => "sec0080" "titulo" => "Binding of mAbs to antigens inhibited by human serum anti-HEV IgG against genotype 4 HEV" ] ] ] 5 => array:2 [ "identificador" => "sec0085" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0090" "titulo" => "Ethical statement" ] 7 => array:2 [ "identificador" => "sec0095" "titulo" => "Funding" ] 8 => array:2 [ "identificador" => "sec0100" "titulo" => "Contributions" ] 9 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-09-02" "fechaAceptado" => "2019-01-18" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1145646" "palabras" => array:5 [ 0 => "HEV" 1 => "Monoclonal antibody" 2 => "Genotype" 3 => "Genotype-specific" 4 => "IgG" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and ObjectivesThis study was undertaken to demonstrate a promising approach for detection and differentiation the serum immunoglobulin G (IgG) against hepatitis E virus (anti-HEV IgG) using a competitive binding assay established with known genotype-specific monoclonal antibodies (mAbs) 2B1 and 4C5. Materials and methodsThe mAb 2B1 derived from genotype 1 hepatitis E virus (HEV) antigen and specifically reacted with genotype 1, 2 antigens; 4C5 induced by genotype 4 HEV antigen was specific to genotypes 3, 4 antigens. The 2B1 and 4C5 were labeled with Horseradish peroxidase (HRP), respectively. Subsequently, the titers of coated antigens and HRP-conjugated mAbs for establishment of competitive binding assay were determined by enzyme linked immunosorbent assay (ELISA). And then, the competitive binding assay was performed to assess the inhibition percentage of mAbs binding to antigens inhibited by different genotypes anti-HEV IgG. ResultsThe results of competitive binding assay revealed that genotype 1 anti-HEV IgG could inhibit the binding of mAb 2B1 to genotype 1 antigen more strongly than that of mAb 4C5 to genotype 4 antigen. Whereas, the genotype 3 or 4 anti-HEV IgG could inhibit the binding of mAb 4C5 to genotype 4 antigen more remarkably than that of mAb 2B1 to genotype 1 antigen. ConclusionsThese findings provided us a valuable approach for detection and differentiation the HEV infection derived from genotypes 1, 2 (human) or genotypes 3, 4 (zoonosis)." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] ] "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "#" "nota" => "Contributed equally to this work." "identificador" => "fn0030" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1022 "Ancho" => 1537 "Tamanyo" => 80324 ] ] "descripcion" => array:1 [ "en" => "Binding of 2B1 to p166W01, 4C5 to p166Chn inhibited by serum anti-HEVs of rhesus monkey inoculated intravenously with genotype 1 or 4 HEV. G1: Serum anti-HEVs of rhesus monkey angainst genotype 1 HEV; G4: Serum anti-HEVs of rhesus monkey against genotype 4 HEV." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1038 "Ancho" => 1557 "Tamanyo" => 87356 ] ] "descripcion" => array:1 [ "en" => "Binding of 2B1 to p166W01, 4C5 to p166Chn inhibited by human serum anti-HEVs against genotype 1 HEV. G1: anti-HEVs against genotype 1 HEV." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 990 "Ancho" => 1512 "Tamanyo" => 81771 ] ] "descripcion" => array:1 [ "en" => "Binding of 2B1 to p166W01, 4C5 to p166Chn inhibited by human serum anti-HEVs against genotype 3 HEV. G3: anti-HEVs against genotype 3 HEV." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 998 "Ancho" => 1476 "Tamanyo" => 89730 ] ] "descripcion" => array:1 [ "en" => "Binding of 2B1 to p166W01, 4C5 to p166Chn inhibited by human serum anti-HEVs against genotype 4 HEV. G4: anti-HEVs against genotype 4 HEV." ] ] 4 => 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:2 [ "leyenda" => "Bold and underline emphasize that the corresponding dilutions of antigen and HRP-conjugated mAb were used to establish the competitive binding assay." "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-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Antigen dilution \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 " colspan="8" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dilutions of HRP-conjugated 2B1</th></tr><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">1:400 \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">1:800 \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">1:1600 \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">1:3200 \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">1:6400 \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">1:12,800 \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">1:25,600 \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">Negative control \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">1:200 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.821 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.234 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.906 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.412 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.056 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.845 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.546 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.065 \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">1:400 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.722 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.945 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.432 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.209 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.987 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.651 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.345 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.023 \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">1:800 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.825 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.287 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.087 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.905 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.754 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.465 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.223 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.045 \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">1:1600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.023 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.705 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.865 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.652 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.506 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.216 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.105 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.076 \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">1:3200 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.906 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.505 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.456 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.321 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.156 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.134 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.054 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.045 \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">1:6400 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.543 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.328 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.204 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.178 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.091 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.065 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.056 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.034 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2106808.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Determination of p166W01 antigen and HRP-conjugated 2B1 dilutions (means, n=4)." ] ] 5 => 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" => "Bold and underline emphasize that the corresponding dilutions of antigen and HRP-conjugated mAb were used to establish the competitive binding assay." "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-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Antigen dilution \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 " colspan="8" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dilutions of HRP-conjugated 4C5</th></tr><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">1:400 \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">1:800 \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">1:1600 \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">1:3200 \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">1:6400 \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">1:12,800 \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">1:25,600 \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">Negative control \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">1:200 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.804 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.567 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.402 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.846 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.365 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.912 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.661 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.067 \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">1:400 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.789 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.487 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.543 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.133 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.832 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.487 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.034 \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">1:800 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.436 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.934 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.698 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.321 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.982 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.678 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.369 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.056 \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 ; 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Jiyue Wena,#, Weizhuo Luc,#, Jihong Mengb,

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jihongmengg@163.com

Corresponding author: Department of Microbiology and Immunology, Southeast University School of Medicine, Nanjing, China; Telephone number: 0086-0551-65161133.

a Department of Pharmacology, Anhui Medical University, Hefei, Anhui, China

b Department of Microbiology and Immunology, Southeast University School of Medicine, Nanjing, China

c Department of Medical Branch, Hefei Technology College, Hefei, Anhui, China

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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Binding of 2B1 to p166W01&#44; 4C5 to p166Chn inhibited by human serum anti-HEVs against genotype 1 HEV&#46; G1&#58; anti-HEVs against genotype 1 HEV&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">HEV is a small&#44; non-enveloped&#44; positive-strand RNA virus known to causes hepatitis E &#40;HE&#41;&#44; which can lead to detrimental prognostics&#44; like sever acute hepatitis&#44; chronic infection in the organ transplanted and immunosuppressed patients&#44; high mortality among pregnant women and live failure <a class="elsevierStyleCrossRefs" href="#bib0155">&#91;1&#44;2&#93;</a>&#46; The genomes of HEV strains consist of three overlapping open reading frames &#40;ORFs&#41;&#44; one of which is ORF<span class="elsevierStyleInf">2</span> that encodes the capsid protein of virus&#44; C-terminal region of capsid protein has been localized as predominant immunogenic domain <a class="elsevierStyleCrossRefs" href="#bib0165">&#91;3&#44;4&#93;</a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">HEV strains infecting humans are classified into four genotypes <a class="elsevierStyleCrossRef" href="#bib0175">&#91;5&#93;</a>&#44; genotypes 1 and 2 are associated with large waterborne epidemic and isolated exclusively from humans&#44; and these two genotypes HEV failed infect pigs in experimental studies&#44; suggesting unlikely potential risk of zoonotic transmission to humans <a class="elsevierStyleCrossRef" href="#bib0180">&#91;6&#93;</a>&#46; Whereas&#44; genotype 3&#44; 4 viruses are mainly responsible for sporadic cases&#44; recognized as zoonotic pathogens&#46; Because genotypes 3&#44; 4 strains have been isolated both from humans and many wild and domestic animals&#44; and have been found cross-species transmission from animals to humans <a class="elsevierStyleCrossRefs" href="#bib0185">&#91;7&#8211;9&#93;</a>&#46; Therefore&#44; genotypes 1&#8211;4 HEV strains are classified into human&#40;H&#41; &#40;genotypes 1 and 2&#41;and zoonosis &#40;Z&#41; &#40;genotypes 3 and 4&#41; groups according to theirs compatible hosts by some people <a class="elsevierStyleCrossRef" href="#bib0200">&#91;10&#93;</a>&#46; So&#44; the confirmation of source of HEV infection from genotypes 1&#44; 2 or zoonotic genotypes 3&#44; 4 is an essential part of hepatitis E &#40;HE&#41; diagnosis and epidemiological investigation&#46; The diagnosis of HE is mainly based on the results of laboratory test&#44; mainly containing the detection of stool virus RNA and serum antibodies&#46; The most widely used method for HE diagnosis is ELISA for its rapid and convenient characteristics <a class="elsevierStyleCrossRef" href="#bib0205">&#91;11&#93;</a>&#46; As we all known&#44; Wantai assay &#40;ELISA&#41; for HEV IgG detection is one of the most commonly used commercial kits&#44; and has the highest sensitivity and specificity <a class="elsevierStyleCrossRef" href="#bib0210">&#91;12&#93;</a>&#46; But till now&#44; there is no simply serodiagnostic approach can disclose the origin of HEV isolates from human or zoonosis&#44; except for genetic sequencing&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Previous study has reported that the recombinant protein p166 &#40;452&#8211;617 aa of ORF<span class="elsevierStyleInf">2</span> protein&#41; could model HEV conformational neutralizing epitope&#40;s&#41; <a class="elsevierStyleCrossRef" href="#bib0215">&#91;13&#93;</a>&#46; In our previous study&#44; we have found the different sensitivity between p166 proteins of different genotypes in detection of human serum anti-HEV antibodies after different genotypes HEV infection <a class="elsevierStyleCrossRefs" href="#bib0220">&#91;14&#44;15&#93;</a>&#46; Moreover&#44; the immunogenicity difference has also been found between the HEV p179 vaccine derived from genotype 4 strains and p239 vaccine &#40;Hecolin&#41; from genotype 1 HEV&#44; the immunogenicity difference may attribute to the genotype-specific epitope&#40;s&#41; assessed by mAbs <a class="elsevierStyleCrossRef" href="#bib0230">&#91;16&#93;</a>&#46; Therefore&#44; we tested the hypothesis in this study that whether the genotype-specific mAbs could be used to detect and differentiate the source of HEV infection&#44; from human or zoonosis&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0040">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0045">Serum samples</span><p id="par0020" class="elsevierStylePara elsevierViewall">Fifty five human serum samples with high antibody level were collected from year 2001 to 2006 <a class="elsevierStyleCrossRef" href="#bib0220">&#91;14&#93;</a>&#46; The year of collection&#44; HEV genotypes and sample size are shown as below&#58; Chad &#40;2004&#44; genotype 1&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;&#44; Hungary &#40;2001&#8211;2006&#44; genotype 3&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&#44; and China &#40;2005&#8211;2006&#44; genotype 4&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41;&#46; The Chad samples were first sent to the Centers for Disease Control and Prevention &#40;CDC&#41; in Atlanta in 2004&#44; serum samples from Hungary were initially referred to the Regional Laboratory for Virology in P&#233;cs&#44; and those from China were referred to the Southeast University School of Medicine and the Second Hospital in Nanjing&#46; Personal identifiers of all serum samples in this study were completely stripped of before being tested at Southeast University&#46; Another eight serum samples were obtained from rhesus monkeys which have been inoculated intravenously with HEV strain W01 &#40;genotype 1&#44; <a href="ncbi-n:JX857689">JX857689</a>&#41; or NJ703 &#40;genotype 4&#44; <a href="ncbi-n:AY789225">AY789225</a>&#41;&#46; Viruses inoculation and sera sample collection were in the charge of GuangXi Center for Disease Prevention and Control <a class="elsevierStyleCrossRef" href="#bib0230">&#91;16&#93;</a>&#46; All serum samples were stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C until further use&#46; The procedures involving animals in this study were approved by the local committee of Animal Use and Protection&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0050">Recombinant proteins</span><p id="par0025" class="elsevierStylePara elsevierViewall">Recombinant plasmid containing p166 nucleotide sequence was constructed and expressed in <span class="elsevierStyleItalic">E&#46; coli</span> according to previous study <a class="elsevierStyleCrossRef" href="#bib0235">&#91;17&#93;</a>&#46; Four His-tagged p166 were respectively generated from W01 &#40;genotype 1&#44; <a href="ncbi-n:JX857689">JX857689</a>&#41;&#44; Mexico-14 &#40;genotype 2&#44; <a href="ncbi-n:M74506">M74506</a>&#41;&#44; US-1 &#40;genotype 3&#44; <a href="ncbi-n:AF060668">AF060668</a>&#41; and China-9829 &#40;genotype 4&#44; <a href="ncbi-n:AY789225">AY789225</a>&#41; strains&#44; designated as p166W01&#44; p166Mex&#44; p166Us and p166Chn&#46; And two GST-tagged proteins&#44; p166Sar and p166Chn were respectively generated from the HEV Pakistani Sar-55 strain &#40;genotype 1&#44; <a href="ncbi-n:M80581">M80581</a>&#41; and the China-9829 strain &#40;genotype 4&#44; <a href="ncbi-n:AY789225">AY789225</a>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0055">Generation of mAbs against p166Sar and p166Chn</span><p id="par0030" class="elsevierStylePara elsevierViewall">The mAbs 2B1 and 4C5 were prepared as previously described <a class="elsevierStyleCrossRef" href="#bib0230">&#91;16&#93;</a>&#44; produced by injecting 10<span class="elsevierStyleSup">6</span> hybridoma cells into the peritoneal cavity of the BALB&#47;c mice&#46; 7&#8211;10 days later&#44; ascites fluid was harvested&#44; filtered&#44; centrifuged&#44; and then purified with protein G affinity column&#46; The purified mAbs were stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C until further use&#46; All experimental procedures were approved by the Ethics Review Committee of Anhui Medical University&#44; which comply with the Guide for the Care and Use of laboratory Animals published by the US National Institutes of Health &#40;NIH publication no&#46; 85-23&#44; revised 2011&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0060">Labeling mAbs with horseradish peroxidase &#40;HRP&#41;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Purified mAbs were dialyzed against 100<span class="elsevierStyleHsp" style=""></span>mM Carbonate&#47;Bicarbonate buffer &#40;pH 9&#46;3&#41; at 4<span class="elsevierStyleHsp" style=""></span>&#176;C over night&#46; And then&#44; antibodies were labeled with HRP according to the manufacturer&#39;s instructions &#40;KPL&#41;&#46; Methods are briefly described as follows&#58; 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg of HRP and 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg of mAb were added into HRP conjugation buffer at a final volume of 0&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#46; After gently stirring at room temperature for 1<span class="elsevierStyleHsp" style=""></span>h&#44; the mixture was left standing at room temperature for 15<span class="elsevierStyleHsp" style=""></span>min&#46; And then&#44; 10<span class="elsevierStyleHsp" style=""></span>&#956;l of the reducing agent was added into the mixture&#46; At last&#44; the same volume of distilled glycerol was added into the mixture for storage and further use&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0065">Competitive binding assay</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0070">Determination of antigens and mAbs titers</span><p id="par0040" class="elsevierStylePara elsevierViewall">The titers of coated antigens and HRP-conjugated mAbs were determined by ELISA&#46; Initially&#44; HRP-conjugated mAbs of two-fold dilutions in 1&#37; casein PBS&#44; ranging from 1&#58;400 to 1&#58;25&#44;600 were prepared and then added in wells&#44; which pre-coated with serial two-fold dilutions &#40;from 1&#58;200 to 1&#58;6400&#41; of p166W01 or p166Chn antigen&#46; After incubating at 37<span class="elsevierStyleHsp" style=""></span>&#176;C for 45<span class="elsevierStyleHsp" style=""></span>min&#44; the ELISA plate was washed for five times with PBS containing 0&#46;5&#37; Tween-20 &#40;PBST&#41;&#46; And then&#44; TMB liquid substrate was added for color development&#44; which was stopped by adding stop solution&#46; Finally&#44; the Optical Density &#40;OD&#41; of each well was read at 450<span class="elsevierStyleHsp" style=""></span>nm&#44; with a 630<span class="elsevierStyleHsp" style=""></span>nm reference wavelength to determine the dilution of coated antigen and HRP-conjugated mAb that give an OD value reading of approximately 1&#46;0&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0075">Competitive binding assay <a class="elsevierStyleCrossRef" href="#bib0240">&#91;18&#93;</a></span><p id="par0045" class="elsevierStylePara elsevierViewall">The p166W01 and p166Chn were used as coating antigens to establish the competitive binding assay&#44; respectively&#46; Anti-HEV sera of saturating concentration were used to assess the inhibition percentage of the binding of HRP-mAb to antigen&#46; The procedure was similar to our previous study <a class="elsevierStyleCrossRef" href="#bib0245">&#91;19&#93;</a>&#44; the p166W01 or p166Chn of optional dilution was used as the coating antigen respectively&#44; the mixture of HRP-conjugated mAb at twice the optional dilution and anti-HEV serum of saturated concentration was added to antigen coated well&#46; The OD value was read at 450<span class="elsevierStyleHsp" style=""></span>nm&#44; with a 630<span class="elsevierStyleHsp" style=""></span>nm reference wavelength&#46; The inhibition percentage was calculated by the following formula&#58; 100<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#91;1<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>&#40;<span class="elsevierStyleItalic">A</span><span class="elsevierStyleInf">450&#44;630</span> of HRP-conjugated mAb and serum anti-HEV IgG&#41;&#47;&#40;<span class="elsevierStyleItalic">A</span><span class="elsevierStyleInf">450&#44;630</span> of HRP-conjugated mAb&#41;&#93;&#46;</p></span></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0085">Isolation and characterization of mAbs against p166Sar or p166Chn</span><p id="par0050" class="elsevierStylePara elsevierViewall">The mAbs were purified using immobilized protein G&#44; and the specificity of mAbs was identified by ELISA with 4 genotypes p166 antigens &#40;p166W01&#44; p166Mex&#44; p166Us&#44; p166Chn&#41;&#44; respectively&#46; The results of ELISA revealed that mAb 2B1 reacted only with p166W01 and p166Mex&#44; but not with p166US or p166Chn&#59; whereas&#44; mAb 4C5 reacted only with p166US and p166Chn&#44; but not with p166W01 or p166Mex&#44; suggesting that 2B1 and 4C5 were genotypes-specific mAbs <a class="elsevierStyleCrossRef" href="#bib0230">&#91;16&#93;</a>&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0090">Determination of antigens and mAbs dilution</span><p id="par0055" class="elsevierStylePara elsevierViewall">p166W01 protein was used as coating antigen to establish the competitive binding assay of mAb 2B1 and serum anti-HEV IgG&#59; p166Chn antigen was used to establish the competitive binding assay of mAb 4C5 and serum anti-HEV IgG&#46; As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; the dilution of p166W01 was 1&#58;400&#44; HRP-conjugated 2B1 was 1&#58;6400&#44;the mean OD value was close to 1&#46;0&#59; whereas&#44; the dilution of p166Chn was 1&#58;800&#44; HRP-conjugated 4C5 was 1&#58;6400&#44; the mean OD value was close to 1&#46;0 &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0095">Binding of mAbs to antigens inhibited by serum anti-HEV IgG of rhesus monkeys</span><p id="par0060" class="elsevierStylePara elsevierViewall">Sera sample containing anti-HEV IgG were collected from rhesus monkeys challenged with genotype 1HEV strains &#40;W01&#41; or genotype 4 HEV strains &#40;NJ703&#41; <a class="elsevierStyleCrossRef" href="#bib0230">&#91;16&#93;</a>&#44; used to evaluate the binding inhibition of mAb 2B1 to p166W01&#44; mAb 4C5 to p166Chn&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; both the binding of mAb 2B1 to p166W01 and mAb 4C5 to p166Chn could be inhibited by the serum anti-HEVs against genotype 1 or 4 HEV&#46; But more high inhibition percentages were obtained from the binding of 2B1 to p166W01 inhibited by genotype 1 anti-HEV IgGs&#44; from 25&#37; to 61&#37;&#46; Whereas&#44; the inhibition percentage of mAb 4C5 to p166Chn inhibited by genotype 1 anti-HEV IgG strain was not more than 26&#37;&#46; On the contrary&#44; the binding of mAb 4C5 to p166Chn was inhibited more remarkably by the gentoype 4 anti-HEV IgG &#40;from 60&#37; to 70&#37;&#41; than that by the genotype 1 anti-HEV IgG &#40;from 0&#37; to 38&#37;&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0100">Binding of mAbs to antigens inhibited by anti-HEV IgG in human serum against genotype 1 HEV</span><p id="par0065" class="elsevierStylePara elsevierViewall">Anti-HEV IgG in human sera infected by genotype 1 strains were also used to further demonstrate the binding inhibition of mAbs to antigens&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; the binding of 2B1 to p166W01 was inhibited remarkably by the genotype 1 anti-HEV IgG&#44; the inhibition percentages were from 57&#37; to 85&#37;&#46; Whereas&#44; genotype 1 anti-HEV IgG could only partially inhibit the binding of mAb 4C5 to p166Chn&#44; the inhibition percentages were not more than 66&#37;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0105">Binding of mAbs to antigens inhibited by human serum anti-HEV IgG against genotype 3 HEV</span><p id="par0070" class="elsevierStylePara elsevierViewall">We followed the same approach to investigate the inhibition percentage of mAbs to antigens by serum anti-HEV IgG against the genotype 3 HEV&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#44; the binding of 4C5 to p166Chn antigen was inhibited more remarkably by genotype 3 anti-HEV IgG&#44; the inhibition percentages were from 45&#37; to 83&#37;&#46; Whereas&#44; each of the same serum could only partially inhibit the binding of 2B1 to p166W01&#44; the inhibition percentages were not more than 61&#37;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;6</span><span class="elsevierStyleSectionTitle" id="sect0110">Binding of mAbs to antigens inhibited by human serum anti-HEV IgG against genotype 4 HEV</span><p id="par0075" class="elsevierStylePara elsevierViewall">The serum samples were collected from human infected by genotype 4 HEV strains&#44; the binding inhibition of mAbs to antigens inhibited by serum anti-HEV IgG was evaluated with same approach&#46; The results were similar to previous descriptions&#44; the binding of 4C5 to p166Chn antigen was inhibited more remarkably by genotype 4 anti-HEV IgG&#44; the inhibition percentages were from 30&#37; to 96&#37;&#46; Whereas&#44; each of the same serum could only partially inhibit the binding of 2B1 to p166W01&#44; the inhibition percentages were not more than 57&#37; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0115">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">HEV infection is an important public health concern not only in developing countries but also in developed ones&#46; The ratio of infection-to-mortality of HEV is generally considered to be small&#44; but this significantly increases in pregnant women&#44; in infants under the age of 2 years&#44; and in adults over the age of 56 years&#46; Moreover&#44; the outbreaks of HEV have been repeatedly reported in India&#44; Nepal&#44; Pakistan&#44; Burma&#44; Mexico&#44; and China <a class="elsevierStyleCrossRef" href="#bib0250">&#91;20&#93;</a>&#44; due to inadequate sanitary conditions&#46; Although only one serotype has been recognized&#44; HEV of genotypes 1&#44; 2 still differed from genotypes 3&#44; 4 in their antigenic and immunogenic characteristics <a class="elsevierStyleCrossRef" href="#bib0230">&#91;16&#93;</a>&#46; Especially&#44; genotypes 3&#44; 4 HEV strains may be capable of infecting cross-species&#44; from chicken to wild birds&#44; and even from animals to human beings <a class="elsevierStyleCrossRefs" href="#bib0255">&#91;21&#44;22&#93;</a>&#46; High prevalence of HEV frequently displayed in Asia and Africa&#46; The anti-HEV-positive rates have been found more than 30&#37; in most Asia and Africa countries&#44; suggesting a high rate of subclinical infection <a class="elsevierStyleCrossRefs" href="#bib0265">&#91;23&#8211;26&#93;</a>&#46; The appearance of anti-HEV antibodies in serum is considered as an epidemiological marker of HEV exposure assessment in a population <a class="elsevierStyleCrossRef" href="#bib0180">&#91;6&#93;</a>&#46; Anti-HEV IgG can be detected within two weeks and lasting for more than 10 years after the virus exposure&#44; and can be used as an index of epidemiological investigation <a class="elsevierStyleCrossRef" href="#bib0285">&#91;27&#93;</a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">As aforementioned&#44; genotypes 1&#44; 2 HEV only infect humans while genotypes 3&#44;4 HEV are zoonotic agents&#44; the main reservoir of HEV3 and HEV4 is domestic pigs&#46; While&#44; genotypes 1&#44; 2 HEV are believed to transmitted via contaminated water&#46; Furthermore&#44; both genotypes 3 and 4 HEV have been reported in chronic infection&#44; however&#44; neither genotype 1 nor genotype 2 HEV has been shown to associate with chronic HE so far <a class="elsevierStyleCrossRef" href="#bib0290">&#91;28&#93;</a>&#46; In addition&#44; previous studies have reported that HEV could transmit by blood transfusion in a number of countries <a class="elsevierStyleCrossRefs" href="#bib0295">&#91;29&#44;30&#93;</a>&#46; Therefore&#44; HE diagnosis and epidemiological investigation&#44; especially&#44; confirmation the source of HEV from genotypes 1&#44; 2 or 3&#44; 4 are essential parts of prevention of HEV transmission&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In present study&#44; we sought to clarify whether the genotype-specific mAbs 2B1 and 4C5 could be used for HE diagnosis and disclosure the source of HEV from human or zoonosis by establishment of the competitive binding assay&#46; The results of competitive binding assay indicated that both the binding of 2B1 to p166W01&#44; 4C5 to p166Chn could be inhibited by the anti-HEV IgG in rhesus monkey sera against genotypes 1 or 4 strains&#46; But the genotype 1 anti-HEV IgG could inhibit the binding of 2B1 to p166W01 more significantly than that of 4C5 to p166Chn&#46; Whereas&#44; genotype 4 anti-HEV IgG in rhesus monkey sera could block the binding of 4C5 to p166Chn more strongly than that of 2B1 to p166W01&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">We next tried to further confirm the differences of competitive inhibition of the binding of mAbs to antigens&#46; Thirty seven human sera samples infected by genotypes 1&#44; 3 or 4 HEV were collected and used to confirm the differently binding inhibition between 2B1 to p166W01 with 4C5 to p166Chn&#46; The results revealed that genotype 1 anti-HEV IgG could inhibit the binding of 2B1 to p166W01 more remarkably than that of 4C5 to p166Chn&#46; Whereas&#44; serum anti-HEV IgG against the genotypes 3 or 4 HEV could inhibit the binding of 4C5 to p166Chn more significantly than that of 2B1 to p166W01&#46; These findings indicated that the binding of genotype-specific mAbs to p166W01 or p166Chn antigen can be blocked at different degree by anti-HEV IgG against genotype 1&#44; 3 or 4&#46; This is the first study that demonstrates the genotype-specific mAbs 2B1 and 4C5 may be used for HE diagnosis and epidemiological investigation of HEV exposure from human or zoonosis by establishment of competitive binding assay&#46; Despite major steps forward in demonstrating a promising approach for detection and differentiation the serum anti-HEV IgG using a competitive binding assay&#44; following questions need to be solved&#44; the clinical phenotype of HE continues to emerges&#59; locally acquired zoonotic hepatitis E is recognized slowly in developed countries&#46; Therefore&#44; further studies are urgently needed to optimize the experimental conditions of competitive binding assay for future development&#46;<span class="elsevierStyleDefList"><span class="elsevierStyleSectionTitle" id="sect0120">Abbreviations</span><span class="elsevierStyleDefTerm">HE</span><span class="elsevierStyleDefDescription"><p id="par0100" class="elsevierStylePara elsevierViewall">hepatitis E</p></span><span class="elsevierStyleDefTerm">HEV</span><span class="elsevierStyleDefDescription"><p id="par0105" class="elsevierStylePara elsevierViewall">hepatitis E virus</p></span><span class="elsevierStyleDefTerm">IgG</span><span class="elsevierStyleDefDescription"><p id="par0110" class="elsevierStylePara elsevierViewall">immunoglobulin G</p></span><span class="elsevierStyleDefTerm">mAbs</span><span class="elsevierStyleDefDescription"><p id="par0115" class="elsevierStylePara elsevierViewall">monoclonal antibodies</p></span><span class="elsevierStyleDefTerm">HRP</span><span class="elsevierStyleDefDescription"><p id="par0120" class="elsevierStylePara elsevierViewall">Horseradish peroxidase</p></span><span class="elsevierStyleDefTerm">OD</span><span class="elsevierStyleDefDescription"><p id="par0125" class="elsevierStylePara elsevierViewall">Optical Density</p></span><span class="elsevierStyleDefTerm">ORFs</span><span class="elsevierStyleDefDescription"><p id="par0130" class="elsevierStylePara elsevierViewall">open reading frames</p></span><span class="elsevierStyleDefTerm">PBST</span><span class="elsevierStyleDefDescription"><p id="par0135" class="elsevierStylePara elsevierViewall">PBS containing 0&#46;5&#37; Tween-20</p></span></span></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Ethical statement</span><p id="par0140" class="elsevierStylePara elsevierViewall">All experimental procedures were approved by the Ethics Review Committee of Anhui Medical University&#44; which comply with the Guide for the Care and Use of laboratory Animals published by the US National Institutes of Health &#40;NIH publication no&#46; 85-23&#44; revised 2011&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Funding</span><p id="par0145" class="elsevierStylePara elsevierViewall">This study was supported by Grants for Scientific Research of BSKY &#40;No&#46; <span class="elsevierStyleGrantNumber" refid="gs1">XJ201612</span>&#41; from <span class="elsevierStyleGrantSponsor" id="gs1">Anhui Medical University</span> and from <span class="elsevierStyleGrantSponsor" id="gs2">Natural Science Foundation of Hefei Technology College</span> &#40;No&#46; <span class="elsevierStyleGrantNumber" refid="gs2">201914KJA020</span>&#41;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Contributions</span><p id="par0150" class="elsevierStylePara elsevierViewall">Participated in research design and experiments&#58; Jiyue Wen&#44; Weizhuo Lu&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Contributed new reagents or analytical tools&#58; Weizhuo Lu&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Performed data analysis&#58; Jiyue Wen&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Contributed to writing of the manuscript&#58; Jiyue Wen&#44; Jihong Meng&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span></span>"
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          "titulo" => "Abstract"
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        2 => array:2 [
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          "titulo" => "Introduction"
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        3 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Materials and methods"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Serum samples"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Recombinant proteins"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Generation of mAbs against p166Sar and p166Chn"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Labeling mAbs with horseradish peroxidase &#40;HRP&#41;"
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            4 => array:3 [
              "identificador" => "sec0035"
              "titulo" => "Competitive binding assay"
              "secciones" => array:2 [
                0 => array:2 [
                  "identificador" => "sec0040"
                  "titulo" => "Determination of antigens and mAbs titers"
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                1 => array:2 [
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                  "titulo" => "Competitive binding assay &#91;18&#93;"
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        4 => array:3 [
          "identificador" => "sec0050"
          "titulo" => "Results"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Isolation and characterization of mAbs against p166Sar or p166Chn"
            ]
            1 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Determination of antigens and mAbs dilution"
            ]
            2 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Binding of mAbs to antigens inhibited by serum anti-HEV IgG of rhesus monkeys"
            ]
            3 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Binding of mAbs to antigens inhibited by anti-HEV IgG in human serum against genotype 1 HEV"
            ]
            4 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Binding of mAbs to antigens inhibited by human serum anti-HEV IgG against genotype 3 HEV"
            ]
            5 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Binding of mAbs to antigens inhibited by human serum anti-HEV IgG against genotype 4 HEV"
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        5 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "Discussion"
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          "titulo" => "Ethical statement"
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          "identificador" => "sec0095"
          "titulo" => "Funding"
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          "identificador" => "sec0100"
          "titulo" => "Contributions"
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        9 => array:2 [
          "identificador" => "sec0105"
          "titulo" => "Conflict of interest"
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        10 => array:1 [
          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2018-09-02"
    "fechaAceptado" => "2019-01-18"
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        0 => array:4 [
          "clase" => "keyword"
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          "identificador" => "xpalclavsec1145646"
          "palabras" => array:5 [
            0 => "HEV"
            1 => "Monoclonal antibody"
            2 => "Genotype"
            3 => "Genotype-specific"
            4 => "IgG"
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    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">This study was undertaken to demonstrate a promising approach for detection and differentiation the serum immunoglobulin G &#40;IgG&#41; against hepatitis E virus &#40;anti-HEV IgG&#41; using a competitive binding assay established with known genotype-specific monoclonal antibodies &#40;mAbs&#41; 2B1 and 4C5&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The mAb 2B1 derived from genotype 1 hepatitis E virus &#40;HEV&#41; antigen and specifically reacted with genotype 1&#44; 2 antigens&#59; 4C5 induced by genotype 4 HEV antigen was specific to genotypes 3&#44; 4 antigens&#46; The 2B1 and 4C5 were labeled with Horseradish peroxidase &#40;HRP&#41;&#44; respectively&#46; Subsequently&#44; the titers of coated antigens and HRP-conjugated mAbs for establishment of competitive binding assay were determined by enzyme linked immunosorbent assay &#40;ELISA&#41;&#46; And then&#44; the competitive binding assay was performed to assess the inhibition percentage of mAbs binding to antigens inhibited by different genotypes anti-HEV IgG&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The results of competitive binding assay revealed that genotype 1 anti-HEV IgG could inhibit the binding of mAb 2B1 to genotype 1 antigen more strongly than that of mAb 4C5 to genotype 4 antigen&#46; Whereas&#44; the genotype 3 or 4 anti-HEV IgG could inhibit the binding of mAb 4C5 to genotype 4 antigen more remarkably than that of mAb 2B1 to genotype 1 antigen&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">These findings provided us a valuable approach for detection and differentiation the HEV infection derived from genotypes 1&#44; 2 &#40;human&#41; or genotypes 3&#44; 4 &#40;zoonosis&#41;&#46;</p></span>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Binding of 2B1 to p166W01&#44; 4C5 to p166Chn inhibited by serum anti-HEVs of rhesus monkey inoculated intravenously with genotype 1 or 4 HEV&#46; G1&#58; Serum anti-HEVs of rhesus monkey angainst genotype 1 HEV&#59; G4&#58; Serum anti-HEVs of rhesus monkey against genotype 4 HEV&#46;</p>"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Bold and underline emphasize that the corresponding dilutions of antigen and HRP-conjugated mAb were used to establish the competitive binding assay&#46;</p>"
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t" scope="col">Antigen dilution&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">1&#58;400&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">1&#58;800&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">1&#58;1600&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">1&#58;3200&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">1&#58;6400&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">1&#58;12&#44;800&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">1&#58;25&#44;600&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Negative control&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">1&#58;200&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46;821&nbsp;\t\t\t\t\t\t\n
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                  """
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                  \t\t\t\t" scope="col">Antigen dilution&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 16652681
Original language: English

DOI:10.1016/j.aohep.2019.01.009

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 October	4	0	4
2024 September	19	2	21
2024 August	13	0	13
2024 July	18	3	21
2024 June	28	0	28
2024 May	16	5	21
2024 April	32	3	35
2024 March	44	4	48
2024 February	32	5	37
2024 January	22	4	26
2023 December	23	1	24
2023 November	19	4	23
2023 October	26	6	32
2023 September	14	2	16
2023 August	24	4	28
2023 July	13	6	19
2023 June	11	2	13
2023 May	44	2	46
2023 April	53	0	53
2023 March	37	5	42
2023 February	44	0	44
2023 January	14	3	17
2022 December	13	3	16
2022 November	13	6	19
2022 October	17	7	24
2022 September	12	14	26
2022 August	10	6	16
2022 July	12	9	21
2022 June	13	4	17
2022 May	10	5	15
2022 April	9	11	20
2022 March	11	10	21
2022 February	10	3	13
2022 January	18	6	24
2021 December	26	6	32
2021 November	22	5	27
2021 October	26	8	34
2021 September	9	11	20
2021 August	15	10	25
2021 July	12	5	17
2021 June	10	9	19
2021 May	21	13	34
2021 April	34	13	47
2021 March	14	5	19
2021 February	20	4	24
2021 January	11	12	23
2020 December	9	4	13
2020 November	14	3	17
2020 October	13	4	17
2020 September	17	7	24
2020 August	20	5	25
2020 July	16	9	25
2020 June	9	4	13
2020 May	14	6	20
2020 April	17	2	19
2020 March	90	8	98
2020 February	51	4	55
2020 January	27	3	30
2019 December	51	5	56
2019 November	45	2	47
2019 October	36	6	42
2019 September	37	11	48
2019 August	44	12	56
2019 July	73	31	104
2019 June	5	17	22
2019 May	8	14	22

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