Bingyu Yan

A genome-wide association study identifies polymorphisms in the HLA-DR region associated with non-response to hepatitis B vaccination in Chinese Han populations

Vaccination against hepatitis B virus is an effective and routine practice that can prevent infection. However, 5-10% of healthy adults fail to produce protective levels of antibody against the hepatitis B vaccination. It has been reported that host genetic variants might affect the immune response to hepatitis B vaccination. Here, we reported a genome-wide association study in a Chinese Han population consisting of 108 primary high-responders and 77 booster non-responders to hepatitis B vaccination using the Illumina HumanOmniExpress Beadchip. We identified 21 SNPs at 6p21.32 were significantly associated with non-response to booster hepatitis B vaccination (P-value <1 × 10(-6)). The most significant SNP in the region was rs477515, located ∼12 kb upstream of the HLA-DRB1 gene. Its P-value (4.81 × 10(-8)) exceeded the Bonferroni-corrected genome-wide significance threshold. Four tagging SNPs (rs477515, rs28366298, rs3763316 and rs13204672) that capture genetic information of these 21 SNPs were validated in three additional Chinese Han populations, consisting of 1336 primary high-responders and 420 primary non-responders. The four SNPs continued to show significant associations with non-response to hepatitis B vaccination (P-combined = 3.98 × 10(-13)- 1.42 × 10(-8)). Further analysis showed that the rs477515 was independently associated with non-response to hepatitis B vaccination with correction for other three SNPs in our GWAS and the known hepatitis B vaccine immunity associated SNP in previous GWAS. Our findings suggest that the rs477515 was an independent marker associated with non-response to hepatitis B vaccination and HLA-DR region might be a critical susceptibility locus of hepatitis B vaccine-induced immunity.

A significant reduction in hepatitis B virus infection among the children of Shandong Province, China: the effect of 15 years of universal infant hepatitis B vaccination

OBJECTIVE To evaluate the effect of the universal infant hepatitis B vaccination program on hepatitis B infection in China. METHODS In 2006, a survey was conducted in Shandong Province, China, among children aged 1-14 years, 15 years after the introduction of universal infant hepatitis B vaccination. The subjects were selected by stratified, multi-stage sampling. Vaccination history was obtained by immunization certificate (when available) or parent recall. Hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) and core antigen (anti-HBc) were detected by ELISA. Hepatitis B infection was defined as the presence of HBsAg and/or anti-HBc. The prevalence rates of HBsAg, anti-HBs and hepatitis B infection obtained in this survey were compared with the results of a survey conducted in 1992 (prior to universal vaccination). RESULTS A total of 3738 children aged 1-14 years were included in the final analysis. A vaccination coverage rate of 93% was achieved in 2006. The prevalence rates of HBsAg and hepatitis B infection decreased from 8% and 46% in the 1992 survey to 1% and 4%, respectively, in the 2006 survey. CONCLUSIONS Universal hepatitis B vaccination in infants can result in a 90.47% reduction in hepatitis B infection in children aged 1-14 years.

CD3Z genetic polymorphism in immune response to hepatitis B vaccination in two independent Chinese populations.

Vaccination against hepatitis B virus is an effective and routine practice that can prevent infection. However, vaccine-induced immunity to hepatitis B varies among individuals. CD4+ T helper cells, which play an important role in both cellular and humoral immunity, are involved in the immune response elicited by vaccination. Polymorphisms in the genes involved in stimulating the activation and proliferation of CD4+ T helper cells may influence the immune response to hepatitis B vaccination. In the first stage of the present study, a total of 111 single nucleotide polymorphisms (SNPs) in 17 genes were analyzed, using the iPLEX MassARRAY system, among 214 high responders and 107 low responders to hepatitis B vaccination. Three SNPs (rs12133337 and rs10918706 in CD3Z, rs10912564 in OX40L) were associated significantly with the immune response to hepatitis B vaccination (P = 0.008, 0.041, and 0.019, respectively). The three SNPs were analyzed further with the TaqMan-MGB or TaqMan-BHQ probe-based real-time polymerase chain reaction in another independent population, which included 1090 high responders and 636 low responders. The minor allele ‘C’ of rs12133337 continued to show an association with a lower response to hepatitis B vaccination (P = 0.033, odds radio = 1.28, 95% confidence interval = 1.01–1.61). Furthermore, in the stratified analysis for both the first and second populations, the association of the minor allele ‘C’ of rs12133337 with a lower response to hepatitis B vaccination was more prominent after individuals who were overweight or obese (body mass index ≥25 kg/m2) were excluded (1st stage: P = 0.003, 2nd stage: P = 0.002, P-combined = 9.47e-5). These findings suggest that the rs12133337 polymorphism in the CD3Z gene might affect the immune response to hepatitis B vaccination, and that a lower BMI might increase the contribution of the polymorphism to immunity to hepatitis B vaccination.

Hepatitis E Virus in Yellow Cattle, Shandong, Eastern China

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BTNL2 associated with the immune response to hepatitis B vaccination in a Chinese Han population

No response to hepatitis B vaccination is a complex phenomenon, which is induced by the combinations of environmental and genetic factors. The aim of the study was to investigate the association between the polymorphisms of the butyrophilin‐like 2 (BTNL2) gene and the immune response to hepatitis B vaccination in a Chinese Han population. A total of 7 single nucleotide polymorphisms in the BTNL2 gene were analyzed in 566 non‐responders and 1,040 high‐responders to hepatitis B vaccination. The alleles T, T, C, A, G of rs3763316, rs3763311, rs9268494, rs3806156, and rs2076530 were associated with no response to hepatitis B vaccination (P = 0.015, odds ratio (OR) = 1.20; P = 0.029, OR = 1.18; P = 2.00E−07, OR = 1.58; P = 0.002, OR = 1.27; P = 2.90E−06, OR = 1.41, respectively). Whereas, the alleles T, C of rs9268501 and rs3763313 played significantly protective roles in the immune response to hepatitis B vaccination (P = 0.007, OR = 0.81; P = 0.004, OR = 0.74). Besides, the risks of no response to hepatitis B vaccination were increased significantly among individuals harbored the haplotypes of G‐T‐A‐T‐C‐A‐G (P = 0.038, OR = 1.48), G‐T‐A‐T‐C (P < 0.0001, OR = 2.34), A‐A (P < 0.0001, OR = 4.08), and C‐G (P < 0.0001, OR = 4.75). However, the haplotype of G‐C‐A‐T‐C (P = 1.00E−04, OR = 0.54) exhibited a protective role in the immune response to hepatitis B vaccination in the study. These findings suggest that polymorphisms in the BTNL2 gene might play a vital role in determining the outcome of the immune response to hepatitis B vaccination. J. Med. Virol. 86:1105–1112, 2014.

Comparison between two population-based hepatitis B serosurveys with an 8-year interval in Shandong Province, China

BACKGROUND Tremendous progress has been made in hepatitis B virus (HBV) prevention and control in the last 30 years in China, but it continues to be a major public health problem. The most recently reported population-based seroepidemiological survey on HBV in Shandong Province in China was published in 2006, and an updated baseline for HBV prevalence was badly needed in the province to identify the change in HBV epidemiology in the last decade. METHODS Two population-based cross-sectional serosurveys were performed among the population aged 1-59 years in the same sample areas in Shandong Province, China in 2006 and 2014, respectively. Data on demographic characteristics were collected. A blood sample was obtained from each person and was tested for hepatitis B surface antigen (HBsAg), antibody against HBsAg (anti-HBs), and antibody against hepatitis B core antigen (anti-HBc). RESULTS Overall, the prevalence rates of HBsAg, anti-HBs, and anti-HBc were 3.39% (95% confidence interval (CI) 2.51-4.26), 44.96% (95% CI 41.34-48.57), and 24.45% (95% CI 22.19-26.71), respectively, among the population aged 1-59 years in the 2006 serovsurvey; the corresponding prevalence rates were 2.49% (95% CI 1.81-3.17), 48.27% (95% CI 45.63-50.92), and 22.56% (95% CI 20.14-24.97), respectively, in 2014. The prevalence rates of HBsAg and anti-HBc were lower in 2014 than in 2006. Conversely, the prevalence of anti-HBs showed an increase. However, none of these differences were statistically significant (all p>0.05). The prevalence of HBsAg showed an increase among persons aged 20-24 years in 2014 (3.83%) compared with 2006 (2.98%) (t=0.45, p=0.67). Among all occupation groups, the prevalence of HBsAg was lower in 2014 than in 2006, while the prevalence of anti-HBc showed moderate increases in students and farmers (all p>0.05). The prevalence of HBsAg decreased more obviously in urban areas (65.49%) than rural areas (7.07%) from 2006 to 2014. CONCLUSIONS The epidemiology of HBV infection has changed in Shandong Province, China over the last decade. More attention should be paid to HBV infection among students and farmers.

A hepatitis E outbreak by genotype 4 virus in Shandong province, China

Hepatitis E vaccine was available in China in 2012, but the priority population for immunization is not clear. In 2013, a hepatitis E outbreak occurred in a company of Shandong province, China where most employees moved from other provinces and dined at the companys cafeteria. A total of fourteen (19%, 14/73) case-patients were identified, and three of them had symptomatic infection with one death. The proportion of symptomatic infection was much higher among those aged ⩾50years than those aged <50years (2/2 vs. 1/12, P=0.03), and higher in males than females (3/8 vs. 0/6, P=0.21). Food in the companys cafeteria might be the possible source of the outbreak. The findings from this outbreak investigation indicate that individuals aged ⩾50years, particularly males, might be the population of top priority for hepatitis E vaccination in China.

Perinatal hepatitis B prevention program in Shandong Province, China

Post-exposure prophylaxis with hepatitis B vaccine (HepB) alone is highly effective in preventing perinatal hepatitis B virus (HBV) transmission and the World Health Organization recommends administering HepB to all infants within 24 h after delivery. Maternal screening for HBsAg and administration of hepatitis B immune globulin (HBIG) in addition to HepB for infants born to HBsAg-positive pregnant women can increase the effectiveness of post-exposure prophylaxis for perinatal HBV transmission. In Shangdong Province, China which has a high prevalence of chronic HBV infection, HepB birth dose and HBIG were integrated into the routine childhood immunization program in 2002 and July 2011 respectively. We assessed progress toward implementation of these measures. Hospital-based reporting demonstrated an increase in maternal screening from 70.7% to 96.9% from 2004–2012; HepB birth dose coverage (within 24 h) remained high (96.3–97.1%) during this period. For infants with known HBsAg-positive mothers, the coverage of HBIG increased from 85.0% (before July 2011) to 92.1% (after July 2011). However, HBIG coverage in western areas of Shandong Province remained at 81.1% among infants with known HBsAg-positive mothers. Preterm/low-birth-weight and illness after birth were the most commonly reported reasons for delay in the first dose of HepB to >24 h of birth. Additional education on the safety and immune protection from HepB and HBIG might help to correct delays in administering the HepB birth dose and low HBIG coverage in the western areas of the Shandong Province.

Temporal trend of hepatitis B surface mutations in the post-immunization period: 9 years of surveillance (2005–2013) in eastern China

Limited information is available about the temporal trend in the prevalence and evolution of hepatitis B virus (HBV) S-gene mutations in the post-immunization era in China. From 2005 to 2013, 1077 hepatitis B cases under 15 years of age reported through Chinese National Notifiable Disease Reporting System (NNDRS) were successfully sequenced of S-gene in Shandong province, China. A total of 97 (9.01%) cases had amino acid (aa) substitution in the “α” determinant of HBsAg. The yearly prevalence from 2005 to 2013 maintained at a relatively stable level, and showed no significant change (P > 0.05). Multivariate logistic regression analysis demonstrated that the prevalence of “α” mutations was independently associated with the maternal HBsAg status (P < 0.05), and not with surveillance year and hepatitis B vaccination (P > 0.05). The hottest mutation position was aa126 (I126S/N and T126A, 29.63%), and aa 145 (G145R/A, 25.93%). Mutated residue 126 tended to occur less frequent, while that of residue 145 was more frequent with increasing year. Our data showed that there was no increase in the frequency of HBV “α” mutations over time during the post-immunization period. However, long-term vaccination might enhance the change of HBV mutational pattern, and G145 mutation was becoming dominant.

Antibody response to hepatitis B vaccine is independently associated with hepatitis B breakthrough infection among adults: Results from a three-year follow-up study in China

Hepatitis B breakthrough infection (HBBI) and its risk factors are rarely reported among adults in China. In 2009-2010 in three townships of China, hepatitis B vaccine (HepB) administration and anti-HBs detection after HepB were conducted among the residents aged 18-59 years. HBsAg, anti-HBs and anti-HBc were detected for these vaccinees in 2013. A total of 252 out of 4701 vaccinees turned to be positive for anti-HBc in 2013, but nobody was positive for HBsAg. The HBBI rate was 5.36% (95% CI 4.73, 6.04). The highest rate was found in age-group of 18-29 years (7.33%, 95% CI: 5.31, 9.82). The rate was significantly different by the residential townships (P < 0.001) and by the antibody response to HepB (P = 0.003). Multivariate analysis showed that anti-HBs response to HepB was the independent risk factor of HBBI. The study documents the association between hyporesponse to HepB and HBBI among adults. It also suggests more attention should be given to new HBV infection among young adults.