Key HLA‐DRB1‐DQB1 haplotypes and role of the BTNL2 gene for response to a hepatitis B vaccine

Abstract

Approximately 5‐10% of individuals who are vaccinated with a hepatitis B (HB) vaccine designed based on the hepatitis B virus (HBV) genotype C fail to acquire protective levels of antibodies. Here, host genetic factors behind low immune response to this HB vaccine were investigated by a genome‐wide association study (GWAS) and Human Leukocyte Antigen (HLA) association tests. The GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including 107 low responders, 351 intermediate responders, and 735 high responders. Classical HLA class II alleles were statistically imputed using the genome‐wide SNP typing data. The GWAS identified independent associations of HLA‐DRB1‐DQB1, HLA‐DPB1 and BTNL2 genes with immune response to a HB vaccine designed based on the HBV genotype C. Five HLA‐DRB1‐DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1‐DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1‐DQB1 haplotypes, and no association was identified for any of the DPB1 alleles. In contrast, no association was identified for DRB1‐DQB1 haplotypes and DPB1 alleles in a comparison between high immune responders and healthy individuals. Conclusion: The findings in this study clearly show the importance of HLA‐DR‐DQ (i.e., recognition of a vaccine related HB surface antigen (HBsAg) by specific DR‐DQ haplotypes) and BTNL2 molecules (i.e., high immune response to HB vaccine) for response to a HB vaccine designed based on the HBV genotype C. (Hepatology 2018).

A prospective trial of vaccine to prevent hepatitis B virus reactivation after hematopoietic stem cell transplantation

“…4). Nonetheless, vaccination is likely to select for escape mutations in the HBsAg gene during immunosuppressive Recently, the response (anti-HBs titers of >10 mIU/mL) to HB vaccine in normal healthy volunteers was reported to be 90% [30]. Furthermore, 64% of post-HSCT patients seroconverted to anti-HBs-positive [31].…”

“…Secondly, the host ability to produce antibody is reduced by immunosuppressive therapies. A recent report indicated HLA-DR-DQ and butyrophilin-like protein 2 to be important in response to HB vaccine [30], and future studies are necessary to better understand these host factors. Discontinuation of immunosuppressive treatment was associated with HBV reactivation after vaccination.…”

Variation of HLA-DPB1 Gene in Hepatitis B Infection

“…Subsequently, the genotypes of DPB1 * 05:01, 09:01, and DPB1 * 02:01, 04:01, and 04:02 were again found to be susceptible to HBV in Japanese [9] and Chinese [10] populations. The studies also found that some DPB1 alleles and rs9277535G related to weak HBV vaccines response [23] , low sensitive of HBV drug therapy [15] , incidence of occult HBV infection [24] , and also prone to hepatocellular carcinoma development [25] .…”

GWAS identifying HLA‐DPB1 gene variants associated with responsiveness to hepatitis B virus vaccination in Koreans: Independent association of HLA‐DPB1*04:02 possessing rs1042169 G ‐ rs9277355 C ‐ rs9277356 A

“…The prevailing HBV genotype is C2 (98.1%) in Korea, and the vaccines used in our infant cohort were designed based on HBV genotype A2. However, HLA‐DPB1*04:02 and HLA‐DPB1*05:01 were responsible for the response to HB vaccines designed based on HBV genotype C, and the current HBV‐A2 vaccines are known to have cross‐reactivity and to confer cross‐protection against non‐A2 HBV genotypes; thus, the genetic backgrounds underlying the response to the HBV‐A2 and the HBV‐C vaccines may be very similar. A previous Taiwanese study showed that immunized infants of mothers with genotype C infection were more likely to develop breakthrough infection than infants of genotype B‐infected mothers due to a higher viral load of genotype C .…”

“…Wu et al demonstrated that rs7770370 in HLA‐DPB1 is the most significant genetic factor for a lower risk of nonresponse to booster HB vaccination in Taiwanese adolescents. Two HLA‐DPB1 alleles ( HLA‐DPB1*04:02 and HLA‐DPB1*05:01 ), plus five HLA‐DRB1‐DQB1 haplotypes and the BTNL2 gene, were associated with the HB vaccine response in Japanese individuals according to Nishida's study …”