Hepatitis B Vaccine, Response To

A number sign (#) is used with this entry because variation in several different genes, including the human leukocyte antigens (e.g., HLA-DR; see 142860), likely influences the response to the hepatitis B vaccine.

Description

More than 2 billion people have been infected with the hepatitis B virus (HBV; see 610424), and more than 350 million of these people are chronic carriers. Each year more than half a million die as a result of acute or chronic HBV infection. Vaccination has been highly successful at preventing new HBV infections and has been implemented into the national immunization programs of more than 150 countries. However, the immune response to HBV vaccination varies greatly among individuals, with 5 to 10% of healthy adults failing to produce protective levels of antibodies. Several factors have been implicated in determining the response to HBV vaccination, including physical factors, such as age, gender, obesity, immunosuppression, and smoking, as well as variation in genes of the immune system (summary by Davila et al., 2010).

Molecular Genetics

Alper et al. (1989) followed up on a previous observation of a bimodal antibody response to hepatitis B vaccine, with about 14% of individuals being low responders. It had been found that the low responders included a greater-than-expected number of homozygotes for the MHC haplotype HLA-B8,SC01,DR3. In the follow-up study of 5 homozygotes and 9 heterozygotes for this haplotype, Alper et al. (1989) found a striking difference in antibody response between the 2 groups. Nepom (1989) pointed out that there are several possible mechanisms for observations such as this. A primary role of HLA class II products is to bind antigenic peptides. The resulting complex is a key signal for activation of T lymphocytes through the T-cell receptor. Immunologic unresponsiveness may also be involved in the pathogenesis of some complex infectious disorders, such as schistosomiasis (see 181460) and leprosy (see 609888), in which persons who are genetically 'high responders' may have immune-mediated sequelae marked by inflammatory, fibrotic, or granulomatous changes, whereas those with a poor response or none at all have a different clinical course. Similarly, HLA-associated differences in susceptibility to autoimmune diseases may be regulated by the same sort of mechanism, e.g., type I diabetes (see 222100) and rheumatoid arthritis (180300).

Davila et al. (2010) used a 2-stage investigation to study genetic variation in 914 immune candidate genes in 1,646 Indonesians who received HBV vaccine. They identified 6 SNPs within the HLA region, rs3817963, rs5000563, rs2395177, rs7192, rs6928482, and rs6906021, that were associated, after correction for multiple comparisons, with failure to produce protective levels of antibodies after vaccination. An additional SNP, rs6789153, located in the 3-prime downstream region of FOXP1 (605515), was also significantly associated with failure to produce protective levels of antibodies. FOXP1 is a transcription factor involved in B-cell development. Davila et al. (2010) proposed that identification of additional non-HLA genes, which are likely to account for up to 50% of heritability of the response to HBV vaccine, could facilitate the design of more effective vaccines.