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Neonates who acquire HBV from their mothers (perinatal) are most susceptible to chronic HBV infection (1, 2, 3), since those who acquire HBV as adults mostly don’t develop chronic infection. Universal 3-dose HBV vaccine in the 1st year of life is quite effective in preventing and controlling HBV infection for upwards of 20 years, the longest vaccinees have been followed up since universal HBV vaccination policies began in the 1990s (4, 5, 6).

How does the HBV vaccine protect against infection? This isn’t fully understood. Then how do we know the vaccine works? A major gap in understanding not just for HBV but for many other diseases, this was the impetus for instead figuring out ‘Correlates of Protection‘, i.e., surrogate markers of protection. In the case of HBV, that’s anti-HBV antibody titers, specifically anti-HBsAg (HBV surface antigen) antibody titers of >or=10mIU/ml). 95 to 100% of vaccinated infants develop this response (7, 8) and are completely protected, provided they complete the series, i.e., 3 vaccine doses (9, 10).

However, anti-HBsAg antibodies wane over time (11, 12, 13). Yet, infants followed for 5, 10, 15 or 18 years seem to be protected against HBV (14, 15, 16, 17, 18), with little or no HBV infection occurring even after 20 to 22 years (19, 20, 21, 22).

How to interpret this? That, even though circulating, presumably protective, anti-HBsAg and other anti-HBV antibodies may have waned, the original HBV vaccine series induced sufficient numbers of long-lasting, stable HBV-specific memory B and T cells to provide active protection and prevent disease (4). All this applies to immunocompetent people.

Risk of HBV infection is not uniform

HBV-vaccinated infants do not all have an uniform risk of getting HBV disease later in life. Risk is higher for those living in HBV-endemic areas where 5 to 30% of the vaccinated can go on to develop HBV infection (23, 24, 25, 26). These are called transient, benign breakthrough infections (27) because unlike the unvaccinated, such vaccinated people don’t develop chronic liver disease (28, 29).

Two overlapping issues remain to be addressed, one, ‘vaccine nonresponders‘, i.e., those with <10mIU anti-HBsAg antibodies after a full primary (i.e., 3-dose) vaccine series, and two, immunocompromised people.

Several factors could contribute to inadequate HBV vaccine response,

  • Vaccine stored improperly. For e.g., if HBV vaccine’s frozen, the HBsAg separates out from the alum adjuvant and loses its immunogenicity, i.e., capacity to drive an immune response (30).
  • Vaccine in gluteal (buttocks) instead of deltoid (shoulder) muscles (31, 32, 33, 34).
  • Old age, presumably because of Immunosenescence, i.e., aging immune system, in particular, insufficient numbers of HBV-specific B and T cells.
  • Obesity (35), presumably because injecting with standard length needle ends up depositing vaccine largely in fat rather than muscle (36), since injecting with longer needles improves their anti-HBsAg antibody titers (37).
  • Chronic kidney (38) or liver disease.
  • Immunosuppressive drugs.
  • Specific HLA haplotypes, specifically presence of DR3, DR7, DQ2 and absence pf A2 or DR1 alleles (39, 40). Individuals with such haplotypes may have poor T cell responses to the HBV vaccine (41).

Thus, even among those who’re vaccinated as infants, some will be at higher risk of getting HBV infection as adults. Other factors increasing lifelong HBV risk include frequent travel to areas of high HBV endemicity, intravenous drug use, health care work, HIV and/or HCV (hepatitis C) infections, liver transplant, being household and sexual partners of HBV positive persons, needing dialysis.

Booster shots could help such individuals as well as vaccine non-responders though as yet there is no consensus on need for and recommendations on boosters (5, 12, 15, 18, 19, 25, 28, 29). In a study of 1937 previously unvaccinated adults HBV-vaccinated in the deltoid muscle, 178 produced <10mIU anti-HBsAg antibodies, i.e., ~9.2% non-responders. One additional jab produced adequate antibody titer in 47% while 2 additional jabs did the trick for 42% of the remaining non-responders (42).

Finally, risks are higher for children born to HBV positive mothers, being highest for those born to mothers positive for both circulating HBsAg and HBeAg (HBV antigens). Supplementing the standard 3-dose universal HBV vaccine with HBIG (Hepatitis B Immunoglobulin) improves their protection (43, 44) though this may increase cost (45). Supplementing universal HBV vaccine with HBIG given within 12 to 24 hours of birth is also 89 to 98% effective in preventing infection and disease in children born to mothers positive for circulating HBsAg and HBV DNA (46).


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