Neonates who acquire HBV from their mothers (perinatal) are most susceptible to chronic HBV infection (1,, ), 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, , ).
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 (, 10).
However, anti-HBsAg antibodies wane over time (, , ). Yet, infants followed for 5, 10, 15 or 18 years seem to be protected against HBV ( , , 16, 17, ), with little or no HBV infection occurring even after 20 to 22 years (19, 20, , ).
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,, , 26). These are called transient, benign breakthrough infections (27) because unlike the unvaccinated, such vaccinated people don’t develop chronic liver disease (28, ).
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 ( , 32, 33, 34).
- Old age, presumably because of , 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 ( ), 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 ( ).
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 (, 12, 15, , 19, , 28, ). 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,) though this may increase cost ( ). 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).
1. Hyams, Kenneth C. “Risks of chronicity following acute hepatitis B virus infection: a review.” Clinical Infectious Diseases 20.4 (1995): 992-1000.
2. Ott, Jördis J., Gretchen A. Stevens, and Steven T. Wiersma. “The risk of perinatal hepatitis B virus transmission: hepatitis B e antigen (HBeAg) prevalence estimates for all world regions.” BMC infectious diseases 12.1 (2012): 131.
3. Centers for Disease Control and Prevention (CDC). The ABCs of Hepatitis Fact Sheet. [Updated 2015].
4. Banatvala, Jangu, Pierre Van Damme, and Stephan Oehen. “Lifelong protection against hepatitis B: the role of vaccine immunogenicity in immune memory.” Vaccine 19.7 (2000): 877-885.
5. Poorolajal, Jalal, et al. “Long-term protection provided by hepatitis B vaccine and need for booster dose: a meta-analysis.” Vaccine 28.3 (2010): 623-631.
6. Kwon, So Young, and Chang Hong Lee. “Epidemiology and prevention of hepatitis B virus infection.” The Korean journal of hepatology 17.2 (2011): 87-95.
7. Hessel, Luc, and David J. West. “Antibody responses to recombinant hepatitis B vaccines.” Vaccine 20.17 (2002): 2164-2165.
8. Michel, M-L., and P. Tiollais. “Hepatitis B vaccines: protective efficacy and therapeutic potential.” Pathologie Biologie 58.4 (2010): 288-295.
9. Jack, A. D., et al. “What level of hepatitis B antibody is protective?.” Journal of Infectious Diseases 179.2 (1999): 489-492.
10. Szmuness, Wolf, et al. “Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States.” New England Journal of Medicine 303.15 (1980): 833-841.
11. Wainwright, Robert B., et al. “Protection provided by hepatitis B vaccine in a Yupik Eskimo population—results of a 10-year study.” Journal of Infectious Diseases 175.3 (1997): 674-677.
12. Huang, Li-Min, et al. “Long-term response to hepatitis B vaccination and response to booster in children born to mothers with hepatitis B e antigen.” Hepatology 29.3 (1999): 954-959.
13. Wu, Judy S., et al. “Hepatitis B vaccination in high-risk infants: 10-year follow-up.” Journal of infectious diseases 179.6 (1999): 1319-1325.
14. van der Sande, Marianne AB, et al. “Long-term protection against carriage of hepatitis B virus after infant vaccination.” Journal of Infectious Diseases 193.11 (2006): 1528-1535.
15. Van der Sande, M. A., et al. “Long-term protection against HBV chronic carriage of Gambian adolescents vaccinated in infancy and immune response in HBV booster trial in adolescence.” PLoS One 2.1 (2007): e753.
16. Hammitt, Laura L., et al. “Hepatitis B immunity in children vaccinated with recombinant hepatitis B vaccine beginning at birth: a follow-up study at 15 years.” Vaccine 25.39 (2007): 6958-6964.
17. AlFaleh, Faleh, et al. “Long-term protection of hepatitis B vaccine 18 years after vaccination.” Journal of Infection 57.5 (2008): 404-409
18. Lu, Chun-Yi, et al. “Humoral and cellular immune responses to a hepatitis B vaccine booster 15–18 years after neonatal immunization.” Journal of Infectious Diseases 197.10 (2008): 1419-1426.
19. But, David Yiu-Kuen, et al. “Twenty-two years follow-up of a prospective randomized trial of hepatitis B vaccines without booster dose in children: final report.” Vaccine 26.51 (2008): 6587-6591.
20. Roznovsky, L., et al. “Long-term protection against hepatitis B after newborn vaccination: 20-year follow-up.” Infection 38.5 (2010): 395-400.
21. Poovorawan, Yong, et al. “Persistence of antibodies and immune memory to hepatitis B vaccine 20 years after infant vaccination in Thailand.” Vaccine 28.3 (2010): 730-736.
22. Poovorawan, Y., et al. “Evidence of protection against clinical and chronic hepatitis B infection 20 years after infant vaccination in a high endemicity region.” Journal of viral hepatitis 18.5 (2011): 369-375.
23. Coursaget, Pierre, et al. “Twelve-year follow-up study of hepatitis B immunization of Senegalese infants.” Journal of hepatology 21.2 (1994): 250-254; Wu, Judy S., et al. “Hepatitis B vaccination in high-risk infants: 10-year follow-up.” Journal of infectious diseases 179.6 (1999): 1319-1325.
24. Whittle, Hilton, et al. “Observational study of vaccine efficacy 14 years after trial of hepatitis B vaccination in Gambian children.” Bmj 325.7364 (2002): 569.
25. Lu, Chun‐Yi, et al. “Waning immunity to plasma‐derived hepatitis B vaccine and the need for boosters 15 years after neonatal vaccination.” Hepatology 40.6 (2004): 1415-1420.
26. Su, Fu-Hsiung, et al. “Hepatitis B seroprevalence and anamnestic response amongst Taiwanese young adults with full vaccination in infancy, 20 years subsequent to national hepatitis B vaccination.” Vaccine 25.47 (2007): 8085-8090.
27. Wu, Qian, et al. “Antibody levels and immune memory 23 years after primary plasma-derived hepatitis B vaccination: results of a randomized placebo-controlled trial cohort from China where endemicity is high.” Vaccine 29.12 (2011): 2302-2307.
28. Banatvala, J., et al. “Are booster immunisations needed for lifelong hepatitis B immunity?.” Lancet 355.9203 (2000): 561-565.
29. FitzSimons, David, et al. “Long-term efficacy of hepatitis B vaccine, booster policy, and impact of hepatitis B virus mutants.” Vaccine 23.32 (2005): 4158-4166.
30. Van Damme, P., et al. “Heat stability of a recombinant DNA hepatitis B vaccine.” Vaccine 10.6 (1992): 366-367.
31. Centers for Disease Control (CDC. “Suboptimal response to hepatitis B vaccine given by injection into the buttock.” MMWR. Morbidity and mortality weekly report 34.8 (1985): 105.
32. Lindsay, Karen L., David A. Herbert, and Gary L. Gitnick. “Hepatitis B vaccine: low postvaccination immunity in hospital personnel given gluteal injections.” Hepatology 5.6 (1985): 1088-1090.
33. Lemon, Stanely M., and Davis J. Weber. “Immunogenicity of plasma-derived hepatitis B vaccine.” Journal of general internal medicine 1.3 (1986): 199-201.
34. Shaw, F. E., et al. “Effect of anatomic injection site, age and smoking on the immune response to hepatitis B vaccination.” Vaccine 7.5 (1989): 425-430.
35. Weber, David J., et al. “Obesity as a predictor of poor antibody response to hepatitis B plasma vaccine.” Jama 254.22 (1985): 3187-3189.
36. Poland, Gregory A., et al. “Determination of deltoid fat pad thickness: implications for needle length in adult immunization.” Jama 277.21 (1997): 1709-1711.
37. Middleman, Amy B., Roberta Anding, and Celestine Tung. “Effect of needle length when immunizing obese adolescents with hepatitis B vaccine.” Pediatrics 125.3 (2010): e508-e512.
38. Peces, Ramón, et al. “Prospective analysis of the factors influencing the antibody response to hepatitis B vaccine in hemodialysis patients.” American journal of kidney diseases 29.2 (1997): 239-245.
39. Walker, M., et al. “Genetics of anti-HBs responsiveness. 1. HLA-DR7 and non-responsiveness to hepatitis vaccination.” Transfusion. Vol. 21. No. 5. 8101 GLENBROOK RD, BETHESDA, MD 20814-2749: AMER ASSOC BLOOD BANKS, 1981.
40. Alper, Chester A., et al. “Genetic prediction of nonresponse to hepatitis B vaccine.” New England Journal of Medicine 321.11 (1989): 708-712.
41. Desombere, Isabelle, et al. “Characterization of the T cell recognition of hepatitis B surface antigen (HBsAg) by good and poor responders to hepatitis B vaccines.” Clinical & Experimental Immunology 122.3 (2000): 390-399.
42. Averhoff, Francisco, et al. “Immunogenicity of hepatitis B vaccines: implications for persons at occupational risk of hepatitis B virus infection.” American journal of preventive medicine 15.1 (1998): 1-8.
43. Marion, S. A., et al. “Long-term follow-up of hepatitis B vaccine in infants of carrier mothers.” American journal of epidemiology 140.8 (1994): 734-746.
44. Chen, Ding-Shinn. “Hepatitis B vaccination: The key towards elimination and eradication of hepatitis B.” Journal of hepatology 50.4 (2009): 805-816.
45. Chen, Solomon Chih-Cheng, et al. “Cost-effectiveness of augmenting universal hepatitis B vaccination with immunoglobin treatment.” Pediatrics 131.4 (2013): e1135-e1143.
46. GREENBERG, DAVID P. “Pediatric experience with recombinant hepatitis B vaccines and relevant safety and immunogenicity studies.” The Pediatric infectious disease journal 12.5 (1993): 438-445.