Response to Hepatitis B Vaccine

Abstract & Commentary

By Lin H. Chen, MD

Dr. Chen is Assistant Clinical Professor, Harvard Medical School, Director, Travel Medicine Center, Mt. Auburn Hospital, Cambridge, MA.

Dr. Chen reports no financial relationships relevant to this field of study.

Synopsis: The combined hepatitis A and B vaccine successfully produces antibody response in previous hepatitis B vaccine nonresponders, and offers another method to manage at-risk nonresponders.

Source: Cardell K, Akerlind B, Sallberg M, et al. Excellent response rate to a double dose of the combined hepatitis A and B vaccine in previous nonresponders to hepatitis B vaccine. J Infect Dis 2008;198:299-304.

The investigators administered a series of double-dose combined hepatitis A and B vaccine at 0, 1, and 6 months to 48 nonresponders and 20 controls (HBV-naïve subjects). Nonresponders were defined as persons who did not have an anti-HBs titer of ≥ 10 mIU/mL despite receiving at least 4 doses of recombinant hepatitis B vaccine. Anti-HBs and anti-HAV were measured before vaccination and 1 month after each dose, with ≥ 10 mIU/mL considered to be protective.

Among 44 nonresponders who completed the study, the following developed protective anti-HBs after each dose of the vaccine: 26 (59%) after the first dose, 35 (80%) after the second dose, and 42 (95%) after the third dose. Among the 20 in the reference group, the following developed protective anti-HBs: 2 (10%) after dose 1, 19 (95%) after dose 2, and 20 (100%) developed protective anti-HBs after the third dose. All subjects developed anti-HAV. Two subjects did not respond after the series. One subject had no detectable anti-HBs and the other had an anti-HBs level of 8.5 mIU/mL.

Comparison of the seroconversion rates between the nonresponders and the reference group supports anamnestic response to revaccination in the nonresponders. Additionally, anti-HBs and anti-HAV titers were lower in the nonresponder group, which suggests that there could be a more general immune responsiveness factor. Investigators analyzed other factors that may influence responsiveness and found that high body mass index (BMI) and smoking were associated with lower anti-HBs. Similarly, they found an association between high BMI and lower anti-HAV.


Hepatitis B is caused by a DNA virus in the Hepadnaviridae family that is transmitted via percutaneous or mucosal exposure. Following exposure, the virus spreads in the blood to reach the liver, where it replicates. Liver function abnormality (ALT) manifests after about 60 days of incubation, and jaundice may present following 90 days of incubation.

Worldwide, 350-400 million persons are chronic HBV carriers.2 Prior to the initiation of the childhood hepatitis B immunization program in the United States in 1991, 200,000-300,000 new cases of hepatitis B were reported annually.3 Since the initiation of the hepatitis B immunization program, the incidence of acute hepatitis B declined dramatically. However, 95% of an estimated 51,000 new HBV infections in 2005 occurred in adults.1 Among the reported cases of new HBV infections in 2005, the highest incidence occurred in adults 25-45 years of age; 79% were associated with high-risk sexual activity or IV drug use, 5% were associated with occupational exposure, healthcare, travel, and household contact, and 16% denied any known risk.1

CDC recommends post-vaccination testing for "persons whose subsequent clinical management depends on knowledge of their immune status, including certain healthcare and public safety workers; chronic hemodialysis patients, HIV-infected persons, and other immunocompromised persons; and sex or needle-sharing partners of HBsAg-positive persons."1 The generally accepted protective anti-HBs level is a titer of ≥ 10 mIU/mL, and approximately 5-10% of vaccines do not develop this level of response. Factors associated with poor or nonresponse to hepatitis B vaccine include: male gender, tobacco smoking, obesity, age > 30 years, immunosuppression, HIV infection, chronic liver disease, alcoholism, chronic renal disease, site of injections (gluteal rather than deltoid), length of needle, and genetic predisposition.4

Strategies to induce anti-HBs of ≥ 10 mIU/mL include: revaccination with hepatitis B vaccine intramuscularly (single dose or series); intradermal administration of hepatitis B vaccine5; administration of a double-dose hepatitis B vaccine; and administering a triple-antigen hepatitis B vaccine (Hepacare, not available in the United States).6,7 Among nonresponders to the 3-dose primary vaccine series, 25-50% responded to an additional vaccine dose, and 44-100% responded to a 3-dose revaccination series.1 Possible infection with HBV should be assessed if nonresponse persists after revaccination.1,4 The response rates of 59% after one double-dose combined hepatitis A and B vaccine and 95% after three doses would offer one more method to induce a protective level of anti-HBs. Results of this study support the possibility that the hepatitis A component acts as an adjuvant to hepatitis B vaccine.

Waning immunity is a natural phenomenon in which anti-HBs levels decline after HBV vaccination, with the quickest decline during the first year. Due to immune memory, an individual who develops protective anti-HBs level after HBV vaccine may remain protected against acute hepatitis B infection in spite of declining anti-HBs. Long-term follow-up of recipients of hepatitis B vaccines in high-endemicity populations have reported breakthrough HBV infection by 15 years after primary hepatitis B vaccination, although the infections were asymptomatic.8-10

The European Consensus Group on Hepatitis B Immunity published a statement in 2000 that immune memory appears to last at least 15 years in immunocompetent persons. The group recommended postvaccination testing specifically in healthcare workers and immunocompromised patients after primary hepatitis B series, and testing the latter group every 6-12 months.11 Among immunocompetent individuals tested (see CDC recommendation above) who have shown adequate anti-HBs levels postvaccination, currently there is no recommendation to test routinely.


  1. Mast EE, Weinbaum CM, Fiore AE, et al. A vomprehensive immunization dtrategy to rliminate yransmission of hepatitis B birus infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: Immunization of sdults. MMWR 2006;55(RR-16):1-33.
  2. Kane M. Global program for control of hepatitis B infection. Vaccine 1995;13(suppl 1):S47-S49.
  3. CDC. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination; recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(RR13):1-19.
  4. Sjogren MH. Prevention of hepatitis B in nonresponders to initial hepatitis B virus vaccination. Am J Med 2005;118 Suppl 10A:34S-39S.
  5. Nagafuchi S, Kashiwagi S, Okada K, et al. Reversal of nonresponders and postexposure prophylaxis by intradermal hepatitis B vaccination in Japanese medical personnel. JAMA 1991;265(20):2679-2683.
  6. Zuckerman JN, Zuckerman AJ. Recombinant hepatitis B triple antigen vaccine: Hepacare. Expert Rev Vaccines 2002;1(2):141-144.
  7. Zuckerman JN, Zuckerman AJ, Symington I, et al; UK Hepacare Study Group. Evaluation of a new hepatitis B triple-antigen vaccine in inadequate responders to current vaccines. Hepatology 2001;34(4 Pt 1):798-802.
  8. Boxall EH, A Sira J, El-Shuhkri N, et al. Long-term persistence of immunity to hepatitis B after vaccination during infancy in a country where endemicity is low. J Infect Dis 2004;190(7):1264-1269.
  9. Lu C-Y, Chiang B-L, Chi W-K, et al. Waning immunity to plasma-derived hepatitis B vaccine and the need for boosters 15 years after neonatal vaccination. Hepatology 2004;40:1415-1420.
  10. McMahon BJ, Bruden DL, Petersen KM, et al. Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up. Ann Intern Med 2005;142:333-341.
  11. European Consensus Group on Hepatitis B Immunity. Are booster immunizations needed for lifelong hepatitis B immunity? Lancet 2000;355:561-565.