Hepatitis B Vaccination
Wanke-Rytt Monika & Kuchar Ernest
Department of Pediatrics with Clinical Assessment Unit,
Medical University of Warsaw, Poland

First Created: 06/29/2016 

Clinical Context

Hepatitis is an inflammation of the liver and viral infections are the most common causes of hepatitis worldwide. There are five main hepatitis viruses, A, B, C, D, and E. Three of them HAV, HBV and HDV are vaccine-preventable infections. Hepatitis B is the most common viral infection of the liver. It is estimated that over 2 billion people worldwide had contracted with the virus (i.e. they have positive serological markers of infection, of which 240 million are chronically infected and 786 000 die annually due to infection)1,2,3. The virus is transmitted through contact with the blood or body fluids of an infected person. The routes of HBV transmission include unprotected sex (vaginal, anal, and oral) and vertical (usually at birth); the virus can also be spread through blood through sharing needles syringes, or other drug-injection equipment, sharing items such as razors or toothbrushes with an infected person, during procedures that breach the continuity of skin or mucous membranes (e. g. injection, taking blood samples, gastroscopy and similar diagnostic procedures, closure of skin wounds, surgery, etc.) as well as by direct contact with the blood or open sores of an infected person2,3. Countries that introduced public vaccination programs and disposable equipment managed to significantly reduce the risk of infection. Despite this fact, every hospitalization and the above-listed factors constitute a risk of infection for unvaccinated persons2. Acute hepatitis B usually develops within the first six months after infection with the virus and generally lasts for a few weeks. More than 90% of healthy adults who are infected with HBV will recover naturally within the first year. However, in patients in whom the infection persists, lasting infection of hepatocytes leads to the development of a long-term form of the disease known as chronic hepatitis B. The younger the age of acute hepatitis B infection, the greater the risk of developing a chronic infection (90% in infants, 25-50% children aged 1-5, 6-10% if >5 years)4. Chronic hepatitis is often asymptomatic, unrecognized, and leads to liver cirrhosis and primary liver cancer in adulthood representing a significant global public health problem. People with chronic HBV infection have a significant 15-25% risk of death from HBV-related cirrhosis and HCC4.

It is predicted that without a successful strategy, HBV will lead to 20 million deaths between 2015 and 20305. To improve public health regarding HBV, a combination of vaccination, prevention of mother-to-child transmission and treatment availability is necessary.

The Vaccine Against Hepatitis B Virus

The vaccine against hepatitis B virus which provides active immuno-prophylaxis against hepatitis B was introduced by the Merck, Sharp, and Dohme pharmaceutical company in the USA in 1981. The current vaccine is 95% effective in preventing infection and the development of chronic liver disease and liver cancer due to hepatitis B. The individual hepatitis B vaccine can be given alone or at the same time as other vaccines such as PCV, hepatitis A, MMR, MenC, rotavirus, pre-school booster. When immunizing against HBV at birth, only a monovalent HBV vaccine should be used. It was a first-generation, plasma-derived vaccine, in which the vaccine antigen was the HBV surface antigen (HBsAg) coating the viral particle. The protein parts containing the HBsAg isolated from the blood of patients infected with HBV were subject to virus inactivation procedures before they were included in the vaccine. The second-generation vaccine made commercially available was developed in 1986 by SmithKline Beecham (now known as GlaxoSmithKline) from Belgium. It used recombinant DNA technology and involved the insertion of a plasmid-encoded HBsAg gene sequence into Saccharomyces cerevisiae yeast cells. The synthesis of HBsAg in rapidly proliferating yeast cells constitutes a potentially infinite source for the production of vaccine material. The recombinant HBsAg is currently used as a vaccine antigen against hepatitis B in both monovalent and combined vaccines. Overall, approximately 1 billion vaccines against the virus have been administered in the years 1981-1999. The vaccines available on the market differ in: yeast species used for the manufacture of HBsAg, HBsAg content, contained preservatives, and vaccination schedules. The efficiency of vaccines against hepatitis B is >90% making the global eradication of HBV feasible in the future6. According to the available statistical data, in 2011, 76.8% of the population received vaccination in comparison to 3% in 1992 (6). There are monovalent or combined vaccines available on the market; bivalent vaccines provide protection against hepatitis A and B and are recommended mainly for adults traveling abroad. Other combination vaccines such as 5-in-1 and 6-in-1 are administered to infants.

Routine Vaccination Of Infants

The hepatitis B vaccine is recommended for all infants born to HBsAg-positive mothers and in many countries also for all infants whose mothers are HBsAg-negative7. The time of the first dose depends on the HBsAg status of the mother, gestational age, and birth weight7. The recommended vaccination schedule is shown in Table 1. Only the monovalent vaccine may be used after a child’s birth whereas from 2 months of age the second and third vaccine dose can be given in a form of either a monovalent or conjugated vaccine. Infants who received the monovalent vaccine after birth can be administered the conjugate vaccine, thereby obtaining 4 doses. This schedule has not been found to impact vaccine efficiency or the immune response7. In the case of infants born to mothers who tested negative for HBs, according to the recommended vaccination schedule in many European countries, the first dose should be administered after the first month of age7.

The routine infant vaccinations aim to eradicate HBV infections. In many countries, the universal immunizations have significantly reduced not only the HBV carrier status over the years but also later complications of hepatitis B infections such as cirrhosis and hepatocellular carcinoma. For example, in 1984 in Taiwan vaccination was initially introduced for babies born to carrier mothers, but in 1986 the schedule included all babies. Before the introduction of vaccination, the percentage of HBs-positive children (carriers) in patients below 15 years of age was 9.8% and the incidence of liver cancer varied from 1.02 to 0.48 per 100 000 births depending on gender8. Twenty years later, the carrier state in the same age group dropped to 1.2% and continues to diminish significantly. A similar decreasing trend concerning the incidence of hepatocellular carcinoma is being observed in vaccinated individuals8.

Infants born to HBsAg-positive mothers. Vaccination of babies born to infected mothers plays a crucial role in the eradication of HBV infections7. The risk of vertical transmission is high and amounts to approximately 90-95% without immunoprophylaxis9. The standard procedure involves concurrent active and passive immunization i.e. vaccination and administration of anti-HBs immunoglobulins at birth, regardless of body weight7. It has been shown that vaccination and immunoglobulin administration up to 12 hours after birth, as well as two subsequent vaccine doses in the first year of age, have a high efficiency of 95%7. Preventative measures based on passive immunization only, have a much lower efficiency of 75 - 80% and should not be used10. Furthermore, children who received 3 doses of vaccine should undergo serological testing (HBsAg and anti-HBs)7. In October 2015, the US Center for Disease Control and Prevention (CDC) shortened the recommended time interval between the last vaccine dose and serologic testing. Instead of testing at the age of 18 months, now it is advised to test children who are at age 9 through 12 months11. This change was dictated by the results of observational studies indicating that the anti-HBs titers continued to decrease with the time between vaccination and testing, resulting in unnecessary administration of additional boosters. It should be noted that the serological test should not be done before age 9 months due to the presence of the immunoglobulin given at birth. The test should neither be performed earlier than 4 weeks after the last vaccine dose due to possible false HBs-positive results7,10. Children who do not respond to vaccination should have the three-dose series (0-1-6) repeated and checked for the HBs antigen. Children who despite these two series of vaccinations did not respond properly are referred to as ‘non-responders’7.

Preterm Infants

It has been proven that the first dose of the vaccine in children with birth weight <2000 g induces a weaker response, hence the World Health Organization (WHO) recommends the 0, 1, 2, 12 months schedule12. However, different recommendations were issued by the American Academy of Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP) which allow either administration of the 1 dose when the child is age 1 month, or discharge from the hospital, but only in if the mother is HBs-negative7, 13. The data shows that premature infants with birth weight >2 kg respond to vaccination as well as children born on their due date7.

Table 1. Recommended schedule of hepatitis B immunoprophylaxis for term infants and preterm infants with birth weight 2 kg (5)

Maternal HBsAg status Single-antigen vaccine Single antigrn + combination vaccine
Dose Age Dose Age
Positive 1 Birth (<12 h) 1 Birth (<12 h)
HBIG Birth (<12 h) HBIG Birth (<12 h)
2 1 to 2 months 2 2 months
3* 6 months** 3 4 months
    4* 6 months**
Unknown*** 1 Birth (<12 h) 1 Birth (<12 h)
2 1 to 2 months 2 2 months
3* 6 months 3 4 months
    4* 6 months
Negative 1 Birth (before discharge) 1**** Birth (before discharge)
2 1 to 2 months 2 2 months
3* 6 to 18 months 3 4 months
    4* 6 months
HBIG: hepatis B immune globulin
* The final dose in the vaccine series should be administrated before age 24 weeks
** These infants should be tasted for antibody to HBsAG (anti-HBs) and HBsAg at age 9 to 12 months or 1 to 2 months after the last dose of the hepatitis B vaccine. Testing should be performer before age 9 months nor within 4 weeks of the most recent vaccine dose
*** Mothers should have blood frawn and tasted for HBsAg as soon as possible after admission for delivery
****On a case-by-case basis and only in rare circumstanses, the first dose may be delayed until after hospital discharge for an infant who weights > 2000 g and whose mother is HBsAg negative, but only if a clinician’s order to withhold the birth dose and a copy of the mother’s original HBsAg-negative laboratory report are documented in the infant’s medical record

Assessment of Post-vaccination Response

Evaluation of antibody levels after vaccination for hepatitis B is recommended only in certain cases which are listed below1:

  • Infants born to HBsAg-positive mothers - should be tested for both HBsAg and anti-HBs mostly at age 9 through 18 months after 3 doses or 1 to 2 months after the last dose.

  • Haemodialysed patients - due to the possible decreased response to the vaccine, their antibody titer should be determined 1-2 months after the last dose in order to plan possible revaccination. ACIP and AAP recommend annual testing of anti-HBs if the anti-HBs level declines to <10 mIU/mL a booster is recommended.

  • Immunocompromised patients - ACIP and AAP recommend annual testing of response to vaccination if the anti-HBs level declines to <10 mIU/mL administration of a booster dose should be considered.

  • Sexual partners of HBV carriers


As shown above, the vaccine against hepatitis B is an effective, safe, and cost-effective medical intervention that prevents hepatitis B infections. Despite this fact, there are several European countries (Great Britain and the Scandinavian countries) which do not have universal and compulsory vaccinations. These countries justify their decision by explaining that hepatitis B infection does not constitute a common problem there, therefore there is no indication to bear the financial burden of universal vaccination16. In the developing countries, the faced financial problems, and the need to strive for sanitation, hygiene policy, access to clean water, and food have priority over the introduction of universal vaccination.

Contraindications and Side Effects

Hepatitis B vaccine is contraindicated in persons with a history of a severe allergy to eggs or other vaccine components. Pregnancy, multiple sclerosis, Guillain-Barré syndrome, autoimmune diseases, and other chronic diseases do not constitute a contraindication to vaccination (7,14).

The hepatitis B vaccine is considered to be safe. The most common side effects include fever (1-6%) and pain at the injection site (3-29%)7. Administration of the first dose immediately after birth was not associated with a higher incidence of sepsis. A large cohort study demonstrated that the incidence of anaphylaxis after vaccine administration is 1.1 per 1 million vaccine doses15.

1. World Health Organization. Hepatitis B. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html (Accessed on April 15, 2015).
2. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11(2):97.
3. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012 Mar;30(12):2212-9. Epub 2012 Jan 24.
4. World Health Organization. Hepatitis B. 2015. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html
5. World Health Organization. Global Health Sector Strategy on viral hepatitis, 2016–2021 http://www.who.int/hiv/topics/hepatitis/strategy2016-2021/en/
6. World Health Organization. Immunization coverage. http://www.who.int/mediacentre/factsheets/fs378/en/ (Accessed on May 19, 2015).
7. Mast EE, Margolis HS, Fiore AE et al A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54(RR-16):1.
8. Chang MH, You SL, Chen CJ et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst. 2009;101(19):1348.
9. Nelson NP, Jamieson DJ, Murphy TV. Prevention of Perinatal Hepatitis B Virus Transmission. J Pediatric Infect Dis Soc. 2014;3 Suppl 1:S7.
10. Beasley RP, Hwang LY, Lee GC, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet. 1983;2(8359):1099.
11. Schillie S, Murphy TV, Fenlon N. Update: Shortened Interval for Postvaccination Serologic Testing of Infants Born to Hepatitis B-Infected Mothers. MMWR Morb Mortal Wkly Rep. 2015;64(39):1118.
12. Bonheoffer J. Siergrist CA, Heath PT. Immunisation of premature infants. Arch Dis Child 2006;91:929-35.
13. American Academy of Pediatrics. Hepatitis B. In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.400.
14. Levy M, Koren G.Hepatitis B vaccine in pregnancy: maternal and fetal safety. Am J Perinatol. 1991;8(3):227.
15. Bohlke K, Davis RL, Marcy SM et al. Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics 2003;112:815
16. http://www.euro.who.int/vaccine/diseases/20090127-15

Hepatitis B Vaccination Hepatitis B Vaccination 06/29/2016
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