The pathogen and the diseaseHBV is a double-stranded enveloped virus of theHepadnaviridae family. HBV replicates in the hepatocytesof humans and other higher primates, but doesnot grow in artificial cell cultures. HBsAg is a lipoproteinof the viral envelope that circulates in the bloodas spherical and tubular particles 22 nanometres in size.HBsAg includes a neutralizing epitope, the a determinant.The outcomes of HBV infection are age-dependent andinclude asymptomatic infection, acute hepatitis B,chronic HBV infection, cirrhosis and HCC. Acute hepatitisB occurs in approximately 1% of perinatal infections,10% of early childhood infections (children aged1–5 years) and 30% of late infections (people aged>5 years). Fulminant hepatitis develops in 0.1–0.6% ofacute hepatitis cases; mortality from fulminant hepatitisB is approximately 70%. The development of chronicHBV infection is inversely related to the age of acquisition,occurring in approximately 80–90% of people infectedperinatally, about 30% of children infected beforethe age of 6 years, and in <5% of infections occurringin otherwise healthy adults.9Comorbidities, including concurrent HIV infection andingestion of alcohol or aflotoxins, or both, may have animportant role in the development of morbidity relatedto hepatitis B. It is estimated that 10% of the 40 millionpeople infected with HIV worldwide are coinfected withHBV. Although HBV infection appears to have a minimaleffect on the progression of HIV, the presence ofHIV markedly increases the risk of developing HBVassociatedliver cirrhosis and HCC. A recent meta-analysisof studies examining overall mortality showed anincreased death rate among HIV-positive people due tocoinfection with HBV both before and after commencementof highly active antiretroviral therapy

People with chronic HBV infection have a 15–25% riskof dying prematurely from HBV-related cirrhosis andHCC.11 It is not possible, on clinical grounds, to differentiatehepatitis B from hepatitis caused by otherviral agents and, hence, laboratory confirmation of thediagnosis is essential. In serological terms, acute HBVinfection is characterized by the presence of HBsAg andimmunoglobulin M (IgM) antibody to the core antigen,HBcAg. During the initial, highly replicative phase ofinfection, patients are also seropositive for HBeAg.Antibody to HBsAg (anti-HBs) is discernible after a fewweeks and is followed by clearance of the HBsAg.Chronic infection is characterized by the persistence(>6 months) of HBsAg (with or without concurrentHBeAg). Persistence of HBsAg is the principal markerof risk for developing chronic liver disease and HCClater in life. The presence of HBeAg indicates that the

blood and body fluids of the infected individual arehighly contagious. Each year, about 10% of chronic casesbecome HBeAg-negative and develop antibody toHBeAg, signalling a change to the low-replication stage.Loss of HBsAg in untreated chronic cases occurs at anestimated rate of 1% per year.Currently, in industrialized countries, at least 7 medicinesare approved for treating chronic HBV infectionand have been shown to delay progression of cirrhosis,reduce the incidence of HCC and improve long-termsurvival. Treatment outcomes have shown dramatic improvementin this fast-moving area of medical research.Several professional organizations (the American Associationfor the Study of Liver Diseases,12 the Asia PacificAssociation for the Study of the Liver13 and the EuropeanAssociation for the Study of the Liver14) have developedguidelines for treating chronic HBV infection.Treatment, however, is not readily accessible in manyresource-constrained settings and is complicated by thetoxicity of the agents, antiviral resistance, the developmentof HBV mutants and the need for long-term follow-up.Anti-HBs of immunoglobulin G-type (IgG) is used as amarker of immunity, and immune globulin containinghigh titres of anti-HBs is used for passive immunization,often in combination with hepatitis B vaccine, immediatelyfollowing a high-risk exposure. However,studies of previously vaccinated people indicate thatdespite low or undetectable antibody titres years aftervaccination, most of these vaccinees were still protected

against asymptomatic and symptomatic HBV infectionsfollowing exposure. The majority of these people alsomounted a typical anamnestic response to revaccination,indicating that long-term protection depends uponmemory T-cells (see Duration of protection and needfor booster injections below). Both the severity of clinicaldisease and the viral clearance correlate with thecellular immune response to various viral proteins.Immune tolerance to viral antigens acquired at birth isbelieved to play an important role in neonatal HBV persistence,whereas the immune mechanisms underlyingchronic HBV infection are poorly defined. Recentresearch has demonstrated an association betweencertain human leukocyte antigen alleles and haplotypes,and the lack of an antibody response to HBV antigens.15Genetically linked host factors may have important implicationsfor recovery from HBV infection and vaccineefficacy.Vaccines and vaccination against hepatitis BRecombinant hepatitis B vaccine was introduced in1986 and has gradually replaced the plasma-derivedhepatitis B vaccine. The active substance in recombinant

hepatitis B vaccine is HBsAg that has been producedin yeast or mammalian cells into which theHBsAg gene (or HBsAg/pre-HBsAg genes) has beeninserted using plasmids. The transformed cells aregrown in large vessels, and the expressed HBsAg selfassemblesinto spherical particles that expose thehighly immunogenic a determinant. The recombinantparticles differ from natural ones only in the glycosylationof the HBsAg. Following thorough purificationfrom host-cell components, alum (and, in certain formulations,thiomersal) is added. A new recombinanthepatitis B vaccine that is intended for adult patientswith renal insufficiency uses alum and lipid A asadjuvants.16Monovalent hepatitis B vaccine should be transportedand stored at 2–8 °C; freezing must be avoided becauseit dissociates antigen from the alum adjuvant. Althoughthe vaccine has been exposed to temperatures of up to45 °C for 1 week and temperatures up to 37 °C for1 month without change in immunogenicity or reactogenicity,exposure to hot environmental temperaturesshould be minimized. Given differences in the manufacturingprocesses, the quantity of HBsAg protein perdose of vaccine that will induce a protective immuneresponse differs among the various vaccine products(from 10 μg to 40 μg per adult dose).Hepatitis B vaccine is available as monovalent formulationsor in fixed combination with other vaccines, includingdiphtheria–tetanus–pertussis (DTP), Haemophilus influenzae type b,

hepatitis A and inactivated

polio. The immune responses and safety of these combinations

of vaccines are comparable to those observedwhen the vaccines are administered separately.17,18,19When immunizing against HBV at birth, only monovalenthepatitis B vaccine should be used. Internationallymarketed hepatitis B vaccines are considered immunologicallycomparable and can be used interchangeably.

Immunogenicity, clinical efficacy and effectivenessThe protective efficacy of hepatitis B vaccination isrelated to the induction of anti-HBs antibodies, but alsoinvolves the induction of memory T-cells. An anti-HBsconcentration of 10 mIU/ml measured 1–3 months afteradministration of the last dose of the primary vaccinationseries is considered a reliable marker of protectionagainst infection.20 The primary 3-dose vaccine seriesinduces protective antibody concentrations in >95% ofhealthy infants, children and young adults.15,21,22,23After the age of 40 years, antibody response ratesdecline gradually.24 Among individuals who did notrespond to a primary 3-dose series with anti-HBs

concentrations of >10 mIU/ml, almost all respond to a3-dose revaccination series.25A recent meta-analysis of randomized controlled trialsof hepatitis B vaccine administered at birth found thatimmunized infants born to mothers infected with hepatitisB were 3.5 times less likely to become infectedwith HBV (relative risk, 0.28; 95% confidence interval,0.20–0.40).26 The vaccine is also effective in reducing

both the incidence of HCC and mortality fromHCC.27,28Delaying the birth dose results in an increased risk ofHBV infection. One study showed that the risk of HBVinfection for infants born to HBsAg-positive mothersincreased significantly when the first dose of hepatitis Bvaccine was received after 7 days compared with thosevaccinated on days 1-3 following birth (odds ratio,8.6).29,30

Vaccine dose and administration

The recommended dose varies by product and with theage of the recipient. In general, the dose for infants andchildren (aged ≤15 years) is half the recommendedadult dose. The vaccine is administered by intramuscularinjection into the anterolateral aspect of the thigh(for infants and children aged <2 years) or into thedeltoid muscle (for older children and adults). Administrationinto the buttock is not recommended becausethis route has been associated with decreased concentrationsof protective antibody and injury to the sciaticnerve. The hepatitis B vaccine does not interfere withthe immune response to any other vaccine and viceversa. Thus, the birth-dose of hepatitis B vaccine canbe administered together with bacillus Calmette–Guérilvaccine, preferably within 24 hours of birth. However,unless formulated as fixed combinations, hepatitis Bvaccine and other vaccines administered during thesame visit should be given at different injection sites.Vaccination schedulesThere are multiple options for incorporating the hepatitisB vaccine into national immunization programmes,and the choice of schedule depends mainly on programmaticconsiderations. Since perinatal or early postnataltransmission is an important cause of chronic infectionsglobally, the first dose of hepatitis B vaccineshould be given as soon as possible (<24 hours) afterbirth even in low-endemicity countries. The birth doseshould be followed by 2 or 3 doses with a minimuminterval of 4 weeks. Longer intervals may increase finalanti-HBs titres, but not seroconversion rates.The primary hepatitis B immunization series conventionallyconsists of 3 doses of vaccine (that is, 1 monovalent

birth dose followed by 2 monovalent or combinedvaccine doses). However, 4 doses may be given

for programmatic reasons (for example, 1 monovalentbirth-dose followed by 3 monovalent or combinedvaccine doses), administered according to the schedulesof national routine immunization programmes. Forolder children and adults, the primary series of 3 doseswith appropriate intervals applies.The timely delivery of a birth dose of hepatitis B vaccine(that is, within 24 hours of birth) should be a performancemeasure for all immunization programmes.To better monitor the delivery of doses given within24 hours of birth, these doses should be counted as abirth dose of hepatitis B vaccine to differentiate themfrom first doses given later. Where subsequent doses ofhepatitis B vaccine are given in combination with otherantigens (often referred to as Combo 1, Combo 2 andCombo 3), the Combo 3 dose will contain the fourthdose of hepatitis B vaccine.Ensuring that all infants receive a dose of hepatitis Bvaccine within 24 hours of birth requires implementationof specific programmatic measures. Increasing thenumber of infants born in facilities or attended bytrained health staff would improve birth dose coverage.Ensuring that there is coordination between immunizationservices and maternal health services is importantso that vaccine is available at the place of delivery orimmediately after birth. Expanding vaccine managementsystems and innovative outreach to provide vaccinefor home births31 will ensure that hepatitis vaccineis available in settings where births take place. Effortsto develop new heat-stable and freeze-stable hepatitis Bvaccine will aid these attempts. In addition, health promotionefforts aimed at parents and training aimed atproviders are needed to increase awareness about theimportance of administering hepatitis B vaccine within24 hours of birth.32Data on immunogenicity suggest that in any age group,interruption of the vaccination schedule does not requirerestarting the vaccine series. If the primary seriesis interrupted after the first dose, the second doseshould be administered as soon as possible and thesecond and third doses separated by a minimum intervalof 4 weeks; if only the third dose is delayed, it shouldbe administered as soon as possible.33Preterm infants should be vaccinated at birth and subsequentlyenter the national hepatitis B vaccinationschedule. However, if an infant’s birth weight is <2000 g,the vaccine dose given at birth should not be countedtowards the primary series and 3 additional dosesshould be given according to the national vaccinationschedule.