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Paolo Bonanni
Department of Public Health, University of Florence, Florence, Italy


Hepatitis B (HB) is one of the major public health problems in the world. In addition to the deaths caused by acute infections (estimated at around 50,000 each year), hepatitis B virus (HBV) is the recognised cause of chronic infections affecting about 350 million people (Kane, 1995). Liver cirrhosis and hepatocellular carcinoma are the most important long term consequences, as they cause an estimated 470,000 deaths per year (W.H.O., 2000).

HBV infection is traditionally highly prevalent (HBsAg carriers > 8% in the general population) in regions of the world like South-East Asia, Sub-Saharan Africa and the equatorial area of South America. However, the prevalent patterns of viral transmission are different, as perinatal transmission from HBeAg positive mothers accounts for a substantial proportion of cases in Asian countries together with a continuing transmission during early childhood, while most cases in Africa are acquired in early childhood by horizontal transmission. In industrialised countries like Western Europe and USA, HBV infection is spread mainly through sexual activity and through parenteral exposure to blood or other body fluids (Alter M., 1990). In countries of Eastern Europe, a high incidence and prevalence of HBV infection in the last decades was often connected to re-use of medical equipment coupled with inadequate methods of sterilisation (Magdzik, 2000).

Hepatitis B vaccine has been available for general use since 1982 in the form of plasma-derived preparations. Given the limited quantities available and the high costs, vaccination policies were initially targeted to high risk groups like health care workers, newborns to HBsAg positive mothers, household contacts of HBV carriers, patients undergoing frequent invasive therapeutic or diagnostic procedures, haemodialysis patients, intravenous drug users, etc. At the mid of the Eighties, the development of preparations obtained by recombinant DNA techniques in yeast or mammalian cells changed the perspectives for public health use of hepatitis B vaccine. As a matter of fact, the virtually unlimited supply and lower costs made it possible to foresee the introduction of routine vaccination programmes in the general population of all countries.

In addition, although vaccination of newborns to HBsAg positive mothers and of cohabitants of virus carriers was undoubtedly important to reduce the number of infections, the drawbacks of immunisation strategies targeting only risk groups became apparent in the 10 years since they were enacted (Bonanni, 1998a). As a first point, in countries where surveillance on acute hepatitis B is in place, no risk factor is identifiable in more than a quarter of acute hepatitis B cases. Secondly, certain risk groups like intravenous drug users and those at risk because of their sexual behaviour are difficult to access and are often already infected by the time they are targeted. Therefore, it was estimated that overall 85% of vaccine doses used in high risk immunisation programmes were administered to healthcare workers, a population which accounted for 5 to 10% of all hepatitis B cases in Europe and North America (Grosheide, 1996; Alter, 1990).

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Monitoring the impact of hepatitis B vaccination

When the decision to introduce a universal programme of hepatitis B vaccination is taken, the first step is to implement it and to monitor coverage. This may be accomplished by comparing the vaccination register (number of subjects receiving the basic immunisation course) with the number of subjects of the same age group supplied by the birth register of each area where the study is performed. If a significant number of irregular immigrants is present, a precise estimate of their number and of their immunisation status should be obtained in order to get the real coverage in that area.

A first consequence of the implementation of routine vaccination is the decline of the incidence of hepatitis B in the age cohorts covered by immunisation. As to this aspect, it is particularly important to investigate the risk factors and reasons of possible cases occurring in age groups subject to recommended or mandatory vaccination. When a case occurs in a vaccinated subject, it should be investigated whether this is due to a wild type or to a mutant virus, in order to monitor the long term effectiveness of the currently used vaccine and foresee possible need of changes in vaccine composition.

As a second step, it is important to monitor the changing prevalence of HBV markers in different age groups which is consequent to the implementation of immunisation programmes.

In the long term, it is possible to verify a decline in the incidence and prevalence of chronic liver diseases (particularly cirrhosis and primary liver cancer).

Safety issues are becoming increasingly important in the perception of the public with regard to acceptance of routine immunisation. Since frequent and minor side effects are usually seen during clinical trials preceding vaccine registration, but rare and important adverse events are reported only after a large use of the new product, it is necessary to perform a continuous post-marketing surveillance to verify the safety in the field.

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1. Implementation and coverage

The number of countries including hepatitis B vaccination in their national immunisation programme increased progressively from 1991 (when they were 20) to the end of the decade (129 in 2000) (Kane, 1998; WHO, 2000). Since the creation of the Global Alliance for Vaccines and Immunization (GAVI), whose main aims include the provision of new and under-used vaccines (particularly HB) to the poorest countries, an acceleration occurred. As a consequence, nations with routine infant immunisation against hepatitis B have reached 154 in June 2002. Of the 74 countries eligible for support from GAVI (Gross National Product <1000 US Dollars), 38 have already received approval to introduce routine hepatitis B vaccination, and many others are in the process of application. However, about 37 million of the 132 million children born each year do not even receive the basic vaccination originally included in the Expanded Programme of Immunization (EPI), 25 million of which live in the poorest countries. Therefore, a big effort needs to be done to improve immunisation services, to provide the basic vaccines to all children and to expand the number of vaccines used including most recent products like HB vaccine. It is not less crucial to build a good surveillance system able to supply data on both coverage and trends of acute and chronic disease incidence. In fact, feedback data on the use and on the epidemiological impact of hepatitis B vaccination have a key role in documenting the importance of immunisation for human health. By the end of 2000, the global coverage with 3 doses of hepatitis B vaccine was estimated at 32%, with many industrialised countries not even reporting data to WHO.

Routine adolescent immunisation without an infant programme was recognised by the World Health Assembly resolution of 1992 as a possible alternative for countries with carrier prevalence less than 2%. However, two observations indicate that childhood immunisation is probably the most effective strategy to reduce the disease burden connected with HBV. First, the infrastructures to deliver vaccines to adolescents are not well developed even in many industrialised countries, and adolescent are often difficult to access. (Tepper, 1999). Second, the recent elaboration of a large set of epidemiological data collected in USA before the implementation of routine childhood immunisation make it possible to estimate that between 12,000 and 25,000 children under 10 years were infected each year not by perinatal transmission (Armstrong, 2001). Since the evolution to chronicity is inversely related to age, this study strongly supports the need for universal infant immunisation to prevent chronic hepatitis B and the substantial burden of hepatitis B-related chronic liver disease that would be acquired during infancy and early childhood with an adolescent-only programme.

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2. Decline in the incidence of acute hepatitis B

A decline of incidence of acute cases of disease in paediatric age groups is not easy to demonstrate because hepatitis B is rarely symptomatic in infants and children (Goldstein, 2001). Thus, the baseline level of incidence is usually already low before routine immunisation. In addition, HBV-related mortality is seen mainly in adult age. However, there are areas with such a high endemicity of infection that it is possible to document the impact of vaccination also by mortality rates. In Taiwan, the average mortality from fulminant hepatitis in infants passed from 5.36/100,000 in 1975-84 (prior to mass vaccination) to 1.71/100,000 in 1985-98 (Kao, 2001).

Proofs of the decreasing incidence of acute hepatitis B after vaccination are available in Europe from Italy, the first industrialised country to introduce routine immunisation of a double cohort of subjects, i.e. infants and 12-year old adolescents.

Data from the Integrated System of Surveillance on Acute Viral Hepatitis (SEIEVA) indicate that, the overall incidence of acute hepatitis B was already declining before the introduction of routine vaccination, since it passed from 12 to 5/100,000 inhabitants between 1985 and 1991. However, the decline connected to the improvement of hygienic and living conditions would not lead to the elimination of viral circulation without a programme of universal vaccination (Bonanni, 1998b). As a matter of fact, the incidence in the age group at highest risk (15-24 years) was halved from 1991 to 1994 (12 and 6/100,000, respectively) and continued to decrease thereafter. In Tuscany, a 49% decline of reported cases in the same age group was registered between 1992 and 1996, and no case occurred in vaccinated adolescents (all cases in the age cohorts subject to mandatory vaccination were in non immunised subjects) (Bonanni, 1999).

The experiences in a highly endemic area in Southern Italy (Afragola), where a pilot project of universal vaccination was launched in 1983, showed a decline of incidence from 63/100,000 before immunisation programme to 3/100,000 in 1997, after 15 years of its implementation (Da Villa, 1998).

In Bulgaria, the universal vaccination of neonates introduced in 1991 rapidly reached over 70% coverage . In 1992, a drop of incidence of hepatitis B in infants reached 5.6/100,000 vs. values of 25-35/100,000 during the 1980s (Gatcheva, 1995).

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3. Changing prevalence of HBV markers and impact of vaccination on chronic liver disease

Data on the decrease of prevalence of HBV markers are accumulating in countries where routine hepatitis B vaccination programmes were implemented. We will cite only a few of them.

In Taiwan, during the 15 years following introduction of mass vaccination, HBsAg prevalence in the population of <15 year olds passed from 9.8% (1984) to 0.7% (1999) (Ni, 2001). In Alaska (an area of traditionally high endemicity), where a programme of vaccination of all infants plus catch-up of susceptibles was initiated in 1983, a ten-year follow-up showed zero HBsAg prevalence in Native Alaskan children <10 years, while 16% of those aged 11-30 years were chronically infected (Harpaz, 2000). In Italy, in the high endemicity area of Afragola, HBsAg prevalence dropped from 13.4% in 1978 to 3.7% in 1997 (from 6.8% to 0.7% in children and adolescent (Da Villa, 1998). In South Africa, the prevalence of HBV carriers in 3-year old children was 12.8% in the pre-immunisation years (Vardas, 1999). After 5 years of implementation of HB vaccination in the framework of EPI, none of about 600 vaccinated children showed HBsAg reactivity (Tsebe, 2001).

Taiwan was the first country where the impact of mass hepatitis B immunisation on the chronic consequences of infection could be demonstrated. In children aged 6-14 years, the incidence of primary liver cancer progressively declined from 0.7/100,000 in the period 1981-86, to 0.57/100,000 in 1986-90, to 0.36/100,000 in 1990-96 (Chang, 1997).

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Real and perceived safety

Before considering the issue of vaccine safety, it is useful to remind that hepatitis B vaccine contains viral surface antigen (HBsAg) obtained either from plasma of chronic carriers or from yeast or mammalian cells by recombinant DNA technique; adjuvants (aluminium salts); and sometimes preservatives (thiomersal or 2-phenoxyethanol).

In clinical trials preceding registration, all commercially available vaccines proved to be safe, and to cause minor side effects in proportion not superior to those registered in subjects receiving placebo, except for local pain, that was reported in up to 30% of vaccinees (Szmuness, 1980; Francis, 1982, Lewis , 2001).

As for all vaccines, only frequent adverse events can be identified during phase 2 and phase 3 clinical trials, while rare effects (<1/1000 doses) can only be seen during post-marketing surveillance (Anthony, 1995).

The occurrence of anaphylaxis after hepatitis B vaccination is proven, although it is a rare event (1/600,000 doses distributed). However, no fatal case is reported.

A number of other adverse events have been reported as temporarily associated with hepatitis B vaccination. Most of them are represented by chronic syndromes with unknown or partially known aetiology. Media attention is frequently attracted by these allegations, causing a fall in the confidence of the public in hepatitis B immunisation. However, it must be distinguished between hypothesis generation and hypothesis testing. It should also be considered that when a possible association between vaccination and adverse event is suggested by surveillance data, case reports and case series, we only see one side of the overall picture. As a matter of fact, we do not know whether the same event is occurring also in non-immunised subjects, and how many vaccines are not experiencing the adverse event.

Verification of causality for these adverse events is not easy, given their rarity, the fact that they occur also in the absence of vaccination, their usual occurrence at old age and the difficulties for many of them to find a biological plausibility.

Among the adverse events whose association with hepatitis B vaccination has been proposed there are chronic fatigue syndrome (CFS), chronic arthritis, lymphoblastic leukaemia, diabetes and demyelinating diseases like multiple sclerosis (MS). The last was the object of a large and still occurring debate, particularly in France and French speaking countries. In France, over 20 million people comprising adolescents and adults were immunised in few years. More than 600 cases of multiple sclerosis were reported by 2001, the majority of which were adult females with a close match to the natural epidemiologic distribution of the disease. The time elapsed between immunisation and onset of symptoms ranged between 1 day and 5 years (mean 60 days)

The possible explanations of multiple sclerosis occurrence after hepatitis B vaccination include: 1) temporal coincidence between vaccine administration and symptoms, without causal relationship; 2) ‘triggering’: HB vaccination might act as a trigger of symptomatic demyelination in subjects already predisposed to develop multiple sclerosis; 3) true causal relationship between hepatitis B vaccination and multiple sclerosis or other demyelinating diseases of the central nervous system.

Nine epidemiological studies were conducted in the last years to estimate the association of vaccination with multiple sclerosis, both first attack and relapse. Overall, although slightly elevated odds ratios were found in the first studies (but without statistical significance), there is lack of experimental data to suggest a link (Touz, 2000; Confavreux, 2001; Zipp, 1999; Sadovnick, 2000; Ascherio, 2001). The most plausible explanation remains temporal coincidence, although a very weak risk or the existence of groups of subjects with a particular sensitivity cannot be rejected. However, the US Institute of Medicine recently reviewed the data and concluded that evidence favoured rejection of a causal relationship between hepatitis B vaccine administered to adults and incident multiple sclerosis or multiple sclerosis relapse. Data on other serious allegations were reviewed, but no one was confirmed so far.

The Global Advisory Committee on Vaccine Safety (GACVS) established by WHO in 1999, upon review of available data, concluded that there is no evidence based on safety to suggest that WHO should consider altering its recommendations that all countries should have universal infant and/or adolescent immunization programs and continue to immunize adults at increased risk of hepatitis B infection as appropriate.

In view of the demonstrated impact of HB vaccination on the epidemiology of acute and chronic hepatitis B, liver cirrhosis and hepatocellular carcinoma, versus a non demonstrable risk of rare adverse events, efforts should be made to properly inform the population on the importance of hepatitis B prevention through immunisation.

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HBV transmission in medical settings

Health care workers (HCWs) are a traditional risk group for hepatitis B. Many studies in the pre-vaccination era showed an increased prevalence of HBV markers when compared to the general population, especially for personnel working in wards like haemodialysis units, infectious diseases, gastroenterology, emergency, surgery. The introduction of recommended hepatitis B immunisation, and its wide use particularly in younger generations of HCWs and in medical and nursing students, together with measures to prevent exposure (CDC, 1989), determined a clear decline in the incidence of HBV in HCWs (Mahoney, 1997). A problem of coverage still exists in older health care workers, who are less compliant to vaccination (Stroffolini, 1998).

However, although at a lower level, a problem of transmission also exists from HCW to patient. A carrier health care worker, especially if performing exposure prone procedures, can infect the patient (Hasselhorn, 2000).

The risk for the health care worker or for the patient can be calculated according to the following formula:

  • R = p x E x t x S
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where R expresses the risk (probability of being infected); p is the prevalence of HBsAg positive subjects among the treated patients or among health care workers, respectively; E is the frequency of exposure to infectious blood or other body fluids; t is the probability of transmission following a single exposure; S is the proportion of susceptible health care workers or patients, respectively.

The risk of transmission of HBV from HCW to patient during invasive surgical procedures was estimated at values of 2400 per million (Bell, 1992), much higher than that for HCV and HIV.

In order to verify the potential danger posed from an infected HCW to patients, it may be useful to perform a quantitative determination of HBV titres. In fact, the detection of HBeAg is not sufficient as a marker of high viremia, since it is not possible to rule out an infection with HBeAg minus mutants, which may be circulating at high titres. (Gunther, 1999). Proof of transmission from an infected HCW to a patient can be supported if genome sequencing shows identity of HBV isolates (Repp, 1993). However, other elements should be considered like the time between exposure and appearance of clinical symptoms, and the possible involvement of more patients in a transmission episode. Of course, other sources of infection for the patients (i.v. drug use, sexual contact with infected subjects, history of blood transfusion, etc.) should be excluded.

In order to prevent HCW-patient transmission, there is consensus that HBeAg positive HBV carriers should not perform exposure prone surgery or other treatments at risk of injury for the operator. This personnel should be assigned to a type of work with minimal risk of transmission.

In the long-term perspective, the growing implementation of universal vaccination programmes and the continuing active offer of immunisation to health care workers should diminish the prevalence of HBV carriers in patients and HCWs, respectively, thus making hepatitis B transmission in medical settings an uncommon event (Bonanni, 2001).

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Importance of mutant viruses

Viral mutations reflect attempts by the virus to evade the mechanisms that potentially endanger its existence and to survive in a hostile environment. HBV mutants may be naturally occurring or originate under the pressure of the host’s immune system or as a reaction against introduced antibodies (Francois, 2001). Several immune escape mutants have been described, the most frequent of which involves the second loop of the a determinant (substitution glycine – arginine at aminoacid 145: G145R mutant). G145R was described as responsible of breakthrough infections in passively/actively immunised infants born to HBeAg positive mothers (Carman, 1990) and during passive immune prophylaxis after transplantation (Hawkins, 1996). Such mutant is viable, infectious, pathogenic (Ogata, 1997), and stable ((Oon, 1998). A number of other mutants have been described, including those involving the preS regions, that can even be partly deleted (Melegari, 1994; Fernholz, 1993). From a public health point of view, there is evidence that at present HBV mutants do not have a substantial impact on the effectiveness of vaccination programmes. In a study on 522 children born to HBsAg positive mothers in Italy from 1985 through 1994 and treated with passive/active immune prophylaxis, it was shown that at 5-14 years from immunisation, 17 children (3.3%) were anti-HBc positive, and 3 also were HBsAg positive. Only one of these carriers had a double mutation within the a determinant of HBsAg. About 97% of children in this cohort avoided HBV infection. The Authors conclude that the emergence of HBV escape mutants does not raise concern about the efficacy of universal vaccination programmes in Italy, where the G145R prototype of such variants was first identified >10 years ago (Mele, 2001).

Nevertheless, it is important to maintain a careful surveillance on the possible expansion of already known variants and emergence of new mutants, particularly as immune populations grow in number. A model-based simulation on the emergence pattern of escape strains was produced starting from epidemiological data on transmission of wild type viruses. Assumptions were made on cross efficacy of the current vaccine (0-100%), relative infectiousness (equal or different for wild type and mutant virus), relative prevalence (unknown) and vaccination coverage at birth (0-100%) (Wilson, 1999). Several interesting information can be drawn from this study: 1) the present vaccine is highly effective against wild type virus; 2) if cross efficacy is low-moderate, in the long term the variant becomes predominant; 3) this, however, would take 50 years in the worst case scenario (no cross efficacy of vaccine against the variant); 4) the mutant virus becomes predominant only if vaccine coverage is intermediate, while both wild type and mutant virus are eliminated if coverage is high. All this confirms that routine vaccination programmes with current vaccines need to be implemented in the entire world. Should mutant viruses become predominant in several decades, changes in the composition of vaccine might be envisaged, including for instance preS1 and preS2 antigens or the most represented circulating variants.

Another public health issue concerning mutants is not related to vaccination but to blood safety (Jongerius, 1998). Since several HBV variants are not reactive in currently HBsAg tests, it should be emphasised the need to make reliable diagnostic assays available for the future.

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Future perspectives

Elimination of HBV transmission and of incidence of new chronic infections is a feasible goal. To achieve this, implementation of childhood vaccination programmes against hepatitis B needs to be extended to all countries. For countries with a gross national product lower than 1000 US Dollars/yr., support from the Global Alliance for Vaccine and Immunization should be sought, including aid to build a good vaccination delivery infrastructure and to reach target coverage for the basic vaccines originally included in EPI programmes (DTP, measles, polio, BCG). When such goals are obtained, a multi-year vaccination plan also for hepatitis B immunisation can be submitted and receive approval for funding from the Vaccine Fund. Some countries are also eligible for GAVI support in the European Region of WHO, and many of them already received approval for their plans. For countries with a higher GNP, resources should be found in the health care budget. Cost-effectiveness analysis for hepatitis B routine vaccination of newborns or infants may help decision makers to implement such programmes. Countries of Northern Europe have not yet taken the decision to introduce routine infant or adolescent vaccination. This is based on low prevalence of HBV infection and on the results of economic analysis which seem to indicate that programmes targeted to risk groups have a potentially better cost-effectiveness than mass immunisation (Williams, 1996). However, consideration should be given to the key point of the ability of the health care system to reach high coverage in risk groups.

In countries where routine infant and/or adolescent vaccination has been implemented, surveillance on acute and chronic infections and diseases should be continued and improved, in order to document the impact of universal immunisation and its long-lasting effectiveness.

Further studies on the possibility to decrease the number of hepatitis B vaccine doses able to confer immunological memory are advisable. As a matter of fact, a study showed that, out of 41 subjects receiving only one dose of recombinant hepatitis B vaccine and boosted after 4 years, 95% reached anti-HBs levels >100 mUI/ml within 14 days (Wistrom, 1999). Of course, the demonstration of the possibility to obtain lasting protection even with 2 or a single dose would make economic difficulties in the introduction of hepatitis B vaccine easier to solve.

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