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March 1997

Volume 5 - Number 2




Hepatitis A

Hepatitis B vaccine news

Hepatitis vaccines

Evaluation of vaccination policies

Hepatitis C

Hepatitis E

Current epidemiological trends


Immunization remains one of the most medically effective and cost-effective means of controlling viral hepatitis. In the case of hepatitis B, it is widely accepted that universal infant immunization is the key to disease prevention, and most countries in Western Europe, North America, Eastern Asia and the Middle East have adopted immunization policies in line with WHO recommendations.

Countries with prevention programmes involving universal vaccination of infants, adolescents or both, are witnessing a decrease in carrier rates and subsequent disease. This issue of Viral Hepatitis highlights some examples of aggressive immunization programmes launched in countries of intermediate or high endemicity that have drastically reduced the burden of disease in the population.

In contrast to these success stories are the numerous challenges that still exist. Many countries where the disease is endemic have been unable to begin universal immunization, and many countries where the disease in non-endemic have been unwilling to do so. This issue points out the challenges we face in the coming decade, not the least of which is maintaining the momentum until all countries have adopted universal immunization. Attaining this goal will require a sustained effort at raising public awareness of the severity of health problems caused by hepatitis B - particularly in light of the competition to HBV vaccine posed by new vaccines on the horizon.

We can also expect a number of new innovations in hepatitis B vaccines. In particular, the introduction of combination vaccines that should improve and simplify vaccine delivery, and the continued progress in the development of novel, DNA-based vaccines that promise to provide advantages over plasma-derived and recombinant-protein vaccines.

The outlook for the use and development of vaccines for other types of viral hepatitis ranges from promising to poor. Hepatitis A vaccine has already been on the market for a number of years and has clearly been shown to be effective. This issue takes a look at hepatitis A vaccination programmes that have been implemented in endemic areas and that have been successful in terminating outbreaks and epidemics. Candidate vaccines for hepatitis E are in the pipeline and evaluations so far are promising. Little progress has been made, however, in overcoming the obstacles to the development of a hepatitis C vaccine. Until a vaccine is available, efforts will need to focus on other means of prevention; for this reason, summaries of studies on the transmission and prevention of hepatitis C are also covered in this issue.

Finally, an overview of the current epidemiological trends for viral hepatitis worldwide presents a concise account of the progress made to date in controlling viral hepatitis, as well as the geographic areas and issues that will present the greatest challenges in the future.

Prof André Meheus

University of Antwerp, Belgium

This edition of Viral Hepatitis is prepared from material presented at the IX Triennial International Symposium on Viral Hepatitis and Liver Disease held April 21-25, 1996, in Rome, Italy.


Dr Johannes Hallauer

Institute for Health Systems Research

WHO Collaborating Centre on Public Health Research

Kiel, Germany

Dr Mark Kane

WHO, Global Programme for Vaccines and Immunization

Geneva, Switzerland

Dr Elizabeth McCloy

Medical Advisor: Special Projects

BMI Health Services

London, UK

Prof André Meheus

WHO Collaborating Centre for Prevention and Control of Viral Hepatitis

Department of Epidemiology and Community Medicine

University of Antwerp, Belgium

Dr Colette Roure

WHO Regional Office for Europe

Copenhagen, Denmark


Dr Pierre Van Damme

WHO Collaborating Centre for Prevention and Control of Viral Hepatitis

Department of Epidemiology and Community Medicine

University of Antwerp, Belgium


Prof Paolo Bonanni

Public Health Department

University of Florence, Italy

Prof Pietro Crovari

Institute of Hygiene and Preventive Medicine

University of Genoa, Italy

Dr José de la Torre

Ministry of Health and Consumer Affairs

Madrid, Spain

Prof Alain Goudeau

Department of Medical and Molecular Microbiology

University of Tours, France

Prof Peter Grob

Department of Medicine

University Hospital Zurich, Switzerland

Prof Wolfgang Jilg

Institute for Medical Microbiology and Hygiene

University of Regensburg, Germany

Dr Daniel Lavanchy

BVI Unit, Division of Communicable Diseases

World Health Organization

Geneva, Switzerland

Dr Harold Margolis

CDC, Hepatitis Branch

Atlanta, Georgia, United States

Prof Georges Papaevangelou

National Centre for Viral Hepatitis

Athens School of Hygiene, Greece


Margaret Van der Elst

Antwerp, Belgium


Mrs Emmy Engelen

Mr Gino Verwimp

WHO Collaborating Centre for Prevention and Control of Viral Hepatitis

Department of Epidemiology and Community Medicine

University of Antwerp, Belgium

VHPB Report on the IX Triennial International Symposium on Viral Hepatitis and Liver Disease held April 21-25, 1996, in Rome, Italy

Hepatitis A

Epidemiology and public health

Hepatitis A virus is widespread throughout the world. However, the epidemiology of the disease varies widely according to socio-economic and hygiene standards. Public health measures for disease control reflect these variations.

HAV infection is spread mainly through contaminated water and food. In areas with very poor standards of hygiene it is principally a disease of childhood with very little clinical morbidity. As socio-economic and hygiene standards improve, the HAV infection rate in children is rapidly reduced. The epidemiology of the disease changes and transmission occurs at a later age, often in adolescence or young adulthood. The result is an increase in disease severity and overall morbidity.

In countries of low HAV endemicity a pattern of periodic outbreaks emerges; most HAV infections are acquired in community-wide epidemics, children are the primary facilitators of disease transmission, and no one risk group drives the epidemic.

Groups at increased risk of HAV infection include persons travelling or working in countries with a high or intermediate endemicity of infection, men who have sex with men, IVDU, persons receiving blood-clotting factor concentrates, persons working with HAV-infected animals or with HAV in the laboratory, contacts of HAV patients, institutionalised populations, childcare workers, waste workers, migrant populations, military personnel, and chronic liver disease patients.

Interrupting hepatitis A outbreaks by immunization

Field trials in the United States and Slovakia indicate that hepatitis A vaccine without concomitant use of immunoglobulin is effective in controlling large epidemics and periodic outbreaks of hepatitis A infection.

Rural Alaska experiences cyclical hepatitis A epidemics every ten to 15 years. Immunoglobulin has not been effective in controlling these outbreaks, the most recent of which occurred in 1992-1993; during that time seven fulminant cases of hepatitis A including four deaths were reported. The highest rate of hepatitis A infection in Alaska has been shown to occur in persons under 15 years of age, over 50 percent of whom show no symptoms of disease.

To determine if vaccine alone could control an outbreak in a population of 22,000, in which 554 HAV acute cases had been reported over a 12-month period, the Alaska Area Native Health Service immunized susceptible persons with one dose of inactivated hepatitis A vaccine. In all, 5,191 persons in 27 remote communities from three geographically distant regions were vaccinated; of these, 71% were under 20 years of age.

The strategy of using hepatitis A vaccine to stop the epidemic in Alaska proved successful. In one village that was monitored, the number of reported cases fell from 25 to 35 per week to under 5 eight weeks after the implementation of the immunization programme. Among those who had received vaccine, no cases were reported after six weeks.

In villages where at least 80 percent of the susceptible population was vaccinated, the epidemic ended within six to eight weeks. However, in a community of 3,050, where only 49 percent of the susceptible population was vaccinated, the epidemic continued for 60 weeks. After the epidemic ended, a second dose was administered to provide long-term immunity to individuals.

The Alaska study found that mass immunization with a one dose schedule can control outbreaks, and that for programmes to be successful at least 80 percent of the susceptible population should be vaccinated.1

A study in Slovakia on the interruption of an outbreak of hepatitis A by vaccination provided similar findings.2 During a large community-wide outbreak of hepatitis A in two adjoining villages in Slovakia, schoolchildren were given hepatitis A vaccine in an attempt to control the progress of the outbreak. Two-thirds of the schoolchildren were immunized with two doses of vaccine, one month apart. The number of vaccine doses was limited, so only seronegative children received vaccine.

Soon after vaccination began, an abrupt decrease in hepatitis A cases in the schools was seen, and cases in the villages also stopped. The study concluded that 'active immunization appears to be preferable to IG inoculation for interruption of community-wide outbreaks of hepatitis A. If vaccine availability is limited, vaccination of schoolchildren may be the most cost-effective approach.'

These findings are supported by a previous trial conducted in 1991-1992 in a closed religious community in New York State, USA, that experienced recurrent outbreaks of hepatitis A. To evaluate the efficacy of hepatitis A vaccine in protecting against disease, 1,037 seronegative children between two and 16 years of age were enrolled in the study at the beginning of an outbreak: 519 received vaccine; 518 received placebo. From day 50 after vaccination 25 cases of clinically apparent hepatitis A occurred in the placebo group and none in the vaccine group. The study concluded that a single dose of hepatitis A vaccine is highly protective against clinically apparent hepatitis A.3

Risk Factors of Patients Reported with Hepatitis A

Denver County, US, 1986-1993

1986 - 1989 1990 - 1993

From H Margolis, CDC

From BJ McMahon, CDC

  1. McMahon BJ, Williams J, Mayer J, Bulkow L, Tanttila H, Snowball M, Beller M. Control of an outbreak of hepatitis A in Alaska using an inactivated hepatitis A vaccine (abstract SB1). Abstract volume 'IX Triennial International Symposium on Viral Hepatitis and Liver Disease, Rome, April 21-25, 1996.
  2. Prikazsky V, et al. Interruption of an outbreak of hepatitis A in two villages by vaccination. Journal of Medical Virology 1994;44:457-459.
  3. Werzberger, A, Mensch B, Kuter B, Brown L, Lewis J, Sitrin R, Miller W et al. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N Engl J Med 1992; 327:453-457.

Hepatitis B vaccine news

Hepatitis B immunization: the challenges ahead

Despite a decline in HBV incidence in both endemic and non-endemic regions, hepatitis B virus infection remains a serious global health problem. Universal infant immunization is the key to disease prevention. In 1991, WHO called for all countries to introduce hepatitis B vaccine into their National Immunization Programmes by 1997. Eighty countries have done so, for the most part as an infant immunization programme.

However, countries where the disease is not endemic have been slow to adopt universal immunization, and many countries in which the disease is endemic have been unable to institute programmes. One of the most important challenges for the coming decade will be to sustain the push for universal hepatitis B immunization until all countries have instituted universal infant immunization programmes.

Other objectives for the future include: sustaining those vaccination programmes that already exist; increasing vaccine coverage; ensuring that all countries are able to maintain a sustainable supply of vaccine; and expanding the use of the vaccine to older children for catch-up immunization.

Examples can be found of hepatitis B immunization programmes that were instituted, then abandoned, because of financial constraints and the inability to procure a steady supply of vaccine. Steps are being taken to remedy this situation. UNICEF, the major supplier of vaccines to the developing world, is beginning to concentrate efforts on countries of greatest need, assisting those countries that have low GNPs, high burdens of disease and good EPI programmes in procuring vaccine.

Further challenges surrounding hepatitis B immunization programmes will be to: develop reliable reporting systems; ensure safe injection techniques; and keep hepatitis B immunization a high public health priority in the face of competition from newly introduced vaccines.

It is recommended that hepatitis B vaccine be used within existing EPI programmes. This is a cost-effective way to introduce a new vaccine, and monitoring systems are already in place for vaccines used within the EPI. In the American region, few countries use the hepatitis B vaccine within the EPI and none have reporting systems in place. In the Western Pacific region, however, the vaccine is used within the EPI and the reporting systems in the region provide models to emulate.

The next decades will witness competition from new vaccines and this trend cannot be ignored: new vaccines such as Hib will be introduced and will compete for a place in the EPI. It is imperative that the merits - both medical and financial - of hepatitis B immunization continue to be stressed. Vaccination is the most cost-effective medical intervention, as stated in the World Bank World Development Report of 1993: 'In most developing countries an "EPI plus" cluster (six vaccines currently in the EPI + HB and yellow fever) in the first year of life would have the highest cost-effectiveness of any health measure in the world today.'

With most countries in Eastern Asia, the Middle East, the southern part of Western Europe and North America using the hepatitis B vaccine in their national immunization programmes, efforts in the next few years will need to focus on the Indian subcontinent, Eastern and Central Europe and the NIS, sub-Saharan Africa and Latin America.

HB immunization challenges

Combination vaccines: the future for immunization

Combination vaccines represent an important and inevitable aspect of the future of immunization. The vaccine schedule, starting at birth and continuing to four, six and 12 years, has become increasingly complex; at present the current EPI vaccination schedule includes 14 or 15 injections requiring numerous visits. The obvious solution is combined vaccines. Some combinations are currently under development and are likely to become available in the near future.

DTP is the cornerstone of childhood immunization programmes, setting the vaccination schedule in every country, and combination hepatitis B vaccines will of necessity be based on the DTP schedule.

The advantages of combination vaccines are considerable, and a combined DTP-HB vaccine would:

In addition to the development of combined DTP-HB vaccines, work is also underway to develop vaccines including poliomyelitis and H influenzae antigens. Future vaccine combinations envisaged are:

'Future childhood vaccines...should be single-dose, administered near birth, combined in novel ways, heat stable, effective against additional diseases, and affordable.' From the Children's Vaccine Initiative, 1993.

From F André, SmithKline Beecham Biologicals

Articles from 'Hepatitis B vaccine news' are based on information presented by Dr G Dusheiko, Department of Medicine, Royal Free Hospital and School of Medicine, London, UK; Dr Mark Kane, World Health Organization, Geneva, Switzerland; Dr Francis André, SmithKline Beecham Biologicals, Rixensart, Belgium.

DNA-based vaccine development promising

Considerable progress has been made towards the development of a DNA-based vaccine for hepatitis B since the first work on DNA vaccines was published three years ago. The current focus is on optimising dosages.

DNA-based immunization against hepatitis B appears likely to provide advantages over plasma-derived and recombinant-protein vaccines, and to overcome the shortcomings inherent in the classic antigen approach to immunization. DNA-based immunization has been shown to overcome non-response to HBsAg in non-responding strains of mice; in chimpanzees, DNA-based vaccination against HBV induces very high anti-HBs titres, indicating that the vaccines may be useful for prophylactic vaccination of humans against HBV.1

With DNA-based vaccines, in contrast to the classic antigens, genetic material is introduced during immunization. Injection of plasmid DNA encoding HBV surface antigen (HBsAg) has been shown to induce rapid, strong and sustained humoral and cell-mediated responses in mice. A strong Cytotoxic T. lymphocyte (CTL) response develops within a week and is maintained for at least several months. High titres of anti-HBs persist for at least 17 months after a single DNA injection, although they can be boosted by a second injection. A booster dose with a DNA vaccine has been shown to produce a significantly better response than a recombinant protein vaccine booster.

DNA immunization, which will be applicable to almost all viral infections, affords numerous advantages over plasma-derived and recombinant vaccines. With DNA vaccines the antigen is synthesised in vivo, allowing easier and cheaper manufacturing and better quality control. In vivo synthesis also opens up the possibility for the development of a therapeutic vaccine. Cloning mutants and virus variants is simplified, and it becomes possible to clone different parts of the gene, and to mix DNA used in vaccines.

Other unique factors associated with DNA-based immunization are: a sustained delivery of antigen; a full range of attenuated response without the risk of infection; no development of immune intolerance; and vaccine stability as DNA vaccines can be kept for nearly a year. In addition, DNA vaccines appear to overcome the problem of non-response.

1. Davis HL. DNA-based immunization to hepatitis B (abstract 148). Abstract volume 'IX Triennial International Symposium on Viral Hepatitis and Liver Disease', Rome, April 21-25, 1996, 41.

Based on information presented by Dr Heather Davis of Ottawa Civic Hospital and University of Ottawa, Canada.

HBV vaccine affords long-term protection, even without booster

When determining policies on booster vaccination, it is necessary to know the duration of vaccine-induced immunity and if immunity persists even after antibodies fall below the generally accepted level of protection (10mIU/ml). When immunity is acquired passively through immunoglobulin, susceptibility to infection increases as antibody levels decrease. 'However, vaccine induces active synthesis of anti-HBs accompanied by immunologic memory for HBsAg that affords ongoing protection independent of antibody level,' according to Dr David West of Merck Research Laboratories, West Point, PA, USA.

This phenomenon of immunogenic memory makes it likely that cost-effective control of HBV infection can be achieved by maximising primary vaccination with little or no need for routine boostering.

For children and adults whose immune status is normal, the routine administration of booster doses of vaccine is not necessary. However, booster doses are recommended in the package insert of the vaccine in some countries, and may be indicated in particular situations such as haemodialysis or other immunocompromised patients.

A review of the published literature on the long-term persistence of immunologic memory found that healthy, vaccinated individuals retain a high level of immunity even after antibody falls below detectable levels. The persistence of immunologic memory for 5-12 years is evident from studies showing that vaccinees with little or no antibody have a rapid rise in antibody after booster. The functional significance of this memory is also suggested when high-risk vaccinees are tracked for serologic signs of breakthrough infections as antibody levels decline. Isolated rises in titres show challenge from HBV, but very few clinically significant breakthrough infections occur. 1

One such study in Thailand - where between 6 and 10 percent of the population are carriers - measured the long-term protective efficacy of hepatitis B vaccine in high-risk neonates of HBs and HBe antigen-positive mothers. The study found that the recombinant-DNA hepatitis B vaccine provides long-term protection against chronic carriage and infection even without a booster dose at month 60.2

Neonates of HBs and HBe antigen-positive mothers were enrolled in the study. Participants were divided into different groups that were vaccinated according to two different immunization schedules, with and without immunoglobulin, and with and without a booster at month 60.

After completing the initial course of immunization, nearly all infants developed anti-hepatitis B surface antibodies that persisted in most responders throughout the follow-up. This held true for infants who did not receive an additional dose of vaccine at month 60 as well. Assuming a 65% rate of chronic carriage at 12 months in unvaccinated neonates, the overall protective efficacy at month 12 of the vaccinated neonates was 96.2%.

The children were followed for six to eight years, and there were no new hepatitis B chronic carrier cases observed in vaccinated neonates beyond two years of age. The high-risk newborns were protected against acute disease even after the fall of antibody levels and the study concluded that there is a good initial response to vaccination in the first year of life and that the vaccine provides immediate and long-term protection against hepatitis B chronic carriage, even without a booster dose.

Another study undertaken to determine the duration of protection and immunity to HB after vaccination with recombinant vaccine came to similar conclusions, finding that humoral immunity to HB appears to persist - despite low or negative anti-HBs - three to eight years after recombinant HB vaccination.3

Additional studies are still needed to define the limits of memory and to validate the vaccine regimen.

'There is no clear evidence of the need for booster doses after a primary series of vaccination has been completed. Long-term studies in high-risk newborns demonstrate protection against acute disease and the chronic carrier stage beyond the fall of antibody levels.'

Protective efficacy (PE) against HBsAg chronic carriage per group and overall. From a study in Thailand on long-term protective efficacy of HB vaccine.


Vaccination schedule (months)

Immuno-globulin administration

Chronic carriage rate

PE* at month 12


0,1,2,12, (60)





0,1,2,12, (60)





0,1,6, (60)





0,1,6, (60)








*This assumes a 65% chronic carriage rate at 12 months of age in unvaccinated neonates.

From Y. Poovorawan, Chulalongkorn University Thailand.

Based on information presented by Dr David West of Merck Research Laboratories, West Point, PA, USA; Dr Yong Poovorawan, Chulalongkorn University, Bangkok, Thailand; and Dr J Van Hattum, University Hospital Utrecht, the Netherlands.

  1. West, D.J., Calandra G.B., Vaccine induced immunologic memory for hepatitis B surface antigen: implications for policy on booster vaccination. Vaccine, 1996; Vol. 14, No11, pp.1019-1027.
  2. Poovorawan, Y., Long-term protective efficacy and antibody follow-up of a hepatitis B vaccine in high-risk neonates with or without month 60 booster (abstract SD4 ). Abstract volume 'IX Triennial International Symposium on Viral Hepatitis and Liver Disease', Rome, April 21-25, 1996, 369.
  3. Van Hattum, J., Persistence of humoral immunity to hepatitis B after vaccination with recombinant hepatitis B vaccine (abstract C277). Abstract volume 'IX Triennial International Symposium on Viral Hepatitis and Liver Disease', Rome, April 21-25, 1996, 271.

Hepatitis vaccines

An overview

Attempts to control the spread of viral hepatitis have met with mixed success. Improved sanitation, for instance, has diminished the importance of HAV in industrialised countries but not in developing regions. Other hepatitis viruses, such as HBV and HCV, have proved more difficult to control. Vaccines remain the best and least expensive method for controlling viral infections, including viral hepatitis.

The requirements for a successful vaccine are that the target virus has a limited number of serotypes and grow well in vitro; the vaccine delivers long-term immunity, is safe, effective, simple to administer and is able to prevent a significant proportion of infection.

The hepatitis B virus (HBV) vaccine was the first hepatitis vaccine and the first recombinant vaccine in the world. Where it has been effectively administered it has had a profound effect on the infection rates for HBV. Administration and coverage with hepatitis B vaccine have often been problematic, however. Initially, many countries favoured a high-risk group immunization policy over one of universal infant immunization. Because high-risk target groups are difficult to define and reach, and because one-third of those infected with hepatitis B have no identifiable risk factor, this strategy had little or no impact on infection and disease in the general population. Universal vaccination has therefore proved the only effective option for controlling hepatitis B infection in the population.

It is too early to assess the impact of the hepatitis A vaccine on the incidence of the disease, but it seems clear that mass vaccination has proved effective in terminating outbreaks and epidemics of hepatitis A.

Still under development, the hepatitis E vaccine is a recombinant vaccine prepared in insect cells. Candidate vaccines are in the pipeline and evaluations so far suggest that they will be highly effective in preventing hepatitis E infection.

The development of a hepatitis C vaccine has proved problematic. Hepatitis C does not have a limited number of serotypes and therefore prospects for the development of a vaccine against HCV in the near future are poor. It appears likely that hepatitis G will present similar obstacles.

Status of viral hepatitis vaccines

Hepatitis virus

Vaccine status




cost, administration



cost, administration



basic science


pre-clinical 'candidate vaccines on the horizon'

applied science


no progress 'too short a time on the scene'

basic science

Based on information presented by Dr RH Purcell of the National Institutes of Health, Bethesda, Maryland, USA.

Evaluation of Vaccination Policies

Public awareness and incentive schemes bolster HB immunization in France

A voluntary, universal immunization programme against hepatitis B has been very successful in France, thanks in large part to an information campaign in schools, on television and in newspapers. The information campaign was aimed at children aged 11 to 13, one of three target groups selected for immunization. The other two groups targeted for vaccination were older adolescents and infants. Incentive schemes and hepatitis B education programmes aimed at general practitioners were used to raise awareness and acceptance of the programme.

Children aged 11-13 were chosen for HBV immunization because they are very close to the risk (sexual activity accounts for nearly half of all HBV cases in France), and are still young enough to be accessible and compliant. It was also discovered after initiation of the information campaign and immunization programme that children in this age group can be very instrumental in spreading programme acceptance to peers and family members.

The programme encouraged compliance of older adolescents targeted for catch-up immunization through financial incentive schemes, such as coupons for reduced prices on second and third vaccine doses. HBV vaccine for infants is administered with the diphtheria/tetanus/pertussis/polio tetravalent vaccine, and a booster is given with MMR. Particularly for infant vaccination, the role of general practitioners in promoting vaccination was crucial to the success of the immunization programme. In France, 76% of all vaccines are given by GPs, and opinion polls show that 98% of GPs recommend HBV vaccination to adolescents.

The programme has been very successful and public awareness has improved tremendously. In 1995, 4.2 million children were immunized against hepatitis B. This compares with only 3.25 million immunized between 1981 (when the vaccine first became available in France) and 1994. The initial failure of the programme is attributed to attempts to control hepatitis B by targeting selected risk groups.

Later attempts to improve coverage included mandatory vaccination of all healthcare workers and medical students, and mandatory screening of pregnant women. Even with these attempts, however, the incidence of hepatitis B did not decline. Only with the realisation that 90% of acute cases of hepatitis B occur in persons over 20 years of age and that sexual activity accounts for nearly half of all cases, did policies, and subsequently vaccine coverage, change.

The main hindrance to vaccination proved to be a lack of information, something that was overcome through media campaigns. The barrier of high cost was also removed when the Ministry of Education negotiated large tenders of vaccine which are paid for by social security.

Hepatitis B immunization in France

Public opinion poll, 1995

Why are your children not immunized against HBV?

Lack of information 36%

Forgetfulness, neglect 20%

Feel it is useless 9%

Vaccine too expensive 1%

Other 34%

No answer 6%

Physician opinion poll, 1995

To whom do you recommend HB vaccination?

GPs Specialists Hospitals Total

infants 23% 15% 20% 20%

adolescents 98% 73% 79% 87%

adults 33% 44% 53% 40%

elderly 5% 13% 7% 8%

risk groups - 5% 2% 2%

travellers - 4% - 1%

Based on information presented by Dr A Goudeau, University of Tours, France.

Long-term benefits of Hepatitis B immunization seen in endemic regions

Hepatitis B vaccine has been used extensively for the past decade, particularly in hyperendemic areas. Examples of mass immunization programmes in high-endemic areas launched early and carried out successfully include programmes in Taiwan, Alaska, and the Gambia. Follow-up of these immunization programmes shows the long-term efficacy of hepatitis B vaccine; indicates a dramatic decrease in hepatitis B transmission; and suggests subsequent prevention of hepatocellular carcinoma (HCC).

A 12-year follow-up study to determine the long-term efficacy of the hepatitis B immunization programme in Taiwan included three independent serologic surveys and the monitoring of HCC in children.

A district in Taipei city was studied in 1984 before the programme began, at five years, and at 10 years. The prevalence of HBsAg decreased from 9.8% in 1984, to 4.8% in 1989, and to 1.3% in 1994. In those born after the start of the programme, HBs-antigen-positive rates decreased to 0.7%. The two other studies supported these findings, all showing decreases in carrier rates over ten years.

The data also suggest that the subsequent prevention of HCC has begun to be seen in children in Taiwan. The annual incidence of HCC in children varied between 4.5 and 7.1 per 100,000 children between the ages of 6 and 14 in the years 1981 to 1991. The incidence had been reduced to 2.4 per 100,000 by 1993.

Decline in incidence of HCC in children age 6 to 14 in Taiwan

1981-1991 4.5-7.1/100,000 (range of incidence rates over a ten year period)

1992 1.7/100,000

1993 2.4/100,000

From DS Chen, National Taiwan University Hospital

A hepatitis B control programme in Alaska shows that mass immunization of an endemic population can dramatically decrease HBV transmission and that screening carriers leads to early disease detection. In 1983 a programme was introduced to screen all Alaskan natives for seromarkers, vaccinate all susceptibles, administer HB vaccine to all infants at birth, screen all HBsAg-positive chronic carriers to detect HCC at a potentially treatable stage, and initiate long-term follow-up studies.

Since 1984, over 30,000 infants and 43,000 children and adults have received HB vaccine. In the highest prevalence area, the incidence of acute hepatitis B fell from over 200 icteric cases per 100,000 in 1981 to 0 cases in 1995.

Surveillance since 1981 shows that no one who responded to the vaccine later developed acute icteric hepatitis or became a chronic carrier, indicating that protection lasts longer than 10 years. Despite the fact that antibody levels drop off rapidly, the protection persists. Screening carriers has also detected HCC at an early enough stage to significantly decrease mortality.

In the highest prevalence area in Alaska, the incidence of acute hepatitis B fell from over 200 icteric cases per 100,000 in 1981 to 0 cases in 1995.

In the Gambia, The Gambia Hepatitis Intervention Study began vaccinating newborns in 1986, and since 1990 all newborns have received HB vaccination as part of the EPI.

To determine the success of the programme cluster samples of children were studied to ensure vaccine immunogenicity. A cohort of over 1,000 children was followed from birth to seven years to ensure the decline in vaccine-induced antibody and infection, and control groups were studied at four years to determine vaccine efficacy (94%).

Twenty-five percent of seven-year-old children had no demonstrable surface antibody and the GMT in the remainder was approximately 2 mIU/ml, yet HBV infection is rare. The follow-up studies concluded that integrating HB vaccine into the EPI leads to an excellent immune response and that even when the antibody level has declined protection against disease remains.

Based on information presented by Dr DS Chen, National Taiwan University Hospital, Taipei, Taiwan; Dr B McMahon, Centers for Disease Control and Prevention, Anchorage, Alaska; Dr A Hall, The Gambia Hepatitis Study Group.

Lessons from HBV control programme in Italy

Italy's aggressive approach to immunization against hepatitis B over the past ten years has resulted in a dramatic decline in HBV infection rates as confirmed by follow-up studies.

Beginning in 1984, the immunization programme initially provided HBV immunization free of charge to newborns of HBsAg-positive mothers, household contacts of chronic carriers, healthcare workers, dialysis and poly-transfused patients, drug addicts and male homosexuals.

In 1991, vaccination of newborns and 12-year-olds became compulsory (for the first twelve years of the programme). The highest rates of infection are among 15 to 24-year-olds, IVDUs and people with more than two sexual partners. The rationale behind infant and catch-up immunization is to vaccinate children before they enter into high-risk behaviour.

Surveys to evaluate the ongoing vaccination programmes show that for 12-year-olds the compliance rate has been high (93.6 percent overall), although this varied widely according to geographic region, with those in the south of Italy having the lowest acceptance rate at 65.1 percent.

Under the programme, all pregnant women are screened and newborns of HBsAg-positive mothers receive vaccine plus immunoglobulin within 24 hours of birth. A random sample of pregnant women in Naples, an area of relatively high endemicity, showed screening coverage of 93%. Of the 3 percent who were HBsAg positive, 90% of the babies were vaccinated at birth and the other 10 percent some days later. No one escaped vaccination, according to Dr Mele of the Institute of Health.

For healthcare workers, vaccination coverage has been found to be 73.3 percent in the north and 51 percent in the south, with coverage rates inversely related to the years of employment. It also emerged from the follow-up that even when there is a known chronic carrier in the house, other members of the household often are not vaccinated. Taken together, the data suggest that vaccination campaigns for teenagers, for those living with chronic carriers and for healthcare workers should be implemented to further raise awareness and coverage.

Hepatitis B immunization policy in Italy

Year instituted



  • Screening of pregnant women; newborns of HBsAg-positive mothers receive vaccine + HBIG.


  • Vaccine provided free for healthcare workers, contacts of chronic carriers, dialysis and poly-transfused patients, drug addicts and homosexuals.


  • Universal infant immunization
  • Catch-up immunization of 12-year-olds for the first 12 years of the programme.

Based on information presented by Dr A Mele of the Instituto Superiore di Sanitá, Rome, Italy.

Hepatitis C Virus

Transmission and prevention

Two studies assessing risk factors and seroprevalence for hepatitis C virus (HCV) in the United States concluded that prevention measures for hepatitis C should target IV drug use and high-risk sexual behaviour.

The third National Health and Nutrition Examination (NHANES III) was undertaken to provide an estimate of the seroprevalence of hepatitis C virus infection in a representative sample of the US population. Study participants were tested for HCV antibody; the study ran from 1988 to 1994, and included 21,267 civilians over the age of six who did not live in institutions.

Based on survey results, the overall prevalence of HCV infection in the United States is 1.8%, or 3,875,000 HCV infected individuals, indicating a large reservoir of infected persons who will need medical care in the future.

The study found that race correlated significantly with infection, which is higher in minority populations: 3.2% of blacks, 2.1% of Mexican Americans, and 1.5% of whites are infected with HCV. In all ethnic groups there is a very low prevalence in the under-20 population, after which it increases. The highest prevalence for whites is in the 30-39 year age group (3.2%); for blacks it is in the 40-49 age group (6.3%); and for Mexican Americans it is the 50-59 age group (6.0%).

Race became insignificant, however, when economic and behavioural circumstances were taken into consideration. The greater the number of sexual partners, the higher the prevalence rates in all ethnic groups; rates were 8-fold higher among adults who had 50 or more sexual partners. Other risk groups include men who have sex with men and crack cocaine users, who have a prevalence rate 10-fold higher than non-users across all ethnic groups.

In an effort to gauge the importance of sexual activity in the transmission of hepatitis C, a study was conducted on risk factors for HCV infection among STD patients in the United States. Three thousand seven hundred and ten patients at STD clinics in five major US cities took part in the trial. Participants - who were heterosexual and HIV-negative - were assessed for initial HCV status and the presence of risk factors at enrolment and during a one year follow up.

It was found that anti-HCV positivity increased with age from 0.8% among 14-19 year olds to 25.7% among those over 35 years old.

According to the study, injecting drugs appears to be the strongest risk factor in HCV infection, and those who had a history of IV drug use were 15.7 times more likely to be positive than those who did not. Also, patients were 30 times more likely to seroconvert if they had injected drugs over the course of the year of the study.

Although IVDU is most strongly related to HCV infection, some high-risk sexual activities, such as sex with an IV drug user, were related to HCV infection. Men who had spent more than 24 hours in jail were also more likely to be positive, as were those who had ever lived with anyone HCV-positive.

IVDU is most strongly related to HCV infection, although some high-risk sexual activity also plays a role in HCV transmission.

Based on information presented by Dr G McQuillan, Centers for Disease Control and Prevention, Atlanta, GA, USA; and Dr B Woodruff, Centers for Disease Control and Prevention, Atlanta, GA, USA and San Francisco Dept of Public Health, San Francisco, CA, USA.

Hepatitis E


Hepatitis E is an enterically transmitted, icteric viral hepatitis with clinical features similar to those of hepatitis A. Hepatitis E has an incubation period of six to eight weeks after exposure, and is highly dangerous for pregnant women, with up to 20 percent fatality rate in women infected in their third trimester of pregnancy. In areas of high endemicity, hepatitis E often occurs in regular outbreaks. The frequency of epidemics and the high mortality rate seen among pregnant women indicate that hepatitis E is an important cause of morbidity and mortality.

A large number of hepatitis E cases occur in Asia, the Indian sub-continent, and South America, usually during periodic epidemics. In non-outbreak periods, sporadic cases of infection are also seen. In countries of low endemicity, sporadic cases also occur, usually among travellers, although transmission of some cases cannot be explained. In low- endemic countries a low incidence of non-travel-related HEV among medical personnel is also seen.

What is known to date about transmission and prevention is that the disease is spread through faecal-oral transmission and can be prevented by maintaining a clean water supply and adequate sanitary living conditions. However, much remains to be learned about HEV, including the means of transmission, the reservoirs for the virus, and the natural history of protective immunity, in order to develop effective strategies for disease prevention.

Recombinant vaccines are currently under investigation, with the focus now on immunogen, adjuvant and immunization schedules.

Based on information presented by Dr K. Krawczynski, Hepatitis Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA.

Current epidemiological trends of viral hepatitis

In Northern Europe

Northern Europe has had a low incidence of viral hepatitis for several decades. With regard to hepatitis A, the majority of people become infected when travelling in a foreign country (travel-related infection accounts for 60% of cases in Sweden, for instance). Cyclical outbreaks are also observed in the drug abusing communities in the region. Estonia, Latvia and Lithuania have substantially higher hepatitis A incidence rates than other northern countries: 44 per 100,000 in Estonia; 79 per 100,000 in Latvia; and 149 per 100,000 in Lithuania.

The incidence of acute hepatitis B has further declined from an already low level in northern countries, and IVDU and sexual transmission remain the main ways in which the infection is spread. The prevalence of hepatitis B virus carriers has increased, however, because of an increase in immigration, although there has not be a comparable increase in acute cases. Approximately 40% of carriers are HBeAg-positive. Again, Estonia, Latvia and Lithuania have higher rates of notified cases of hepatitis B than the rest of the region: 9 per 100,000 in Estonia; 14.8 per 100,000 in Latvia; and 12.3 per 100,000 in Lithuania.

The most common cause of viral hepatitis in the northern region of Europe is now hepatitis C virus, though the number of cases reported remains low. It is estimated that the incidence of hepatitis C varies from a low of 0.02% in Finland to a high of 2.2% in Lithuania. Genotypes 1, 2 and 3 are found in northern countries, with the majority of cases being genotype 1. Nosocomial transmission of hepatitis C is also emerging as an increasingly important problem in the region.

Hepatitis D virus, introduced into Sweden and Norway in the 1970's, has not spread outside the IV-drug using community and case numbers are low. A few cases of hepatitis E have been reported, most with a history of travel to endemic areas.

Based on information presented by Dr E Nordenfelt of the Swedish Institute of Infectious Disease Control.

In Southern Europe

Although the morbidity and mortality of viral hepatitis have decreased, the disease is still a concern in Southern Europe.

Improvements in hygiene and standards of living have led to a decrease in incidence of hepatitis A infection in Southern Europe: Mediterranean countries have shifted from high-to-intermediate endemicity to intermediate-to-low endemicity. Transmission of HAV in Southern Europe occurs through shellfish consumption (43%); contact with an HAV case (15%); travel (16%); no known risk factor (13%); contaminated water (9.3%); day care (3%); and IVDU (0.3%). Exposure to hepatitis A is now less common in childhood and a growing number of young adults are thus susceptible to the residual circulating virus.

The incidence and prevalence of hepatitis B have also declined, with WHO reporting an average annual incidence of 6 HBV cases per 100,000 for the area. Rate of reported cases, however, underestimates the real burden of HBV infection, and it is estimated that an incidence of 37 cases per 100,000 is a more accurate figure. Most infection occurs in the 15 to 24-year-old age group.

Hepatitis C accounts for approximately 20% of acute cases of viral hepatitis in the region. A significant proportion of cases (>40%) have no known risk factor. Hepatitis C virus infection is rare in children and infection rates increase with age. Since screening programmes have been initiated, transfusion-associated cases have virtually disappeared.

The Mediterranean has an intermediate prevalence for hepatitis delta, although HDV infection is endemic in Southern Italy and Greece. Universal vaccination and selective vaccination policies for HBV are currently being implemented to control HBV and HDV. A reduction in acute delta infection can be partly attributed to measures taken to reduce HBV infection.

Infection rates for HEV range from 1 to 6 percent in the region. Hepatitis E accounts for only a low proportion (3-7%) of acute viral nonA, nonB, nonC hepatitis in Spain, Greece and Italy. About 10 percent of acute and 15 percent of chronic hepatitis cases in the region cannot be associated with any of the recognised hepatitis viruses, suggesting that other not yet identified hepatotropic viruses may be in circulation.

Based on information presented by A Zanetti of the Institute of Virology, University of Milan, Italy.

In Eastern Europe and the Newly Independent States

The incidence of viral hepatitis varies greatly throughout the region of Eastern Europe and the Newly Independent States as evidenced by national surveillance data obtained from the Czech Republic, the Russian Federation and the Turkmenistan Republic. Incidence per 100,000 of notified viral hepatitis cases in the last decade in these countries varied from: 16 to 50 in the Czech Republic; 136 to 227 in the Russian Federation; and 298 to 1100 in the Turkmenistan Republic.

Despite differences in disease incidence, the rate of acute viral hepatitis has declined by the following degree in each country over the past decade: 1.7 times in the Russian Federation; 2.5 times in the Turkmenistan Republic; and 3 times in the Czech Republic.

From serologic testing of patients with acute hepatitis, hepatitis A was found in 21% of patients in Prague; 45% in Moscow; and 68% in Ashgabad. Similar rates of hepatitis B were found in Prague and Moscow (46-47%) while lower rates were found in Ashgabad (17%). The proportion of hepatitis C varied from west to east ranging from 11% in Prague to 6% in Moscow to 4% in Ashgabad.

Hepatitis delta and hepatitis E were absent in Prague; infections in Moscow and Ashgabad ranged from 1.3 to 2.1% for HDV to 0.1%-1.3% for HEV. Unclassified viral hepatitis was found in 18% of patients in Prague; 1% in Moscow; and 8% in Ashgabad.

Editor's note: The situation and progress made in Eastern and Central Europe and the Newly Independent States will be covered in the forthcoming issue of Viral Hepatitis detailing the VHPB meeting held in Siofok, Hungary.

Based on information presented by Dr M Favorov of The Centers for Disease Control and Prevention, Atlanta, GA, USA, and The DI Ivanovsky Institute for Virology, Moscow, Russia.

In Asia

Because of wide variations in social, economic and public health systems in the region, Asian countries have quite different epidemiological trends in viral hepatitis. A lack of public awareness about viral hepatitis in the region has increased the difficulty of controlling the disease.

Hepatitis A infection rates remain static in India, Pakistan, Bangladesh, and Nepal. Marginal improvements in rates of infection have been made in China, Indonesia, Malaysia and Thailand, while a substantial decline in rates of infection can be seen in Japan, Taiwan, Australia, Hong Kong and Singapore.

The incidence and severity of hepatitis A infection in adults is increasing in Asian countries. Hepatitis E, another waterborne infection, shows similar patterns of epidemiology. HEV is the commonest cause of large hepatitis outbreaks in China, the Indian Subcontinent and Burma, and small outbreaks also occur in other countries of the region.

The hepatitis B carrier rate and infection has declined in Japan, Taiwan, Hong Kong, Singapore, Australia and New Zealand. Some progress has been made to control the disease in China, Thailand, Malaysia and Indonesia. Countries in the Indian subcontinent, however, have witnessed an increase in the carrier pool and in liver disease. HBV remains the commonest cause of chronic liver disease and hepatocellular carcinoma in all countries in the region, with the exception of Japan.

Hepatitis C antibody-positive rates vary from 0.1% to 5% in the region. HCV is the most common cause of chronic liver disease and hepatocellular carcinoma in Japan (75%) but is less important in other Asian countries.

Based on information presented by Dr BN Tandon of All India Institute of Medical Sciences, New Delhi, India.

In Africa

Hepatitis A remains hyperendemic in Africa. In the poorest countries, very early infection of all children is still occurring. In countries where socioeconomic conditions and hygiene are improving, it is likely that the rate of infection is lessening, though this has yet to be documented.

HBV infection is hyperendemic in Africa, with decreases in carrier rates as a result of vaccination seen in only a few countries. Across Africa, about 75 percent of the population is exposed to HBV at some time in their lives and about 10 percent become chronic carriers. 230,000 deaths each year can be attributed to HBV-induced diseases, and 70% of hepatocellular carcinoma in black Africans is related to HBV infection. Despite the obvious need, many African countries have not yet implemented universal infant vaccination.

Little information is available on HDV prevalence, but the available data suggests that prevalence varies greatly among regions - from 31% carrier rates in parts of Kenya to less than 1% in Ethiopia and South Africa. Information on HCV carrier rates is also patchy, with carrier rates ranging from a low of 0.7% to as much as 5.5% in Cameroon. Outbreaks of hepatitis E do occur in Africa, but carrier rates are largely unknown. No information is available on hepatitis G virus.

Based on information presented by Dr MC Kew of the Department of Medicine, University of Witwatersrand, Johannesburg, South Africa.

In Australia and the Western Pacific region

Rapid economic growth in the Asia-Pacific region has resulted in a reduction in enteric hepatitis A infections early in life. As a result, many young adults are susceptible to HAV infection. Also, as the prevalence of infection has declined, a pattern of outbreaks has emerged when breaches of sanitation occur.

Most countries in the region have adopted some hepatitis B vaccination programme, usually infant immunization. National immunization programmes for HBV are having a major impact. Where there are good coverage rates, there has been a dramatic decline in incidence, and in the carrier rate in childhood.

Information on other hepatitis viruses is patchy. It is clear that hepatitis C virus is common and industrialised countries in the region screen all blood donors for the virus. HDV is endemic in parts of northern Asia but very uncommon in other parts of the region.

Based on information presented by Dr ID Gust of CSL Limited, Parkville, Victoria, Australia.

In North America

Hepatitis A is the commonest type of viral hepatitis reported in North America. Children are the major reservoir of infection. Few groups can be identified as having a high-risk of infection and most people become infected during community-wide epidemics.

Having risen in the mid-1980's, acute hepatitis B infection has now declined. This is probably due to vaccination programmes and behaviour changes among certain risk groups. However, the number of newly infected persons remains high.

The incidence of acute hepatitis C has declined since the mid-1980's. Few cases are now associated with blood transfusion. Instead, intravenous drug use is the identifiable source of most infections. Serologic surveillance has identified an unexpectedly large population of persons infected with HCV.

Acute viral hepatitis infections per year in the United States









Based on information presented by Dr Harold Margolis of the Centers for Disease Control and Prevention, Atlanta, GA, USA.

The Viral Hepatitis Prevention Board works under the auspices of the Society of Occupational Medicine and the European Public Health Association. The Board is supported by grants from the pharmaceutical industry (SmithKline Beecham Biologicals, Pasteur Mérieux MSD, Merck Vaccine Division) but has strict scientific independence.

Viral Hepatitis is published and produced by the VHPB, and printed by Jacqmain Ltd., Wilrijk, Belgium.

For further information please contact the VHPB Executive Secretariat at:

The VHPB Executive Secretariat

Epidemiology and Community Medicine

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