Summary and conclusion
Hepatitis A is an acute, usually self-limiting disease of
the liver caused by hepatitis A virus (HAV). HAV is transmitted from person to person,
primarily by the faecal-oral route. The incidence of hepatitis A is closely related to
socioeconomic development, and sero-epidemiological studies show that prevalence of
anti-HAV antibodies in the general population varies from 15% to close to 100% in
different parts of the world. An estimated 1.5 million clinical cases of hepatitis A occur
each year. In young children HAV infection is usually asymptomatic whereas symptomatic
disease occurs more commonly among adults. Infection with HAV induces lifelong immunity.
In areas of low endemicity, hepatitis A usually occurs as single cases among persons in
high-risk groups or as outbreaks involving a small number of persons. In areas of high
endemicity most persons are infected with HAV without symptoms during childhood. This
explains why clinical hepatitis A is uncommon. In countries of low and intermediate
disease endemicity, adult disease is seen more often. Hepatitis A may represent a
substantial medical and economic burden. Currently, four inactivated vaccines against HAV
are internationally available. All four vaccines are safe and effective, with long-lasting
protection. None of the vaccines are licensed for children less than one year of age.
The results of appropriate epidemiological and
cost-benefit studies should be carefully considered before deciding on national policies
concerning immunization against hepatitis A. As part of this decision process, the public
health impact of hepatitis A should be weighed against the impact of other
vaccine-preventable infections, including diseases caused by hepatitis B, Haemophilus
influenzae type b, rubella and yellow fever.
In countries highly endemic for hepatitis A, almost all
persons are infected in childhood with the virus without showing symptoms, effectively
preventing clinical hepatitis A in adolescents and adults. In these countries, large-scale
vaccination programmes are not recommended. In countries of intermediate disease
endemicity, where a relatively large proportion of the adult population is susceptible to
HAV, and where hepatitis A represents a significant public health burden, large-scale
childhood vaccination may be considered as a supplement to health education and improved
In regions of low disease endemicity, vaccination against
hepatitis A is indicated for individuals with increased risk of contracting the infection,
such as travellers to areas of intermediate or high endemicity.
Public health impact
Hepatitis A is an acute, usually self-limiting infection
of the liver caused by hepatitis A virus (HAV). The virus has a worldwide distribution and
causes about 1.5 million cases of clinical hepatitis each year. Humans are the only
reservoir of the organism. Transmission occurs primarily through the faecal-oral route,
and is closely associated with poor sanitary conditions. The most common modes of
transmission include close personal contact with an infected person and ingestion of
contaminated food and water. The virus is shed in the faeces of persons with both
asymptomatic and symptomatic infection. Under favourable conditions HAV may survive in the
environment for months. Bloodborne transmission of HAV occurs, but is much less common.
The average incubation period is 28 days, but may vary
from 1550 days. Approximately 1012 days after infection the virus can be
detected in blood and faeces. In general, a person is most infectious from 1421 days
before the onset of symptoms, through to 7 days after the onset of symptoms.
Antibodies against HAV develop in response to infection
and seroprevalence can be used as a marker of viral transmission in a community. The
lowest seroprevalence is found in the Nordic countries (about 15%). In Australia, other
parts of Europe, Japan and in the United States, 40%70% of the adult population has
demonstrable antibodies to HAV. Practically all adults living in developing areas of the
world have serological evidence of past infection.
The risk of developing symptomatic illness following HAV
infection is directly correlated to age. In children below six years of age, HAV infection
is usually asymptomatic, with only 10% developing jaundice. Among older children and
adults, infection usually causes clinical disease, with jaundice occurring in more than
70% of cases. Therefore, highly HAV-endemic regions are characterized by asymptomatic
childhood infection, with only the occasional occurrence of clinical hepatitis A.
For practical purposes, the world can be divided into
areas of low, intermediate and high disease endemicity, although there may be regional
differences in endemicity within a country. In areas of low endemicity the disease occurs
mainly in adolescents and adults in high-risk groups (e.g. homosexual men, injecting-drug
users), persons travelling to countries of intermediate and high HAV endemicity, and in
certain subpopulations (e.g. closed religious communities). Some of these groups may also
experience periodic outbreaks of hepatitis A. In areas of low endemicity, occasional food
and waterborne outbreaks of hepatitis A occur. In areas of intermediate endemicity,
transmission occurs primarily from person to person in the general community, often with
periodic outbreaks. In these countries many individuals escape early childhood infection,
but are exposed later in life when clinical hepatitis occurs more frequently. In these
areas, most cases occur in late childhood and early adulthood.
In areas of high disease endemicity, where the lifetime
risk of infection is greater than 90%, most infections occur in early childhood and are
asymptomatic. Thus, clinically apparent hepatitis A is rarely seen in these countries.
Countries in transition from developing to developed economies will gradually move from
high to intermediate endemicity, and hepatitis A is likely to become a more serious
problem in these areas.
Although hepatitis A is mostly self-limiting and rarely
fatal, the disease may represent a substantial economic burden, particularly in countries
with low and intermediate incidence rates. In the United States, a region of relatively
low hepatitis A endemicity, calculations based on surveillance data from 1989 indicated
annual medical and work-loss costs of approximately US$ 200 million.
The pathogen and the disease
HAV is a member of the Picornaviridae family that
includes both the enteroviruses and rhinoviruses of humans. Being the only species member,
it constitutes its own genus named hepatovirus. HAV is a non-enveloped (naked) virus of
2728 nm diameter without morphological features differentiating it from other
picornaviruses. Four structural proteins encapsulate the RNA genome. Neutralization sites
for anti-HAV antibodies are mainly contained in two of these proteins. Although six
genotypes of HAV have been identified, there appears to be no variation detectable by
serology in these neutralization sites. The virus is relatively stable at low pH and
moderate temperatures, but is inactivated by high temperature (almost instantly at
85°C/185°F), and by formalin or chlorine. HAV itself is not cytopathic and the
liver-cell damage is caused by the cell-mediated immune response.
The clinical course of acute hepatitis A is
indistinguishable from other types of acute viral hepatitis. Symptoms typically include
fever, malaise, anorexia, nausea and abdominal discomfort, followed by dark urine and
jaundice. The severity of disease and mortality increases in older age groups. The
convalescence following hepatitis A may be slow, and is characterized by fatigue, nausea
and lack of appetite. Complications of hepatitis A include relapsing hepatitis,
cholestatic hepatitis and fulminant hepatitis. Fulminant hepatitis occurs in approximately
0.01% of clinical infections and is characterized by rapid deterioration in liver function
and a very high fatality rate. Chronic infection with HAV does not occur. No specific
antiviral therapy is currently available.
The aetiological diagnosis is made by the demonstration
of IgM antibodies to HAV (IgM anti-HAV) in serum. Detection of the virus or viral antigens
in the stool is of limited value for routine diagnosis.
Protective immune response
Protective antibodies develop in response to infection
and persist for life. The protective role of anti-HAV antibodies has been demonstrated by
the protection against hepatitis A resulting from passive immunization with serum immune
globulin. The effect of mucosal immunity on HAV infection is not known.
Justification for vaccine
Although usually a self-limiting disease without serious
sequelae and with a low case-fatality rate, human suffering may, as a result of infection,
be considerable. In addition, direct and indirect medical costs including the infection
control measures involved, may impose a considerable economic burden on society.
Cost-benefit analyses from the United States suggest that large-scale immunization
programmes might result in cost savings in some communities. However, depending on the
costs associated with clinical disease and vaccination (vaccine and administration), such
cost-benefit figures will vary considerably between different countries.
In the long term, socioeconomic development will reduce
transmission of hepatitis A, particularly through improved sanitation and health
education. Unfortunately, in some parts of the world socioeconomic development is slow. No
drugs against HAV are currently available, and antiviral medication is unlikely to become
a realistic alternative to appropriate vaccines. Immune globulin may be used for pre- and
post-exposure prophylaxis, for example, shortly before entering a disease-endemic area or
just after likely HAV exposure. However, passive immunization with immune globulin gives
only short-term protection (three to five months) and is relatively costly compared to the
long-term immunity from vaccination.
Several vaccines against hepatitis A are now available
that are highly efficacious and provide long-lasting protection in adults and in children
above one to two years of age. In countries where clinical hepatitis A is an important
health problem, immunization is likely to be a cost-effective public health tool to
control the disease.
Hepatitis A vaccines
Techniques for growing HAV in cell culture have made it
possible to generate sufficient amounts of virus for vaccine production. Several
inactivated or live attenuated vaccines against hepatitis A have been developed, but only
four inactivated hepatitis A vaccines are currently available internationally. All four
vaccines are similar in terms of efficacy and side-effect profile. The vaccines are given
parenterally, as a two-dose series, 6-18 months apart. The dose of vaccine, vaccination
schedule, ages for which the vaccine is licensed, and whether there is a paediatric and
adult formulation varies from manufacturer to manufacturer. No vaccine is licensed for
children younger than one year of age.
Three vaccines are manufactured from cell-culture-adapted
HAV propagated in human fibroblasts. Following purification from cell lysates, the HAV
preparation is formalin-inactivated and adsorbed to an aluminium hydroxide adjuvant. One
vaccine is formulated without preservative; the other two are prepared with
2-phenoxyethanol as a preservative. The fourth vaccine is manufactured from HAV purified
from infected human diploid cell cultures and inactivated with formalin. This preparation
is adsorbed to biodegradable, 150 nm phospholipid vesicles spiked with influenza
haemagglutinin and neuramidase. These virosomes are thought to directly target
influenza-primed antibody-presenting cells as well as macrophages, thus stimulating a
rapid vaccine-induced B-cell and T-cell proliferation in the majority of vaccinees. A
combination vaccine containing inactivated hepatitis A and recombinant hepatitis B
vaccines has been licensed since 1996 for use in children aged one year or older in
several countries. The combination vaccine is given as a three-dose series, using a 0, 1,
6 month schedule.
Hepatitis A vaccines are all highly immunogenic. Nearly
100% of adults will develop protective levels of antibody within one month after a single
dose of vaccine. Similar results are obtained with children and adolescents in both
developing and developed countries. The protective efficacy of the vaccine against
clinical disease was determined in two large trials. Among almost 40 000 Thai children
aged 116 years the protective efficacy was 94% (95% confidence intervals:
82%99%) following two doses of vaccine given one month apart. Among approximately
1000 children aged 216 years, living in a highly disease-endemic community in the
United States, the efficacy of one dose of vaccine was 100% (95% confidence intervals:
Although one dose of vaccine provides at least short-term
protection, the manufacturers currently recommend two doses to ensure long-term
protection. In studies evaluating the duration of protection of two or more doses of
hepatitis A vaccine, 99%100% of vaccinated individuals had levels of antibody
indicative of protection five to eight years after vaccination. Kinetic models of antibody
decay indicate that the duration of protection is likely to be at least 20 years, and
possibly lifelong. Post-marketing surveillance studies are needed to monitor
vaccine-induced long-term protection, and to determine the need for booster doses of
vaccine. This is especially true in areas of low disease endemicity where natural boosting
does not occur.
Millions of persons have now been vaccinated against HAV.
The current vaccines are well tolerated and no serious adverse events have been
statistically linked to their use. Contraindications to hepatitis A vaccination include a
known allergy to any of the vaccine components. Hepatitis A vaccine may be administered
with all other vaccines included in the Expanded Programme on Immunization and with
vaccines commonly given for travel. Concurrent administration of immune serum globulin
does not appear to influence significantly the formation of protective antibodies.
WHO position on hepatitis A
The currently available vaccines against hepatitis A are
all of known good quality and in line with the above WHO recommendations. However, they
are not licensed for use in children less than one year of age. The efficacy in children
below one year of age is variable owing to interference by passively acquired maternal
antibodies. Although the current vaccines result in long-term protection when given as two
injections 618 months apart, high levels of immunity are obtained after one dose.
Studies addressing the duration of protection following a single dose of vaccine are
encouraged. Planning for large-scale immunization programmes against hepatitis A should
involve careful analyses of the cost-benefit and sustainability of different appropriate
hepatitis A prevention strategies, as well as an assessment of the possible long-term
epidemiological implications of vaccination at different levels of coverage.
In countries where hepatitis A is highly endemic,
exposure to HAV is almost universal before the age of 10 years. In such countries clinical
hepatitis A is usually a minor public health problem, and large-scale immunization efforts
against this disease should not be undertaken. In developed countries with low endemicity
of hepatitis A and with high rates of disease in specific high-risk populations,
vaccination of those populations against hepatitis A may be recommended. The high-risk
groups include injection-drug users, homosexual men, persons travelling to high-risk
areas, and certain ethnic or religious groups. However, it should be noted that
vaccination programmes targeting specific high-risk groups may have little impact on the
overall national incidence of disease.
In areas of intermediate endemicity, where transmission
occurs primarily from person to person in the general community (often with periodic
outbreaks), control of hepatitis A may be achieved through widespread vaccination
Recommendations for hepatitis A vaccination in outbreak
situations depend on the epidemiology of hepatitis A in the community, and the feasibility
of rapidly implementing a widespread vaccination programme. The use of hepatitis A vaccine
to control community-wide outbreaks has been most successful in small, self-contained
communities, when vaccination is started early in the course of the outbreak, and when
high coverage of multiple-age cohorts is achieved. Vaccination efforts should be
supplemented by health education and improved sanitation.
Although the burden of disease associated with hepatitis
A is considerable in many countries, the decision to include hepatitis A vaccine in
routine childhood immunization programmes should be made in the context of the full range
of immunization interventions available. This includes hepatitis B, Hib, rubella and
yellow fever, and, in the near future, pneumococcal vaccines, all of which are likely to
have a more profound public health impact.
This chapter was last published as a WHO position paper:
Hepatitis A vaccines: WHO position paper. Weekly Epidemiological Record, 2000,
75:3842 and is available on the Internet at http://www.who.int/wer/pdf/2000/wer7505.pdf.
Number of doses
|Inactivated, given by the
Second dose 618 months after first (timing varies
May not be necessary; manufacturers propose at 10 years
Hypersensitivity to previous dose
Mild local and systemic reactions
Not protective before one year of age
* A combination vaccine containing inactivated hepatitis
A and recombinant hepatitis B vaccine is available for use in children aged one year or
older in several countries, and is given as a three-dose series, using a 0, 1, 6 month
Centers for Disease Control and Prevention. Prevention of
hepatitis A through active or passive immunization. Recommendation of the Advisory
Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report,
Feinstone SM, Gust ID. Hepatitis A Vaccine. In: Plotkin
SA, Orenstein WA, eds. Vaccines (3rd ed.). Philadelphia: WB Saunders Company; 1999.
Innis BL, Snitbhan R, Kunasol, et al. Protection against
hepatitis A by an inactivated vaccine. Journal of the American Medical Association,
Public health control of hepatitis A: Memorandum from a
WHO meeting. Bulletin of the World Health
Organization, 1995, 73:1520.
Werzberger A, Mensch B, Kuter B, et al. A controlled
trial of a formalin-inactivated hepatitis A vaccine in healthy children. New England
Journal of Medicine, 1992, 327:453457.
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Updated 4 February 2003