Hepatitis A
Annexes
' ANNEXE PAGES -------------------------------------------------------------------
World distribution map ------------------------- world_distribution_map.html
From: Centers for Disease Control and Prevention (CDC), Atlanta, USA: 10 Endemicity patterns (low, intermediate and high) of hepatitis A virus infection worldwide. (Note: this map generalizes available data and patterns may vary within countries).9 Click here for: Worldwide endemicity of HAV infection (table)
World distribution map
http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep16.gif
Worldwide endemicity of HAV infection --------------- worldwide_endemicity.html HAV endemicity Regions by epidemiological pattern Average age of patients (years) Most likely mode of transmission Very high Africa, parts of South America, the Middle East and of south-east Asia under 5 - person-to-person - contaminated food and water High Brazil's Amazon basin, China and Latin America 5-14 - person-to-person - outbreaks/ contaminated food or water Intermediate Southern and Eastern Europe, some regions of the Middle East 5-24 - person-to-person - outbreaks/ contaminated food or water Low Australia, USA, Western Europe 5-40 - common source outbreaks Very low Northern Europe and Japan over 20 - exposure during travel to high endemicity areas, uncommon source Worldwide endemicity of HAV infection 5, 11, 42, 44, 45 Click here for: World distribution map
Worldwide endemicity of HAV infection
Electron Microscopy (EM) picture ------------------ em_picture.htm
From: Centers for Disease Control and Prevention (CDC), Atlanta, USA: 10 Electron microsopy (EM) picture of human hepatitis A virus.
Electron Microscopy (EM) picture
http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep06.gif
Genetic structure of hepatitis A virus -------------------- genetic_structure.htm
Delineation, to scale, of the genome of HAV with its 5'-linked VPg protein, 5'-nontranslated region, single long open reading frame, 3'-nontranslated region and polyadenylated 3'-end. The RNA is translated into a precursor polyprotein that is cleaved to generate mature proteins.6 Click here for: 5' NCR structure of HAV
Genetic structure of hepatitis A virus 
Proposed secondary structure of the 5' NCR of HAV RNA ----------------- secundary_structure.htm
From: Lemon SM and Robertson BH. Current perspectives in the virology and the molecular biology of hepatitis A virus. Seminars in Virology, 1993, 4:285-295, 25 with permission. Proposed secondary structure of the 5' NCR of HAV RNA (strain HM175/wild-type). This model is based on a combination of phylogenetic comparisons, thermodynamic predictions, and nuclease digestions of synthetic RNA between nucleotides 300 and 735. Major structural domains are indicated by Roman numerals beginning at the 5' terminus. Domains contributing to the HAV internal ribosome entry site are included in the box, although the boundaries are not precisely determined. Sites of mutations that appear to enhance HAV replication in cell culture are indicated (arrows). Two possible pseudoknots are indicated by shaded interactions near the 5' terminus. The two initiation codons for the open reading frame (nucleotides 735 to 737 and 741 to 743) are underlined.18 Click here for: Genetic map of HAV
Proposed secondary structure of the 5' NCR of HAV RNA 
Predicted outcome of HAV infection ---------------- predicted_outcome.htm
Predicted outcome Parameter Children (<5 years) Adults Inapparent infection 80-95% 10-25% Anicteric or icteric disease 5-20% 75-90% Complete recovery 99+% 98+% Chronic disease none Mortality rate: <14 years 0.1% 15-39 years 0.3%
">>40 years 2.1% From: Hollinger FB and Ticehurst JR. Hepatitis A virus. In: Fields BN, Knipe DM, and Howley PM, eds. Fields Virology, 3rd ed. Philadelphia, Lippincott - Raven, 1996:735-782, 18 with permission (http://lww.com).
Predicted outcome of HAV infection
Typical serological course ---------------------- humoral_response.htm From Stapleton JT and Lemon SM. Hepatitis A and hepatitis E. In: Hoeprich PD, Jordan MC, Summary of clinical, virologic and serologic findings in uncomplicated acute
Typical serological course 
and Ronald AR, eds. Infectious Diseases, 5th ed. Philadephia, Lippincott Co, 1994:790-797, 40
with permission (http://lww.com).
Role of non-human primates in the transmission of HAV ----------------- role_of_nonhuman_primates.htm
Various monkey species such as chimpanzees, owl monkeys, cynomolgus monkeys, rhesus monkeys, stump-tailed monkeys, African green monkeys, tamarins, marmosets and squirrel monkeys are susceptible to HAV.8, 15, 18, 20, 22, 24, 29, 36 HAV-induced disease in non-human primates resembles human disease, but is usually milder, or subclinical, followed by complete recovery.8, 18, 20, 29 HAV can be transmitted experimentally to these animals, but the presence of anti-HAV antibody in the sera of newly captured monkeys shows that infection may also spread in the natural habitat of non-human primates. HAV isolates from several naturally infected monkeys were shown to represent strict simian HAV strains, closely related antigenically to human HAV strains.8, 14, 20, 22, 24 A molecular comparison of the human HM175 and the simian PA21 and PA33 strains of HAV has shown that, despite major divergence at the nucleotide level (>10%), the viruses share immunodominant neutralization epitopes. Infection of owl monkeys with either virus provides high, although incomplete (mild symptoms, relapsing hepatitis) protection against later intravenous challenge with the other virus.14, 24 Well documented is the natural transmission of human HAV from experimentally infected animals to humans. Still unknown is the susceptibility of humans to true simian HAV strains. If it could be shown that simian strains do not induce disease in humans despite virus replication and subsequent seroconversion, simian strains might be used as live, attenuated vaccines. If, on the other hand, HAV-immune people challenged with simian HAV strains developed signs of hepatitis, even a global immunization programme could never achieve the eradication of HAV, because monkeys would constantly represent a natural reservoir of virus.
Role of non-human primates in the transmission of HAV
Estimated number of cases per continental region .------------------------ estimated_number.htm
From: Hadler SC. Global impact of hepatitis A virus infection changing patterns. In: Hollinger FB, Lemon SM, and Margolis HS, eds. Viral Hepatitis and Liver Disease. Baltimore, Williams & Wilkins, 1991: 14-20, with permission (http://lww.com).
Estimated number of cases per continental region
REGION 1990 POPULATION (in millions) INCIDENCE (per 100,000 per year) cases (per year) North America 275 10 28,000 Central and South America 453 20-40 162,000 Europe 791 5-60 278,000 Africa and Middle East 827 20-60 251,000 Asia 2893 10-30 676,000 Oceania 28 15-30 5,000 Total 1,399,000
Recommendations for use of hepatitis A vaccine and IG --------------- recommendations.htm
Hepatitis A vaccination provides preexposure protection from HAV infection. It is recommended for persons who are at increased risk for infection and for any person wishing to obtain immunity. Persons who seek immunological protection, but are allergic to vaccine components should receive IG. The administration must be repeated if protection is required for periods exceeding 5 months. For persons who require repeated IG, screening of their immune status is useful to avoid unnecessary doses of IG. Persons who have been exposed to HAV and who have not previously been vaccinated should be administered a dose of IG (0.02ml/kg) within two weeks of exposure.39 Persons who have received a dose of hepatitis A vaccine at least 2 weeks before exposure to HAV do not need IG. Mass postexposure vaccination to contain the spread of HAV in established outbreaks has been well documented and proven efficacious in ceasing emerging epidemics.21 Serologic screening of contacts of infected individuals for anti-HAV before they are given IG is not recommended because screening is more costly than IG and would delay its administration. The prospective duration of antibody persistence can be estimated to last at least 20 years. However, a booster vaccination after 10 years is recommended for protection, as long as no long-term follow-up data are available.19, 21, 27 Click here for: Recommended doses of IG
Recommendations for use of hepatitis A vaccine and IG
Recommended doses of IG for hepatitis A preexposure and postexposure prophylaxis --------- recommended_doses.htm
setting duration of coverage IG dose preexposure short-term 0.02 ml/kg long-term (3 - 5 months) 0.06 ml/kg° postexposure 0.02 ml/kg ° repeat every 5 months if continued exposure to HAV occurs 9 Click here for: Recommendations for use of hepatitis A vaccine and IG
Recommended doses of IG for hepatitis A preexposure and postexposure prophylaxis
Recommended dosages of available vaccines --------------- recommended_vaccine_dosages.htm
Havrix® (SmithKline Beecham Biologicals) Vaqta® (Merck & Co., Inc.) * 0 months represents timing of the initial dose. Subsequent numbers indicate months after the initial dose. For travellers who seek medical advice less than 2 weeks before travelling, a double dose is recommended (two injections, single dose; or one injection, double dose). This induces antibodies in over 90% of individuals within 2 weeks, and will most probably protect against infection. Alternatively, a dose of IG (0.02 ml/kg body weight) may be given with the first dose of vaccine. When hepatitis A vaccine is administered concomitantly with pooled IG for immediate protection, separate syringes and different sites must be used. Persons allergic to vaccine components should follow the recommendations for the use of IG. Persons who have anti-HAV from prior infection do not need to be vaccinated, but do not react adversely to immunisation. Studies for the development of safe and efficacious live-attenuated vaccines are currently in progress. HAV vaccines are stable and can be stored for at least two years at 4°C without loss of immunogenicity.21 Click here for: Vaccine safety Click here for: Vaccination strategies
Recommended dosages of available vaccines
Group Age
(years) Dose
(ELISA Units, EL.U.) Volume No. Doses Schedule
(months)* Children and Adolescents 2-19 720 EL.U. 0,5ml 2 0, 6-12 Children and Adolescents 1-18 360 EL.U.
(US$ 19.50)° 0,5ml 3 0, 1, 6-12 Adults >18 1440 EL.U.
(US$ 56.90)° 1.0 ml 2 0, 6-12
Group Age
(years) Dose
(Units, U) Volume No. Doses Schedule
(months)* Children and Adolescents 2-17 25 U 0.5 ml 2 0, 6-18 Adults >17 50 U 1.0 ml 2 0, 6
° Prices are the average wholesale costs per single-unit dose in the United
States 9
Vaccine safety ------------------ vaccine_safety.htm Havrix®, Vaqta®, Avaxim®, Epaxal® and Twinrix® have excellent safety profiles and are highly immunogenic in humans.3, 18, 19, 32 Nearly 100% of vaccinees will develop protective levels of antibody within 1 month of the first dose of vaccine. Side effects are local, of low intensity and short duration, involving a generally clinically insignificant soreness at the injection site. Safety of the vaccines has not been determined during pregnancy. Because the available vaccines are inactivated, no special precautions need to be taken in vaccination of HIV-1 positive or otherwise immunocompromised persons, although they may be less responsive.21 Click here for: Recommended dosages of available vaccines Click here for: Vaccination strategies
Vaccine safety
Vaccination strategies ------------------- vaccination_strategies.htm The best vaccination strategy for a region depends on the epidemiology of HAV, the risk groups involved, the duration of protection, the possibility of postexposure protection, and the cost of the intervention.45 Groups at high risk of HAV infection as a result of behaviour, lifestyle or occupation should be the primary target of a hepatitis A vaccination programme.45 It is important to note that for many cases of hepatitis A risk factors and sources of infection cannot be identified. Immunization programmes directed only to high risk groups would miss those with unidentified risks, and would therefore not reduce the impact of the disease or eliminate hepatitis A.17 In most developing countries hepatitis A is not a real public health priority, since it is acquired in early childhood when infections are usually asymptomatic. These countries do not at present need to consider universal hepatitis A immunization programmes.17 Click here for: Recommended dosages of available vaccines Click here for: Vaccine safety
Vaccination strategies