Introduction
    Hepatitis A is primarily contracted through the oral ingestion of foods or drinks contaminated with the hepatitis A virus (HAV). The disease may result in inapparent infection in the majority of children. However almost all the adults exhibit acute hepatitis symptoms, and fulminant hepatitis and renal insufficiency may occur on rare occasions. The rate of infection has decreased in Japan with the improvement in the living environment and the generation under 50 years of age has almost no immunity. Since HAV-endemic regions are numerous in the developing countries close to Japan, travelers to those countries were protected against this disease with immunoglobulin. However the inactivated vaccine made from purified HAV was authorized in 1994, and optional immunization has become available from 1995.
Pathogenic virus
    HAV belongs to the hepatovirus gender of the family Picornaviridae. The virus particle is a naked icosahedron with a diameter of 27 nm. The gene consists of a positive-stranded RNA with approximately 7,500 bases in which the VPg protein is linked to the 5'end and the poly A tail is linked to the 3' end. The structure and properties of the HAV particle, the genetic structure and functions and the particle formation are fundamentally common to other Picornaviruses. The HAV has 7 genotypes, but there is only one serotype. HAV can be propagated in cultured cells. Nevertheless the propagation rate is slow compared to other picornaviruses even with a cell culture-adapted strain, and no cytopathic effect (CPE) is generally exhibited. The liver is the target organ to replicate but it does not destroy the infected liver cells directly like other hepatitis viruses. Hepatitis occurs via the host immunoresponse. HAV is thermostable and acid-resistant and is resistant to drying. It is resistant to detergents, proteases and liposoluble substances such as ether, however it loses its infectivity under high pressure sterilization, UV radiation, formalin treatment, and treatment with chlorine agents and iodine agents.
Epidemiology
    HAV is distributed all over the world. Since it is an infection transmitted orally, it occurs primarily during the infancy and early childhood period in HAV endemic regions where the sanitary environment is poor. In many cases the disease ends up in inapparent infection in infants and young children, and the incidence of hepatitis is low and there are no outbreaks in such regions. The rate of infection decreases when water supply and sewerage systems are upgraded and the living environment is improved, and susceptible individuals accumulate and out breaks are observed. The large-scale outbreak affecting around 300,000 persons that occurred in Shanghai, China, in 1988 is a case in point. Large outbreaks are stopped when the living environment is further improved. The antibody carriage was surveyed by age groups in the general Japanese population on serum specimens in 1973, 1984 and 1994. This survey showed clearly that the antibody carriage curve shifted to the elderly in response to the survey interval and that the incidence of HAV infection was low in Japan during the last 30 years and longer. Now the antibody carriage rate seems to be extremely low in subjects under 50 years of age. Therefore this creates a condition where infection is easily contracted by travelers to foreign countries, through eating and drinking, in institutions for mentally handicapped people, household contacts, etc. Moreover there is a correlation between the age at which the disease is contracted and the clinical course of hepatitis A, and symptom aggravation in elderly subjects has become a serious problem. Though the clinical symptoms are mild in case of infection in young children, the latter may become a new source of infection in their surroundings. The characteristics of recent hepatitis A infection in Japan can be summarized as follows from data collected up to October 2003 in a survey on the trends of infection outbreaks. 1) About 500 cases are reported every year, 90 percent of which being infection contracted in Japan; 2) the primary source of infection is oysters or is caused by certain food products and drinks; 3) by age of onset, the infection is rare in infants and schoolchildren, and it tends to strike elderly people; 4) approximately 10 percent of all the patients are people returning to Japan from abroad, and most of them have contracted the disease in China, India or South East Asia; 5) hepatitis A is subjected to seasonal fluctuations. In Japan, the prevalence is low in fall, and it increases from winter to spring and early summer.
Clinical course
    The excretion of the virus begins in the feces about one week after the infection, and it continues for 2~4 weeks. A small amount of virus also appears in the blood during viral excretion. The incubation period is approximately 2~6 weeks, and serum transaminase (ALT or GPT, AST or GOT) rises, following fever, malaise and other symptoms. The infection is accompanied by anorexia and symptoms of the digestive organs, such as vomiting, etc. Jaundice, swollen liver, dark urine, pale stools, etc. are observed in typical cases. IgM type anti-HAV antibodies appear during ALT and AST elevation. They are used for the serological diagnosis during the acute stage. The peak of IgM type antibodies is about one month after onset. Then they rapidly decline and turn negative after three months.
Usually the patients recover after a course of one to two months. Compared to other acute viral hepatitis, the clinical symptoms of hepatitis A are characterized by strong hepatic symptoms such as fever, cephalea, myalgia, and abdominal pain, etc. However the improvement of the clinical symptoms and of the liver disorders is rapid. In tests of the hepatic functions, the values of AST, ALT, ALP, LDH, etc. tend to be higher than other acute forms of hepatitis, but the abnormal values return to normal usually within two months.
Treatment
There is no specific treatment method. In principle the patient is hospitalized during the acute stage and confined to bed. During hospitalization, symptom aggravation, fulmination and the presence or absence of non-hepatic symptoms are observed, and a treatment adapted to the symptoms is given.
Prevention and role of the vaccine
In addition to general protective methods such as the encouragement of hand washing, etc., intramuscular injections of immune globulin were given before to people traveling to HAV-endemic regions. Since the persistence of the protective efficacy was short, long time residents in contaminated areas had to receive booster doses, whence the need for a hepatitis A vaccine. Initially research was focused on the development of a live vaccine, an inactivated vaccine and a recombinant vaccine. Then a formalin-inactivated vaccine obtained by purifying HAV propagated in cultured cells became commercially viable. SmithKline Beecham's vaccine was licensed in Europe in 1992, and a vaccine co-developed by Kaketsuken (The Chemo-Sero-Therapeutic Research Institute), Denka Seiken and Chiba Serum Institute received approval in Japan in 1994. Optional immunization became available in Japan from July 1995. Vaccines manufactured by several companies are currently employed in Europe and in the US, and they are exported to South East Asia too. The vaccines made in Europe and in the US are adsorbed preparations added with aluminum adjuvant. How the Japanese vaccine is a lyophilized product containing no adjuvant and antimicrobial agent such as thimerosal, etc.
Subjects in whom vaccination is indicated
Travelers to countries where HAV is prevalent, personnel working in welfare institutions, high-risk groups such as male homosexuals and users of blood preparations, individuals afflicted with chronic liver ailments, drinking or eating establishments that may propagate the infection to other people, employees of food marketing companies, etc., are indicated for immunization.
Vaccine
    Strain KRM003 isolated from the feces of patients in Fukuoka prefecture in 1979 and adapted to cell culture is used for the Japanese vaccine. The vaccine is made by purifying to a high degree the virus particles that have been propagated in GL37 cells of African green monkey kidney origin, inactivating with formalin and lyophilization. Although the genotype of the KRM003 strain is IIIB, there is only one HAV serotype. Therefore it can antigenetically respond to all HAV.
The vaccine contains 0.5 m.g antigen protein per 0.5ml-dose. It has been added with stabilizing agents, such as lactose (25 mg), D-sorbitol (5 mg), L-sodium glutamate (0.5 mg), arginine hydrochloride (0.5 mg) and polysorbate 80 (0.01 mg). It also contains the following buffering agents: sodium chloride (4 mg), sodium hydrogenphosphate (0.58 mg), sodium dihydrogen phosphate (0.1 mg) and potassium chloride (0.1 mg). The vaccine is prepared by dispensing 0.65 ml of this solution into each vial and freeze-drying. The expiration date is three years at no more than 10C..
Inoculation method
    Vaccination is given to subjects aged 16 and over. Immunization of small children has not yet been approved.
The vaccine is reconstituted with 0.65 ml of the accompanying diluent (distilled water for injection of the Japanese Pharmacopeia). In standard inoculation, two 0.5-ml doses are given subcutaneously or intramuscularly at a 2~4 week interval, and a 0.5-ml booster is inoculated after a gap of about 6 months. In case of urgency such as travel abroad, the immunity can be obtained by giving two 0.5-ml doses at a two-week interval. However it is advisable to give a third booster dose in order to maintain the level of antibodies for a long time.
Persistence of the efficacy and of the immunity
    According to the results of clinical studies, 100% of the antibodies turned positive after one dose of the vaccine, and the mean antibody titer was approximately 500 mIU/ml when giving two shots at a 2~4 week interval. Although the antibody titer fell to about 300 mlU/ml after six months, it rose to around 3000 mIU/ml when inoculating a third dose at that point of time, and an antibody titer of about 400 mlU/ml was maintained even after five years. Since the infection control level is apparently around 10 mlU/ml, a long infection protective efficacy may be expected with the standard inoculation method. However since the lower limit for the determination of HAV antibody by means of many in vitro diagnostic kits is 100 - 500 mlU/ml, the diagnosis may in some cases be antibody-negative even after the inoculation of the vaccine.
Studies with one dose of 0.25 ml and 0.5 ml have been performed from infants to small children, and the immune response was found to be good.
Adverse reactions
    Local redness, pain, systemic malaise, fever, etc. are observed in only a few percents of the vaccine recipients. No serious adverse reactions have been observed in particular small children included.
Conclusion
    Whereas 90 percent of foreigners other than Japanese visiting Nepal are immunized against hepatitis A, the vaccination rate for the Japanese travelers is a mere 5 percent. With the remarkable improvement in the hygiene conditions in Japan, hepatitis A has become relatively rare. Nevertheless developing countries such as those in South East Asia are HAV-enclemic areas. It is therefore necessary to understand well the difference in terms of level of sanitary environment between Japan and foreign developing countries and to receive vaccination against preventable diseases including hepatitis A.