Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
Corresponding Author: Professor Chuan-Yong Guo, PhD, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. E-Mail: firstname.lastname@example.org
Hepatitis A is the second most common vaccine-preventable travel-associated infectious disease and hepatitis A virus (HAV) is the most common cause of viral hepatitis. The incidence of infection is closely related to sanitary conditions and the level of economic development.
We evaluated HAV incidence, infection-related risk factors, and HAV vaccination rates in international travelers through retrospective analyses using major databases, such as CENTRAL, MEDLINE, EMBASE, and the current literature describing epidemiological data for HAV infection in recent years.
Results and Conclusions
We found that the incidence of HAV infection in developed countries is very low. As international travel increases, the incidence of hepatitis A among travelers remains high and likely leads to regional outbreaks. Travelers should visit the Centers for Disease Control and Prevention website or Infectious Disease Prevention Center of their countries to learn about the incidence of infectious diseases associated with their destination before going abroad to determine if they should be vaccinated.
Hepatitis A is the second most common infectious disease in travelers and the most common cause of viral hepatitis. The hepatitis A virus (HAV) is a small nonenveloped single-stranded RNA virus that replicates in hepatocytes and interferes with liver function, promoting an immune response that causes liver inflammation. In approximately 0.2% of clinical cases, infection results in acute liver failure and death, and this risk increases with age and the presence of chronic liver disease. HAV is transmitted through direct person-to-person contact, exposure to contaminated water or shellfish, or the consumption or handling of contaminated uncooked fruits and vegetables.
The average incubation period for HAV is 28 days, and the clinical manifestations vary. For example, some people may be asymptomatic, some show mild clinical symptoms, and some present with severe hepatitis. HAV infection symptoms may include the abrupt onset of fever, malaise, loss of appetite, nausea, abdominal discomfort, and jaundice, and these can last from weeks to several months. In children younger than 6 years infected with HAV, more than 50% are generally asymptomatic and the remaining present with mild symptoms. Although 10% of infected individuals have prolonged or relapsing symptoms over 6 to 9 months, chronic HAV infection does not occur. The overall case-fatality ratio (CFR) is 0.3%; however, among adults over 50 years, the CFR is 2.7%. The CFR is also higher in individuals with chronic liver disease, including chronic viral hepatitis. Diagnosis of hepatitis A depends primarily on the detection of serum anti-HAV IgM antibodies, which are detectable 5 to 10 days postexposure and gradually disappear 6 months postinfection. However, anti-HAV IgG can also develop in the early stages and last a lifetime. Because HAV vaccines are not widely used, most individuals develop anti-HAV IgG-acquired immunity through infection.
The Epidemiology of HAV Globally
Approximately 1.5 million clinical cases of HAV infection occur worldwide annually, but the rate of infection is probably as much as ten times higher. The HAV endemicity level for a population is determined by the results of age-seroprevalence surveys. In 2010, the World Health Organization published a systematic review of the global prevalence of and susceptibility to HAV infection. Worldwide, geographical areas can be characterized with high, intermediate, low, or very low levels of endemicity for hepatitis A (Figure 1).
The seroprevalence of antibodies to HAV (total anti-HAV), as measured in selected cross-sectional studies among each country's residents, is shown in Figure 1. The levels of endemicity are related to hygienic and sanitary conditions in each area. The estimates demonstrate that all high-income regions have very low HAV endemicity levels, all low-income regions have high endemicity levels, and most middle-income regions have a mix of intermediate and low endemicity.
In developing or underdeveloped countries, such as Africa, parts of South America, the Middle East, and India, HAV infection is very common. Most infections are acquired during early childhood. Infections that occur at an early age are often asymptomatic. Therefore, reported rates of infection in these areas are relatively low, and outbreaks are not common. In countries with intermediate endemicity, such as China, some Eastern European countries, and some Southeast Asian countries, community-wide outbreaks may occur. For example, in Shanghai, China in 1988, 30 million people were infected with HAV owing to consumption of contaminated shellfish. In developed countries, such as North America, Western Europe, Scandinavia, Australia, and Japan, HAV infection is less common. Infection rates in children are generally low, though peak rates of infection and reported disease tend to occur in adolescents and young adults. Infections in these developed countries occur in specific settings and are mainly associated with travel.[1, 4]
The Travel-Associated Risk of HAV Infection
In developed countries, there is a general lack of immunization against HAV, although it is considered an important travel-associated infection. A systematic review of HAV seropositivity rates in Canada, a country with low endemicity, demonstrated that the seroprevalence in Canadian-born children was approximately 1% in ages 8 to 13, 1% to 6% in 20 to 24 years, 10% in 25 to 29 years, and 17% in 30 to 39 years, with subsequent age-associated increases. Compared with Canadian-born individuals, subjects born outside Canada were approximately six times more likely to be seropositive. Furthermore, travel to high-risk areas by individuals aged 20 to 39 was associated with a significant increase in anti-HAV seropositivity. This study indicated that HAV infection occurred more often in adults, and the increase in HAV prevalence among young adults coincided with disease importation and an increased frequency of risk factors, most likely behavioral-related ones. Epidemiological studies have demonstrated that in Germany in 2007 and 2008 approximately 60% of people infected with HAV had no travel history to endemic areas. Additionally, young immigrant patients who had recently visited family in areas with a high HAV infection risk accounted for most imported disease cases.
In the past, the risk of HAV infection in unvaccinated travelers was considered to be 3 per 1,000 individuals per month of travel to a developing country in good quality accommodations. Those who ate and drank under poor hygienic conditions had a higher risk (20 per 1,000 individuals per month traveled).[12, 13] Currently, with improvements in sanitary conditions, the risk of infection for nonimmune travelers who visit high- and medium-endemic areas has been reduced to 6 to 30 per 100,000 individuals per month traveled. Interestingly, the risk to travelers differs from one area to another. An analysis of 636 cases of travel-related hepatitis between 1997 and 2005 demonstrated that the areas associated with the highest incidence of disease were East Africa, the Middle East, and the Indian subcontinent. Visiting friends and relatives (VFR) travelers represented 83, 91, and 70% of the cases to these three regions; the highest incidence was found in children 0 to 14 years where 88% of the cases were VFR travelers. So travelers, especially children, who are VFR in endemic areas constitute a high-risk group for acquiring hepatitis A. Travel to areas endemic for HAV infection constitutes a considerable risk; our research shows the importance of improving the environment and developing health policies. Vaccination before traveling to a medium- or high-endemic area could be a safe and effective means of preventing travel-related HAV infection.
Sporadic cases are reported frequently. For example, since September 2008, 26 cases of HAV infection with a history of travel to Egypt have been reported in France. Investigations indicated that the most likely source of infection was a Nile river cruise that was common to the majority of cases. In 2004, 351 tourists who traveled to Egypt from nine European countries were infected with HAV, which was likely due to consumption of contaminated orange juice. Therefore, it is important to provide appropriate preventive information to travelers VFR in high infection risk areas, especially individuals raised in developed countries who lack immunity.[17, 18] In the United States in 2007, among cases for which exposure information was collected, the most common risk factor for HAV infection was international travel (approximately 18% of cases). About 85% of travel-related cases were associated with travel to Mexico, Central America, or South America. The spread of HAV infection in the United States continues to decline; however, cases among nonimmunized travelers to HAV-endemic countries have accounted for any increase in HAV infection. For US residents traveling abroad, the risk of HAV infection is associated with living conditions, duration of travel, and the incidence of HAV infection in the destination country. The US–Mexico Border Infectious Disease Surveillance Project, a study that analyzed characteristics of acute viral hepatitis cases from January 2000 to December 2009, demonstrated that 1,437 cases of acute HAV infection, 311 cases of acute hepatitis B virus (HBV) infection, and 362 cases of acute hepatitis C virus (HCV) infection were reported from five Mexican and two US locations. Mexican HAV infection cases most frequently reported close personal contact with a known case, whereas US cases most often reported cross-border travel. Case–control studies conducted in Italy have shown that the incidence of acute hepatitis A declined from 4 cases per 100,000 people in 1991 to 1.4 cases per 100,000 people in 2006, and the incidence of acute HAV infection was highest among persons aged 15–24 years. The CFR was 2.9 deaths per 10,000 people. Presently, most acute HAV infections are due to contaminated shellfish consumption, travel to endemic areas, and contact with patients with acute HAV infection. For those who live or visit rural areas, the risk of acute HAV infection is highest in those who travel long distances to remote areas or eat and drink in poor sanitary conditions. In developing countries, travelers who follow the “standard” itineraries with respect to accommodations and eating behavior may also develop travel-related hepatitis.
In addition, a study by Heudorf and colleagues showed that there were no significant differences in incidence of hepatitis A between business travelers and tourist travelers. Some special groups, such as those with human immunodeficiency virus (HIV) and immunocompromised travelers appear to be more susceptible to hepatitis A than immunocompetent travelers; however, a recent study has a different conclusion. One study by Mikati and colleagues included 149 travelers of whom 70 travelers (47%) were immunocompromised. Immunocompromised travelers had similar infectious diseases exposure risks to hepatitis A as immunocompetent travelers. Most of the reported travel-related illnesses were of minor nature.
Prevention of Travel-Related HAV Infection
HAV infection prevention measures for travelers include education regarding infectious diseases and food and water precautions as well as vaccination.
Table 1 summarizes the main types of HAV vaccine available, the volume per dose, and the vaccination schedule across the world. Monovalent vaccines are made of inactivated HAV adsorbed to aluminum hydroxide as an adjuvant. A full vaccination series includes two doses. The first dose provides protective anti-HAV titers for at least 12 months, and the second dose increases the duration of protection. Combination vaccines include combination hepatitis A-hepatitis B vaccine (Twinrix Junior, Twinrix, GlaxoSmithKline, Rixensart, Belgium) and combination hepatitis A-typhoid vaccine (Vivaxim, Sanofi Pasteur, Lyon, France). The HAV-HBV combination vaccine generally consists of three doses given on a 0-, 1-, and 6-month schedule. For travelers to HAV endemic areas, there is a rapid vaccination schedule given on a 0-, 7-, and 21-day schedule, and an additional dose should be given after 12 months to maintain long-term immunity. The combination hepatitis A-typhoid vaccine Vivaxim is made of formaldehyde-inactivated HAV and typhoid Vi capsular polysaccharide. Each 1.0 mL dose of mixed vaccine contains 160 enzyme-linked immunosorbent assay (ELISA) units of inactivated HAV antigens and 25 µg purified typhoid Vi capsular polysaccharide strain Ty2. A single dose of Vivaxim should be given on day 0 (day of vaccination), and a second dose of monovalent hepatitis A vaccine should be given between 6 and 36 months after the first dose. The immunogenicity of the combination vaccine is equivalent to that of the monovalent hepatitis vaccines when tested after completion of the licensed schedule. Anti-HAV antibodies persist for at least 20 years. For a person exposed to HAV, the HAV vaccine can provide effective immune protection, but this effect has not been fully confirmed.
Table 1. Inactivated hepatitis A vaccines available: recommended dosages and schedules
Volume per dose
ELISA = enzyme-linked immunosorbent assay; HAV = hepatitis A virus.
Vivaxim first dose: single dose of Vivaxim on day 0; second dose: for long-term protection, a second dose of monovalent hepatitis A vaccine should be given between 6 and 36 months after the first dose.
Avaxim (Sanofi Pasteur)
0.5 mL (160 ELISA units of inactivated HAV antigens)
0, 6–12 months
Havrix Junior (GlaxoSmithKline, Zeist, The Netherlands)
0.5 mL (720 ELISA units of inactivated HAV antigens)
0, 6–12 months
Havrix 1440 (GlaxoSmithKline, Rixensart, Belgium)
1 mL (1440 ELISA units of inactivated HAV antigens)
HAV vaccination can cause some side effects, such as injection site pain (15%–19%), which is more common in children, headache (14%–16%), and general fatigue (5%). No serious adverse events in children or adults have been reported that could be definitively attributed to the vaccine. The current practice of injecting purified immunoglobulin (Ig) intramuscularly has proved to be safe and rarely produces side effects. Ig is a blood product and could theoretically lead to the spread of blood-borne diseases; however, there has been no report of the transmission of infectious diseases, such as HBV, HCV, HIV infections, or syphilis. The safety of the HAV vaccine for pregnant women is uncertain, but the vaccination-associated risk for pregnant women and for fetal growth is very low. The decision to vaccinate a pregnant woman with the HAV vaccine should be based on the individual's risk of HAV exposure. Pregnancy is not currently a contraindication for using Ig treatment. Thus, all susceptible people traveling for any purpose, frequency, or duration to countries with high or intermediate HAV endemicity should be vaccinated or receive Ig before departure. The first dose of hepatitis A vaccine should be administered as soon as travel to countries with high or intermediate endemicity is confirmed.
Children born in developed countries often lack protection against HAV and can be easily infected. Therefore, they should be vaccinated. Children older than 2 years develop protective antibodies in 97 to 100% of cases 1 month after the first injection. In infants younger than 12 months, acquired maternal antibodies can interfere with the immune response induced by HAV vaccines. In these cases, Ig is an option, but is not routinely recommended.
For most healthy people younger than 40 years, one dose of the monovalent HAV vaccine administered at any time before departure can provide adequate protection. The full vaccination should be completed according to the injection schedule for long-term protection. The seroconversion rate progressively increases with time after immunization, being only 80% after 2 weeks but 99% after 1 month. The combination vaccine may take longer to induce detectable antibodies because of smaller vaccine doses. Cases of HAV infection despite vaccination have been reported. One case report described a young man who was vaccinated against HAV with an aluminum-adsorbed vaccine (Havrix 1440, GlaxoSmithKline) 11 days before leaving for Kenya and who contracted an acute symptomatic HAV infection. He was diagnosed with an HAV infection after he returned home, but his symptoms were mild and he had a good recovery. The infection may be related to the short time period between immunization and departure date (only 11 days); however, the mild symptoms suggest that he did acquire some level of protection. For most people older than 40 years, immunocompromised people, or people with chronic liver disease or other chronic disease, HAV infection is more life-threatening, and the HAV vaccine may not be as effective. Suggestions for treating these individuals include giving an initial dose of vaccine along with Ig (0.02 mL/kg) at a separate anatomic injection site at least 1 month before travel. For HIV-positive travelers, hepatitis A vaccine (Epaxal, Berna Biotech Ltd, Bern, Switzerland) was well tolerated and was at least as immunogenic as reported for aluminium-adsorbed vaccines. Epaxal can be considered an immunogenic and safe hepatitis A vaccine in HIV-positive patients.
Those with an allergy to a vaccine component and infants younger than 12 months should also receive a single dose of 0.02 mL/kg body weight, which provides protection against HAV for up to 3 months. If traveling for a long time, ie, more than 3 months, an Ig dose of 0.06 mL/kg should be administered, which must be repeated if the duration of travel is >5 months. Immune globulin (IG) is also recommended for postexposure prophylaxis; a single dose of IG (0.02 mL/kg) will provide certain protection against HAV infection. Decision between a monovalent vaccine or the HAV-HBV combination vaccine should be made based on serology and HBV prevalence at the destination site. HBV is also an important infectious disease that is transmitted mainly from mother to child and through body fluids. Up to one in four travelers are considered at increased risk of exposure to HBV due to sexual activity, body piercing, tattooing, and other high-risk activities. The combined HAV-HBV vaccine reduces the number of required injections and is cost-effective. There is no significant difference in the immunogenicity and tolerability of combined vaccine compared with the monovalent vaccine. In addition to vaccination or IG therapy, travelers need to be aware of the importance of drinking water safety. Prior to consumption, drinking water should be disinfected by boiling or with chlorine.
In conclusion, HAV is one of the most common travel-associated infectious diseases and can be effectively prevented by vaccination. Individuals traveling to HAV-endemic areas should take the initiative to be vaccinated unless the inoculation schedule is unsuitable or there are contraindications. IG also has good effect for short-term prevention, or as a remedial measure after exposure. Personal protection measures are also important, such as avoiding unhealthy, contaminated food or drinking water; boiling or cooking food and water for ≥1 minute to 85°C will inactivate HAV.
This project was supported by the National Natural Science Foundation of China (Grant No.81270515, 81101579, 81072005, 81172312); Shanghai Science and Technology Foundation (Grant No.11430702400); Chinese Foundation for Hepatitis Prevention and Control the WBN Research Foundation(Grant No.20100021); Shanghai Municipal Health Bureau Foundation (Grant No. 2011287, 2012107).
Declaration of Interests
The authors state that they have no conflicts of interest to declare.