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Vaccination is an effective strategy to prevent and control the transmission of hepatitis A. Hepatitis A immunization program has been taken into effect since 2001 in Tianjin, China. This study evaluated the effectiveness of strategies in the prevention and control of hepatitis A. Data of serological survey, annual hepatitis A incidence, immunization coverage and the positive rate of hepatitis A IgG before and after the immunization program in residents under 15 years old were used to do the analysis. The results indicated that hepatitis A vaccine induced a striking decrease of hepatitis A incidence and a significant increase in the positive rate of anti-HAV IgG among the children younger than 15 years old. Hepatitis A vaccination in children was proved to be effective in the prevention and control of hepatitis A in Tianjin, China.
Hepatitis A is an acute infectious disease caused by hepatitis A virus (HAV). In developing countries, its prevalence is very high among children, with the seroprevalence rate up to 100% in adolescence.1,2 Hepatitis A represents a serious public health problem, causing substantial economic burden. It was estimated that about 1.4 million individuals are infected with HAV annually in the world.3 In China, the incidence of hepatitis A ranks first among all types of viral hepatitis in the 1990s.4 More than 300000 hepatitis A cases were reported during a shellfish-associated outbreak in Shanghai in 1988.5,6 A national seroprevalence survey in 1992 demonstrated that the anti-HAV positive rate for hepatitis A was about 80.9% in China. Vaccination has long been proved to be effective since the ancient battle toward various infectious diseases.7 HAV-vaccination has been adopted in many countries such as Italy, Spain, Israel, and the USA.8-11 In China, a national vaccination program against hepatitis A was launched in the late 1990s,12,13 and the incidence decreased from 56/100000 to 10/100000 or even lower in the following 2 decades.
However, fewer studies have been conducted to systematically evaluate the effectiveness of hepatitis A immunization program in China. In this study, we reported a systematic study on the consequence of hepatitis A immunization in the city of Tianjin.
Tianjin, a coastal city near Beijing, has an urban population of over 14 million and is the fourth largest city in China. Hepatitis A was endemic in this city before the year of 1995, when there was no anti-HAV vaccine available.
The incidence rate of hepatitis A in 1990 was 25.26/100000 in Tianjin, accounting for 30.43% of total viral hepatitis cases.13 And the peak incidence rate was observed in 1993, with the rate being 27.03/100000. Since then, the increasing trend has been ceased, mainly attributed to the introduction of hepatitis A vaccine, and the incidence rate dropped to 2.89/100000 in 2000. In this study, a total of 1,363 cases were collected from 2001 to 2010. The incidence rate decreased to 0.85/100000 in 2005 0.26/100000 in 2010 after the expanded program on immunization and its implementation in 2001. A significant decrease of 91.0% was displayed in 10 y. Meanwhile, the proportion of hepatitis A among all types of viral hepatitis has also declined substantially from 4.39% to 0.97% in the ten-year period.
According to the previous reports,14,15 from 1992 to 2000, the incidence of hepatitis A was highest among adolescence under 15 y old, especially in the children aged from 5 to 10 (41.28/100000). After the immunization program, however, such pattern of age distribution disappeared. Moreover, males have higher incidence than females (0.78/100000 vs. 0.37/100000). The sex ratio of the cases was 2.08:1. In addition, two peaks in March and August were observed before the immunization program (Fig. 1). Since 2005, however, with the development of the immune efficacy on booster, the incidence peaks have gradually disappeared.
There were totally 18 districts and counties in Tianjin, including 6 urban districts, 4 town districts, 3 seashore districts, and 5 rural counties. Prior to the immunization program (from 1990 to 1999), the highest incidence rate was found in the 5 rural counties (24.93/100000), followed by the 3 seashore districts (14.53/100000), the 6 urban districts (11.60/100000), and the 4 town districts (9.36/100000). After the immunization program, the annual incidence rate during 2001–2010 declined sharply. The incidence rate became 1.53/100000 in the 5 rural counties, 1.11/100000 in the 6 urban districts, 0.99/100000 in the 3 seashore districts, and 0.74/100000 in the 4 town districts, respectively (Fig. 2).
In our study, under-reporting survey in residents was performed for every three years. Since hepatitis A is classified as a category B notifiable infectious disease in China, we surveyed in terms of the under-reporting rate of category B infectious diseases. In 2001, the misdiagnosis rate and under-reporting rate of category B infectious diseases were 15.1% and 75.8%, while only one hepatitis A case was misdiagnosed. In 2004, the under-reporting rate of category B infectious diseases was 28.8%, and no hepatitis A case was missed or misdiagnosed. In 2007, the under-reporting rate of category B infectious diseases was 74.5%. The internet-based reporting system of infectious diseases was established in China in 2004. Consequently, the under-reporting rate of category B infectious disease in medical institutes declined gradually from 22.2% in 2005 to only 0.5% in 2010. In addition, the under-reporting rate of viral hepatitis declined from 34.8% to 0.7% during the year 2005 to 2010; no hepatitis A case was missed (Table 1).
Hepatitis A vaccine was first introduced in Tianjin in 1995, which mainly targeted at pre-school children. A total of 110000 people were vaccinated in 1996. However, the vaccination rate among children under 15-y-old in 1999 was only 38.25%. In 2000, pilot immunization strategy was implemented in some districts and extended to all districts in the next couple years. Besides, new target groups were introduced, including first-year students in primary schools, first-year students in middle schools and high-risk groups of HAV. The vaccination coverage in targeted population was estimated to be 56–90% using vaccination records in the period from 2001 to 2008, and the rate increased to 89% in 2008 (Table 2). In 2009, two-dose series of hepatitis A inactive vaccine with 6 to 12-mo interval began to be administered to boost the immunity. The vaccination rate of the two-dose inactive vaccine among age-appropriate children was 98% in 2009, and 99% in 2010, respectively.
The hepatitis A antibody survey was performed in 1999, 2005, and 2010. A total of 681 residents aged ≤50 y from He’bei District (urban center), Dong’li District (town area), Bao’di District (rural area), and Tang’gu District (seashore area) in 1999 were selected as samples. The percentage of samples tested positive for anti-HAV IgG was 63.7%, and that for age under 15-y old was 29.9%. The positive rate increased with age.
In 2005, 2350 residents were selected as samples from all the 18 districts. The total positive rate of anti-HAV IgG was 72.3%, the standardized rate with the population was 81.9%, and the positive rate of those under 15-y old was 61.8%. Among all the samples, the rates were 61.4% for children aged from 1 to 10, 65.9% for those from 11 to 20 y old, 76.84% for those from 21- 30 y old, 80.28% for those from 31–40, 94.8% for those from 41 to 50 y old, and 95.9% for those from 51 to 60 y old. The positive rates of anti-HAV IgG increased with ages, when were compared among different age groups using stratified χ2 and trend χ2 tests (χ2 = 161.01, P < 0.0001), and had statistical significance between groups (χ2 = 200.80, P < 0.0001).
In 2010, 1896 residents were chosen as samples. The total positive rate of Anti-HAV IgG was 85.3%, and the positive rate of those under 15-y old was 78.3%. As shown in Table 3, the positive rate was raised from 29.9% to 78.3% from 1999 to 2010 in those under 15. In particular, the most obvious improvement is the positive rate in infants, which was increased from 11.9% (1999) to 80.0% (2010). In addition, we also found that the positive rate was raised with age in all the districts.
Hepatitis A is a highly prevalent disease and is caused by overt infection of hepatitis A virus (HAV) which has 7 genotypes but only 1 serotype. Therefore vaccination can neutralize different genotypes of HAV to control hepatitis A.16 Although environmental and health conditions have been improved in recent 20 y, hepatitis A virus still exists in the environment, and hepatitis A has long been a serious public health problem in Tianjin until 2000. Consequently, herd immunization is realized to be the crucial measure.17 However, after the implementation of the immunization strategy, Tianjin has experienced a sharp decline in hepatitis A incidence and a significant increase in the prevalence of anti-Hepatitis A virus antibody.
With the development in health education and hygiene, environmental condition and health system, various ways have been brought along to control hepatitis A. However, the most effective approach is immunization.18 In this case of Tianjin, hepatitis A vaccine played a critical role in eliminating hepatitis A.13,14 The incidence of HAV decreased gradually since the vaccination was first introduced in Tianjin in 1995. And the epidemic situation was effectively controlled after the immunization strategy was implemented in 2001. Almost 1132000 doses of Hepatitis A vaccines had been dispensed in the following decade. The coverage rate of the target population reached 99% in 2010. Hepatitis A vaccine may have provided significant protection to children and to the entire population as well.13 As the incidence declines, the epidemic pattern of hepatitis A has also changed. Most strikingly, not only the peak of incidence in the group from 5 to 10 y old but also the seasonal and periodic peaks disappeared. The difference in the incidence between rural and urban districts was also gone and the distribution of cases was highly scattered. According to statistics, inactive vaccine was used in more than 100 countries in 2009, among which 18 countries, including China, brought this vaccine into the routine immunization program.19
Moreover, a curve fitting method was applied in our previous study to compare epidemic trends of both hepatitis A and bacillary dysentery in two periods 1990–1999 and 2000–2009. Both diseases had a similar cubic curve mode before the immunization program, but the epidemic trend of hepatitis A changed to an exponential model since the incidence rate of hepatitis A decreased sharply after the program. As the survey showed, the incidence of hepatitis A in 2009 decreased by 88.9% while bacillary dysentery only decreased by 32.2% compared with that in 2000, indicating vaccination was an effective approach.
Report of hepatitis A in Tianjin has high sensitivity. Epidemic data were collected through the passive surveillance system covering all local medical institutions in Tianjin, including health clinics, regional hospitals, and top-level hospitals. And medical practitioners are required to report the cases once their patients fulfill the case definition of hepatitis A. Moreover, internet-based reporting system of infectious diseases was established in China in 2004, and quality of the reporting system has been evaluated since then. Surveys were performed in departments of medicine, pediatrics, gynecology, dermatology, infectious diseases, and emergency. Outpatient logs and inpatient records, patient prescriptions, and/or lab test results were randomly selected to survey the under-report rate of category B infectious diseases, and the rates of under-reporting were found to decrease each year. The survey showed no hepatitis A under-diagnosis and under-report. Besides, with the development of the diagnosis criteria and diagnostic techniques, the diagnosis accuracy of Hepatitis A cases keeps increasing year by year. Although viral hepatitis can be caused by multiple types of viruses with similar clinical manifestations, the viral type is determined by serum analysis.20 This technology is very popular in hospitals in Tianjin and above 94% patients with hepatitis A have been assayed since 2006.
Till now, the vaccination strategy has been performed for over 10 y in Tianjin. The anti-HAV IgG prevalence analysis showed an increase from younger groups to older groups. Attributed to the large population, inadequate sanitation, and poor hygiene which favored HAV circulation and transmission,21 the older population gained high anti-HAV IgG prevalence mainly from natural infection during a long period of time. In contrast, the high prevalence in the group under 5 y old may be principally due to the HAV vaccination.22 Although the positive rate of anti-HAV IgG rises with age, it is inadvisable to conclude that hepatitis A is no longer an important epidemic disease. Some studies showed that the susceptible population is increasing gradually after the vaccine intervention.7 In Europe, the incidence of hepatitis A is very low, but they still spare no effort to strengthen the surveillance.23 Therefore, the prevention and control of hepatitis A is a long battle rather than a short-term project.
In summary, the incidence of hepatitis A dropped sharply, the prevalence of anti-Hepatitis A virus antibody significantly increased, and near elimination of hepatitis A was achieved in the decade after the implementation of the immunization strategy. Therefore, the hepatitis A vaccine proved to be a successful approach in prevention and control of hepatitis A in Tianjin, China.
Hepatitis A is a category B infectious disease in China, therefore mandatory report is required. The epidemic data were obtained from annual report of notifiable infectious diseases in Tianjin. Cases were collected through passive surveillance from local medical institutions to Centers for Disease Control and Prevention (CDC). Cases are defined by the national criteria and principles of management for viral hepatitis A (GB17010-1997) and diagnostic criteria for viral hepatitis A (WS298-2008).Briefly, patients with hepatitis A were identified according to the symptoms of digestive tract (fever, fatigue, anorexia, vomiting, or abdominal distention, constipation, etc.), hepatomegaly with tenderness or hepatic tenderness, substantial elevation of alanine aminotransferase (ALT) by liver function test, positive anti-HAV IgM, as well as history of contaminated food intake 2–7 wk before the onset of symptoms, or a contact history with patients of hepatitis A, and/or history of travel in epidemic areas.
Population data came from statistical yearbook of Tianjin. A series of cross-sectional studies in residents were performed every 3 y. A total of 40000 residents in 18 districts were investigated according to stratified cluster sampling.
We conducted an under-reporting survey to ensure the reliability of the epidemiology data. The clinics and hospitals in 18 districts were selected to survey the under-reporting rate. The clinical records in Internal Medicine outpatient and emergency, pediatrics outpatient and emergency, and inpatient ward were checked.
The immunization program for hepatitis A and the planning for elimination of hepatitis A were implemented in 2001. The vaccine was distributed to the population including one-year-old children, students in the first year of primary and middle schools. A 1-dose schedule of live attenuated vaccine and 2-dose schedule of inactivated vaccine at half-year intervals were recommended. The first dose was administered at the 18th month and a second dose should be administered 6–12 mo later for inactivated vaccines. The coverage of vaccination was estimated by vaccine dispensing and routine immunization reporting system.
The anti-HAV-IgG activities of population aged 1–60 y in 18 districts were collected by seroprevalence surveillance in 1999, 2005, and 2010 with the un-proportional stratified group sampling strategy. The volume of venous blood was 3 mL, collected from every subject, centrifuged to get serum, and stored at –20 °C for the ELISA assay. Reagents were purchased from DiaSorin Company. The results were considered to be positive when the optical density (OD) was less than cut off value (COV) by ELISA Reader.
The data were summarized by arithmetic mean and standard deviation. The difference of positive rate of anti-HAV IgG in residents by age and districts was performed using stratified chi-square test in SPSS v.15.0 software. P < 0.05 was considered statistically significant.
No potential conflicts of interest were disclosed.
The authors are grateful to all workers in district CDC, to Guo Zeyu and Zhao Yixin in the Tianjin Health Bureau for providing special help, and to Abram Wagner from the University of Michigan for comments and help on early versions of this manuscript.