Changing epidemiological characteristics of Hepatitis A and warning of Anti-HAV immunity in Beijing, China: a comparison of prevalence from 1990 to 2017

ABSTRACT

Backgroud: Beijing was hyper-endemic for hepatitis A until the 1990s and has been vaccinating against hepatitis A since 1994. The objective is to study the epidemiology and changes of antibody level of hepatitis A from 1990 to 2017.

Methods: A multistage randomized cluster sampling serological cross-sectional study was conducted in individuals over one year old in 1992, 2006 and 2014 in Beijing. Venous blood samples were collected to test anti-HAV antibody. The incidence data of hepatitis A were obtained from National Notifiable Disease Reporting System (NNDRS) and CDC statistics in Beijing. The vaccination data of hepatitis A immunization were acquired from Beijing Immune Information System.

Results: From 1990 to 2017, the reported incidence rate of HAV in Beijing declined from 59.41/100,000 in 1990 to 0.80/100,000 in 2017. The average age of HAV infection was postponed from individuals under 20 years old to individuals over 20 years old. After hepatitis A vaccine was introduced to Beijing, the outbreak of hepatitis A decreased sharply. Adjusted anti-HAV positive rate in general population was 68.23%, 81.73% and 82.47% respectively in 1992, 2006 and 2014. Due to hepatitis A vaccination conducted in children, the anti-HAV positive rate in individuals under 20 years old increased from 1992 to 2014, while in individuals over 20, this rate was barely changed. The coverage rate in target population was higher than 99% after hepatitis A vaccine was integrated into Expanded Program on Immunization (EPI).

Conclusion: Incidence rate of hepatitis A in Beijing has decreased dramatically from 1990 to 2017. Hepatitis A vaccine plays an important role in protecting individuals under 20 years old. A higher proportion of adults will be susceptible to hepatitis A virus due to the decay of antibodies as they grow up from childhood to adulthood, which may result in possible outbreak of hepatitis A.

Introduction

Hepatitis A, caused by hepatitis A virus (HAV), is mostly transmitted via fecal–oral route either by contaminated food, water ingestion or via person-to-person contact.¹ Infection in young children is generally asymptomatic, while in older children and adults, infection is usually icteric.² In developing countries, its prevalence is very high among children, with the seroprevalence rate up to 100% in adolescence.^3,4 China, especially in the north of the country, was hyper-endemic for hepatitis A until the middle 1990s.⁵ The incidence of hepatitis A ranked first among all types of viral hepatitis in the 1990s.⁶ A national seroprevalence survey in 1992 demonstrated that the anti-HAV positive rate for hepatitis A was about 80.9% in China.⁷ Hepatitis A vaccines are highly effective in preventing both clinical hepatitis and in reducing disease spread.¹ In China, a national vaccination program against hepatitis A was launched in the late 1990s, and the incidence decreased from 56/100 000 to 10/100 000 and even lower in the following 2 decades.¹

Beijing has been vaccinating against hepatitis A since 1994. The fee of vaccine and administration, however, prevent some parents from having their children vaccinated. Since 2008, hepatitis A vaccine was integrated into National Expanded Program on Immunization (EPI) and the government required that all infant receive hepatitis A vaccinations with no charge to parents. In Beijing, all infants get one dose of inactivated hepatitis A vaccine at 18 and 24 months old. In 2011, expanded immunization of hepatitis A vaccine was carried out. Children born after 2002 who had not been vaccinated against hepatitis A would receive 2 dose of free inactivated hepatitis A vaccine. Benefit from vaccine program and economic development, there has been no outbreak of hepatitis A in Beijing Since 2004.

In China, hepatitis cases have been reported separately by virus type since 1990. National Notifiable Disease Reporting System (NNDRS) is a hospital-based, passive national surveillance system that has included all county hospitals in 31 provinces.¹ Before 2003, cases were reported monthly to county Centers for Disease Control and Prevention (CDC) via hardcopy (case and hardcopy-based NNDRS), and through prefecture and provincial CDC to national authorities ¹. In 2004, national CDC revised the reporting system, establishing an online electronic version (case and computer-based).¹ Epidemiological characteristics of hepatitis A were acquired from NNDRS including age, sex, location of residence, and date of onset et al.

The objective of this study is to analyze the epidemiological characteristics of hepatitis A, as well as the antibody of hepatitis A in Beijing from 1990 to 2017. At the same time, combined with the data of vaccination rate, we aim to provide support for prevention and control of hepatitis A in Beijing.

Results

Anti-HAV positive rate between 1992, 2006 and 2014

2742 individuals (1272 males) in 1992, 5078 individuals (2372 males) in 2006 and 6705 individuals (3170 males) in 2014 were interviewed and tested for anti-HAV IgG antibody. Age of individuals were 27.48 ± 15.93, 42.61 ± 18.52 and 38.08 ± 18.08 respectively in 1992, 2006 and 2014. Age-specific anti-HAV positive rate were showed in Table 1 and Figure 1. Anti-HAV positive rate in general population was 73.56%, 85.44% and 81.86% (χ² = 167.92, P＜0.05) and adjusted rate was 68.23%, 81.73% and 82.47% respectively in 1992, 2006 and 2014. Anti-HAV positive rate ranged from low to high with the increase of age in 1992 and 2006 before hepatitis A vaccine was integrated into the national EPI. In 2014, anti-HAV positive rate was high in individuals under 10 years old and over 20 years old. Anti-HAV positive rate was less than 50% in individuals under 20 years old in 1992. In contrast, this rate was high in individuals under 20 years old in 2014 because of hepatitis A vaccine. In individuals over 20 years old, anti-HAV positive rate in each age group showed few differences in 1992, 2006 and 2014. Compared with 2006 and 2014, anti-HAV positive rate in individuals over 20 years old even decreased from 89.09% in 2006 to 84.03% in 2014. Age-specific anti-HAV positive rate among vaccinated individuals under 20 years old in 2014 was showed in Figure 2. The anti-HAV positive rate in vaccinated group was higher than 90% between 1 to 6 years old, and decreased to 80% between 7 to 8 years old. This rate dropped to just 61.97% between 10 to 14 years old and gradually back to 80% between 17 to 20 years old.

Table 1.

Age-specific positive anti-HAV rate in Beijing in 1992, 2006 and 2014.

	1992			2006			2014
Age (Year)	No. of tested	No. of positive	Positive rate (%)	No. of tested	No. of positive	Positive rate (%)	No. of tested	No. of positive	Positive rate (%)
1～	169	30	17.75	66	32	48.48	249	214	85.94
5～	292	102	34.93	154	92	59.74	213	176	82.63
10～	248	115	46.37	232	138	59.48	184	109	59.24
15～	130	67	51.54	263	190	72.24	348	191	54.89
20～	193	151	78.24	325	235	72.31	766	541	70.63
25～	288	235	81.60	276	176	63.77	734	557	75.89
30～	389	338	86.89	354	275	77.68	635	459	72.28
35～	344	310	97.12	437	368	84.21	533	419	78.61
40～	377	366	90.08	1064	956	89.85	1172	1012	86.35
50～	312	303	97.12	1010	985	97.52	1052	1021	97.05
60～	0	0	-	896	891	99.44	817	788	96.45
Total	2742	2017	73.56	5077	4338	85.44	6703	5487	81.86
Adjusted rate*			68.23			81.73			82.47

Adjusted rate*: The resident population of Beijing in 2014 as the standard population

Figure 1.

Charging of positive anti-HAV rate in Beijing in 1992, 2006 and 2014.

Figure 2.

Age-specific positive anti-HAV rate among vaccinated population under 20 years old in 2014.

The incidence rate and outbreak of HAV in Beijing

From 1990 to 2017, the overall reported incidence rate of HAV in Beijing declined from 59.41/100,000 in 1990 to 0.80/100,000 in 2017, with a peak in 1999 mainly due to hepatitis A outbreak in part of the suburban students. The numbers of reported HAV cases and incidence rate from 2004 to 2017 were shown in Table 2. The incidence rate of HAV has dropped to below 1/100,000 now. The number of reported HAV cases decreased continually especially in individuals under 20 years old. The number of reported HAV cases over 20 years old decreased from 2000 to2008 and has kept between 100 and 200 cases from 2009 to 2017. The average age of HAV infection was postponed from individuals under 20 years old to individuals over 20 years old.

Table 2.

The number of reported HAV cases and incidence rate from 2004 to 2017.

	0–10 years old		10–20 years old		Over 20 years old
Year	Case number	Incidence Rate (1/100,000)	Case number	Incidence Rate (1/100,000)	Case number	Incidence Rate (1/100,000)
2004	22	2.52	34	1.96	399	3.27
2005	18	1.42	24	0.92	307	2.67
2006	12	0.93	21	0.83	293	2.54
2007	22	1.61	12	0.48	229	1.92
2008	15	1.03	14	0.57	238	1.91
2009	3	0.19	6	0.25	147	1.13
2010	4	0.24	6	0.25	117	0.87
2011	3	0.31	3	0.14	109	0.66
2012	0	0.00	3	0.20	79	0.45
2013	2	0.15	3	0.21	83	0.46
2014	0	0.00	3	0.20	140	0.77
2015	0	0.00	1	0.07	107	0.58
2016	0	0.00	0	0.00	141	0.75
2017	1	0.06	4	0.26	169	0.91

From 1990–1993, there were 192 outbreaks of hepatitis A in Beijing. After hepatitis A vaccine was introduced to Beijing in 1994, the outbreak of hepatitis A decreased sharply. After hepatitis A vaccine was introduced, the vaccine coverage rate was very low, therefore the outbreaks could not be effectively prevented. In 1999, the number of hepatitis A outbreaks was particularly high. The reason was the low coverage rate of hepatitis A vaccine and poor sanitation in suburban schools that results in students’ infection outbreak. With the increase of vaccine coverage rate, there was no hepatitis A outbreak after 2004. (Figure 3)

Figure 3.

Outbreaks of Hepatitis A in Beijing from 1990 to 2004.

Hepatitis A vaccine immunization in Beijing

Hepatitis A vaccine was integrated into the national EPI program since 2008. After hepatitis A vaccine was included in the EPI, hepatitis A vaccine coverage data began to be collected routinely. From 2008 to 2016, 2,081,035 children received the first dose of hepatitis A vaccine and the coverage rate of first dose was 99.93%. 1,909,710 children received the second dose of hepatitis A vaccine and the coverage rate of second dose was 99.89%. The coverage rate of hepatitis A vaccine in Beijing from 2008 to 2014 was showed in Table 3.

Table 3.

The coverage rate of hepatitis A vaccine in Beijing from 2008 to 2014.

	First dose			Second dose
Year	Children should vaccine	Children actually immunized	Vaccine rate (%)	Children should vaccine	Children actually immunized	Vaccine rate (%)
2008	108,596	108,491	99.90	54,154	54,102	99.90
2009	185,142	185,086	99.97	140,687	140,574	99.92
2010	197,508	197,181	99.83	167,839	167,625	99.87
2011	259,600	259,501	99.96	245,533	245,367	99.93
2012	238,115	238,087	99.99	262,870	262,838	99.99
2013	266,990	266,969	99.99	243,493	243,464	99.99
2014	275,511	275,472	99.99	268,598	268,544	99.98
2015	270,574	270,386	99.93	246,348	246,244	99.96
2016	280,428	279,862	99.80	282,260	280,952	99.54
Total	2,082,464	2,081,035	99.93	1,911,782	1,909,710	99.89

Discussion

China, especially in the north of the country, was hyper-endemic for hepatitis A until the 1990s.^5,8 Disease surveillance data describes a dramatic decrease in incidence rate of reported hepatitis A in Beijing from 1990 to 2017. Before hepatitis A vaccine was introduced in 1994, the overall incidence rate of hepatitis A in Beijing was between 40 to 50 cases per 100,000 individuals which were very high. After hepatitis A vaccine was introduced, the overall incidence rate of hepatitis A decreased, and less than 1 case per 100,000 individual was reported since 2008. This rate was similar to that of developed countries, such as the United States of America (0.4–0.6 per 100,000 population between 2009 and 2013),⁹ Germany (1 per 100,000 population in 2012),¹⁰ Denmark (1 per 100,000 population in 2012),¹⁰ and the Netherlands (0.7 per 100,000 population in 2012).¹⁰ Several factors may contribute to this change. First, with substantial development of economic, hygiene, environmental and public education, fewer people were infected with hepatitis A via water and food. These factors contributed to the rapid decline in HAV risk in China during the 1990s.¹¹ Second, the most effective approach to control hepatitis A is immunization. The number of reported HAV cases under 20 years old decreased continually due to the effect of hepatitis A vaccine in children. The outbreaks of hepatitis A decreased sharply after vaccine was introduced into Beijing After hepatitis A vaccine was introduced, the vaccine coverage rate was very low, so the outbreaks could not be effectively prevented. In 1999, there were several outbreaks of hepatitis A in primary and middle school in Beijing. Therefore, the incidence of hepatitis A in 1999 increased dramatically comparing with the previous year. After emergency vaccination, hepatitis A outbreak had been controlled. Since the introduction of free hepatitis A vaccine in 2008, the epidemic situation of hepatitis A was effectively controlled. The number of reported HAV cases under 20 years old has been kept below 10 cases per year after 2009 and reported HAV cases mainly converged in individuals over 20 years old. Almost 3,990,745 doses of hepatitis A vaccine had been dispensed after 2008. The coverage rate of target population reached more than 99%.

In Beijing, three seroepidemiological studies were conducted in 1992, 2006 and 2014. The data of 1992 reflected anti-HAV positive rate of natural infection period. The data of 2006 reflected anti-HAV positive rate of fee-charging vaccine period. The data of 2014 reflected anti-HAV positive rate of free-charging vaccine period. In 1992, the anti-HAV positive rate was 73.56% and increased with age which reflected natural infection. The anti-HAV positive rate in 2006 and 2014 were 85.44% and 81.86% respectively. Compared with 1992, the anti-HAV positive rate was significantly increased because of increased anti-HAV positive rates in individuals under 20 years old with the wider coverage of vaccine. While, in individuals over 20 years old, anti-HAV positive rate in each age group had no significant changes in 1992, 2006 and 2014. Compared with 2006 and 2014, anti-HAV positive rate in individuals over 20 years old even decreased from 89.09% in 2006 to 84.03% in 2014 with substantial development of economic and hygiene. anti-HAV positive rate increased in individuals under 20 years old but decreased in individuals over 20 years old, which resulted in little change of anti-HAV positive rate in whole age group between 2006 and 2014. The vaccine group under 20 years old has a higher anti-HAV positive rate than unvaccinated group, but the rate of individuals over 20 years old is the same. This demonstrates the impact of immunization, and also the natural infection remains. Exposure to hepatitis A virus could confer lifelong immunity.⁸ Several studies reported that the vaccine induced immunity last to a certain extent and protect the body from infection,^12-15but vaccine-induced immunity is different from immunity acquired from natural infection. We still don’t know what is going on in 20 years or even 50 years after vaccine. From the seroepidemiological studies in 2014, we could find the antibody attenuation trend in vaccinated children. The anti-HAV positive rate in vaccinated group between 10 to 14 years old was just 61.97% which suggested that the persistence of our vaccine may not last long enough. If immunity caused by vaccine decreases when immunized children become adults, some outbreak may occur, the symptoms in adults will be serious and disease burden will increase. Further research should be done to determine whether there is a need to booster immunization in this population between 10 to 14 years.

A potential limitation of the study is that the incidence rate of hepatitis A and the coverage rate of hepatitis A vaccine were based on passive surveillance data and reports of vaccine inoculation. The accuracy of the reported data cannot be verified by the available data. Second, inoculation information of hepatitis A vaccine in individuals over 18 years old in seroepidemiological studies was from study objects’ self-reported data, so there may be recall bias involved. But inoculation information of hepatitis A vaccine in individuals under 18 years old was based on inoculation record.

In summary, the incidence rate of hepatitis A in Beijing decreased dramatically from 1990 to 2017. Hepatitis A vaccine plays an important role in protecting individuals under 20 years old. A higher proportion of adults will be susceptible to hepatitis A virus due to the decay of antibodies as they grow up from childhood to adulthood, which will result in possible outbreak of hepatitis A in Beijing. Further research should be done to determine whether there is a need to booster immunization in children between 10 to 14 years old.

Materials and methods

Study design and subjects

A multistage cluster sampling was used for the three serological cross-sectional studies in general population over one year old in 1992, 2006 and 2014，respectively，in Beijing. Firstly, four urban districts – Dongcheng, Xuanwu, Fengtai, Haidian and three suburban districts – Tongzhou, Daxing, Changping were sampled as survey districts in 1992. Five urban districts – Dongcheng, Xicheng, Xuanwu, Chaoyang, Haidian and five suburban districts – Changping, Tongzhou, Fangshan, Miyun, Huairou were sampled as survey districts in 2006 and 2014 respectively. Secondly, three spots in each survey district in 1992 and two spots in each survey district in 2006 and 2014 were sampled randomly. Thirdly, subjects aged over one year old in each spot were selected by random numbered table. A self-designed questionnaire was used to collect the basic information and history of hepatitis A vaccine immunization. Venous blood samples were collected from each subject to test anti-HAV.

Laboratory tests

The serum samples were tested for anti-HAV antibodies using a domestic ELISA reagent (Tangshan medical biology Technology Development Company, Tangshan, China) in 1992 and using Abbott-Architect i2000 (Chemiluminescence Microparticle Immunoassay, Abbott, Chicago, USA) in 2006 and 2014. Anti-HAV positive was defined as S/CO≥ 1.

Case data

The epidemic data of hepatitis A were obtained from annual NNDRS in Beijing. Cases were defined by national criteria and principles of management for viral hepatitis A (GB17010-1997) and national diagnostic criteria for viral hepatitis A (WS 298–2008). Age, sex, location of residence, and date of onset of cases were collected and analyzed.

Immunization data

The immunization data of hepatitis A vaccine were acquired from Beijing Immune Information System which included the number of children who should be vaccinated and the actual number of vaccinated. The coverage rate of hepatitis A vaccine at 18th month and 24th month is calculated.

Ethics

The study was approved by the medical ethics committee in China CDC in 1992 and approved by the medical ethics committee in Beijing CDC in 2006 and 2014. Written inform consent was obtained from each adult or parent/guardian of each child. The procedure of the study was in accordance with the Good Clinical Practice Guidelines and the ethical standards of the Helsinki Declaration.

Statistical analysis

Hypothesis testing was 2-sided with an α value of 0.05. Positive rate was defined as an anti-HAV IgG S/CO≥ 1. Statistics were performed using SPSS 18.0 software. Percentage between different groups was compared using the χ² or Fisher’s exact test. P＜0.05 was considered statistically significant.

Abbreviations

NNDRS

National Notifiable Disease Reporting System

HAV

Hepatitis A virus

EPI

National Expanded Program on Immunization\

CDC

Centers for Disease Control and Prevention;

Funding Statement

This work was funded by Beijing Municipal Health and Family Planning Commission.

Disclosure of potential conflicts of interest

No potential conflict of interest was reported by the authors.

Acknowledgments

We acknowledge all the adults who took part in the study and all the personnel from the Beijing Center Disease Control and Prevention, District Center for Disease Control and Prevention who took part in collection of samples. We also acknowledge Hui Li and Li Wang from Chinese Academy of Medical Sciences and Peking Union Medical College to give valuabe advice to this paper.