Epidemiology and transmission of hepatitis A in Shaanxi (western China) after more than ten years of universal vaccination

Introduction

As a foodborne disease, the incidence of hepatitis A (HepA) is highly associated with environmental sanitation and economic status (Aggarwal & Goel, 2015). It is usually caused by drinking unclean water or by eating rural food that was contaminated by the hepatitis A virus (HAV), and it appears to be more severe in older populations and populations with underlying medical conditions (WHO, 2010). The prevalence of HepA in China has experienced a significant decline after the introduction of the HepA vaccine into the Expanded Program on Immunization as a complimentary childhood vaccine (Ren et al., 2017), The recommended immunization schedule entails either one dose of live attenuated HepA at 18 months or two doses of inactivated HepA, with the initial dose administered at 18 months and a subsequent dose at 24 months (Wang et al., 2020). HepA was initially prioritized for the urban region and was expanded to province-wide use in Shaanxi by 2010. The declining morbidity of HepA among children, leads to increased susceptibility in older generations who are more likely to suffer from the more severe disease (Wang et al., 2020), highlighting the significance of HepA as an important disease in terms of public health and its burden on the medical system.

Previous seroprevalence studies clearly indicate that a sizable adult population lacks immunity to HAV (Wang et al., 2020), but the percentage and age patterns varied greatly from one province to another across China, higher immunity levels were found in Xinjiang and lower in Shanghai (Zhang et al., 2017; Zhu et al., 2013). Compared to economically developed provinces, the availability of recent epidemiological data for less developed provinces is limited or severely limited. Shaanxi, one of the biggest provinces in western China, had a population of 40 million in 2020. As a less advanced province, its transmission characteristics of HepA are not only affected by migration and food distribution within China but also affected by the imported food from high-endemicity countries and citizens who travel to countries with a high incidence of HepA. As reported in the epidemiological data of Shaanxi province, we evaluated the prevalence of hepatitis A cases. Vaccination programs were also evaluated with serum anti-HAV IgG to determine their impact on hepatitis A incidence.

Materials & Methods

Results

Epidemiological characteristics of reported cases in Shaanxi

As shown in Fig. 1, the annual incidence of HepA was 55.31/100,000 person-years before the HepA vaccine was introduced, then it declined significantly. Since 2008, HepA vaccines have been included in the planned immunization program, and the number of reported cases of HepA gradually decreased, from 3.44/100,000 person-years in 2008 to 0.65/100,000 person-years in 2020. From 2008 to 2019, a total of 4.7 million children were vaccinated, until 2019, almost all children aged 1.5–9 years in Shaanxi were vaccinated for HepA (Fig. 1). In the years before the HepA vaccine was included as a free vaccine in the EPI system (2005–2008), the HepA incidence among younger age groups (0–19 years) accounted for the largest proportion (31.9%–42.9%), In 2013, the number of reported cases aged 0–19 years declined sharply to 10.4%, and in 2020, it had declined to less than 2% (Fig. 2A). This phenomenon was more pronounced in children aged 0–9 years (Fig. 2B). This was accompanied by individuals aged 40–49 years who occupied a relatively larger proportion of the total. From 2015–2020, infections were more likely to occur in people in their 40s and those over the age of 60. Infections were initially mainly diagnosed in males (63%), but after 2018 there was almost a 50/50 split between males and females (Fig. 3). In the pre-vaccine era, hepatitis A incidence was highest among students, children in kindergarten, and farmers. However, the proportion of students and children in kindergarten decreased significantly after 2012, which was nearly 80% lower than that of the peak. In contrast, farmers remained the predominant occupation associated with HepA. It is noteworthy that there has been a gradual increase in the incidence of HepA among service providers over time (Fig. 4).

Discussion

It is well established that socioeconomic improvements are highly related to the incidence of HepA and the rate of HepA vaccination (Aggarwal & Goel, 2015; Zhang et al., 2008). In recent decades, GDP per capita increased rapidly in China, but with significant differences in the rate of increase. Provinces were categorized into three regions—eastern, central, and western indicating high (eastern) to low (western) socio-economic development. Similarly, the morbidity of HAV infection decreased in all three regions with the highest incidence shifting from the eastern region to the western region (Sun et al., 2019). However, the passive reporting system of HepA ignored asymptomatic infections, incidence rates could be underestimated by only a single aspect. For this reason, seroprevalence studies can provide a more accurate picture of the circulation of HAV. Previous research estimated that China has decreased from a high to an intermediate HAV endemicity (Aggarwal & Goel, 2015; Wang et al., 2020). This study provides a new aspect of HAV transmission characteristics in China under a similar vaccination policy among provinces with different economic statuses.

First, we collected details of reported cases in Shaanxi province with a less developed economy and a low rate of HepA vaccination among adults. Then we also performed a serological study since seroprevalence in the adult population is very much influenced by the time during which the overall level of endemicity in a certain region shifted from high to low. We found the prevalence of HepA decreased over time, especially for children and adolescents. It is credited mostly to HepA vaccination, but also to public awareness, improved social hygiene, and improvements in sewage treatment and water quality. However, the overall decrease in incidence was accompanied by a progressive rise in the average age of reported cases. This may be a result of the inclusion of the EPI only targeting children older than 18 months. This phenomenon has been observed in many countries where EPI for children was deployed (Jacobsen, 2018). While farmers and individuals who live in rural areas are still the key populations of HepA, the probable reasons were: using well water as a source of drinking, and a relatively compromised sewage treatment system (Chen et al., 2011). Although the total incidence of HepA dramatically decreased (Fig. 1), the estimated anti-HAV seroprevalence rate among individuals aged 30 was still high, indicating the continuous local circulation of HAV. Unlike other studies from either developing (Aggarwal & Goel, 2015) or developed regions (Carrillo-Santisteve et al., 2017), Shaanxi presented a U-shaped pattern of age-specific anti-HAV seroprevalence. Individuals born prior to the national introduction of the HepA vaccine (1992–2008) had lower anti-HAV seroprevalence than earlier (>87.8%) and later birth cohorts (80.9%). There are several contributing factors: first, as a developing country, China used to be a high HAV endemicity country (Sun et al., 2018), the anti-HAV seroprevalence usually increases with age, and most senior citizens were supposed to have acquired immunity through natural infection at an early age. In Shaanxi, more than 90% of individuals aged 28 years and over has immunity to HAV. Similar findings were observed across nearly all provinces in China (Wang et al., 2020). Second, the years from 2008 to 2011 form the transitional period for HepA integration into the EPI in China. Our study revealed that in Shaanxi, the target population achieved a coverage rate exceeding 99%, while individuals born after 2008 exhibited an anti-HAV seroprevalence rate of 80.9%. This robust evidence underscores the significant impact of HepA vaccination on the distribution of anti-HAV seroprevalence. Third, vaccinated children would not be efficient transmitters and represent a reservoir of HAV in the community, along with improvement of the social-economic situation and public education, fewer individuals would expose to HAV before they reach adolescence or adulthood. This may explain why unvaccinated individuals born between 1992 to 2008 had the lowest anti-HAV seroprevalence rate.

In terms of transmission routine, we had a low yield rate of HAV RNA from reported cases, a possible reason we have explained in our previous study, one potential explanation for the observed low rate could be attributed to the heightened sensitivity but limited specificity of the case reporting criteria in accurately identifying genuine HepA cases (Hu et al., 2021). Therefore, we are unable to find out the genomic relationship between those cases. The possible causes for this phenomenon are as follows: first, due to the limitation of our sample size, we cannot identify the actual transmission routine of HepA. In outbreak settings, without the inclusion of testing of all contacts, the identification of chains of transmission may be incomplete. Secondly, recall bias may have occurred because we asked interviewees to recall eating habits. some people failed to recognize that semi-cooked seafood still can contain pathogens, and cooking food fully and preparing raw and cooked food separately were always the key messages to avoid food-borne diseases. There was evidence of community spread in the study, and the source of the infection was unknown to the majority of participants. In order to have effective control, contact tracing and stopping transmission from contacts are essential.

Achieving a low incidence of HepA will require not only maintaining high coverage levels in the childhood vaccination program but implementing tailored strategies for provinces/municipalities with different endemicity. Generally, immunization program implementation with a catch-up strategy may be needed to avoid a possible future HAV outbreak. In this study, we demonstrated a U-shaped curve of age-specific HAV susceptibility prevalence in Shaanxi, where those born between 1980–2008 were most susceptible. However, a catch-up vaccination among young adults may not be cost-effective in high-endemicity provinces/municipalities where susceptibility in adults was low. In the case of Xinjiang, as well as the rural areas of many provinces/municipalities, more efforts need to be done for strengthening routine childhood immunization programs since timely vaccination for children was low (Liu et al., 2020; Sun et al., 2019). In addition, studies have demonstrated that anti-HAV seroprevalence was higher in rural areas than in urban areas, possible reasons could be that people are still drinking underground water or spring water in some rural areas (Chen et al., 2011; Ning, Zhengyi & Chaozhong, 2016), and use unsafe sanitation facilities which can facilitate HAV from the waste find their way into the local water supply (Kaifa et al., 2018; Kun, Hongying & Lunhong, 2018). Therefore, it is also important to promote better sanitation and safe drinking water. In provinces/municipalities with moderate endemicity, it is imperative to closely monitor the transmission characteristics of HAV in order to assess the effectiveness of preventive measures aimed at limiting risky behaviors. For instance, laboratory-based surveillance for HepA should be developed, allowing for early detection and precision investigation of outbreaks, describing transmission patterns, and better-targeted disease control (Hu, Collier & Xu, 2019). Evaluations that identify feasible approaches to mitigate the risk of HAV outbreaks due to the immunity gap are urgent priorities.

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