Hepatitis B virus (HBV) is responsible for one of the most critical human viral infections. The virus is responsible for acute and chronic liver diseases, ranging from a healthy carrier state to cirrhosis and finally hepatocellular carcinoma (HCC).1 According to the latest World Health Organization (WHO) report, 257 million people are estimated to live with chronic HBV infection worldwide, and mortality has reached to 900,000 deaths in recent years, mostly from complications such as HCC or cirrhosis.2

The overall prevalence of HBV infection in the world was estimated at 3.6%, but it depends on the geographic area. The prevalence of chronic HBV (positive HBV surface antigen or HBsAg) ranges from less than 2% in some areas with a low-prevalence situation (e.g. Western Europe) to 2–7% in intermediate-prevalence regions (eg, Mediterranean countries, and the Middle East) to more than 8% in high-prevalence areas (e.g. Western Africa).3–5

According to the reports of WHO in 2001 and of the Centers for Disease Control and Prevention (CDC) in 2005, the prevalence of chronic hepatitis B infection among Iranian population ranges between 2–7%.6,7 This wide range of prevalence is due to the different geographical areas in the country with variable customs and cultures.8–11

The important point in the management of HBV infection is that it emerges regardless of available therapeutic modalities such as interferon and antiviral therapies. There is no definite cure for HBV infection.12 On the other hand, the presence of antibody to hepatitis B surface antigen (anti-HBs) was associated with resistance to reinfection, including differing serologically-defined subtypes or serotypes.13 This raised the possibility that a neutralizing antibody either from an immune globulin or vaccine-induced might protect against HBV infection, since the hepatitis B vaccine was shown to prevent HBV infection effectively.14 Thus, strategies such as neonatal vaccination against hepatitis B, particularly those born to HBV infected mothers is the most effective strategy to diminish the spread of HBV in the community.15

In July 2016, the WHO announced its new "Global Health Sector Strategy on Viral Hepatitis, 2016-2021″ outlining a plan to reduce transmission of all hepatitis viruses and their disease burden.16 The goals for 2020 are 30% declining in new HBV infections, and also an HBsAg prevalence in children of no more than 1.0% and, by 2030, a 90% decline in new infections with a prevalence in children of no more than 0.1%. The specific goal for the prevention of mother-to-child transmission is to improve delivery of a birth dose of vaccine from the 2015 worldwide baseline of 39% to 50% by 2020 and 90% by 2030 with HBV testing in all pregnant women and development of new interventions based on antiviral treatment.16

The epidemiology of HBV has been extensively studied in the pre-vaccine era, but after introducing the vaccine, few studies have addressed this issue. On the other hand, these studies have had different results and reported the effectiveness of hepatitis B vaccination from low to high.17

In the Islamic Republic of Iran, mass vaccination against HBV infection started in 1993. This program has launched a new era of hepatitis B control and was one of the first large-scale HBV programs in the region. It was mandatory for neonates born after this time to be vaccinated using a recombinant HBV surface antigen with classic three consecutive doses. In this survey, we assessed the impact of the national HBV mass vaccination program on the chronic carriage of HBV and the rate of HBV acquisition in the Iranian population 25 years after implementation of the national vaccination program.

Study Design: retrospective or historical cohort study for the evaluation of HBV vaccination impact.

Data analysis

All data were double entered and analyzed with IBM SPSS Statistics for Windows version 20.0 (IBM Corp. 2011. Armonk, NY: IBM Corp.). Descriptive statistics were first provided at 95% confidence interval (95% CI). The Chi-square test was run to compare categorical variables. A p-value less than 0.05 was considered statistically significant.

According to the obtained incidence rates, the risk ratio (RR) and 95% CI were calculated, as was the vaccine effectiveness (VE) using the formula: VE = (1-RR) *100 and the 95% CI were estimated using the Taylor series,

VEL1 = (1-RRU2) × 100

VEU3 = (l-RRL4) × 100

Hepatitis B is a serious infectious disease in Iran and our region. For that reason, we evaluated the impact of neonatal hepatitis B vaccination on HBV infection seromarkers in Iranians who were fully vaccinated at birth and compared it with an unvaccinated group. Based on the national serosurvey in 1980, prevalence of HBsAg in Iranian population was about 3.5% for all age groups, including young children.23 A review article published by Merat et al.10 in the 1980s indicated that 3% of the Iranian population were chronic HBsAg carriers. In 1996, in another national study by Zali et al., the rate of HBV carriers ranged between zero and 3.9% with an average of 1.7%.24 Older males living in rural areas with poor sanitation, low socioeconomic status, and family close contact were the main risk factors for hepatitis B infection in Iran at the time the study was conducted. Based on the results of our study, among unvaccinated individuals, HBV infection was associated with history of a family member with hepatitis B infection, but no such association was seen in the vaccinated group. One possible reason for this finding is that vaccination may not only have a direct effect on reducing HBV infection, but may also reduce the risk hepatitis B infection in family members. Therefore, it is recommended that in future studies, this relationship be investigated in more detail.

The findings from our study revealed that the mean HBsAg prevalence in the Iranian population is now close to 0.9% with a significant decline in the vaccinated population with a rate of 0.6%. In respect of the WHO goal of 1.0% prevalence of HBsAg by 2020,25,26 it seems that Iran already achieved it. Therefore, a universal infant immunization program in Iran had a major role in the control of the HBsAg carriage. These findings are compatible with other international studies.27,28 A series of long-term follow-up reports in the literature with vaccinated infants has shown that the universal immunization with the hepatitis B vaccine starting at birth has intensely reduced the subsequent development of chronic hepatitis B infection in the vaccinated population. Moreover, it affects both HBsAg carrier state and subsequent HBV complications such as HCC. These beneficial effects were detected in regions of both high endemicity27–29 and a low endemicity of HBV infection.16,25,30–33 Also, in an important report of the WHO Western Pacific Region, in 22 of 36 countries, including China, the prevalence of HBsAg positivity was 8% or more before the introduction of hepatitis B vaccination. With broadening hepatitis B vaccination coverage, including implementation of infantile vaccination program, the prevalence of HBsAg among children born in 2012 had decreased to less than 1% in 24 of 36 countries.34 Also, in another study in Malaysia, HBsAg seroprevalence among 7–12-year-old children decreased from 1.6% in 1997 to 0.3% in 2003 after implementing a universal infant vaccination program in 1990.35

In the other part of our study, we demonstrated a significant difference in the prevalence of HBV infection (by documenting HBV seromarkers) between vaccinated and unvaccinated groups. These finding confirms the results of other researchers on the effectiveness of the HBV vaccination as a means to decrease the prevalence of HBV infection and its complication such as cirrhosis and HCC.36–38 Also, our findings are consistent with those found in Italy, the pioneer of systematic vaccination in the world in 1991 in adolescents aged 12 years,39 where hepatitis B rates reduced from 5.1 per 100,000, in 1991 to 1.3 in 2005.40

In our study, the effectiveness of hepatitis B vaccination against chronic carriage of HBV was 51% 25 years after immunization, and the effectiveness against infection was 29%. This figure shows the effectiveness of the universal infancy vaccination program in Iran, but these figures are lower in comparison with other similar studies carried out in areas with high endemicity. In those areas, systematic vaccination has reduced the prevalence of HBsAg by as much as 90% in some reports.21,41 For understanding this discrepancy, we have two important explanations. First of all, there is some difference between the statistical method for the detection of vaccine effectiveness and mechanical models of vaccine effects. In other words, dynamic epidemiological models have to rely on spatiotemporally determined data, whereas epidemiological data regularly act static, and therefore are more responsive to the tools of statistics.42 So, we can find some differences between true vaccination effectiveness and calculated effectiveness in static studies. As a second explanation, advancing age has been shown to be a factor that adversely affects the immune response to hepatitis B vaccination or to other vaccines.43 Thus, after 25 years of infantile vaccination program, it is more likely for infection cases to occur which can affect vaccine effectiveness. Therefore, the present study had a lower vaccine effectiveness than studies conducted shortly after vaccination.

According to WHO recommendation, this strategy (global vaccination) should be continued and also other vaccination strategies such as vaccination in high-risk groups can be used in combination. It should be mentioned that the isolated at-risk approach is not the most effective strategy for reducing HBV prevalence, even in low-endemicity countries, as it is very labor intensive and more expensive to implement.44 It has been known that to reach a rapid impact on disease incidence, the ideal hepatitis B immunization strategy is implementation of universal vaccination in children or adolescents, or both.45

The present study had some strengths, such as cohort study design and evaluation of the long-term effects of hepatitis B vaccination among people who were sexually active.

One of the limitations of our study was resistance to be part of the study as participation was voluntary. Another probable limitation was the lack of specific data on the vaccination history in the health cards of the study participants, but this was resolved by searching for information from other available data sources, so the effect of this limitation was reduced.

The present study showed the impact of the national universal infantile HBV vaccination program in Iran, and we demonstrated for the first time HBV vaccination effectiveness after 25 years of program implementation. According to our findings, Iran has successfully integrated the hepatitis B vaccine into routine immunization programs and has achieved a very significant effect on decreasing the HBsAg carrier rate among those born in 1994 and afterwards. The rate of hepatitis B surface antigen decreased gradually from 3.5% before the vaccination program to 0.6% among the vaccinated group in recent years. The WHO goal of reducing HBsAg prevalence to 1.0% by 2020 has certainly been reached. In respect to better vaccination effectiveness and minimizing the disease prevalence in the country, catch-up hepatitis B vaccination programs for adolescents before high school entrance can provide immunity for the population. At this time, our data suggest that the addition of school-based programs to universal hepatitis B immunization of infants might be helpful for further decreasing HBV infection rate in our country and its consecutive complications.List of abbreviationsHBV

Hepatitis B virus