Hepatitis B in Saudi Arabia Eight Years after HBV Vaccination Introduction into EPI Programme

On October 1. 1989, the Hepatitis B Virus (HBV) vaccine was added as the "seventh" primary immunogen of the Extended Programme of Immunization (EPI) in Saudi Arabia ('). In 1990, another programme was launched by the Ministry of Health to vaccinate all school children. Eight years after the mass vaccination programme, the efficacy of HBV vaccine was evaluated in a community-based study covering all the regions of the country.

For a population survey of the prevalence of HBsAg, the sample size of children required to determine a prevalence to within 10% of an earlier reported prevalence of about 7.5% [2] at a confidence level of 95%. was estimated at 4741 samples. This sample size was distributed proportionally according to the population of each of the 14 health regions into which the Kingdom of Saudi Arabia is divided. The selection of children was accomplished using a stratified cluster sampling technique. Each of the 14 regions was stratified into urban and rural areas and a list of Primary Health Care Centers (PHCC) in each area was compiled and a sample of PHCC was selected for each urban and rural areas. The catchment population of each selected PHCC was further subdivided into cluster of households defined by visible landmarks such as roads or mosques. A simple random sample of clusters was selected and the required number of households was visited.

A total number of 4791 children (2361 males, 2429 females) were investigated: of whom 4087 children had completed the three doses of the 10 ugm recombinant HB vaccine. The number of children who had been vaccinated according to the EPI programme (0. 3, 5 months), and since 1993 at 0. 5, and 124 weeks was 3663. while the remainder had received the vaccine at school entry at the age of 6 years according to the catch-up programme. After informed consent, 5-10 cc of blood was obtained from each child. Along with each sample, a form was filled indicating the child's age, sex, and exact region along with HBV vaccination details. The blood was allowed to clot and sera were separated by centrifugation. Sera was kept at €”20°C, until the required number of samples of the specific region were completed, after which they were sent for analysis to the Virology Laboratory at King Khaled University Hospital in Riyadh. A p-value <0.05 was judged to reflect a significant difference; a p-value between 0.05 and 0.1 was judged to reflect a trend.

Among the 4791 vaccinated Saudi children, 15 were found to be HBsAg positive, giving an overall prevalence rate of 0.31%. Only one HBsAg was also anti-HBs and anti-HBc-positive with anti-HBs titer of 15 lU/L. HBsAg positivity was 0.16% among children vaccinated at birth, compared to 0.7% among those who started vaccination at school entry. The prevalence of anti-HBc among children vaccinated at birth was 0.2%, and among those vaccinated at school entry was 1.2%. The overall HBsAg carrier rate was found to have dropped from 6.7% in 1989 to 0.3% in 1997 (p< 0.00001). Similarly, there was a significant reduction in the prevalence of anti-HBc from 4.2% in 1989 to 0.46% in 1997 (p<0.00001).

The overall seroconversion rate to HB vaccine among 4087 children up to 12 years of age was about 77%. The seroconversion rate in children vaccinated at birth was 3666 children (77%), compared to 1181 children (71%) in those who were vaccinated at school entry (p=0.0001). The seroconversion rate increased to 77.5% among 9-10 year olds. and reached 85% among 11-12 year olds. The highest seroconversion rate (93%) was found among children less than one year of vaccination, compared to 66% in children after eight years of vaccination.

After eight years of receiving the third vaccine dosage, close to 65% of the children had anti-HBs titer of more than 10 IU/L, compared to only about 28% who had anti-HBs titer of more than 100 lU/L after the same time period.

The seroconversion rate after eight years of vaccination was similar in all 14 regions of Saudi Arabia and did not fall below 71%. There was no significant difference in seroconversion between sexes or rural versus urban areas.

The endemicity of Hepatitis B virus (HBV) in Saudi Arabia is well established [2]. Acquisition of HBV infection occurs mainly by the horizontal route in early life, and by the age of 10 years, about 7% are HBsAg carriers and about 20% are positive for at least one HBV marker[3]. HBV infection significantly contributes to HBV-related morbidity and mortality among Saudi patients. The availability of a safe and efficacious HBV vaccine has led to the feasibility of an effective control of HBV infection, especially in endemic countries [4].

Prior to adding the HBV vaccine to the EPI Programme in Saudi Arabia, a baseline survey of viral hepatitis markers in the kingdom had been established [3]. At the beginning of 1990, mass vaccination of all school children was also started. The main objective of these programmes was to prevent the chronic carriage of HBV infection by reducing the reservoir of HBV and HBV-related chronic liver disease in the Saudi population. The effect of TAB vaccine eight years after the start of the mass vaccination programme is the first to be reported from the Middle East. Similar long-term effects of HB vaccine have been reported from several other countries [5,6].

Comparing results of this study with a prevaccination survey conducted in 1989 in the same area and among the same age groups[1], the overall HBsAg carrier rate showed a striking decline from 6.7% to 0.31% (p<0.00001). A similar striking decline from 4.2% to 0.46% (p<0.00001) was also noted in the prevalence of anti-HBc. This difference in HBV infection between 1989 and 1997 surveys could not be explained by improvement of hygiene standards or change in population immunity. Similar studies(5.6) have attributed the marked decline in HBV infection mainly to the effect of HBV vaccine introduction into the EPI programme.

The decline in the rate of HBV infection (HBsAg or anti-HBc) was less pronounced among children who were vaccinated at school entry compared to those vaccinated at birth. This decline, when translated in calculation of the efficacy of HB vaccine against HBsAg carriage was 95% and 99% at school entry and at birth, respectively. On the other hand, the introduction of FIB vaccine to the EPI programme parallel to its introduction to children at school entry contributed significantly to the change of dynamics of HBV infection among unvaccinated children who lived in the same area and had to wait 1-5 years till the time of their vaccination. The risk of infection among these children was reduced as the cycle of horizontal transmission had been broken and due to the reduction in the infection pool.

In this study, close to 77% of children 1-12 years of age were found to have antibody to HBsAg (anti-HBs >10 IU/L) 8 years after the start of the nationwide vaccination programme. This result is similar to those reported from other countries with regards to seroconversion rate and efficacy of the vaccine(5.6). The relative increase in seroconversion among children in the 7-12 year age group can be explained by the short time interval between vaccination and evaluation. Also, the small number among children aged 11 years may play a factor.

Among the 15 children who were found to be HBsAg-positive, three children (2 brothers and one sister) and two (2 brothers) belonged to the same family and lived at the same house. These 5 children were also HBeAg-positive, indicating that perinatal or horizontal HBV transmission as the most likely route of infection. The remaining 7 HBsAg-positive children were vaccinated at school entry or after, which may explain their early exposure to HBV infection. Other possibilities include poor response to HBV among these children, or infection due to steady decline in anti-HBs titer. Only one HBsAg-positive child was also anti-HBc and anti-HBs-positive with an anti-HBs titer of >10 IU/L. This break-through infection could be due to HBV mutant infection and merits further investigation.

The results of this study demonstrate the tremendous impact of the mass HB vaccination programme on the seroepidemiology of HBV infection in Saudi Arabia. HBV vaccination seemed to protect most children from infection and from becoming HBV carriers. The ultimate goal of preventing HBV-related chronic liver disease and hepatocellular carcinoma in Saudi Arabia is foreseeable in the near future.