Hepatitis B virus (HBV) is a vaccine-preventable viral infection, which can cause chronic hepatitis, cirrhosis and hepatocellular carcinoma. The World Health Organization (WHO) estimates that 254 million people were living with HBV globally in 2022, resulting in an estimated 1.1 million deaths per year.¹

These carriers are more prevalent in developing and low-income countries.^2,3 There are an estimated 65 million chronic hepatitis B surface antigen (HBsAg) carriers in Africa, including approximately 2.7 million in South Africa.¹ South African studies have identified higher rates of HBV infection in males than females and in rural rather than urban areas.⁴

The WHO recommendations on childhood vaccination advise three doses of HBV vaccine for all children, with the first dose being administered as soon as possible but preferably within 24 h of birth.⁵ In South Africa, HBV vaccination was introduced into the Expanded Programme on Immunization (EPI) in April 1995 and is administered at 6 weeks, 10 weeks and 14 weeks of age, with an additional targeted birth dose for infants whose mothers tested HBsAg positive during pregnancy.⁶

Childhood vaccination is important not only to prevent vertical transmission but also to prevent horizontal infection, which is the principal route of transmission in Africa, including South Africa.^7,8 Following the introduction of HBV vaccination into the South African EPI, there was a reduction in HBV prevalence in children, with HBsAg positivity rates dropping to 0.0% in children with unknown HIV status and 2.7% in children living with HIV.⁶ A recent systematic review reported protective anti-hepatitis B surface antibody (HBsAb) levels in 63.2% of individuals 10 years after childhood vaccination, declining by 6.6% per follow-up year.⁹ Both age at vaccination (lower prevalence of immunity in those vaccinated in infancy versus those vaccinated after 1 year or age) and the level of HBV endemicity (higher prevalence of immunity in highly endemic areas) affect rates. However, 90.34% of individuals showed an anamnestic response to a booster dose of vaccine, and the duration of functional immunity, which provides protection from infection, therefore likely persists despite waning antibody levels.⁹

Healthcare workers (HCWs) are considered at high risk of HBV exposure and have a four times greater probability of contracting HBV than the general population because of occupational exposure to blood and body fluids, as well as needlestick and sharps injuries.^10,11 The risk of transmission following a percutaneous needlestick injury is 6% – 30% for HBV and approximately 0.3% for HIV.^12,13 Up to 37% of HBV infections in HCWs result from occupational exposure via needle stick injuries.¹⁴ Studies in South Africa have established that 24% of needlestick injuries occur in primary care nurses and 69% among junior doctors per annum.^15,16 Hepatitis B virus infection among HCWs remains high in South Africa, with HBV DNA positivity reported at 8.6%.¹⁷ Despite the recommendation from the South African National Department of Health that all healthcare students and in-service HCWs should receive three doses of HBV vaccine and have post-vaccination testing to confirm adequate antibody responses, vaccination coverage rates remain low among these groups.^18,19,20 Coverage among healthcare students is impacted by institutional policies that often require students to pay for their own vaccination and post-vaccination testing. With many students requiring financial support, it becomes a challenge for these students to be vaccinated as required.²⁰ In order to guide vaccination policies for healthcare students who have received childhood vaccination as part of the EPI, this study aimed to investigate HBV immunity in these young adults and the response to booster vaccination.

While both international and South African National Department of Health guidelines recommend a course of three doses of HBV vaccine for HCW, vaccination policies for healthcare students in South Africa are governed by the individual academic institutions and are poorly standardised.²⁰ Policies surrounding vaccination of healthcare students are further complicated by the need to consider the changing vaccination profiles of new students, most of whom will now have been born after the implementation of universal HBV vaccination in South Africa. It is therefore necessary to establish how frequently incoming students who were born after the introduction of childhood HBV vaccination have protective HBsAb levels prior to booster vaccination and whether a single booster is sufficient to stimulate protective levels in the remainder. To this end, 122 healthcare students were recruited from two South African academic institutions in central South Africa. Only one participant provided childhood immunisation records to confirm receipt of three doses of HBV vaccine during routine EPI vaccinations.

The remainder were unaware of their vaccination status and without access to their childhood immunisation records. This indicates the need for exploring alternative methods of documenting immunisation interventions to improve record keeping and provide better continuity of care.

Prior to receiving the first booster vaccine dose, most participants had negative (52%) HBsAb results below the level considered reliably protective against HBV infection. These data support available South African data where inadequate HBsAb levels were noted in 56% of healthcare students in Gauteng prior to boosting.²² This may be because of waning immunity as a result of the time which had elapsed since childhood vaccination, non-response to childhood vaccination or missed or incomplete childhood vaccination.

Confirmation of antibody responses through laboratory testing is not included in the EPI in South Africa, and it is therefore possible that some of the participants had inadequate responses to their initial vaccinations. Although HBV vaccines are highly immunogenic and effective at preventing HBV transmission, HBV vaccination induces protective antibody levels in 85% – 93% of South African infants, with slightly lower response rates in those living with HIV (78%).⁶ Waning immunity likely accounts for most cases with inadequate HBsAb levels, which was supported by the rapid HBsAb production following exposure to a booster HBV vaccine dose. This anamnestic response on re-exposure to the antigen supports immunological memory induced by the initial vaccine course and is the mechanism by which individuals can remain protected even when antibody levels have waned.⁹ One month following the first booster dose, only 8% of participants remained HBsAb negative. The absence of an adequate antibody response in the 8% of students who remained HBsAb negative following the first vaccination indicates inadequate memory responses to prevent infection in the event of an exposure, likely because of absent or incomplete infant vaccination or non-response to the infant vaccination.

Following the third booster, all participants had HBsAb levels above 11 mIU/mL, and only one individual would be considered a low responder (10 mIU/mL – 100 mIU/mL). The rest of the students were high responders, defined as HBsAb levels above 100 mIU/mL.²³

No non-responders were identified among this group; however, non-response to HBV vaccination is known to occur in 5% – 10% of individuals vaccinated against HBV and is associated with various factors including age, sex, obesity, smoking and immunosuppression.²³ A previous study among South African healthcare students found non-response to three doses of vaccine in 7% (n = 5/71) of their study participants.²²

This emphasises the importance of post-vaccination testing in healthcare students to confirm immunity prior to possible exposure in a clinical environment.

No statistically significant differences were found at any of the three time points when HBsAb results were grouped by sex or race. Race has previously been identified as having a significant association with pre-vaccination HBsAb levels in South African healthcare students, with higher levels among Indian than black students.²² While this was not substantiated by our data, the small number of participants in certain subgroups may have contributed to this lack of statistical significance.

Prior to the introduction of HBV vaccination in South Africa, the prevalence of HBsAg was 9.6% among South Africans adults, with 76% showing evidence of previous exposure as indicated by having one or more serological markers for HBV.⁷ Public sector laboratory data from South Africa showed a decreasing trend in HBsAg positivity rates between 2015 and 2019 and also in incidence rates of acute HBV infection, likely because of the efficacy of childhood vaccination in preventing HBV transmission.²⁴ Similar trends of decreasing seropositivity have been observed in numerous other countries following the introduction of HBV vaccination.^25,26,27 In this study, serological evidence of previous resolved infection was identified in a single participant who tested positive for both HBsAb and HBcAb at baseline, thus a positivity rate of 1%, supporting the efficacy of the childhood vaccination programme.

The study’s findings must be seen in the light of its limitations. These include selection bias that may have been introduced because of the limited sample size, with 122 of approximately 320 eligible students agreeing to participate in the study. While the reasons for non-participation were not elucidated, it is possible that there were differences between students who chose to participate and those who declined. Possible sampling bias may also limit the generalisability of the findings by the inclusion of students from only two institutions from a single province, as well as the predominance of females (61%). A study performed among healthcare students at the University of the Witwatersrand showed similar gender and race distribution of participating students, with a predominance of black (80%) and female students (70%).²²

The unavailability of vaccination records is also a limitation of this study as participants may not have been vaccinated as infants or may have received subsequent doses that they were unaware of. It is also possible that some of the participants may not have received one or more doses of the childhood vaccination schedule at 6 weeks, 10 weeks and 14 weeks of age because of incomplete vaccination coverage, which can occur in the EPI programme. While the participants were all born after the implementation of HBV vaccination, the available WHO estimates for national immunisation coverage for receipt of the third dose of HBV vaccine in South Africa from 1997 to 2000 ranged from 74% to 88%.²⁸ This variability in prior vaccination may have impacted the study’s findings regarding baseline immunity and the attribution of baseline and probable anamnestic immune responses to infant vaccination.

The findings highlight the need for better documentation of vaccination history, particularly given the incomplete coverage, which is well documented in the South African EPI programme. This could be addressed by implementing a national electronic immunisation registry of both childhood and adult vaccinations to improve long-term record retention. In addition, standardised vaccination and immunity testing policies for tertiary academic institutions would aid in ensuring that all healthcare students are adequately protected from HBV prior to exposure in a clinical setting. One approach would be to perform baseline HBsAb testing followed by one or more booster doses before retesting to identify those without adequate antibody levels. This is more cost effective than a post-exposure management approach.²¹ As most current healthcare students will have received HBV vaccine as infants, another approach is to test HBsAb levels following a single dose of vaccine, with administration of additional doses where needed.²⁰

Given the low cost of recombinant HBV vaccines, it has also been suggested that administration of three doses of vaccine prior to determining HBsAb levels may be more cost effective.²⁰ As per international guidelines, post-vaccination serological testing is essential in such programmes to confirm adequate immunity and to allow education and appropriate management of non-responders.^5,21 This would also simplify long-term occupational health policies in the healthcare setting as further boosters are not required in immunocompetent individuals who have a documented response to HBV vaccination.^5,29 Cost efficacy studies would assist in confirming which vaccination and testing algorithm would be most cost efficient in the South African setting and allow assessment of the feasibility of implementation of institutionally funded programmes, where not already in place. Institutional funding would improve coverage among healthcare students, particularly those requiring financial assistance and from historically disadvantaged universities.²⁰ Similar institutional policies are also required for various other vaccine-preventable infectious diseases to which healthcare students may be occupationally exposed.

This study confirmed the persistence of long-term immunological memory in healthcare students following vaccination as infants, with 92% of participants having evidence of protective levels of HBsAb following a single booster dose. It also highlights the importance of routine testing for HBsAb levels following vaccination in high-risk groups to confirm adequate protection in the event of occupational HBV exposure. This is critical to identify individuals who require three doses of HBV vaccine because of an inadequate response to a single booster and identify non-responders following the full course which, although not seen in this study, is a well-established phenomenon.