Vertical transmission of hepatitis B despite immunoprophylaxis

HSA would like to update healthcare professionals on several cases of vertical transmission of hepatitis B (HB) despite immunoprophylaxis with both HB immunoglobulin (HBIG) and HB vaccine. The infants were born to HB carrier mothers and had received a single dose of HBIG at birth and completed a three-dose regimen of HB vaccine. As of end-September 2012, HSA has received a total of 21 reports of HB immunoprophylaxis failure.

In Singapore, two brands of monovalent HB vaccine are currently marketed (Engerix-B^®, GlaxoSmithKline and HBvaxPRO®, Merck Sharp & Dohme). Hexavalent vaccines such as Infanrix Hexa®, which contains HB antigen, may be used for second or third dose of HB vaccination. Three brands of HBIG are available in the market, namely HyperHEP B®(previously named BayHEP B^®) from Skyquest, Anti-Hepatitis B Immunoglobulin Grifols® and Niuliva® Solution, both from Grifols Asia Pacific.

Review of the case reports

The 21 case reports of HB immunoprophylaxis failure were submitted to HSA in 2012 following screening for HB status (conducted in 2011 or 2012) or captured via a retrospective review. The screening was possibly triggered by MOH's 2011 advisory to screen infants born to HB carrier mothers after they had completed their primary course of HB vaccination, as well as an ongoing research study at a tertiary hospital.

Of these reports, six cases involving children born before 2009 were excluded from HSA's causality assessment due to a lack of critical information such as the brand of the implicated HBIG and HB vaccine and/or whether the children were infected within the first two years of life. The remaining 15 cases all involved the use of HyperHEP B^® and Engerix-B^®. Details of the HB vaccination schedule and brand of HB vaccine implicated are provided in Table 1.

Table 1. Details of the vaccination schedule and the brand of HB vaccine implicated in cases of hepatitis B vertical transmission despite immunoprophylaxis

Year of birth	Number of cases	Vaccination schedule for HB vaccine (Engerix-B®)
		At birth, Month 1, Month 6	Day 3, Month 1, Month 6	Day 3, Month 1, Month 18
1997, 2003, 2004, 2005	1 per year	Excluded from causality assessment due to lack of critical information
2007	2
2009	6	5[a]	1[b]	-
2010	8	6	1	1
2011	1	-	1	-
Total	21	11	3	1

^[a] Infanrix Hexa^® was given as the third dose for 1 infant
^[b] HBvaxPRO^® was given as the second dose

Of the 15 cases that were assessed, only one infant tested negative for HB virus (HBV) DNA viral load, HBe antigen (HBeAg) and HB surface antigen (HBsAg) but positive for antibodies against HBe and HBs (anti-HBe and anti-HBs) at two years of age, indicating transient infection.

As shown in Table 1, there were slight differences in the HB vaccination schedule among the 15 infants included in the assessment. With regard to the use of different brands of HB vaccine, monovalent HB vaccines are considered immunologically comparable based on studies conducted. It is recommended for infants born to HB carrier mothers to use monovalent HB vaccines for all three doses for optimal protection due to lack of data on the interchangeability between hexavalent and monovalent HB vaccines for these infants. Although two infants did not receive monovalent HB vaccine as the third dose or as scheduled, the first two doses of the vaccine should confer some protection. In addition to the HB vaccine, all the 15 infants received HBIG at birth for immunoprophylaxis against HB.

For these cases, the rates of immunoprophylaxis failure were estimated using data from the National Immunisation Registry (NIR) on the number of infants receiving HBIG at birth. The failure rates of 0.90%, 1.35% and 0.16% in 2009, 2010 and 2011, respectively, were found to be within the expected incidences reported in literature.¹

Factors associated with immunoprophylaxis failure

HB vaccination and one dose of HBIG, administered within 24 hours after birth, are 85-95% effective in preventing both HBV infection and the chronic carrier state, whereas HB vaccine, administered alone within 24 hours after birth, is 70-95% effective in preventing perinatal HBV infection.¹ The use of HBIG alone reduced HBV occurrence by an average of 50%,dependent on the maternal HBeAg status.²

In several prospective trials, immunoprophylaxis failure ranging from 8% to 32% has been reported among HBeAg positive mothers with high HBV DNA levels.³ Risk factors analysis suggested that maternal HBeAg positivity and detectable HBV DNA were the most important factors associated with mother-to-child transmission despite immunoprophylaxis.^3,4 This may be attributed to intrauterine transmission, which is estimated to occur in <5% infants.⁴ Further studies indicate that a serum HBV DNA level ≥8 log10 copies/mL was considered an important factor leading to immunoprophylaxis failure. In addition, HBV DNA in cord blood was a significant independent risk factor for such failure.³

While some studies have identified mutations in surface HBsAg, such as those in the “a” determinant to which HBIG/HB vaccine elicits antibodies to bind, as possible causes of immunoprophylaxis failure,⁵ others suggest that the mutations account for only a marginal role.^6,7 In contrast, other obstetrical and perinatal factors such as the mode of delivery,⁸ premature birth, low birth weight and birth length³ have not been found to be conclusively linked to immunoprophylaxis failure.

Discussion

a) Possible causes of the increase in the number of reports

A more in-depth analysis of the immunoprophylaxis failure cases to determine their possible cause is difficult due to the lack of information on the serologic profile of the mothers at birth. In addition, the increase in the number of reports could also be due to heightened awareness among healthcare professionals following MOH's advisory in 2011 to screen infants born to HB carrier mothers for seroconversion three months after completing the primary course of HB vaccination. More cases of vertical transmission of HB may have surfaced through proactive screening.

b) Assessment of product quality

A total of nine batches of Engerix-B^® and four batches of HyperHEP B^® were implicated in the cases of vertical transmission. A review of the certificates of analysis for the implicated batches found them to conform to the current registered product specifications before lot release. Registered changes since 2009 to the chemistry, manufacturing and controls (CMC) of Engerix-B® and HyperHEP B^® have been examined to reconfirm that the changes have no impact on product quality and safety.

Conclusion

It is difficult to identify the root cause of vertical transmission of HB in these cases in view of incomplete data and the multi-factorial nature of immunoprophylaxis failure. Literature reports of failures of within 5% to 32% have been reported due to multiple reasons.

As HSA continues to monitor the issue, healthcare professionals are strongly encouraged to report all cases of HB infection despite immunoprophylaxis to the Vigilance Branch of HSA.

References

1. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index4.html
2. BMJ 2006; 332(7537):328-336
3. J Viral Hepatitis 2012; 19:e18-e25
4. J Viral Hepatitis 2011; 18:468-473
5. Curr Opin Infect Dis 2005; 18(3):261-266
6. Vaccine 2004; 22:2791-2799
7. Gut 2004; 53:1499-1503
8. Liver Int 2009; 29(s1):133-139

The editorial team would like to thank Dr Thoon Koh Cheng, Head and Consultant (Infectious Diseases Services, Department of Paediatrics) and Dr Liew Woei Kang, Visiting Consultant (Rheumatology & Immunology, Paediatric Subspecialties) from KKH for their clinical inputs in the above article.

Published: 28 Dec 2012

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