Non-response to hepatitis-B vaccination
Non-response to hepatitis-B vaccination |
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Key words: Hepatitis B, immunisation, vaccine, antibody response.
Introduction
More than 340 million people in the world are chronic carriers or sufferers of hepatitis-B virus (HBV) infection1. Vaccination of individuals at risk of exposure to HBV has been considered to be the main method of controlling the morbidity and mortality associated with HBV infection. The situation is different in the UK. Approximately 0.4% of the UK population are carriers of HBV(1). The vaccine recommended for those who are at risk of acquiring HBV infection is recombinant DNA vaccine either Engerix-B or HB-VAX II. Both recombinant vaccines2 contain nonglycosylated hepatitis-B surface antigen (HBsAg) particles that have been purified, adsorbed on aluminium hydroxide and preserved with thimosal. Manufactures`s data claim more than 90% response to hepatitis-B vaccination. However, the response rate is much lower in clinical practice. Males aged 15 to 20 shows an 80 % response and that in ages 50 or above show 60% response. The response rate is better in females with 97% and 82% in the similar age groups.(ref)
What is non-response?
Vaccine response is measured by the titre of hepatitis-B surface antibody (HBsAb). The sensitivity of assay is 2 to 5mIU/ml. A level of 10 mIU/ml is taken as a measurable response. Less than 10 are considered as non-response, 10 to 100 is considered as hypo-response and above 100 mIU/ml as adequate response. In peoples with a titre level less than 10, current recommendation is to revaccinate. An additional booster is recommended for hyporesponders. At levels over 100, a booster is still advised after 3 to 5 years. However, the need for booster vaccination after decay in antibody is a subject of debate world-wide.
Causes of non-response
Several factors can be responsible for non- or hypo-response3,4 (table ). A recent study showed lower response in healthy homosexual men compared to healthy healthcare workers4. An association with different HLA-DR alleles has been found in different studies. Those with HLA phenotype of B44, DRB1*0701, DQB1*0201 were nearly four times likely to be non-responders compared to responders. It is possible that the response may be specific to HBV surface antigen recognition. The ability to produce antibody in response to a specific protein is controlled by dominant autosomal class II genes of the major histocompatability complex (MHC). Much effort has been devoted to overcome the class II linked non-responsiveness to hepatitis-B vaccine. Several immunomodulators in the form of interferons have been tried with vaccination but the results are conflicting and without significance(1).
Kinetics of Vaccine response
The HBsAb titre declines after the vaccination(3). A booster injection results in a rapid increase in antibody titre (HBsAb) within 4 days reaching the highest titre during a month followed by rapid decline in the next 12 months and more slowly thereafter.
Revaccination with different vaccine
A significant shift in antibody levels has been observed with HB-VAX II in previous non-responders to Engerix-B5. Nearly 60% of non-responders or hyporesponders developed adequate antibody response. However, there is no randomised controlled trials looking into the difference in efficacy of these two products and from a practical point of view, both of them are equally immunogenic and are interchangeable2.
A new triple S antigen recombinant hepatitis-B vaccine which incorporated the pre-S1 and pre-S2 components of the surface antigen overcame the non-response in 69% of healthcare workers with a history of persistent non-response to conventional hepatitis-B vaccines6. However, this vaccine is not licensed for use in the UK.
Non-response and susceptibility to infection
No empirical data is available for the HBsAb titre required for protection against HBV infection. The minimal protective titre is assumed to be 10mIU/ml and immunological memory is thought to be able to protect even after the titre level becomes undetectable. There are no reports of cohort studies of healthy non-responders to vaccination for a sufficient number of person-years to closely estimate susceptibility to infection1. However, several placebo-controlled studies have shown that vaccinated subjects who did not respond to the vaccine by developing anti-HBs titre were infected at the same rate as the unvaccinated controls. A case of acute hepatitis B has been described in a patient who had hypo-response to hepatitis-B vaccination7.
Problems
The existing vaccines may not protect against HBV variants with mutation in the S-protein8. Such variants have been observed in high risk infants who became infected despite the administration of vaccine and immuno globulin soon after birth. The emergence of resistant variants could possibly be due to selection pressure associated with extensive immunisation in endemic areas.
Table 1: Various factors responsible for low response
Male sex
Homosexuality
Advancing age
Site and route of injection (not gluteal but deltoid muscle)
High Body mass index (BMI)
Immunosuppression
HLA type: Lower response in B8, B44, DR3 homozygous
References
1. Zuckerman JN, Zuckerman AJ. Current topics in Hepatitis B. Journal of Infection 2000;41: 130-36
2. Lemon SM, Thomas DL. Vaccines to prevent viral hepatitis. NEJM 1997; 336: 196-204
3. Zuckerman JN. Non-response to Hepatitis B vaccines and kinetics of anti-HBs production
4. Das S, Brassington M, Drake S et al. Response to hepatitis B vaccine in healthy homosexual men: a retrospective case-control study. Vaccine 2003 Sept.8;21 (25-26):3701-05
5. Boxall E, Dennis M. HBVax II in non-responseders to Engerix B. Vaccine 1998;16:877-79
6. Zuckerman JN, Sabin C, Craig FM et al. Immune response to new hepatitis B vaccine in healthcare workers who had not responded to standard vaccine: randomised double blind dose-response study. BMJ 1997;314:329-33
7. Huengsberg M, Radcliff K, Boxall E. Hepatitis B infection post Engerix B vaccination. Genitourinary Medicine 1993;69:406-7
8. Carman WF, Zanetti AR, Karayiannis P et al. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990; 336:325-29
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