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Studies on Hepatitis B Vaccination and Factors Associated withthe Vaccine Response
Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hepatitis B virus causes liver disease and up to 2 billion people have been in contact with the virus world wide. It can cause both acute and chronic disease. The routes for transmission are through blood, mother to infant at time of delivery and sexually. Chronic hepatitis B infection is a risk factor for development of liver cirrhosis and hepatocellular carcinoma. Prevention of hepatitis B virus infection is highly desirable. Since the early1980s hepatitis B vaccine has been available. It can effectively prevent the disease and has been found to be safe. The World Health Organisation, WHO, has recommended all countries to implement the vaccine in their children’s vaccination programmes and many countries have followed this recommendation. In Sweden so far the recommendation is vaccination of identified risk groups for hepatitis B. Health care workers who are at risk of having blood contact in their work is one such risk group.

In a large study on health care workers who were intradermally vaccinated with the hepatitis B vaccine, 960/1406 (68.3%) developed protective levels of antibodies to HBsAg (anti-HBs; defined as >10 mIU/mL) after three doses. After administering of an additional fourth dose to non-responders the response rate was 1187/1335 (88.9%). Risk factors for non-response were smoking and age above 40 years. Also, the vaccine response rates improved during the study and a risk of giving a too small dose with intradermal administration was also identified. This suggests that intradermal administration is dependent on well trained personnel.

A genetic factor which has been proposed to be associated with a non-responder status to HBV vaccination is the HLA haplotype of the host. In a study in on 69 responders and 53 non-responders the haplotypes were therefore determined. It was found that [DQB1*0602; DQA1*0102; DR15] and [DQB1*0603; DQA1*0103; DRB1*1301] were more likely to be found in responders (p<0.025 and p<0.05 respectively). In non-responders the haplotype [DQB1*0604; DQA1*0102; DRB1*1302] was found more frequently (p<0.005). This study supports that the HLA class II of the host is involved in the ability to respond to the HBV vaccination.

To further test the genetic link between the HLA of the host and a non-responder status, relatives to known intradermal non-responders with known haplotypes for DQA1, DQB1 and DRB1 were vaccinated in the same way, intradermally. The response rate in the relatives was 15/26 (58%) which is lower than expected suggesting a genetic influence on the vaccine response. In this study 5/6 with the haplotype [DQB1*0604; DQA1*0102; DRB1*1302] were non-responders which is in line with the previous data that this haplotype is correlated to hepatitis B vaccine non-response.

Finally, to test a strategy by which we could induce an effective anti-HBs seroconversion in non-responders we revaccinated these with the combined hepatitis A and B vaccine intramuscularly at a double dose. Already after the first revaccination dose 26/44 (60%) responded with protective antibodies compared to 2/20 (10%) in a vaccine naïve reference group, suggesting an anamnestic response. After three doses 42/44 (95%) responded in the non-responder group and 20/20 (100%) in the reference group. All participants in the study responded to the hepatitis A antigen.

In conclusion these studies show that intradermal vaccine administration can be used and is effective, and that the ability to respond is influenced by several, including genetic, factors. Importantly a non-responder status to hepatitis B vaccination is not absolute, a double dose of the combined HAV and HBV vaccine effectively overcomes this non-response in most individuals.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 67 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1127
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-20800ISBN: 978-91-7393-634-7 (print)OAI: oai:DiVA.org:liu-20800DiVA: diva2:236075
Public defence
2009-10-20, Elsa Brändströmsalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2012-05-09Bibliographically approved
List of papers
1. Intradermal hepatitis B vaccination in health care workers. Response rate and experiences from vaccination in clinical practise
Open this publication in new window or tab >>Intradermal hepatitis B vaccination in health care workers. Response rate and experiences from vaccination in clinical practise
1999 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 31, no 2, 197-200 p.Article in journal (Refereed) Published
Abstract [en]

Health care workers at risk for hepatitis B virus infection are recommended for vaccination. Low-dose intradermal (i.d.) administration of vaccine has been suggested as a less expensive alternative to intramuscular (i.m.) inoculation. To evaluate the i.d. vaccination route, health care workers were included in a prospective study. The subjects were vaccinated with 0.1 ml (= 2 microg) recombinant vaccine (Engerix B, SmithKline Beecham) i.d. at 0, 1 and 6 months. Two months after the third vaccination, measurement of the anti-HBs level was conducted. An anti-HBs level > or =10 IU/l was considered protective. Those with an anti-HBs level <10 IU/l were given a fourth dose with new serological control after another 2 months. The results are based on the 1406 subjects that it was possible to evaluate. The seroconversion rate to protective anti-HBs level after 3 doses was 68% and after 3 or 4 doses 89%. Factors associated with a lower response rate were increasing age (p<0.05) and smoking (p<0.001). Sex or body mass index had no influence on the results. Vaccination technique seems to be of utmost importance when the i.d. route is used. Well instructed and experienced nurses are required and quality control with follow-up of overall seroconversion rate within each centre is needed.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20796 (URN)10.1080/003655499750006272 (DOI)10447332 (PubMedID)
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2017-12-13Bibliographically approved
2. Haplotypes comprising subtypes of the DQB1*06 allele direct the antibody response after immunisation with hepatitis B surface antigen
Open this publication in new window or tab >>Haplotypes comprising subtypes of the DQB1*06 allele direct the antibody response after immunisation with hepatitis B surface antigen
1998 (English)In: Tissue Antigens, ISSN 0001-2815, E-ISSN 1399-0039, Vol. 52, no 4, 374-380 p.Article in journal (Refereed) Published
Abstract [en]

Two HLA class II haplotypes, HLA-[DQB1*0602; DQA1*0102; DR15] and HLA-[DQB1*0603; DQA1*0103; DRB1*1301] were found to be less common in 52 nonresponders compared with 68 responders, P<0.025 and P<0.05 respectively, after vaccination with hepatitis B surface antigen (HBsAg). Another haplotype, HLA-[DQB1*0604; DQA1*0102; DRB1*1302], had a significantly higher frequency in the nonresponders (P<0.005). The nonresponders and responders were nonsmoking, healthy individuals with an antibody concentration of <10 IU/l and >100 IU/l respectively. The three haplotypes comprise either of three different DQB1*06 subtypes. Two of the seven amino acids that differ between the two responder alleles DQB1*0602 and *0603 and the nonresponder allele *0604 are located in the peptide-binding groove of the DQB1 molecule. In addition to this finding, amino acid 86 in the DRB1 molecule seems to determine the response against HBsAg. DRB1*1301 and DR15 in the responder haplotypes have a Val at this position while the nonresponder haplotype has a Gly. These results suggest a role for both the DQB1*06 alleles and the DRB1 alleles *1301, *1302 and DR15 to direct either a response or a nonresponse against HBsAg. Sixteen HLA class II genotypes were found to be shared by 25 nonresponders and 32 responders. This finding of HLA-identical nonresponders and responders indicates an influence of other genetic factors in addition to the HLA system in the response to HBsAg.

Keyword
Frequency, haplotype, HIA class II, nonresponders, nonsmoking, responders
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20797 (URN)10.1111/j.1399-0039.1998.tb03058.x (DOI)9820601 (PubMedID)
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2017-12-13Bibliographically approved
3. Hepatitis B vaccination in relatives to known non-responders: A family study
Open this publication in new window or tab >>Hepatitis B vaccination in relatives to known non-responders: A family study
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Hepatitis B can be prevented by hepatitis B vaccine in most individuals. However about 5 –10% of all individuals fail to produce a protective antibody level to hepatitis B surface antigen(anti-HBs), after standard vaccination procedure with three vaccine doses. The mechanismsfor non-response are multi-factorial and not clearly understood. Non-response in this studywas defined as anti-HBs < 10 mIU/ml after at least 4 doses of intradermal hepatitis B vaccine.In this study we vaccinated relatives to known non-responders to hepatitis B vaccine. Thestudy subjects were chosen among relatives to non-responders with known HLA class IIhaplotypes. Recombinant hepatitis B vaccine was administered intradermally at 0, 1 and 6months. For those with anti-HBs <10 mIU/ml after three doses an additional dose was givenfollowed by new anti-HBs measurement. A total of 8 probands and 26 relatives wereincluded. Of the 26 relatives 15/26 (58%) responded to the vaccination schedule compared tothe expected 90-95%. This data therefore support the theory that genetic factors play animportant role in the antibody response to hepatitis B vaccine. The study population wasthough too small to conclude the role of specific genetic factors related to response and nonresponse.

Keyword
Hepatitis B vaccine, non-responders, genetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20798 (URN)
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2010-01-14Bibliographically approved
4. Excellent response rate to a double dose of the combined hepatitis A and B vaccine in previous nonresponders to hepatitis B vaccine
Open this publication in new window or tab >>Excellent response rate to a double dose of the combined hepatitis A and B vaccine in previous nonresponders to hepatitis B vaccine
2008 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 198, no 3, 299-304 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Hepatitis B vaccine has been shown to be highly efficient in preventing hepatitis B. However, 5%-10% of individuals fail to develop protective levels (>or=10 mIU/mL) of antibodies to hepatitis B surface antigen (anti-HBs) and are considered to be nonresponders.

METHODS: A total of 48 nonresponders and 20 subjects naive to the HBV vaccine received a double dose of combined hepatitis A and B vaccine (Twinrix) at 0, 1, and 6 months. The levels of anti-HBs and antibodies to hepatitis A virus (anti-HAV) were determined before vaccination and 1 month after each dose.

RESULTS: Among 44 nonresponders, protective anti-HBs levels were found in 26 (59%) after the first dose and in 42 (95%) after the third dose. Among the control subjects, the corresponding figures were 10% and 100%, respectively. All subjects seroconverted to anti-HAV. The titers of both anti-HBs and anti-HAV were lower in the previously nonresponsive subjects (P< .01).

CONCLUSION: Revaccination of nonresponders to the standard hepatitis B vaccine regimen with a double dose of the combined hepatitis A and B vaccine was highly effective. This is most likely explained by the increased dose, a positive bystander effect conferred by the hepatitis A vaccine, or both.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20799 (URN)10.1086/589722 (DOI)18544037 (PubMedID)
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2017-12-13Bibliographically approved

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