Comparison of effectiveness of hepatitis B revaccination schemes in healthy non-responders

The immune response to the injected hepatitis B surface antigen (HBsAg) can
vary greatly in healthy subjects. Whereas most healthy vaccinees develop an
adequate antibody response, defined as an anti-hepatitis B surface antigen
(anti-HBs) titer of >100 IU/l, 5-10% of immunocompetent persons fail to develop
a protective immune response and never reach an anti-HBs titre exceeding 10
IU/l; these are defined as non-responders (NR). The most commonly chosen
strategy is to give an additional series (1-3 vaccinations) of conventional
intramuscular vaccinations, leading to seroconversion in 61% of the
revaccinated.

The protective efficacy of hepatitis B vaccination is directly related to the
induction of anti-HBs antibodies. An antibody titre of >=10 IU/l measured 1-3
months after the administration of the last dose of the primary vaccination
series is considered to be a reliable marker of immediate and long-term
protection against infection, and those who have an anti-HBs titer of >=10 IU/l
are considered to have protective immunity.

Non-responsiveness to the vaccine has major implications for health care
workers and sexual partners of HBV (hepatitis B virus). In terms of biological
mechanisms, non-responsiveness to hepatitis B vaccination has been associated
with the presence or absence of specific of MHC alleles. The most pronounced
associations with non-responsiveness were with excess of HLA-DR3, -DR7, -DQ2
and -DP11 and with absence of HLA-DR1, -DR5, -DR2, -DQ5 and -DP4 [8] and [9].
Other characteristics correlated with an inadequate anti-HBsAg response are;
older age, obesity, male gender, and cigarette smoking

Several strategies to increase the immune response to the hepatitis B vaccine
in NR, besides additional series of standard vaccinations, have been
investigated such as vaccination with HBsAg combined with other antigens or
additional adjuvants, or alternative routes of administration. In this trial we
investigate 3 different hepatitis B vaccines (Fendrix, Twinrix and HBVAXPRO
40micrograms) in comparison to the standard series of Engerix-B or HBVAXPRO
(both 20 micrograms).

To determine the efficacy of 3 different Hepatitis B vaccines (HBVAXPRO 40
micrograms, Fendrix and Twinrix) in Hepatitis B vaccine non-responders
(ant-HBsAg < 10 IU/L) after one (standard) series of Hepatitis B vaccination
with HBVAXPRO-10 Engerix-B-20 micrograms per vaccination. Primary eindpoint:
anti-HBsAg antibody titer. Secondary endpoint: time to seroprotection
(anti-HBsAg >= 10 IU/l) and adverse events.

Design
Prospective randomised controlled multicenter trial

Recruitment
Participants will be recruited in the Leiden University Medical Center and
various Municipal Health Centers in the Netherlands.

Interventions
Participants will be randomised into one of the following groups:
- group I: control: HBVAXPRO 10 µg or Engerix-B 20 µg, 3 vaccinations month
0,1 and 2
- group II: Twinrix 20 µg, 3 vaccinations month 0,1 and 2
- group III: Fendrix 20 µg, 3 vaccinations month 0,1 and 2
- group IV: HBVAXPRO 40 µg, 3 vaccinations month 0,1 and 2

- anti-HBsAg antibody titers will be measured at 0, 1, 2 and 3 months. In
addition, participants will be asked to report posiible adverse events after
vaccination in a dairy.

Power calculation
Based on the expected difference of 15% seroconverters in the control and
experimental group (with α: 0.05 en β: 0.20), 120 persons should be included
per group.

Ethical approval
This trial will be submitted to the Central Dutch Committee of Human Research
(Centrale Commissie Mensgebonden Onderzoek (CCMO)

Analysis:
Data will be analysed with SPSS 16.0 software (SPSS Inc. Chicago, IL, USA).

Participants will be randomised into one of the following groups:
- group I: control: HBVAXPRO 10 µg or Engerix-B 20 µg, 3 vaccinations month
0,1 and 2
- group II: Twinrix 20 µg, 3 vaccinations month 0,1 and 2
- group III: Fendrix 20 µg, 3 vaccinations month 0,1 and 2
- group IV: HBVAXPRO 40 µg, 3 vaccinations month 0,1 and 2

We believe that the risk associated with participation is negligable, as the
vaccines which are investigated are registered in the Netherlands, albeit not
for Hepatitis B non-responders. On the contrary, if our hypothesis is correct,
the non-responders will hopefully mount a lifelong protective response against
Hepatitis B virus infection in this trial. In our opinion, the extra burden of
the vaccinations and blood drawing is acceptable in comparison to this
anticipated benefit.