We have underlined how celiac disease is characterized by a low responsiveness to vaccinations such as HBV vaccine, and both for the widespread of celiac disease, that is high in prevalence of morbidity, and for the wild range of not response to HBV vaccine. The problem of unresponsiveness could represent a matter of world health, because the group of non-responders patients could be considered as a large reservoir of HBV-susceptible people that will persist as healthy carriers, leading to a diffusion of the diseases even in healthy subjects.
This problem drew the literature research towards possible reassessments of immunization strategies to protect this population and to achieve the goal of universal protection.
It would be important, therefore, to assess the possible vaccination strategy in order to reduce this “healthy-reservoir” of infection. On this regard, new vaccination strategies for celiac patients were proposed in literature: the first one the use of booster doses of HBV vaccine by intramuscular route (IM), the second one is the performance of booster doses of HBV vaccine by intra-dermal route (ID).
In their scientific paper, Zingone et al[44
] gave an IM dose of HBV vaccine to celiac patients with anti HBs titre < 10 mIU/mL and found that, one month after vaccination completion, all showed anti-HBs titer between 10 and 100 mIU/mL. They concluded that celiac patients may require higher doses of vaccine and/or more injection to achieve full protection. Supporting this hypothesis, in 2008, Ashaili et al[43
] studied 25 celiac patients and control subjects who were negative for anti-HBs. HBV vaccine was administered to all celiac patients and control subjects in three doses, at month 0, 1, 6 by intramuscular injection into the deltoid muscle. Four weeks after the last dose, anti-HBs was measured quantitatively. Seventeen celiac patients (68%) and all control subjects (100%) were found to respond to HBV vaccination[44
On the other hands, supporting the hypothesis of a possible role of gluten in the unresponsiveness to HBV vaccine in celiac patients and in severe liver disease[40
], Nemes et al[41
] recommended a revaccination by IM route for celiac patients after treatment with gluten-free diet. They administered a dose of IM vaccine to anti-HBs-negative patients with CD during a controlled gluten-free diet and found that 97.3% of them seroconverted after revaccination. They concluded that the no responder status to primary HBV vaccination is not permanent in CD and may improve after gluten exclusion.
The second strategy addresses on the use of ID booster of HBV vaccine in non-responders patients. The rational of this is that in contrast to IM, which relies on a T-cell mediated response, vaccines introduced directly into the skin activate a dendritic-cell-mediated immune response through a lower doses of antigen[65
According to these results, in 2010, Leonardi et al[66
] revaccinated celiac patients who were non-responders to HBV vaccination with a 2 mg dose of recombinant hepatitis B vaccine administered intradermally. After the first ID dose we found that 40% of patients achieved anti-HBs titer ≥ 1000 mIU/mL, 20% between 100 and 1000 mIU/mL, and 15% between 10 and 99 mIU/mL.
In order to compare the efficacy and the safety of the two HBV vaccination strategy (IM vs
ID) in a non-responder population, in 2011, Leonardi et al[67
] re-vaccinated non-responder celiac patients with ID or IM vaccine. The Authors found a higher percentage of “responders” after the first booster dose (ID = 76.7% vs
IM = 78.6%) and a deeper increase after the third dose (ID = 90% vs
IM = 96.4%) of vaccine in both groups. These data seem to suggest that both ID and IM route are effective options to administer a booster dose of HBV vaccine in celiac patients. However the ID route seems to be a better vaccination strategy, as demonstrated by the higher percentage of patients with an anti-HBs title > 1000 IU/L found in ID than in IM group.
In literature there are no other studies comparing the efficacy of HBV vaccination administered by IM or ID route in celiac patients. The two different methods are extensively compared in other pathologic conditions in which we observed a low responsiveness to HBV vaccination. For example in a meta-analysis about the HBV vaccination response in patients with chronic kidney disease, the authors found that pooling of study results demonstrated a decreased risk of failure to respond to HBV vaccine among patients who were vaccinated by intradermal vs
There is another topic that should be considered. Actually it is still not clear if non-responder patients are characterized by an immunological anergy since birth, or they lose their immune competence during the time. With this regard, there is general consensus in literature that successfully vaccinated people who have lost antibodies years after primary vaccination usually show a rapid anamnestic response when boosted[68
]. This means that the immunological memory for HBsAg can outlast antibody detection, providing long-term protection against the disease and the development of the carrier state. Hence, there should be no need to administer booster doses of vaccine to ensure long-term protection in subjects initially responding to vaccination[22-25
]. Thus, it is still not clear if celiac non-responders show an immunity anergy since birth and do not respond since the first dose of vaccination or they loose their antibody protection with the flow of time, as physiologically happens in normal people, even if in a shorter period of time, remaining, thus, protected by an intra-cellular immunity.
For this reason it would be important an early identification of potential “pure” non-responsive patients through the identification of specific markers of unresponsiveness. Recent acquisitions show a possible role of toll-like receptors, cytokines and cytokine receptors polymorphisms associated with no response to hepatitis B vaccine in healthy population. As a matter of fact, Chen et al[46
] hypothesized that the variations in these structures may act individually or cooperatively in the influence of the duration and intensity of immune response elicited by the hepatitis B vaccine, finding that 4 specific SNPs in the IL-4
genes were closely associated with the serum anti HBsAg response to HBV vaccine. These cytokines and TLR2 seemed to be associated with a status of hepatitis B vaccine-induced protective humoral immune response. If an early identification of responsiveness to HBV vaccine could be speculated in general population by the analysis of specific SNPs, it could be postulated the use of the same analysis in celiac patients, in whom the rate of non-responsiveness is higher, representing a specific marker of the “pure” non-responders. Nevertheless, further studies should clarify the role of these polymorphisms and their possible use as markers of un-responsiveness to HBV vaccine.
In conclusion, we suggest that all patients with CD should be revaccinated to achieve the goal of universal protection. In consideration of the possible relationship between anti-HBs titers and compliance with GFD, they should be revaccinated after the decrease of specific celiac antibodies, that usually occurs after about 1 year of a strict GFD. We also suggest the use of the intradermal route for the revaccination of these patients. The increase of anti-HBs antibodies is in fact satisfactory after ID injection in all patients, a lower dose of the vaccine can be used for immunization and the cellular immune responsiveness to HBsAg can be easily assessed by the development of a skin reaction at the injection site[31
]. Thanks to the appearance of this reaction there is no need to test the serum anti-HBs concentration after the booster dose to value the vaccine efficacy, and this could represent a less expensive strategy for the Health Organization to perform HBV booster doses[69
]. A recent retrospective cost-benefit analysis of ID hepatitis B vaccination reported a cost reduction exceeding 50% compared with a standard IM vaccine regimen[63
]. Moreover the ID route would allow a lower performance of venous withdraws in all patients, reducing the costs linked to serial follow-up withdraws. In literature it is also demonstrated that strong immunological memory persists more than 10 years after immunisation of infants and adolescents with a primary course of vaccination[70
]. Furthermore, we suggest to administer a booster dose of vaccine every 10 years to all celiac patients, independently their status of “pure” unresponsiveness, and as they are genetically predisposed to loose their anticorpal memory, these boosters would favour a better immunologic strategy in order to protect celiac non-responders from a possible HBV infection.