Low Dose Intradermal Vaccination Is Superior to High Dose Intramuscular Vaccination for Hepatitis B in Unresponsive Hemodialysis Patients

Abstract

After two intramuscular (IM) vaccination protocols (40 μg at 0, 1, 2, and 6 months), patients who were unresponsive to hepatitis B vaccination were collected from three HD centers. The aim of this study was to compare the effectiveness of intradermal (ID) and repeated IM vaccination protocols. Thirty-three of 639 HD patients were found to be unresponsive. Patients were randomly assigned into two groups: one to receive 80 μg ID and the other 160 μg IM vaccination protocol. Both ID (p = 0.000) and IM (p = 0.03) groups disclosed statistically significant seroconversion rates six months after the last vaccination dose. The seroconversion rate was 94.1% in the ID and 50% in the IM groups—showing a significant improvement in the ID group (p = 0.011). A low-dose ID is superior to standard IM vaccination protocol and also more cost-effective in unresponsive HD patients.

Keywords:

• hemodialysis
• hepatitis B
• unresponsiveness

INTRODUCTION

In a healthy population, seroconversion rates are very high, showing more than 95% seroprotection with hepatitis B vaccines.[1] However, the rates are not as good for hemodialysis (HD) patients as for other immunocompromised subjects: the seroconversion rates in HD patients are between 50–80%.[2]

With the use of erythropoietin preparates, which result in low blood transfusion rates, a reduction is seen for the hepatitis B infection in HD units.[2] Nevertheless, vaccination is more important for HD patients than the normal population because of the high risk due to intravenous interventions and therapies.[3] Both the humoral and cellular immune responses are defective in HD patients.

Unresponsiveness to the hepatitis B surface antigen was speculated to be a result of poor antigen presentation, leading to an inadequate T-helper cell response.[4] Other than immunocompromised status, factors affecting the response to hepatitis B vaccination include age, gender, human leukocyte antigen (HLA) groups, nutritional status, route of administration, and antigen dosage.[3–6]

To improve vaccine response, double-dose vaccination protocol is recommended for HD patients.[7] Moreover, instead of a three-dose schedule, a four-dose schedule is used.[8] In several studies, intradermal (ID) vaccination was compared with standard intramuscular (IM) protocol in CAPD and HD patients.[8],[9] The results found out that ID was superior to IM vaccination protocol regarding seroconversion rates. The dermal dendritic cell in the skin was speculated as one of the most potent antigen-presenting cell leading to primary immune response.[10] However, in a recent study, there was no difference between those two routes of administration.[11]

In this study, after two 40 μg intramuscular (IM) vaccination protocols (0, 1, 2, and 6 months), patients who were unresponsive to hepatitis B vaccination were collected from three HD centers. The aim of this study was to compare the effectiveness of intradermal (ID) and repeated IM vaccination protocols in unresponsive HD patients.

SUBJECTS AND METHODS

The study included 639 HD patients, consisting of 366 men and 273 women, whose data were retrieved from three HD centers (Adana, Iskenderun, and Sanliurfa) belonging to Başkent University Faculty of Medicine, Hospital of Adana, Adana, Turkey. All patients were on a regular program of three four-hour HD sessions per week on a hollow-fiber dialyzer. Cuprophane membranes and bicarbonate-based dialysate were used in all cases.

Each patient had received standard IM vaccination protocol [four doses of 40 μg DNA-recombinant hepatitis B vaccine (Genhevac B, Pasteur) at 0, 1, 2, and 6 months]. Patients whose HBs-Ab titers were found <10 IU/L were defined as unresponsive patients. The same protocol was repeated for unresponsive HD patients. Despite having two times IM vaccination protocol, patients who were unresponsive to Hepatitis B vaccination were collected for the study. Patients who were not willing to receive vaccination or who received immunosuppressive treatment were excluded.

Twenty men and 13 women, totaling 33 (5.16%) of 639 HD patients, were found to be unresponsive to standard IM vaccination protocol. These patients were randomnly assigned into two groups. Intradermal group consisted of 17 patients and received 8 times ID (10 mcg per week) vaccination protocol on the volar surface of forearm. Intramuscular group consisted of 16 patients and received standard IM vaccination protocol in deltoid muscle. Two patients were dropped out from IM group (one exitus, one went to another HD center) during the study. Thirty-one patients consisting of 19 men and 12 women with a mean age of 53.4±17.4 years completed the study. At six months after the last vaccination dose, response rates and AntiHBs Ag titers were investigated for the entire study group.

Blood work included serum BUN, creatinine, calcium, phosphorus, albumin, total cholesterol, triglyceride, hemoglobin, CRP, PTH, Fe, saturation of transferring, and ferritin. Additionally, age, gender, dialysis vintage, normalized protein nitrogen appearance (nPNA), body mass index (BMI), Kt/V, and having erythropoietin or vitamin D therapy were investigated for all patients.

Each patient's weekly dialysis dose was calculated in Kt/V, and nPNA was used to estimate daily protein intake. For each laboratory parameter investigated, a three-month average was calculated. Serum hemoglobin levels were assessed using a Coulter STKS machine (Coulter Electronics Inc., Miami, Florida, USA). Serum albumin, creatinine, blood urea nitrogen, calcium, phosphorus, triglyceride, total cholesterol, iron, and TIBC were measured by a calorimetric method (Beckman Cx-7 Autoanalyser, Beckman Instruments-Inc, Diagnostic Systems Group, Brea, California, USA). Serum ferritin levels were measured by an immunometric assay method (Immulite machine, Immulite Euro/DPC Ltd, Gywnedd, Wales, UK). Serum CRP levels were measured using a turbidimetric latex agglutination method (Biosystems SA, Barcelona, Spain). Intact parathormone levels were measured by radioimmunoassay (DSL-8000 ACTIVE Intact PTH IRMA Kit, Diagnostic Systems Laboratories, Inc., Webster, Texas, USA). HBs Ag was determined with third generation microparticle enzyme immunoassay for the qualitative detection of HbsAg (AxSYM HbsAg (V2), Abbott Laboratories, Abbott Park, Illinois, USA ).

Statistical analysis was performed using SPSS software (Statistical Package for Social Sciences, version 10, SPSS Inc, Chicago, Illinois, USA). All values are expressed as mean ± SD, and p < 0.05 was considered statistically significant. Fischer's exact test, the Mann-Whitney U test, the student t-test, and the Wilcoxon signed rank test were used for statistical assessments.

RESULTS

Thirty-one patients consisting of 19 men and 12 women with a mean age of 53.4±17.4 years completed the study. The etiologies of end-stage renal disease for these patients were diabetes mellitus for 10 patients (32.26%), hypertension for 5 patients (16.13%), glomerulonephritis for 4 patients (12.90%), amyloidosis for 2 patients (6.45%), tubulointerstitial nephritis for 4 patients (12.90%), and unknown etiology for 6 patients (19.36%).

Initial serum HBs-Ab levels were 2.54±2.74 IU/L and 4.89±3.33 IU/L for ID and IM groups, respectively. There was no difference between the two groups regarding age, gender, duration of HD, laboratory parameters, body mass index, Kt/V, and normalized nitrogen protein appearance (p > 0.05). Demographical and laboratory parameters of HD patients are shown in Table 1.

Table 1 Demographical and laboratory parameters of HD patients

	ID (median/mean)		IM (median/mean)		p
Initial HBs-Ab (IU/L)	2	2.54 ± 2.74	4.3	4.89 ± 3.33	>0.05
Age (years)	60	56.24 ± 15.66	55.5	49.93 ± 19.22	>0.05
Dialysis vintage (months)	28	32.12 ± 14.77	29.5	42.21 ± 40.18	>0.05
BUN (mg/dL)	89	87.18 ± 10.90	84.5	89.14 ± 24.51	>0.05
Creatinine (mg/dL)	10.7	10.42 ± 2.45	9.2	9.89 ± 2.55	>0.05
Calcium (mg/dL)	9.2	8.93 ± 0.73	8.5	8.51 ± 0.96	>0.05
Phosphorus (mg/dL)	5.3	4.72 ± 1.44	5.8	5.68 ± 2.18	>0.05
Albumin (g/dL)	3.9	3.98 ± 0.27	3.7	3.78 ± 0.38	>0.05
T. cholesterol (mg/dL)	184	187.47 ± 56.23	176	169.21 ± 48.14	>0.05
Triglyceride (mg/dL)	166	187.94 ± 78.78	180	193.79 ± 86.66	>0.05
Hemoglobin (mg/dL)	10.1	10.33 ± 1.13	9.9	10.19 ± 1.53	>0.05
CRP (mg/L)	3	7.53 ± 10.57	4	11.86 ± 20.25	>0.05
PTH (pg/mL)	200	289.77 ± 239.38	305	441.43 ± 457.20	>0.05
Fe (μg/dL)	59	60.24 ± 17.74	58.5	59.86 ± 19.56	>0.05
Saturation of transferrin (%)	29	32.71 ± 15.05	29	31.14 ± 10.74	>0.05
Ferritin (ng/mL)	392	527.24 ± 422.01	387	465.29 ± 265.33	>0.05
NPNA (g/kg/day)	1.2	1.18 ± 0.12	1.19	1.16 ± 0.19	>0.05
BMI ((kg/m^2)	23	23.65 ± 2.12	23	23.21 ± 3.58	>0.05
Kt/V (urea)	1.2	1.25 ± 0.10	1.2	1.26 ± 0.11	>0.05
Erythropoietin(IU/week)	4000	3411.77 ± 2647.14	4000	4214.29 ± 3285.83	>0.05
Vitamin D (μg /week)	0	0.65 ± 1.62	0	1.00 ± 1.84	>0.05

The seroconversion rate (HBs-Ab titer >10 IU/L) was 94.1% in ID and 50% in IM group six months after the last vaccination dose. Sixteen of 17 patients in ID group disclosed statistically significant seroconversion rates (p = 0.000), and seven of 14 patients in the IM group showed statistically significant seroconversion rates (p = 0.03). However, a comparison of the two groups regarding seroconversion rate revealed significantly better results in ID group (p = 0.011). ID vaccination was superior to IM vaccination not only qualitatively, but quantitatively as well. Mean HBs-Ab titer in ID and IM groups were 209.6±239.8 IU/L and 52.8±117.9 IU/L, respectively (p = 0.003; see Table 2)

Table 2 Comparison of response rates and HBs-Ab titers of two groups six months after the last vaccination dose

	Intradermal	Intramuscular	p
HBs-Ab quantitative(IU/L)	209.59 ± 239.79	52.79 ± 117.94	0.003
HBs-Ab qualitative	16 (94.1%)	7 (50%)	0.011

DISCUSSION

A lack of response to hepatitis B vaccination has remained a problem in HD patients despite new efforts with new agents or adjuvants. Adjuvanted hepatitis B vaccination (HB-AS04), granulocyte macrophage stimulating factor, levamisole, and tetanus toxoid administrations were used to increase response rates in HD patients.[1],[10],[12],[13] However, cost-effectiveness has been another problem that needed to be addressed. Vaccination for hepatitis B at early stages of chronic kidney disease was found to reach seroprotective ranges more successfully in a previous study. Moreover, vaccination at early stages of chronic kidney disease was recommended to lower the cost in hemodialysis patients.[14] In another study, the annual administration of the vaccine booster was found to be more cost effective than screening HBs-Ab titers in HD patients.[15]

Intradermal vaccination was found to be more effective than other administration routes in both HD and peritoneal dialysis patients.[8],[9] However, in another study, no difference was found between ID and IM vaccination in HD patients.[11] Studies comparing the administration routes that used different vaccination schedules and doses conflicted with the present conclusion about the effectiveness of ID and IM vaccination.

There appears to be only one previous manuscript that compared ID and IM vaccination protocols in unresponsive HD patients.[16] In that study, the standard IM vaccination protocol was 40 μg three times for each HD patient. Unresponsive patients were 34.20% of the study group, versus 5.16% in our study group. The low rate of unresponsive patients in our study could be explained with higher doses and repeated IM vaccination protocol.

For unresponsive patients, the total vaccination dose was same with the present study (80 μg) for ID vaccination protocol (5μg 16 times per week). However, IM vaccination dose was 80 μg (40 μg two times per month). The results showed that ID was superior to IM administration.[16] In the above-mentioned study, the vaccination protocol for IM group was not the standard protocol used in HD patients. In the present study, despite a half dose used in the ID group, seroconversion rates were nearly two times (94% vs 50%) higher than the IM group, a statistically significant difference. Regarding mean serum antiHBs-Ab titers, the difference was more significant in favor of ID vaccination. Because of high response rates (94.84%) to the first two IM vaccination protocols, the number of unresponsive patients was low in this study. The resulting small sample size was a limitation of this study.

The factors that could affect the response rate were not different in both ID and IM groups. Thus, the low dose ID is superior to standard IM vaccination protocol —as well as more cost-effective—in unresponsive HD patients. However, repeated vaccination protocols significantly increase seroconversion rates in unresponsive HD patients. Changing the administration route of vaccination for hepatitis B could be an effective procedure for unresponsive HD patients.