Effects of Oral Levamisole as an Adjuvant to Hepatitis B Vaccine in HIV/ AIDS Patients: A Randomized Controlled Trial

Background

Human immunodeficiency virus (HIV) infected patients are also frequently exposed to the hepatitis B virus (HBV), due to the common routes of transmission, therefore, prevention of hepatitis B results in decreased complications of the disease.

Objectives

Since the immune response of HIV patients to hepatitis B vaccination is less robust than that found in healthy individuals, this study aimed to evaluate the effect of a levamisole adjuvant on increasing the immune response.

Patients and Methods

In this study, 89 HIV infected patients, without a history of HBV infection or vaccination, were randomly allocated into experimental (44 patients) and control (45 patients) groups. HBV vaccination was performed using the Hepavax-Gene TF vaccine, 40 μg three times at intervals of; zero, one, and three months. Levamisole 50 mg twice a day or a placebo, was administered to the experimental and control groups, respectively, for a period of six days before to six days after the vaccination. Immune response was evaluated by measuring hepatitis B surface antibodies (HBsAb) concurrently with the second and third vaccine administration, and at one and three months at the conclusion of the vaccination program.

Results

The immune response following the threevaccinations was higher in those who were receiving levamisole compared with the controls (90% vs. 65.38%) (P = 0.05). Furthermore, the immune response and the mean antibody titer following the repeated vaccination in the experimental group showed a higher increase than in the control group. The immune response and the mean titer of antibody were not associated with; age, sex, body mass index, history of smoking and/or intravenous drug use in either of the groups. However, regarding CD4+ cells more than 200 cell/mm3, mean antibody production significantly increased in both groups.

Conclusions

Using levamisole with the hepatitis B vaccination can increase the immune response and antibody titer mean in HIV infected patients. Since these patients have a more complete response with CD4+ cells more than 200 cell/mm3, vaccination and effective adjuvants seem to be most beneficial when CD4+ cells are greater than 200 cell/mm3, in HIV infected patients.     

Vaccination against hepatitis B in patients with chronic liver disease awaiting liver transplantation.

BACKGROUND: Most transplant centers in the United States immunize patients awaiting liver transplantation against hepatitis B to prevent acquisition of hepatitis B through transplantation (de novo hepatitis B). A recent study showed that only 16% of patients with cirrhosis awaiting liver transplantation responded to single-dose recombinant vaccine. METHODS: We studied the immunogenicity of double-dose recombinant vaccine in patients with cirrhosis awaiting liver transplantation. RESULTS: Over a 4-year period (January 1994 to December 1997), 140 patients with cirrhosis without past or current hepatitis B infection were given double-dose recombinant vaccine (40 microg of Engerix B; SmithKline Beecham, Philadelphia, PA) at 0, 1 to 2, and 2 to 4 months. Hepatitis B surface antibody (HBsAb) was measured 1 to 3 months after completing vaccination. The response rate was 37%. However, HBsAb titers became undetectable in 35% of the responders during the post-transplant follow-up period. One hundred and thirty-seven patients underwent 144 liver transplantation procedures during the study period, and 3 patients developed de novo hepatitis B (2.2%). Livers transplanted from hepatitis B core antibody (HBcAb)-positive donors was the source of de novo hepatitis B in all cases. Two of the 3 patients who developed de novo hepatitis B were immunized before transplantation and one of them was a responder. CONCLUSION: Although the response rate to double-dose recombinant vaccines is higher than the previously reported response to single-dose vaccine, it still is less than optimal.     

Antibody to human immunodeficiency virus (HIV) and suboptimal response to hepatitis B vaccination

STUDY OBJECTIVE: To analyze the relation between human immunodeficiency virus (HIV) infection and the antibody response to plasma-derived hepatitis B vaccine. DESIGN: Open-label longitudinal cohort study; blinded laboratory studies. SETTING: University-affiliated municipal hospital. Patients: Homosexually active men with negative assays for hepatitis B surface antigen (HBsAg), hepatitis B core antigen, and antibody to HBsAg; recruited in a sexually transmitted disease clinic or referred from community practitioners. INTERVENTIONS: Immunization with 20 micrograms of plasma-derived hepatitis B virus vaccine intramuscularly, repeated after 1 and 6 months; standardized evaluation at entry and at 1, 2, 6, and 7 months. MEASUREMENTS AND MAIN RESULTS: Low antibody response or nonresponse to vaccination occurred in 7 of 16 HIV-seropositive patients, compared with 6 of 68 HIV-seronegative patients (P = 0.002). Median levels of antibody to HBsAg 7 months after the first vaccine dose were 205.3 sample ratio units for HIV-seronegative patients and 15.5 sample ratio units for HIV-seropositive patients. By multivariate analysis, vaccine response was associated with HIV antibody status and not with cytomegalovirus infection, lymphocyte subset results, or impaired cutaneous delayed hypersensitivity. CONCLUSIONS: Infection with HIV is associated with suboptimal antibody response to plasma-derived hepatitis B virus vaccine. Determination of antibody levels after vaccination in HIV-seropositive patients may be warranted.     

Hepatitis B vaccine by intradermal route in non responder patients:An update

Vaccination is the main prophylactic measure to reduce the mortality caused by hepatitis B virus(HBV)infection in healthy subjects since the immune response to hepatitis B recombinant vaccination occurs in over 90%of general population.Individuals who develop an antiHBs titer less than 10 mIU/mL after primary vaccination cycle are defined"no responders".Many factors could cause a non response to the HBV vaccination,such as administration of the vaccine in buttocks,impaired vaccine storage conditions,drug abuse,smoking,infections and obesity.Moreover there are some diseases,like chronic kidney disease,human immunodeficiency virus infection,chronic liver disease,celiac disease,thalassaemia,typeⅠdiabetes mellitus,down’s syndrome and other forms of mental retardation that are characterized by a poorer response to HBV vaccination than healthy subjects.To date it is still unclear how to treat this group of patients at high risk of hepatitis B infection.Recent studies seem to indicate that the administration of HBV recombinant vaccine by the intradermal route is very effective and could represent a more useful strategy than intramuscular route.This review focuses on the use of anti hepatitis B vaccine by intradermal route as alternative to conventional intramuscular vaccine in all non responder patients.A comprehensive review of the literature using PubMed database,with appropriate terms,was undertaken for articles in English published since 1983.The literature search was undertaken in September 2013.     

Prevalence of isolated antibody to hepatitis B core antigen in an area endemic for hepatitis B virus infection: implications in hepatitis B vaccination programs

Of 1,801 Chinese subjects, age 1 to 90 years, screened for hepatitis B surface antigen and antibody (HBsAg, anti-HBs) and antibody to hepatitis B core antigen (anti-HBc), 214 (11.9%) had an isolated, positive anti-HBc result; anti-HBc was reproducibly present in the initial sera in only 66% and persisted after an interval of 2 weeks to 3 months in only 73%. There was a strong correlation between the rates of reproducibility and persistence of isolated anti-HBc and the initial anti-HBc titers. Thirty-two subjects with persistent, isolated anti-HBc received four doses of hepatitis B vaccine (5 micrograms, HEVAC B) at 0, 1, 2 and 12 months: 56% developed a primary anti-HBs response in response to hepatitis B vaccine, 16% developed an anamnestic or secondary anti-HBs response, and 28% were undetectable for anti-HBs even after four doses of vaccine. The low rates of reproducibility and persistence of anti-HBc together with the high rate of primary anti-HBs response to hepatitis B vaccine in subjects with isolated anti-HBc raise doubts as to the reliability of anti-HBc (Corzyme, Abbott Laboratories, North Chicago, Ill.) as a single screening test for hepatitis B infection prior to vaccination and suggests that subjects with isolated anti-HBc, in particular those with low anti-HBc titers, be included in vaccination programs.     

Safety and efficacy of vaccination against hepatitis B in patients with rheumatoid arthritis

BACKGROUND: Hepatitis B infection and vaccination against it have been implicated in the potential triggering or flare of some autoimmune diseases, including rheumatoid arthritis (RA). However, the safety of hepatitis B vaccination in patients with pre-existing RA is not known. OBJECTIVES: To assess the safety and antibody response of immunisation with a recombinant DNA hepatitis B vaccine in patients with RA. PATIENTS AND METHODS: The study comprised 44 patients with RA, of whom 22 received three doses (the second and third dose being given after one and six months) of a recombinant DNA hepatitis B vaccine (study group) and 22 did not receive the vaccine (control group). Both groups had comparable proportions of women and similar mean age (51 years). Clinical assessment before and two and seven months after the first immunisation included evaluation of daytime pain with a 10 cm visual analogue scale, duration of morning stiffness, and number of tender and swollen joints. Erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) were measured at each visit. Antibodies to hepatitis B surface antigen (HBsAg) were determined by a commercial enzyme linked immunosorbent assay (ELISA) test kit. RESULTS: Hepatitis B vaccination was not associated with an appreciable deterioration in any clinical or laboratory measure of disease. The measures of disease activity of the patients and controls during the study period did not differ significantly: p=0.76 for daytime pain, p=0.1 for morning stiffness, p=0.24 and p=0.3 for tender and swollen joints respectively, p=0.08 for CRP, and p=0.12 for ESR. Fifteen of the 22 patients responded to vaccination, with an antibody level against HBsAg of 10 IU/l after seven months. Lack of response was associated with older age and higher scores of daytime pain. CONCLUSIONS: Hepatitis B vaccination is safe in RA and produces antibodies in 68% of the patients.     

Hepatitis B vaccine boosters: Is there a clinical need in high endemicity populations?

The Steering Committee for the Prevention and Control of Infectious Diseases in Asia recently conducted a survey of primary-care physicians in Asia, which revealed that many physicians administer boosters in their clinical practice and that there is considerable variation and uncertainty among physicians regarding this practice. This paper serves as a response to physicians' uncertainties by reviewing the literature regarding the administration of hepatitis B vaccine boosters in high endemicity areas and presenting the Steering Committee's guidelines for booster administration. While there are few data to support a need for routine hepatitis B vaccine boosters as a public health measure, they help to provide reassurance of immunity against breakthrough infection in certain risk groups. In clinical practice, primary-care physicians must exercise their judgment regarding the need for booster vaccination on an individual basis. This paper examines the available literature on the administration and value of hepatitis B vaccine boosters, explores the differences between the public health approach and clinical practice, and provides guidelines for those who use boosters in high endemicity Asian populations. Relevant articles were identified through searches of MEDLINE (1975-2003) and the Cochrane Library, using 'hepatitis B' and 'booster' as primary search terms. Guidelines for those who decide to administer hepatitis B vaccine boosters include: boosting approximately 10-15 years after primary vaccination; boosting rather than not when monitoring of antibody levels is not feasible; boosting immunocompromised patients when the antibody to hepatitis B surface antigen titer falls below 10 mIU/mL; and boosting healthcare workers based on the endemicity of the particular country.     

Immune response after hepatitis A vaccination in haemodialysis patients: Comparison with hepatitis B vaccination

This study evaluates the immune response of 20 haemodialysis (HD) patients vaccinated with hepatitis A (HA) vaccine and eight patients vaccinated with hepatitis B (HB) vaccine. Twenty patients and 22 healthy adults were immunized three times (months 0, 1 and 6) intramuscularly with a 0.5 μg dose. All members of both groups were positive for the antibody to hepatitis A virus (anti-HAV) after three vaccinations. The geometric mean titres at 7 months were similar in both groups. No serious side effects were observed. Eight of the HD patients with HA vaccination were injected with yeast-derived hepatitis B vaccine. The three doses of 10 μg were administered intramuscularly at 0, 1 and 6 months. The occurrence of antibody to hepatitis B surface antigen (anti-HBs) was late in HD patients and the anti-HBs level in HD patients was lower than that in healthy subjects. These results indicate that this HA vaccine has good immunogenicity compared with the HB vaccine and that the standard three doses of HA vaccine given at 0, 1 and 6 months are safe and effective even in HD patients.     

Response to hepatitis B vaccination by liver transplant candidates

Liver transplantation (OLTx) is a procedure offered to individuals with advanced liver disease who are expected to live less than a year. Despite improvement in the care of transplant recipients, these patients are exposed to large volumes of blood and, as a result, are at risk to acquire hepatitis. Currently, the only vaccines available for the prevention of hepatitis are those that induce a response to HB_sAg. In this study, 144 patients awaiting OLTx and 15 controls were vaccinated three times, once a month, intramuscularly in the deltoid using the Merck Hepatovax plasma-derived vaccine. This schedule was continued regardless of whether or not OLTx occurred before the series was completed. For the 15 controls, the response rate was 93% and for individuals with end-stage liver disease, it ranged from 44 to 54% (P<0.004). No difference in the percentage of those developing antibody was detected between groups based upon disease indication or whether the vaccination series was completed before or after OLTx. Of the following: WBC, lymphocytes (percent and number), CD3+ cells (percent and number), CD4+ cells (percent and number), CD8+ cells (percent and number), CD4+/CD8+ ratio, and B cells (percent and number), only the absolute WBC (P<0.05) distinguished between those who did and did not develop antibody. These data suggest: (1) those with chronic liver disease respond less well to Hepatovax than do controls; (2) a rapid sequence of vaccinations is capable of producing antibody in normals and those with liver disease; (3) no difference is evident between those who completed their vaccination schedule before or after OLTx; and (4) among patients with chronic advanced liver disease, a higher total WBC is associated with an increased rate of seroconversion.     

Hepatitis B vaccine boosters: Is there a clinical need in high endemicity populations?

The Steering Committee for the Prevention and Control of Infectious Diseases in Asia recently conducted a survey of primary-care physicians in Asia, which revealed that many physicians administer boosters in their clinical practice and that there is considerable variation and uncertainty among physicians regarding this practice. This paper serves as a response to physicians' uncertainties by reviewing the literature regarding the administration of hepatitis B vaccine boosters in high endemicity areas and presenting the Steering Committee's guidelines for booster administration. While there are few data to support a need for routine hepatitis B vaccine boosters as a public health measure, they help to provide reassurance of immunity against breakthrough infection in certain risk groups. In clinical practice, primary-care physicians must exercise their judgment regarding the need for booster vaccination on an individual basis. This paper examines the available literature on the administration and value of hepatitis B vaccine boosters, explores the differences between the public health approach and clinical practice, and provides guidelines for those who use boosters in high endemicity Asian populations. Relevant articles were identified through searches of MEDLINE (1975–2003) and the Cochrane Library, using 'hepatitis B' and 'booster' as primary search terms. Guidelines for those who decide to administer hepatitis B vaccine boosters include: boosting approximately 10–15 years after primary vaccination; boosting rather than not when monitoring of antibody levels is not feasible; boosting immunocompromised patients when the antibody to hepatitis B surface antigen titer falls below 10 mIU/mL; and boosting healthcare workers based on the endemicity of the particular country.     

Determination of Hepatitis B Surface Antibody Titer in Vaccinated Children with Major Thalassemia in Kerman-Iran

Background: Thalassemia patients are more susceptible to hepatitis than the normal population due to the frequent blood transfusions. Objective: To determine the immune response of children with major ß-thalassemia, by measuring anti-hepatitis B surface antibody (anti-HBs Ab) following the last HBV vaccine injection. Methods: This study was carried out on 215 thalassemic children who received three standard intramuscular recombinant HBV vaccines. Children age ranged between 1-4.5 with a mean age of 3.37 years. Based on the time lapsed since last vaccine injection, the subjects were divided into three groups; 0-15 months, 15-30 months and 30-45 months, respectively. Based on the serum levels of anti-HBs antibody, subjects were categorized as: good responders (anti-HBs >100 IU/Lit), low responders (anti-HBs 10-100 IU/Lit) and non-responders (anti-HBs <10 IU/Lit). Results: The mean range of anti-HBs level in the above mentioned groups were 205.34, 128.8 and 54.25 IU/lit, respectively (P<0.0001). In girls, the mean antibody level was 104.2 and in boys it was 95.8 IU/Lit (P>0.05). Out of 215 selected individuals 75 (35%) were good responders, 65(30%) low responders and 75 (35%) non-responders. Conclusion: Standard HBV vaccination in thalassemic children results in an immune response in more than 65% of the subjects. Therefore, assessment of anti-HBs antibody level, 45 months after the last vaccination, is recommended.     

Duration of immunity after hepatitis B vaccination: efficacy of low-dose booster vaccine

Although the efficacy of hepatitis vaccine is well documented, the duration of immunity of healthy adults after vaccination is unknown. We studied 245 hospital employees 3 years after primary vaccination with hepatitis B vaccine to determine the prevalence of immunity indicated by levels of antibody to hepatitis B surface antigen of 10 mIU/mL or greater; and to compare the immunogenicity of low-dose intradermal vaccine with standard-dose intramuscular vaccine in persons found to be seronegative. Thirty-eight percent of employees studied had antibody levels less than 10 mIU/mL. Low levels were associated with smoking, older age, and higher body-mass index. Seventy-eight percent of persons with low antibody levels responded to a single booster vaccine. Two micrograms of intradermal vaccine was as effective as 20 micrograms of intramuscular vaccine in inducing an antibody response; however, intradermal vaccine was associated with more local reactions (42% compared with 17%). Many healthy adults will need periodic boosters of hepatitis B vaccine to maintain production of antibody to hepatitis B surface antigen; low-dose intradermal booster schedules may be feasible.     

Hepatitis B vaccination alone is not adequate for the categorizing of adult subjects with isolated anti-HBc

Abstract To evaluate the meaning of isolated antibody to hepatitis B core antigen (anti-HBc), 88 Chinese subjects with isolated anti-HBc received rescreening of hepatitis B virus (HBV) markers. Eighty (90.9%) of them were still positive for this antibody and 29 were also found to be positive for antibody to hepatitis B surface antigen (anti-HBs). The remaining 51 subjects (58.0%) were positive for anti-HBc alone; 50 of them received a four-dose schedule of hepatitis B (HB) vaccine. After the initial dose, only one vaccinee disclosed an amnestic anti-HBs response, that is, anti-HBs titre > 1000 miu/mL. Forty-five vaccinees completed the vaccination schedule and 44 (97.8%) had anti-HBs response. The anti-HBs responses in 25 of these vaccinees were compared with 25 age- and sex-matched normal susceptible vaccinees. The anti-HBs response rates in both groups were the same (96 vs 96%). However, the geometric mean titre was significantly lower in the vaccinees with isolated anti-HBc (512 mIU/mL vs 4688 mIU/mL, P < 0.001). Prevaccinated sera were available in 49 vaccinees with isolated anti-HBc for detection of antibody to hepatitis B e antigen (anti-HBe) and HBV DNA; 37 (75.5%) of them had one or two of these markers. As we regarded the rescreening of HBV markers, response to hepatitis B vaccination and presence or absence of anti-HBe and/or HBV DNA together for categorizing the 88 subjects with isolated anti-HBc, at least three-quarters of them had past infection of HBV. The subjects with false positive anti-HBc test were a minor group. We concluded that the presence or absence of amnestic anti-HBs response to HB vaccination is not a reliable indicator for categorizing subjects with isolated anti-HBc. Rescreening of HBV markers, with addition of anti-HBe and HBV DNA, may be helpful in determining the necessity of HB vaccination.     

Hepatitis B vaccination

Alcoholics are at risk to develop hepatitis B infections, chronic active hepatitis, and even hepatoma. Hence, immunization with hepatitis B vaccine is recommended. However, immune abnormalities may coexist which alter their responsiveness to vaccination. This study compares the immune response to this vaccine in controls (group I), alcoholics without overt liver disease (group II), and alcoholics with clinical liver disease (group III). By the seventh month after the initial vaccination, 89% in group I, 70% in group II, and 18% in group III had a response >36 RIA units. The magnitude of the response was significantly different in groups I, II, and III (19,456 vs 8,326 vs 153 RIA units, respectively; P <0.05, group I vs III). In those who did not respond, a significant (P < 0.02) lower helper/inducer (T ₄)class of lymphocytes was observed as compared to patients who exhibited an adequate response. These observations suggest: (1) that the response to hepatitis B vaccine is a T-cell-dependent event and (2) that in this population, using the existing vaccine, postvaccination evaluations of antibody concentrations are needed before protection against hepatitis B infection can be assumed.This research was funded by the Veterans Administration, Cincinnati, Ohio; and Merck, Sharp and Dohme Laboratories.     

Low Prevalence of Vaccination or Documented Immunity to Hepatitis A and Hepatitis B Viruses Among Individuals with Chronic Liver Disease

BackgroundDespite national guidelines emphasizing the importance of vaccination or documenting immunity to hepatitis A virus and hepatitis B virus for patients with chronic liver disease, the success of adhering to these recommendations is suboptimal. We aim to evaluate the prevalence of vaccination or documented reactivity to hepatitis A antibody and hepatitis B surface antibody among US adults with chronic liver disease.MethodsUsing 2011-2018 National Health and Nutritional Examination Survey data, adults with nonalcoholic fatty liver disease, alcoholic liver disease, hepatitis B, and hepatitis C were evaluated to determine prevalence of vaccination (self-reported completion) and hepatitis A antibody reactivity or hepatitis B surface antibody reactivity.ResultsOverall prevalence of vaccination or hepatitis A antibody reactivity was lowest among individuals with nonalcoholic fatty liver disease (60.8%; 95% confidence interval [CI], 57.9-63.6) and alcoholic liver disease (61.8%; 95% CI, 59.0-64.6), and highest among individuals with hepatitis B (82.9%; 95% CI, 76.8-89.0). Prevalence of vaccination or hepatitis B surface antibody reactivity was much lower: 38.6% (95% CI, 35.7-41.4) in nonalcoholic fatty liver disease, 40.7% (95% CI, 34.4-47.0) in chronic hepatitis C virus, and 47.1% (95% CI, 44.3-49.9) in alcoholic liver disease.ConclusionAmong US adults with chronic liver disease, prevalence of vaccination or documented reactivity to hepatitis A antibody and hepatitis B surface antibody was alarmingly low. These observations are particularly concerning given that underlying chronic liver disease increases risks of severe liver injury and decompensation from acute hepatitis A or hepatitis B infections.     

Double-dose double-phase use of second generation hepatitis B virus vaccine in patients after living donor liver transplantation: Not an effective measure in transplant recipients

Aims:  Post-transplant active immunization for chronic hepatitis B patients has been attempted in several studies with controversial results. We assessed the effect of a double-dose double-phase vaccination regimen among partial living donor liver recipients.
Methods:  Eighteen patients who underwent liver transplantation (LT) for chronic hepatitis B and two non-hepatitis B virus (HBV)-infected patients who received hepatitis B core antibody (HBcAb)-positive donor organs were recruited 18–78 months after LT. All were on hepatitis B immunoglobulin (HBIG) mono-prophylaxis before and throughout vaccination, to maintain hepatitis B surface antibody (HBsAb) titers of more than 100 IU/mL. Recombinant hepatitis B surface antigen vaccine (40 µg) was administered intramuscularly during weeks 0, 4, 8, 24, 28 and 32.
Results:  The patients consisted of 15 males and five females with a median age of 52 (39–59) years. None developed a sufficient HBsAb titer above 500 IU/mL by week 48. In two patients whose maximum HBsAb titer increased to above 300 IU/mL, we attempted to skip HBIG, but shortly thereafter the titer dropped below 100 IU/mL and HBIG administration was resumed. Although the HBIG dose was reduced during and after vaccination, cessation of administration was not achieved.
Conclusion:  Double-dose double-phase use of second generation recombinant vaccine was not effective in this study population. The selected population should be targeted for a conventional vaccine regimen, and different approaches, such as strong adjuvant or pre-S containing protein, should be further tested in a larger number of patients after LT for chronic hepatitis B.     

The effect of high dose and short interval HBV vaccination in individuals with chronic hepatitis C

OBJECTIVES: The efficacy of the standard hepatitis B virus (HBV) vaccination schedule in individuals with chronic hepatitis C is reported to be reduced. Our aim was to assess the response rate to high dose, short interval HBV vaccination in such individuals. METHODS: A total of 152 individuals with chronic hepatitis C were vaccinated with 40 microg of vaccine administered monthly for 3 months. Twenty-six individuals with no evidence of liver disease underwent the same vaccination schedule and were considered to be the control group. Hepatitis C virus (HCV)-positive subjects who did not seroconvert to anti-hepatitis B surface positivity after the third dose of the vaccine (nonresponder) were vaccinated with a fourth dose of vaccine (booster dose, 80 microg). RESULTS: One hundred nine of the 152 individuals with chronic hepatitis C (72%) seroconverted to anti-hepatitis B surface positivity (> 10 mIU/ml), as compared to 24 of the 26 controls (92%, p < 0.05). Although individuals with chronic hepatitis C responded less frequently to high dose, short interval HBV vaccination than did the controls, no differences in terms of effective immunity (>100 mIU/ml) were evident among the two groups of responders (51% vs 54%). Also, no difference in response was reported between individuals with chronic active hepatitis C and controls (92% vs 80%). The response rate was significantly lower in cirrhotics than in the noncirrhotic group (54% vs 80%, p < 0.001). Besides cirrhosis, no other demographic or bioclinical factor was found to influence the response to vaccination. After the additional booster dose, the overall response was increased to 74% of the cirrhotics and 88% of the noncirrhotics. No major HBV vaccine-related adverse effects were seen. CONCLUSIONS: A high dose, short interval HBV vaccination schedule is safe in individuals with chronic hepatitis C. From these data, it is suggested that a high dose and a short interval between HBV vaccinations may produce an effective and early antibody response in such patients.     

Granulocyte-macrophage colony-stimulating factor enhances the efficacy of hepatitis B virus vaccine in previously unvaccinated haemodialysis patients

The response to vaccination with recombinant hepatitis B virus (HBV) vaccine is poor in haemodialysis patients. A defect in the antigen-presenting cells may be responsible for this hyporesponsiveness. To overcome this and to improve the response to HBV vaccine in dialysis patients, we used granulocyte–macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant. Fifteen consecutive patients with chronic renal failure (CRF), commenced on dialysis, were stratified to receive either 40μg HBV vaccine (Engerix-B) at 0, 1, 2 and 6 months (group A, n =9) or 3μg kg^–1 GM-CSF (Leucomax) on day 1 followed by the vaccination schedule described above (group B, n =6). All patients were negative for hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (anti-HCV) and human immunodeficiency virus (HIV) serology. Titres of antibody to HBsAg (HBsAb) were quantitatively assayed, using enzyme-linked immunosorbent assay (ELISA), at 1, 2, 6 and 7 months from the first dose of vaccination. Only 44% of the patients in group A developed protective antibody levels (mean HBsAb: 22 IU l^–1) Fifty per cent of responders developed protective antibody levels (HBsAb >10 IU l^–1) only after the fourth dose of vaccination. In contrast, all six patients (100%) in group B developed protective levels of HBsAb (mean HBsAb: 70 IU l^–1) ( P <0.02). Sixty-seven per cent of the responders were protected after only the second dose of vaccination ( P =0.046). No serious adverse effects of GM-CSF were observed in group B. Hence, haemodialysis patients respond poorly to HBV vaccine. GM-CSF is a safe vaccine adjuvant capable of stimulating an earlier and a stronger antibody response to HBV vaccine in haemodialysis patients.     

Decreased immunogenicity of recombinant hepatitis B vaccine in chronic hepatitis C

The immunogenicity of hepatitis B vaccine is unknown for patients with chronic hepatitis C, although hepatitis B vaccination is highly recommended in these patients. We therefore studied in a prospective open trial of 59 patients with chronic hepatitis C (mean age 42 years, hepatitis C for >10 years, Child-Pugh score < or = 5) and 58 healthy hospital staff persons the rate of nonresponse (anti-HBs <10 mIU/mL at 9 months) to recombinant hepatitis B vaccine (Gen H-B-Vax(R),10 microg intradeltoidal at month 0, 1, and 6). Nonresponse was observed in 18/59 (31%) patients with chronic hepatitis C and 5/58 (9%) healthy staff persons (P <.005) (vs. 7% in historical controls; P <.005), low response (anti-HBs 10-99 mIU/mL) in 19% of patients with chronic hepatitis C and 17% of staff persons. High-dose booster vaccination led to seroconversion in 12/15 (80%) of primary nonresponders. Primary nonresponse to HB vaccine was related neither to presence of early-stage liver cirrhosis nor magnitude of serum hepatitis C virus (HCV) RNA concentration, nor explained by the presence of human leukocyte antigen (HLA) types (B8 DR3, B44, DR7, DQ2) predisposing to low antibody response to hepatitis B surface antigen. The rate of primary nonresponse to the standard regimen of recombinant hepatitis B vaccine is surprisingly high in patients with longstanding chronic hepatitis C. Therefore, the antibody to HBV surface antigen (anti-HBs) titer response should be determined in these patients. Depending on the response titer, higher booster doses may be required to achieve and maintain seroprotection in these patients.     

富含C、G碱基的核甘酸片段增强乙型肝炎表面抗原免疫反应

目的 研究如何高效率激发机体对HBsAg的体液和细胞免疫反应,寻求治疗乙型肝炎的有效方法。方法 合成全硫代修饰的富含C、G碱基的核甘酸(CpG ODN)片段作为免疫佐剂,与HBsAg按一定比例混合免疫小鼠,研究其增强HBsAg免疫反应的作用。实验分为单纯HBsAg组、HBsAg CpG ODN组、商用乙肝疫苗(与HBsAg亚型相同)组、商用乙肝疫苗 CpG ODN组4组。HBsAg及商用乙肝疫苗用量为1．67μg／次,CpG ODN为16．5μg／次。采用两剂免疫方案,间隔15d,末次免疫后15d,取血测抗-HBs;取脾细胞作细胞毒性T淋巴细胞(CTL)实验。结果 4组抗-HBs A值分别为0．109、0．435、0．422及0．575;CTL反应值分别为8．5％、37．0％、1．5％和28．0％,实验中未观察到明显的毒副作用。结论 (1)CpG ODN能明显增强HBsAg的体液免疫反应;(2)CpG ODN也能增强HBsAg的细胞免疫反应;(3)CpG ODN与商用乙肝疫苗中的铝剂有协同作用,两者联用可同时诱导高效价的抗体反应和有效的细胞免疫反应。进一步评价其安全性和有效性,可望用于临床治疗慢性乙肝病毒感染。