Low dose intradermal versus high dose intramuscular hepatitis B vaccination in patients on chronic hemodialysis

Patients with end-stage renal disease on hemodialysis (HD) are at high risk for hepatitis B infection. We randomly assigned 86 new patients on HD to receive either 40 microg intramuscular (group 1) or 20 microg intradermal (group 2) recombinant hepatitis B vaccine, in three doses at 0, 1, and 4 months. All patients were seronegative at baseline for hepatitis B surface antigen (HBs-Ag), hepatitis B surface antibody (HBs-Ab), and hepatitis B core antibody (HBc-Ab). HBs-Ab seroconversion rate and antibody titer (ELISA assay) were compared in 27 patients of group 1 and 35 patients of group 2 at 1 month, and in 20 patients of group 1 and 26 patients of group 2 at 6 months after the last vaccine dose. The seroconversion rates (HBs-Ab titer >10 IU/L) were 55.6% and 50% in group 1, and 54.3% and 50% in group 2, at 1 and 6 months, respectively (p = NS). Patients' age, body mass index, serum albumin concentration, and sex distribution were similar in the responders and nonresponders. Intradermal hepatitis B vaccination used at half dose may be a cost saving alternative to intramuscular vaccination in patients on HD. However, the low overall seroconversion rate mandates seeking alternative ways of vaccination in this patient population.     

Immune response to a recombinant hepatitis B vaccine in hemodialysis patients

A 20-microgram dose of a recombinant hepatitis B vaccine was given at 0, 1, 2 and 6 months to 24 hemodialysis patients. From month 7 (i.e., 1 month after the fourth injection), 58.3% (14/24) of the patients had developed protective levels of antibodies against hepatitis B surface antigen (anti-HBs). In patients responding to vaccination, the fourth injection led to an abrupt rise of the anti-HBs titres which reached their maximum 2 months later, that is, in month 8. At that time, the geometric mean titre of anti-HBs was 145.79 mlU/ml. Eighteen months after the start of vaccination, 50% (12/24) of the patients were maintaining protective levels of anti-HBs antibodies. It is noteworthy that these results could be obtained with a considerably lower dosage than previously recommended.     

Prevention and treatment of hepatitis B in patients on hemodialysis and vaccination of hemodialysis health personnel against hepatitis B

The prevalence and incidence of hepatitis B in hemodialysis patients in Croatia have been estimated to 1.3% and 0.03%, respectively. HBV infection in dialysis patients is usually asymptomatic, has a prolonged course, and progresses to chronic HBsAg hepatitis in 50% of cases. Some 15%-40% of HBsAg carriers on dialysis will develop cirrhosis, liver decompensation or hepatocellular carcinoma. Strict adherence to the standard infection prevention measures, continuous monitoring of HBV markers in patients on hemodialysis, patient and personnel immunization and hepatitis B treatment in hemodialyzed patients are mandatory. Each new patient in a dialysis center must be tested for HBV markers irrespective of prior immunization. All patients in the center should be routinely screened every 3-4 months. HBV immunization is mandatory for all patients on dialysis. In patients with uremia the anti-HBs antibody production is decreased (antibodies will develop in 50%-60% of cases after immunization). It is recommended to immunize all patients with progressive kidney disease, preferably in the preterminal stage. Hepatitis B therapy is recommended in all patients with biopsy proven chronic liver disease. Patients should be treated with standard interferon alpha and/or lamivudine, or peginterferon alpha monotherapy. Hepatitis B treatment is most important in kidney and/or liver transplant candidates. HBV immunization is obligatory for all hospital personnel who are in close contact with infected patients and infective materials.     

Clinical and immunological efficacy of intradermal vaccine plus lamivudine with or without interleukin-2 in patients with chronic hepatitis B

To evaluate therapeutic immunostimulation nine chronic hepatitis B patients received six monthly intradermal vaccinations with HBsAg in combination with daily lamivudine. Another five patients received six doses of the vaccine and daily lamivudine together with daily Interleukin-2 (IL-2) s.c. within 3 months in an open-labeled trial. Clinical efficacy was assessed by alanine transaminase levels and HBV serology. The induction of specific T and B cell responses was analyzed serially by 3H-thymidine uptake, ELISA and ELISPOT assays. After the therapy was stopped, seven of nine vaccine/lamivudine and two of five vaccine/lamivudine/IL-2 recipients did not have detectable HBV DNA. Four complete responders cleared the virus and had normalized ALT levels, however, one of these patients showed transient disease reactivation followed by spontaneous viral clearance and normal ALT five months later. Low frequencies of anti-HBs producing B cells and HBV specific T helper cells secreting predominantly interferon-gamma were induced by i.d. vaccine therapy. The ELISPOT technique demonstrated transient induction of HBV peptide specific cytotoxic T cells in seven HLA-A2 positive chronic HBV carriers. The preliminary data from this study demonstrate that the HBV surface antigen vaccine in combination with antiviral or immunomodulating drugs induced antiviral immune responses and consequently viral elimination may be achieved in patients with unfavorable prognosis.     

乙型肝炎疫苗长期免疫效果评价及免疫持久性研究

目的 评价我国新生儿乙型肝炎(乙肝)疫苗免疫后的长期保护效果,为乙肝防控和乙肝疫苗HepB免疫策略提供参考.方法 用横断面调查和分层整群抽样的方法,在乙肝疫苗免疫效果观察监测点收集1987-1996年出生(13～22岁)、全程接种乙肝血源疫苗的人群,以及1997-2008年出生(1 ～ 12岁)、全程接种乙肝重组酵母疫苗人群的血清样本和资料;用微粒子酶免疫法检测HBV感染指标,结合本底资料和乙肝疫苗免疫史进行分析.结果 在河北正定、广西隆安、上海黄浦、青海同德和湖南湘潭5个监测点共收集1～12岁重组酵母疫苗免疫人群样本8133例,13 ～22岁血源疫苗免疫人群样本4848例,5个监测点的HBsAg平均阳性率均显著低于本底值,疫苗总体保护效果分别为86.04％～96.14％;河北正定、青海同德和湖南湘潭的年龄分布差异无统计学意义,广西隆安和上海黄浦的结果显示19～22岁人群HBsAg阳性率偏高;Anti-HBs阳性率随免疫年龄增长而下降,重组疫苗免疫人群从1～2岁组的86.84％下降至11～12岁组的46.40％,17 ～18岁组的Anti-HBs阳性率处于较低水平,而19～22岁组出现升高;几何平均浓度(GMC) ＜10 mIU/ml(Anti-HBs阴性)的比例随着年龄增长逐渐升高,100～999.99 mIU/ml和≥1000 mIU/ml的比例随着年龄的增长呈现下降趋势.结论 血源疫苗免疫后13～ 22年、重组酵母疫苗免疫后1～12年的总体保护效果良好;不必开展加强免疫,建议加强监测18岁以上人群的Anti-HBs水平,对GMC＜10 mIU/ml者开展加强免疫.     

Low-dose (2 micrograms) hepatitis B vaccination in medical students: comparable immunogenicity for intramuscular and intradermal routes

In a randomized controlled trial, 165 healthy medical students were immunized either by the intramuscular route (IM group) or by the intradermal route (ID group) with low-dose (2 micrograms) plasma hepatitis B vaccine (HB-VAX) at months 0, 1, 2, and 6. At month 7, protective immunity (anti-HBs greater than 10 IU/l) was observed in 90% (95% confidence interval [Cl]: 84-97) of group IM and in 94% (95% Cl: 89-99) of group ID; also geometric mean titres (IM: 533 IU/l; ID:541 IU/l) were very similar at month 7. Sixty-six (IM: 29; ID: 37) of 107 vaccinees with anti-HBs less than 1,000 IU/l at month 7 received a 2 micrograms booster injection at month 12. Long-term immunity (anti-HBs greater than 1,000 IU/l) was finally observed in 58% for group IM and 66% for group ID. For low-dose hepatitis B immunization, which reduces costs to about 16%, the IM route is to be preferred in young healthy individuals in view of an ease of administration, avoidance of long-term local side effects, and the known protective immunity of intramuscularly induced anti-HBs antibodies.     

Different immune responses after intradermal and intramuscular administration of vaccine against tick-borne encephalitis virus

A single multisite intradermal (ID) administration of the same dose used for regular intramuscular (IM) immunisation with vaccine against tick-borne encephalitis virus (TBEV) resulted in seroconversion of all vaccinees within three weeks: with the regular IM schedule, two vaccinations were necessary for all vaccinees to seroconvert. After the first ID vaccination, antibodies of the IgM class against TBEV (anti-TBEV-IgM) were observed in all vaccinees; after the first IM vaccination, only three out of nine vaccinees showed an IgM response. The geometric mean titer (GMT) of anti-TBEV-IgM in seropositives was 5–20-fold higher in the ID group and similar to that after natural infection. The GMT of antibodies of the IgG class against TBEV (anti-TBEV-IgG) was also higher in the ID group but with a less marked difference. Hemagglutination-inhibiting (HI) antibodies appeared earlier and persisted longer after one or two ID injections; after a third vaccination, HI antibody levels were similar in both groups. Side effects after ID vaccination were limited to local reactions. These results indicate that follow-up injections may be omitted or at least reduced after ID administration of the vaccine dose usually used for IM vaccination schedules. However, additional studies in larger groups of vaccinees are necessary before ID vaccination can be recommended for general use.     

Reduced antibody reactivity to hepatitis C virus antigens in hemodialysis patients coinfected with hepatitis B virus.

Antibody reactivities to hepatitis C virus (HCV) antigens and to synthetic peptides derived from different parts of the HCV genome (core, NS4, and NS5) were evaluated in HCV-infected hemodialysis patients. In the RIBA 3 assay, NS5 was significantly less recognizable by sera of hemodialysis patients compared to other HCV-infected subjects. Among hemodialysis patients, those coinfected with hepatitis B virus (HBV) (positive for hepatitis B surface antigen [HBsAg+]) showed a reduction in reactivity to C33 and C100. Sera of only 23% of the hemodialysis patients (37 of 161) reacted with more than three of eight peptides tested, significantly fewer than the 60% (12 of 20) of the sera of other HCV-infected patients tested (P = 0.001). This immunosuppression was also manifested by a reduced frequency of recognition of additional peptides on follow-up. An even more reduced reactivity was observed among the HBV-coinfected patients (HBsAg+). The low-responder hemodialysis patients were not infected with any particular genotype of HCV, and the same HCV genotypes observed in the whole group of hemodialysis patients (1a, 1b, 2a, and 3a) were found circulating in the low-responder group. Even in this low-responder population, the good performance of two peptides (peptide 716, corresponding to a portion of the core, and peptide 59, corresponding to a portion of NS4) corroborates the immunodominance of the conserved epitopes within these peptides.     

Eighteen-year follow-up cohort study on hepatitis B and C virus infections related long-term prognosis among hemodialysis patients in Hiroshima

This study aimed to investigate the prevalence trend of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and their genotype distribution among hemodialysis patients, determining their long-term prognosis and the risk factors to the mortality. This cohort study used both the medical data and the blood samples of hemodialysis patients at nine dialysis centers in Hiroshima from 1999 to 2017. Hepatitis B surface antigen (HBsAg) and anti-HCV were screened and then amplification was done to positive sera by polymerase chain reaction for genotyping. Data were employed for multiple regressions to determine the associated risk factors. A total of 3968 patients were subdivided into three groups: who started hemodialysis before 1990, during 1991 to 2001, and after 2002. The periodic prevalence of HBsAg decreased from 2.8% to 1.3% and that of anti-HCV from 33.3% to 9.5% in the three groups. By multiple regressions, the adjusted hazard ratio of diabetes mellitus (DM) ranges from 1.59 to 2.12 and that of HCV RNA positivity ranges from 1.18 to 1.48 (P < .05). Heart failure is the primary cause of death in all groups. Genotype C2 is predominant for HBV and genotype 1b is predominant for HCV. The decreasing trend of both HBV and HCV was found in the cohort. DM and HCV RNA were the significant risk factors leading to poor prognosis among hemodialysis patients. The similar genotype distribution of both HBV and HCV was found as general population. This alarmed to provide early diagnosis, prompt, and adequate treatment to HCV infection among hemodialysis patients.     

Genetic prediction of nonresponse to hepatitis B vaccine

In previous studies of the antibody response to hepatitis B vaccine in 598 subjects who received a full course of vaccination, we observed a bimodal response, with about 14 percent producing less than approximately 1000 radioimmunoassay (RIA) units. An analysis of the major histocompatibility complex (MHC) HLA and complement types of 20 of the subjects with the lowest responses indicated a greater-than-expected number of homozygotes for the extended or fixed MHC haplotype [HLA-B8, SC01, DR3]. This finding suggested that the lack of a normal response was a recessive MHC-linked trait. In this study, we prospectively vaccinated five homozygotes and nine heterozygotes for this haplotype in the expectation that the homozygotes would produce much lower levels of antibody than the heterozygotes. When the antibody response was assessed two months after the third injection, four of the five homozygotes had produced very low levels (approximately 1000 units or less) of antibody (mean, 467 RIA units; range, less than 8 to 1266), whereas all nine heterozygotes produced more than 2500 RIA units (mean, 15,608; range, 2655 to 28,900) (P less than 0.01). We conclude that the usual response to hepatitis B surface antigen is due to the presence of a dominant immune-response gene in the MHC and that a low response is due to the absence of such a gene and the presence on both chromosomes of MHC haplotypes (such as [HLA-B8, SC01, DR3]) that indicate such a response.     

Viral hepatitis in hemodialysis patients

Hemodialysis patients are one of the high-risk groups for viral hepatitis, especially hepatitis C virus(HCV) infection. Although using recombinant human erythropoietin to treat anemia and introducing HCV testing of donated blood have been expected to reduce the incidence of HCV infection, occasional transmission of HCV to hemodialysis patients still occurs. The epidemiological and phylogenetic analysis provides the evidence for nosocomial infection of HCV in hemodialysis units. On the other hand, the discrepancy between results of anti-HCV antibody and HCV RNA is observed in some hemodialysis patients, indicating that the isolation of patients positive for anti-HCV antibody is not effective for the prevention of transmission of HCV. The strict enforcement of universal precaution such as carefully changing gloves should be more important for the prevention of nosocomial infection.     

乙型肝炎疫苗免疫19年后乙型肝炎病毒感染流行规律的变化

目的探讨乙肝疫苗长期免疫地区人群HBV流行规律的变化趋势。方法整群抽样结合横断面调查，用固相放射免疫法检测研究对象血清HBV感染标志并进行分析。结果（1）平均HBsAg阳性率为7．5％，0～19岁人群HBV感染指标显著低于≥20岁人群。（2）0～19岁人群HBsAg阳性率1985年高于2005年；1985年的抗-HBs水平随着年龄增长而上升，从1～岁组的12．4％到60～岁组的53．8％，而2005年0～19岁组的抗-HBs随着年龄的增长而下降；1985年抗-HBc阳性水平随着年龄增长而上升，2005年的0～19岁组的仅为2．8％～26．8％，显著下降。结论研究人群中HBV流行规律发生显著变化，0～19岁人群的HBV感染率远低于20岁以上人群，证实乙肝疫苗预防HBV感染取得显著成果。     

乙型肝炎疫苗的研究新进展

乙型肝炎疫苗(HepB)接种是阻断乙型肝炎病毒(HBV)传播、预防乙型肝炎的最有效方法。HepB可以分为预防性疫苗和治疗性疫苗。本文综述了HepB及其佐剂的研究新进展,指出乙型肝炎治疗性疫苗以及新型疫苗佐剂是当前HepB研究的重要方向。此外,针对HepB的免疫不良反应和无(弱)应答问题提出应对措施。     

Thymopentin as adjuvant therapy to hepatitis B Vaccination in formerly non- or hyporesponding hemodialysis patients

Immunologic Research - Thirteen patients who were on chronic hemodialysis for renal failure received booster vaccination with 40 μg HB-Vax while receiving thymopentin as adjuvant therapy. A...     

T-lymphocyte number and function and the course of hepatitis B in hemodialysis patients.

To study the relation between general cellular immunity and the course of hepatitis B within a group of chronic hemodialysis patients, T-lymphocyte number and function were investigated in 13 persistently hepatitis B surface antigen (HBSAg)-positive patients, in 32 HBSAg-negative patients, and in 11 patients who had recovered from hepatitis B and compared with that of 21 age-matched controls. Phytohemagglutinin-induced lymphocyte stimulation in vitro and the number of circulating T-cells in the HBSAg-positive group were significantly decreased as compared with those of the recovered group and the controls. Lymphocyte stimulation by pokeweed mitogen and by an antigen cocktail showed the same tendency, but no significant differences between the HBSAg-positive and the recovered groups. Uremic sera from the three patient groups had similar depressive effects on phytohemagglutinin induced lymphocyte stimulation of controls. Serum immunoglobulin G, (IgG), IgA, and IgM were normal in the three patient groups. It is concluded that chronic hemodialysis patients, who have become persistent HBSAg-carriers, have a significantly decreased T-lymphocyte number and function as compared with hemodialysis patients who are able to eliminat hepatitis B virus (HBV). The difference could not be ascribed to the HBV infection itself. This indicates that T-cells play an important role in the elimination of HBV in hemodialysis patients.