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.     

Yeast recombinant hepatitis B vaccine

Summary Human hepatitis B virus vaccine was prepared using antigen produced by recombinant technology in yeast (Saccharomyces cerevisiae). The highly purified antigen had the correct amino acid sequence and assumed the appropriate conformational structure to present the immunologic determinants (epitopes) that are needed to stimulate an appropriate immune response. Yeast-derived vaccine, was safe and was equally immunogenic and protective against hepatitis B as plasma-derived vaccine, as demonstrated in tests carried out in animals and in human beings. The yeast-derived vaccine produced by the Merck Sharp & Dohme Research Laboratories was licensed for general use in the Federal Republic of Germany in May and in the United States of America on July 23, 1986. It represents the first licensed vaccine of any kind produced by recombinant technology, and establishes the precedent for new vaccines to be made using this methodology.

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Rekombinante Hepatitis B-Vakzine aus Hefe

Zusammenfassung Zur Herstellung einer humanen Hepatitis B Virus-Vakzine wurde Antigen verwendet, das mittels rekombinanter Technologien aus Hefe (Saccharomyces cerevisiae) gewonnen wurde. Das hochgereinigte Antigen besitzt die exakt richtige Aminosäuresequenz und nimmt eine für die Präsentation der immunogenen Determinanten (Epitope) erforderlichen Tertiärstruktur ein und erfüllt somit die Voraussetzungen für die Auslösung einer entsprechenden Immunantwort. Untersuchungen in Tieren und beim Menschen zeigten, daß die aus Hefe gewonnene Vakzine sicher ist und eine der aus Plasma hergestellten Vakzine vergleichbare immunogene und protektive Wirkung hat. Die in den Forschungslaboratorien von Merck Sharp & Dohme mittels Hefezellen entwickelte Vakzine wurde im Mai 1986 in der Bundesrepublik und am 23. Juli dieses Jahres in den Vereinigten Staaten von Amerika zugelassen. Sie ist die erste mittels rekombinanter Technologien gewonnene, lizensierte Vakzine überhaupt und ist der Wegbereiter für neue mit dieser Methode entwickelte Impfstoffe.

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This paper, in slightly different form, was presented at the Ninth International Congress of Infectious and Parasitic Diseases, Munich, West Germany, in Session V4, on July 24, 1986.     

Long-term effect of low dose recombinant interferon therapy in patients with chronic hepatitis B

Thirty three heterosexual chronic hepatitis B virus (HBV) carriers were randomized, with stratification for disease activity, to receive intramuscular recombinant interferon alpha-2a (r-IFN) at doses of 4.5 megaunits thrice weekly for 4 months, or no treatment. During r-IFN treatment, serum HBV-DNA levels fell in all, but 2 patients. Final evaluation at 16 months after randomization revealed that the rate of complete response, i.e., loss of both HBV-DNA and HBeAg with ALT normalization was 22.2% (2 of 9 cases) in patients on interferon and 12.5% (1 of 8 cases) in untreated patients for the group with high serum alanine aminotransferase (ALT) and with piecemeal necrosis on liver biopsy on entry. The corresponding value was 25% (2 of 8 cases) in treated and 12.5% (1 of 8 cases) in untreated patients with low liver disease activity. Overall, a complete response was thus observed in 23.5% of treated patients and in 12.5% of controls. None of the patients on therapy became HBsAg negative. It is concluded that treatment of heterosexual patients with chronic hepatitis B with r-IFN in the dose regimen used here was not associated with a significant higher rate of serologic and clinical response compared to controls, independently of pretreatment biochemical and histologic activity of liver disease.     

The effect of zinc sulfate on immunologic response to recombinant hepatitis B vaccine in elderly: Zinc sulfate and immunologic response to recombinant hepatitis B vaccine

Background

Hepatitis B is the major cause of chronic hepatitis and cirrhosis in Iran. Sanitation and immunization is one of the most effective measures for prevention of the disease which is now widely used in developing countries. However, the immune response to the vaccine varies by age.

Objectives

To determine the effect of zinc sulfate on immune response to hepatitis-B vaccine in elderly.

Patients and Methods

In a clinical trial on 140 subjects aged ?40 years with a body mass index (BMI) <30 kg/m2, and without any co-morbid disease were recruited. Those who had negative hepatitis B core antibody (102 persons) were randomly allocated to two groups. The trial group received hepatitis B vaccine plus 200 mg zinc sulfate daily for 30 days and the control group received vaccine plus placebo.

Results

52 of 102 people were female (51%). The two studied groups were comparable in terms of age, gender, and smoking habits. The mean antibody production in the intervention and control groups was 116.93 and 157.37 mIU/mL, respectively (p=0.22). No statistical differences were observed between the two groups in terms of proportion of people who were protected after vaccination (26.0% and 36.5% in people with and without zinc, respectively).

Conclusions

This study revealed that zinc sulfate has no effect in level of immunity among elderly.     

Immunogenicity of recombinant hepatitis B virus vaccine in patients with and without chronic hepatitis C virus infection： A case-control study

AIM： To compare the response of standard hepatitis B virus （HBV） vaccination between patients with chronic hepatitis C virus （HCV） infection and healthy individuals. METHODS： This is a prospective case-control study. A total of 38 patients with chronic HCV infection and 40 healthy controls were included. Vaccination was performed by injection of 20μg recombinant HBsAg into the deltoid muscle at mo 0,1 and 6. Anti-HBs concentration was determined 3 mo after the last dose and compared between the two groups. The response pattern was characterized as （1） high-response when the anti-HBs antibody titer was 〉 100 IU/L, （2） low-response when the titer was 10-100 IU/L. and （3） no-response when the titer was 〈 10 IU/L. RESULTS： In the patient group, there were 10/38 （26.3%） non-responders, 8/38 （21.1%） Iow-responders and 20/38 （52.6%） high-responders. The corresponding values in the control group were 2/40 （5.0%）, 7/40 （17.5%） and 31/40 （77.5%）, respectively. The response pattern was statistically different between the two groups. In multivariate analysis, smoking was a significant confounder, while HCV infection lost its significant correlation with lower antibody response. CONCLUSION： Patients with chronic HCV infection tend to respond weakly to HBV vaccination compared to healthy individuals, though this correlation is not independent according to multivariate analysis.     

Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection

To examine the long-term effect of interferon (IFN) therapy in patients with chronic hepatitis B virus (HBV) infection, particularly on survival and hepatocellular carcinoma (HCC) prevention, 101 male patients with chronic hepatitis B in a randomized controlled trial were followed up for 1.1 to 11.5 years after the end of therapy. Of the 101 patients, 34 patients received a placebo (control), and 67 patients were treated with IFN (31 patients were treated with IFN alone and 36 patients were treated with IFN after prednisolone priming). Follow-up studies included clinical, biochemical, and virological aspects and HCC screening every 3 to 6 months. Twenty-eight (42%) of the 67 IFN-treated patients and 8 (24%) of the 34 untreated patients seroconverted by the end of the trial. During follow-up, 22 (56%) of the 39 patients who did not seroconvert in the treated group and 5 (19%) of the 26 patients who did not seroconvert in the control group showed a delayed sustained response (P <.005). The cumulative incidence of sustained response was highest in the steroid priming group (P =.049 vs. the IFN-alone group; P =.028 vs. the control group). HCC was detected in 1 (1.5%) of the 67 treated patients and 4 (12%) of the 34 untreated patients (P =.043). The interval between entry and HCC detection was 3.5 to 8.2 years. The cumulative incidence of HCC development was significantly higher in the control group than in the treated group (P =.013). In contrast, the cumulative survival rate was higher in the treated group than the control group (P =. 018). Multivariate analysis showed that IFN therapy, preexisting cirrhosis, and the patient's age at entry are significant independent factors for both survival and HCC development. The results suggest that IFN has long-term beneficial effects in terms of HBV clearance, reduction of HCC, and prolonging survival.     

Arthus reaction to recombinant hepatitis B virus vaccine.

A severe, local, inflammatory, late-phase reaction accompanied by skin necrosis occurred after an infant was given an intramuscular injection of recombinant hepatitis B virus vaccine. The clinical course and appearance of the rash were typical of an Arthus reaction. Although not identical to this case, prior reported cases of complement-mediated reactions occurring after hepatitis B virus infection or vaccination provide theoretical support for this diagnosis.     

Antiviral effect of recombinant gamma interferon in chronic hepatitis B virus infection: a pilot study

A pilot study has been designed in order to determine the tolerance and effectiveness of recombinant interferon gamma (rIFN-gamma) in chronic hepatitis B virus (HBV) infection. Eight HBsAg, HBeAg, HBV-DNAp and HBV-DNA-positive patients were randomly assigned to one of two groups. In group 1, 0.25 mg of rIFN-gamma/m2 body surface was administered daily for 28 days to 4 patients. In group 2, 0.10 mg of rIFN-gamma was administered to 4 patients under the same conditions. All the patients concluded the treatment and were observed over 11 more months. During treatment, 6 out of 8 patients showed decreased levels of HBV-DNA and HBV-DNAp. In addition, by the 8th month of follow-up, six patients became negative for HBV-DNAp and 2 for HBcAg; all patients remained positive for HBV-DNA. At the end of the study, only 2 patients remained negative for HBV-DNAp, 4 for HBcAg and one became negative for HBV-DNA. No differences in antiviral effect were observed between the two groups. Furthermore, the T4/T8 lymphocytes ratio increased during therapy. In conclusion, rIFN-gamma may play a role in the treatment of chronic HBV infection.     

拉米夫定联合胸腺肽加乙肝疫苗治疗慢性乙型肝炎的临床观察

目的观察拉米夫定联合胸腺肽加乙肝疫苗治疗慢性乙型肝炎的临床效果。方法100例未曾接受过抗病毒治疗的慢性乙型肝炎患者随机分为治疗组和对照组,治疗组50例,给予拉米夫定100mg,每日一次口服,同时乙肝疫苗10μg皮下注射,每两周一次,胸腺肽20mg肌肉注射,隔日一次,共计26周,随后继续使用拉米夫定和乙肝疫苗26周,总疗程52周;对照组给予拉米夫定100mg·d-1,疗程52周。结果治疗结束时治疗组ALT下降、HBeAg/抗-HBe血清转换率明显高于对照组,差异有显著性(P<0·01),但HBVDNA下降差异无显著性(P<0·01),停药后随访6月、12月,治疗组ALT及HBVDNA下降、HBeAg/抗-HBe血清转换率明显高于对照组比,差异有显著性(P<0·01)。治疗组的完全应答率与对照组比,差异有高度显著性(P<0·01)。结论拉米夫定联合胸腺肽加乙肝疫苗能明显提高临床疗效及HBeAg/抗-HBe血清转换率及HBVDNA阴转率,且无明显毒性反应。     

Eight years of hepatitis B vaccination in Colombia with a recombinant vaccine: factors influencing hepatitis B virus infection and effectiveness.

OBJECTIVE: To evaluate the effectiveness of a recombinant hepatitis B vaccine used in endemic areas of Colombia, as well as risk factors associated with hepatitis B virus (HBV) infection and carriage after vaccine introduction. METHODS: A cross-sectional study was carried out in urban and rural areas of the Colombian Amazon, a highly endemic area for hepatitis B infection. Children under 12 years of age and their mothers were selected for the study using one-stage cluster sampling (N=2145) and were examined for HBV serological markers and antibodies against surface antigen (anti-HBs). RESULTS: There has been a reduction of 60-75% in the prevalence of HBV infection and hepatitis B surface antigen (HBsAg) carriage since HBV vaccination was introduced. Receiving the first dose of HBV vaccine at more than two months after birth was one of the factors associated with HBV carrier status. Maternal HBV infection was also associated with infection in the child. CONCLUSIONS: The recombinant Cuban hepatitis B vaccine has contributed to the reduction of the infection in this highly endemic area, though further efforts are required to improve timely vaccination for children at high risk.     

慢性HBV感染免疫治疗新进展

慢性HBV感染有发展为肝硬化和肝细胞癌高风险.IFN-α、拉米夫定、阿德福韦、恩替卡韦是目前批准用于HBV感染的治疗药物.这些药物是防止慢性HBV感染者发展为肝硬化和肝细胞癌的唯一策略.然而,以发生HBeAg血清转换、血清丙氨酸转氨酶正常和血清HBVDNA水平转阴作为评价疗效标准,这些药物的治疗效率仅占接受治疗者的20%-30%.应用拉米夫定或阿德福韦长期治疗可能导致药物耐药,从而导致延长了应用其他核苷类似物治疗的期限.目前抗病毒治疗的缺陷使我们有必要寻找更好的治疗策略.而提高慢性HBV感染者病毒特异性T细胞活性的特异性和非特异性免疫治疗策略为抗HBV感染提供了新的治疗方向.这些免疫治疗策略包括,过继性HBV免疫、PEG干扰素和治疗性疫苗等.     

The management of chronic hepatitis B infection

Chronic hepatitis B infection is frequently diagnosed within the genitourinary clinic setting with sexual transmission the commonest route of acquisition in the United Kingdom. Only 3--5% of adults who contract acute hepatitis B will progress to chronic infection, and these individuals can be identified by the presence of hepatitis B surface antigen (HBsAg) in the bloodstream 6 months after infection. Individuals at highest risk of long-term complications such as cirrhosis and hepatocellular carcinoma, carry HBeAg and have high levels of circulating hepatitis B virus (HBV) deoxyribonucleic acid (DNA). Therapy should be targeted towards this group of patients. Two forms of therapy are now licensed for use in chronic hepatitis B infection: interferon-alpha and lamivudine. Seroconversion occurs in 30--40% of patients treated with interferon and treatment is often limited by toxicity. Lamivudine is well tolerated with seroconversion rates of 15--20% at one year, rising with increasing duration of therapy. Long-term monotherapy is limited however by the development of resistance mutations and combination nucleoside therapy is likely to become the treatment of choice in the future. Patients with chronic hepatitis B should be counselled regarding transmission, partner vaccination and alcohol intake and co-infection with other hepatitis viruses should be excluded.     

Combination therapy with lamivudine and famciclovir for chronic hepatitis B infection.

BACKGROUND & AIMS: Lamivudine suppresses hepatitis B replication, but drug-resistant mutants emerge with long-term therapy. In vitro data suggest that lamivudine and famciclovir might synergistically inhibit hepadnaviral replication. We reviewed our experience with lamivudine and famciclovir in 24 patients with chronic hepatitis B infection. METHODS: Patients with chronic hepatitis B infection and detectable HBV DNA received lamivudine and famciclovir combination therapy. The primary end point was HBV DNA suppression at week 48. Follow-up was reviewed for those who remained on combination therapy beyond the first 48 weeks. RESULTS: Thirteen treatment-na?ve HBeAg-positive subjects received 48 weeks of therapy; all had undetectable HBV DNA levels (less than 2.5 pg/mL) at week 48. Three patients underwent HBeAg seroconversion at week 48 and discontinued therapy. Ten patients remained on combination therapy; 3 developed YMDD (tyrosine-methionine-aspartate-aspartate) mutations at year 2, although HBV DNA levels remained below 2.5 pg/mL at a mean of 39 months. A second heterogeneous group of 5 subjects including interferon therapy failures and those with HBeAg-negative infection also received 48 weeks of combination therapy, with 1 subject developing redetection of HBV DNA by week 48. YMDD mutations were noted in the other 4 subjects at year 2, although just 1 subject had HBV DNA greater than 2.5 pg/mL at 39 months of therapy. CONCLUSIONS: In this small pilot study, 48 weeks of therapy with lamivudine and famciclovir was effective in suppressing HBV replication. A randomized controlled trial is required to define the role of combination therapy with lamivudine and famciclovir in delaying the clinical emergence of resistant strains.     

Impaired response to recombinant hepatitis B vaccine in HIV-infected persons.

We studied the immunogenicity of the standard schedule of recombinant hepatitis B vaccine (20 micrograms per dose at months 0, 1, and 6) in 21 anti-human immunodeficiency virus (HIV)-positive persons. Relatively low titers of anti-HBs developed in only five subjects (23.8%) 1 month after the third dose; all five had T4 cell counts greater than 700 cells/mm and none of the 11 subjects with a T4 cell count below this value responded. Five of the 16 nonresponders to the vaccine later had acquired immunodeficiency syndrome (AIDS)-related complex (two) and AIDS (three), while none of the responders did. Our results show that anti-HIV-positive persons are poor responders to the recombinant hepatitis B vaccine, and that the absence of a response is an indicator of a more severe immune deficiency and of a poor prognosis. An optimal regimen of hepatitis B vaccination in HIV-infected persons is still to be established.