Long-term immunogenicity of an inactivated virosome hepatitis A vaccine

The aim of this study was to predict the long-term protection induced after immunisation with inactivated, aluminium-free virosome hepatitis A vaccine. The study population consisted of adult volunteers enrolled in four different clinical trials. Lower 95% confidence interval limits and seroconversion rate were calculated by using a linear mixed model to estimate the persistence of serum antibodies over time. To assess the robustness of the mathematical model, several sensitivity analyses were performed with more conservative protective threshold (20 mIU/ml vs. 10 mIU/ml), higher yearly decline rate, and exclusion of volunteers who had increasing titres over time. Based on 190 volunteers with at least two valid assessments of titres from year 3 onward, the median duration of protection was 55.5 years, with a lower limit of the 95% CI of 48.7 years. Duration below 25.3 years was predicted for only 5% of the subjects. Women tended to have higher titres to start with, but their rate of decline was higher, resulting in similar duration of protection overall. The use of a more conservative threshold, higher yearly decline rate, and exclusion of volunteers with increasing titres over time did not affect these results. According to this model, 95% of the volunteers should have anti-HAV titres above the minimum protective threshold for 20 years or more following immunisation with two doses of this aluminium-free vaccine.     

Safety and immunogenicity of a recombinant hepatitis B vaccine

A hepatitis B vaccine produced in yeast by recombinant DNA technology was evaluated using 5-micrograms and 10-micrograms doses in a randomized trial lasting 7 months in 110 male armed forces recruits aged 17-19 years. Results were compared to those of an identical trial of a plasma-derived vaccine. No allergic reactions were observed, and the rate of mild side effects was similar to the plasma-derived vaccine. Seroconversion rates in the first month were 60% (33/55) and 67% (37/55) with the 5-micrograms and 10-micrograms doses of the recombinant vaccine, respectively. All participants seroconverted by 3 months, and none lost antibody. These results are very similar to those for plasma-derived vaccine. Comparison of titres of antibody to hepatitis B surface antigen (anti-HBs) showed a slightly higher level with the 10-micrograms than with the 5-micrograms dose of the recombinant vaccine. Geometric mean titres of anti-HBs after the booster dose were similar in the 5-micrograms and 10-micrograms dose recombinant vaccine groups (2,620 and 2,748 IU/l, respectively) and in the 5-micrograms plasma-derived vaccine group (3,591 IU/l) but significantly higher (9,227 IU/l) with the 10-micrograms dose of the plasma-derived vaccine. These results confirm the safety and immunogenicity of the recombinant vaccine, although further study is needed on the duration of immunity.     

COVID-19 vaccine immunogenicity among chronic liver disease patients and liver transplant recipients: A meta-analysis

Background/AimsData of coronavirus disease 2019 (COVID-19) vaccine immunogenicity among chronic liver disease (CLD) and liver transplant (LT) patients are conflicting. We performed meta-analysis to examine vaccine immunogenicity regarding etiology, cirrhosis status, vaccine platform and type of antibody.MethodsWe collected data via three databases from inception to February 16, 2022, and reported pooled seroconversion rate, T cell response and safety data after two vaccine doses.ResultsTwenty-eight (CLD only: 5; LT only: 18; both: 2; LT with third dose: 3) observational studies of 3,945 patients were included. For CLD patients, seroconversion rate ranged between 84% (95% confidence interval [CI], 76–90%) and 91% (95% CI, 83–95%), based predominantly on neutralizing antibody and anti-spike antibody, respectively. Seroconversion rate was 81% (95% CI, 76–86%) in chronic hepatitis B, 96% (95% CI, 93–97%) in non-alcoholic fatty liver disease, 85% (95% CI, 75–91%) in cirrhosis and 85% (95% CI, 78–90%) in non-cirrhosis, 86% (95% CI, 78–92%) for inactivated vaccine and 89% (95% CI, 71–96%) for mRNA vaccine. The pooled seroconversion rate of anti-spike antibody was 66% (95% CI, 55–75%) after two doses of mRNA vaccines and 88% (95% CI, 58–98%) after third dose among LT recipients. T cell response rate was 65% (95% CI, 30–89%). Prevalence of adverse events was 27% (95% CI, 18–38%) and 63% (95% CI, 39–82%) among CLD and LT groups, respectively.ConclusionsCLD patients had good humoral response to COVID-19 vaccine, while LT recipients had lower response.     

DTaP-sIPV联合疫苗中SabinIPV 免疫原性研究

目的 探讨吸附无细胞百白破-Sabin株脊髓灰质炎联合疫苗（DTaP-sIPV）的制备工艺,并比较不同配比的DTaP-sIPV中Sabin株脊髓灰质炎灭活疫苗（SabinIPV）三针基础免疫大鼠的中和抗体效价,为确定联合疫苗的最佳制备工艺及抗原剂量配比提供参考.方法 用不同配比的SabinIPV,制备两批DTaP-sIPV,进行各项指标的检定及稳定性试验,并联合单独的Sabin IPV和GSK制备的DTaP-wIPV对56只Wistar大鼠进行3针免疫,每针间隔1个月,每次免疫后30 d采血并分离血清,采用微量中和试验测定血清中抗脊髓灰质炎病毒3个型别的中和抗体效价.结果 两批DTaPsIPV的各项检定指标均符合〈中国药典〉三部（2005版）要求,且稳定性良好.大鼠经3针基础免疫后,其Ⅰ、Ⅱ、Ⅲ型脊髓灰质炎病毒中和抗体的几何平均滴度均显著上升,3针免疫后抗体阳转率已经达到100%.结论 经此制备的DTaP-sIPV安全、稳定、有效,且DTaP-sIPV中的SabinIPV在大鼠中有良好的免疫效果,经3针免疫可产生高水平的中和抗体.     

Different genotypes of hepatitis C virus are associated with different severity of chronic liver disease

The presence of the “Japanese type” NS4 region was investigated in two series of patients (53 from Italy and 58 from Japan) with hepatitis C virus (HCV)-related chronic liver disease. The two populations were homogeneous as regard to age, male/female ratio, histological diagnosis, and serum aminotransferase activities. Genomic amplification was carried out by “nested” poly-merase chain reaction (PCR) with a pair of primers synthesized according to the sequence of JK-1 isolated in Japan. The presence of viral replication was confirmed further by PCR amplification of the 5′NC region. The NS4 region of the Japanese strain was detected in 24 sera (45%) from Italy and in 44 (71%) from Japan. NS4-posi-tive patients were significantly older and showed an ALT serum level significantly lower (P < 0.01) than NS4 negative cases in each group. Cirrhosis was significantly (P < 0.0007) more common in NS4-positive than in NS4-negative patients. The HCV genotype was subsequently obtained according to Okamoto. All the NS4-positive patients were infected by Type II, whereas in NS4-negative patients all four genotypes were present though Type II still constituted the majority. Cirrhosis was associated exclusively with Type II both in NS4-positive and -negative subjects. These data indicate that, although the pos-itivity for NS4 “Japanese” region seems to be associated with a more aggressive liver disease, the most prevalent Type II predicts more specifically those who are likely to develop cirrhosis. Since the same findings were obtained in two population from different areas of the world, the genotype of HCV appears to be one of the major determinants of the progression of chronic active hepatitis to cirrhosis. © 1994 Wiiey-Liss, Inc.     

Immunogenicity and safety of a new inactivated hepatitis a vaccine in a comparative study

A multicentre, controlled, randomised, open, comparative trial including 839 healthy adult volunteers was carried out in order to compare the immunogenicity and reactogenicity of two vaccines against hepatitis A virus (HAV) during primary immunization and after booster injection. The first vaccine was produced by Pasteur Mérieux (PM), and the second vaccine by Smith-Kline Beecham (SKB). The vaccination schedule consisted of 2 doses (months 0, 6) for PM and 3 doses (months 0, 1, and 6) for SKB. Two weeks after the first dose, the seroconversion rates among initially HAV seronegative subjects (n = 608) were 93.4% and 76.1% for the PM and SKB vaccines, respectively, the corresponding geometric mean titres (GMTs) were 59.0 mlU/ml versus 30.8 mlU/ml (modified RIA HAVAB assay, Abbott Laboratories). Two months after the beginning of immunization (one dose versus two doses) the GMTs were 138.4 and 161.6 mlU/ml, respectively. At month 7, the seroconversion rates were 100% for both vaccines, and the GMTs were 4, 189 and 3, 163 mlU/ml, respectively. After the first dose of vaccine, 24.6% and 19.6% of the PM and SKB vaccinees reported local reactions. The rates for systemic reactions were 27.2% and 25.0%, respectively. Lower rates for local and systemic reactions were seen after booster injections and statistical differences were not observed between the two vaccines. The study also demonstrated that vaccination was as well tolerated in subjects with anti-HAV antibodies as in HAV seronegative subjects. Logistic regression analysis revealed a significant vaccine effect on seroconversion rates only at week 2 (P<10^?4). The same conclusions were drawn from the analysis of GMT by multivariate regression. When both times (week 2 and week 8) were analysed together, a statistically significant effect of interaction between time and vaccine was observed, indicating that the kinetics of antibody responses were different. © 1995 Wiley-Liss, Inc.     

Sabin IPV基础免疫后不同时间的中和抗体水平研究

目的 探讨不同剂量配比的Sabin株脊髓灰质炎灭活疫苗(Sabin IPV)基础免疫后中和抗体的持续时间及加强免疫前后中和抗体水平的变化.方法 用不同配比的Ⅰ、Ⅲ型脊髓灰质炎病毒原液制备两批Sabin IPV,并使用GSK制备的DTaP-w IPV作为阳性对照组,对18只Wistar大鼠进行3针基础免疫后,每间隔3个月采血直到加强免疫前,并同时于加强免疫后1个月采血,并对血清中抗脊髓灰质炎病毒3个型别的中和抗体效价进行初步研究.结果 大鼠采用0、1、2月免疫程序进行3针免疫后,Ⅰ、Ⅱ、Ⅲ型脊髓灰质炎病毒中和抗体的几何平均滴度随着时间的变化均有所下降,但绝大部分组大鼠的血清中和抗体阳转率仍维持在100％,在加强免疫后,各组的三个型别的中和抗体水平在短期内明显升高.结论 Sabin IPV有良好的免疫持久性,并在加强免疫后,可产生更高水平的中和抗体.     

DNA structure in peripheral blood lymphocytes from patients with chronic viral liver damages

We studied DNA damages (single-strand breaks and alkali-labile sites) in peripheral blood lymphocytes from patients with chronic viral hepatitis and cirrhosis of mixed etiology. The structure of DNA was estimated fluorometrically by changes in the intensity of ethidium bromide fluorescence. Monoinfection with hepatitis B and C viruses was not accompanied by considerable changes in DNA structure in peripheral blood lymphocytes from patients with chronic diseases. The incidence of DNA damages in lymphocytes increased in patients with hepatitis G virus and TTV monoinfection. This is probably related to replication of these viruses in nucleated blood cells. Our results suggest that hepatitis C virus potentiates damaging effect of hepatitis G virus on DNA in lymphocytes.     

Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in patients with non-cirrhotic and cirrhotic chronic viral hepatitis

AIMS: Hepatocellular carcinoma (HCC) frequently develops in patients with chronic viral hepatitis, especially in the cirrhotic stage. We retrospectively studied whether the presence of the putative preneoplastic lesions large liver cell dysplasia (LLCD) and/or small liver cell dysplasia (SLCD) in a needle liver biopsy of these patients are a risk factor for the development of HCC. Methods and results: The presence of LLCD and SLCD in the needle liver biopsy taken at the initial work-up of 115 patients with chronic hepatitis B or C was assessed retrospectively. LLCD and SLCD were present in the initial biopsy of, respectively, 35 (30%) and 25 patients (22%). During a mean follow-up of 107 months, 16 patients (14%) developed HCC and this occurred significantly more frequently in patients with cirrhosis, age > or = 55 years, LLCD or SLCD. Cirrhosis and LLCD were independent risk factors for HCC development. CONCLUSIONS: Our findings indicate that the presence of LLCD in a needle liver biopsy of patients with viral-induced chronic liver disease is an independent risk factor for the development of HCC. If these results are confirmed, the presence of LLCD can be used to identify a subgroup of patients at high risk for HCC requiring more intensive screening.     

Infection with GB virus C and hepatitis C virus in drug addicts,patients on maintenance hemodialysis,or with chronic liver disease in Nepal

Infection with GB virus C (GBV-C) and hepatitis C virus (HCV) was surveyed in various populations in Kathmandu, Nepal. GBV-C RNA and HCV RNA were detected in four (2%) and none, respectively, of 181 normal controls. Viral RNAs were detected significantly more frequently (P < 0.001) in 32 (44%) and 43 (60%), respectively, of 72 users of illicit intravenous drug, and in three (14%) and one (5%) of 22 patients on maintenance hemodialysis. The three hemodialysis patients with GBV-C RNA had been transfused with more blood units than the 19 without GBV-C RNA (51 ± 21 vs. 5 ± 3 units, P < 0.01), and one was co-infected with HCV. Of 145 patients with chronic liver disease, GBV-C RNA was detected in four (3%) and HCV RNA in 12 (8%); only one patient with GBV-C RNA was without markers of HCV or hepatitis B virus infection. In the 32 drug addicts infected with GBV-C, genotypes were G1 in two (6%), G2 in 26 (81%), G3 in three (9%), and the remaining one (3%) was coinfected with G2 and G3. GBV-C genotypes in the 13 individuals in the populations other than drug addicts were G2 in 11 (85%) and G3 in two (15%). HCV genotypes in the 43 drug addicts with viremia were I/1a in 21 (49%), V/3a in 19 (44%) and I/1a plus V/3a in two (5%); these genotypes were not prevalent in normal controls and patients with chronic liver disease in Nepal. These results indicate that GBV-C infection is prevalent in healthy subjects in Nepal at a frequency (2%) comparable with those in the other countries and that GBV-C transmits efficiently by intravenous drug abuse among drug addicts and by transfusion in hemodialysis patients. J. Med. Virol. 53:157–161, 1997 © 1997 Wiley-Liss, Inc.     

国产甲型肝炎灭活疫苗的安全性和免疫原性研究

目的 评价一种国产甲型肝炎（甲肝）灭活疫苗对人体的安全性和免疫原性。方法 为Ⅰ期临床试验。31名对甲肝易感的成年人被随机分为两组,实验组16个,接种国产甲肝灭活疫苗,对照组15人,接种史克必成公司生产的甲肝灭活疫苗。按0、3程序进行接种。国产疫苗剂量为每针1000U／0．5ml,史克疫苗剂量为每针720ELISAU／1ml。观察并比较两种接种后的局部和全身反应以及接种后1、3、4个月血清抗体阳转率和滴率。结果 两组初免和加强接种后个别接种对象表现轻微局部或全身反应,未发现肝功能损害。初次免疫后1个月、3个月和加强后1个月,国产疫苗的抗体阳转率分别为94％,100％和100％;史克疫苗为73％,80％和100％。国产疫苗抗体几何平均滴度分别为139．2mIU/ml、137．7mIU/ml和1066．7mIU/ml;史克必成疫苗分别为104．3mIU/ml、111．3mIU／ml和760．7mIU／ml。结论 国产甲肝灭活疫苗具有良好的安全性和免疫原性。     

Histological difference between complete responders and nonresponders to interferon therapy of the livers of patients with chronic hepatitis C

Liver histology was compared in patients with chronic hepatitis C to note the differences between responders and nonresponders to interferon treatment. Fifty-eight patients were administered interferon in varying doses and over various periods, and were then followed up for 1 year. According to the improvement status of serum alanine aminotransferase (ALT) levels during this period, the patients were classified into complete responders who showed complete normalization of ALT; partial responders who exhibited a significant decrease, but not complete normalization of ALT. Before application of the interferon treatment, liver biopsies were analyzed in four parameters and given scores from 0 to 5 for three groups in cord with no prior knowledge of the efficacy. The parameters included necroinflammation, fibrosis/lobular distortion, portal lymphocytic reaction and portal (or fibrous septal) outline destruction. Results indicated that there were no significant differences in the score of necroinflammation and portal lymphocytic reaction between the complete responder group and the nonresponder group. In contrast, the complete responder group exhibited weaker fibrosis/lobular distortion and less portal outline destruction than the non-responder group. The partial responder group was more akin to the former group in these parameters. Thus, it is safe to conclude that liver histology may predict the efficacy of interferon treatment.     

HBsAg阳性儿童和健康儿童对国产甲型肝炎灭活疫苗免疫原性和安全性的观察

目的：观察HBsAg阳性儿童对国产甲型肝炎灭活疫苗的免疫原性和安全性。方法：随机选取121名1－10岁健康儿童和10名同龄的HBsAg阳性儿童，抗－HAV均阴性，接种唐山怡安生物工程有限公司研制的甲型肝炎灭活疫苗。接种剂量为500U／剂和1000U／剂两组，免疫程序为0和6个月，并在初免后30d，第二针后30和180d用ELISA方法检测抗－HAV。结果：HBsAg阳性儿童和健康儿童接种500U／剂和1000U／剂甲型肝炎灭活疫苗后抗体阳转率均为100％。第二针免疫后30d抗体平均几何滴度500U／剂组分别为4684．9mIU和4535．6mIU；1000U／剂组分别为5399．8mIU和7347．1mIU。二者比较差异无显著性，免疫后亦未见异常反应，初免后1年抗体水平仍然很高。结论：HBsAg阳性儿童接种国产甲型肝炎灭活疫苗具有良好的免疫应答，同时也是安全的。     

微载体培养MEK和Vero细胞试制甲肝灭活疫苗

目的探索微载体培养细胞大量制备甲肝病毒抗原及其灭活疫苗的可行性。方法使用 Cytodex- 1培养恒河猴胚肾细胞和 Vero细胞制备 HAV ,经过初步纯化、甲醛灭活、吸附佐剂 ,制成甲肝灭活疫苗 ,免疫昆明种小白鼠 ,测定免疫原性。结果 HAV X株和 W株抗原滴度分别为 1∶ 2 5 6、1∶ 12 8,感染滴度 (log TCID5 0 / m l)分别为 8.5 0、8.17,与静止培养获得的滴度相当。小鼠抗 HAV抗体第 45 d达到峰值 ,滴度分别为 1∶ (96 .0± 78.4)、1∶ (12 8.0± 70 .1)。结论实验性甲肝灭活疫苗具有良好的免疫原性 ,应用微载体培养细胞制备甲肝灭活疫苗是可行的。     

Antibody persistence and immune memory in healthy adults following vaccination with a two-dose inactivated hepatitis A vaccine: long-term follow-up at 15 years

Long‐term persistence of vaccine‐induced immune response in adults was assessed annually for 15 years following primary immunization with a two‐dose inactivated hepatitis A vaccine. In 1992, 119 and 194 subjects aged 17–40 years and naïve for hepatitis A virus (HAV) were enrolled in two studies to receive 1,440 ELISA units (El.U) of inactivated hepatitis A vaccine (Havrix?, GlaxoSmithKline Biologicals, Belgium) according to a standard 0, 6 or an extended 0, 12 months schedule, respectively. Serum samples were taken 1 month after the second vaccine dose and every consecutive year up to 15 years after primary vaccination for measurement of anti‐HAV antibody concentrations (NCT00291876 and NCT00289757). At year 15, 100% (48/48) and 97.3% (108/111) of subjects vaccinated at 0, 6 or 0, 12 months remained seropositive for anti‐HAV antibodies, with geometric mean concentrations (GMCs) of 289.2 and 367.4 mIU/ml, respectively. An additional dose of HAV vaccine (1,440 El.U) was administered to the six subjects who had become seronegative for anti‐HAV antibodies since year 11. All subjects mounted a humoral immune response to the additional HAV challenge dose, although post‐challenge anti‐HAV antibody levels remained low in one subject. These studies represent the longest annual follow‐up of hepatitis A vaccine in healthy adults. The immune response induced by two doses of this inactivated HAV vaccine was shown to persist for at least 15 years. No difference in long‐term antibody persistence was observed between the two primary vaccination schedules, reinforcing the potential for flexibility in the timing of the second primary vaccine dose. J. Med. Virol. 83:1885–1891, 2011. © 2011 Wiley‐Liss, Inc.     

Further evaluation of a live hepatitis A vaccine in marmosets.

Live, attenuated F' hepatitis A vaccine virus was studied in vivo in Saguinus labiatus marmosets for possible reversion to virulence, for possible establishment of persistent infection and for its capacity as a parenterally administered vaccine to induce immunity to oral infection. Serial transmission of the virus in S. labiatus, using infectious stool extracts for the second and third passages, produced no evidence of reversion of the F' vaccine virus to virulence. Monitoring for live HAV in stools over a 135-day period post-inoculation of marmosets with the F' vaccine revealed no evidence of persistent infection. Vaccinated animals were also shown to be resistant to infection on challenge by the oral route as well as by the previously demonstrated parenteral route.     

Immunoglobulin-containing cells in liver biopsies of patients with chronic hepatitis and primary biliary cirrhosis

The numbers of IgA, IgM and IgG-containing cells were studied by means of an indirect immunoperoxidase technique and morphometry in liver biopsies of patients with primary biliary cirrhosis and chronic hepatitis, in whom serum immunoglobulin concentrations were also determined. In patients with primary biliary cirrhosis the absolute and relative number of IgM-containing cells in the liver was significantly higher, whereas the absolute and relative number of IgG-containing cells in the liver was significantly lower compared to patients with chronic hepatitis. IgM-containing cells in liver biopsies of patients with primary biliary cirrhosis correlated strongly with their serum IgM levels. It is concluded that determination of the pattern of immunoglobulin containing cells in liver biopsies may help in the differentiation of primary biliary cirrhosis from chronic hepatitis and that local production of IgM in the liver may contribute significantly to the high serum IgM levels in patients with primary biliary cirrhosis.     

Adrenergic receptors in the liver parenchyma of children with chronic hepatitis

Research Center for Molecular Diagnosis, Ministry of Health of the USSR, Moscow Research Institute of Pediatrics, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR M. Ya. Studenikin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 113, No. 2, pp. 127–129, February, 1992.     

Relationship between HBcAg in serum and liver and HBV replication in patients with HBsAg-positive chronic liver disease

The expression of hepatitis B core antigen (HBcAg) in serum and in hepatocytes was evaluated in relation to HBV replication. Fifty chronic HBsAg carriers with histological evidence of liver disease were studied, including 24 HBeAg-positive patients, 2 HBeAg/anti-HBe-negative patients, and 24 anti-HBe-positive cases, two of them with evidence of delta agent infection. Serum HBV-DNA was evaluated in all patients and related to HBcAg examined at the same time in frozen liver biopsies by immunofluorescence and to HBcAg detected in the corresponding serum by a recently developed radioimmunoassay. HBV-DNA was present in serum in 20 (83%) HBeAg-positive patients, all positive for serum HBeAg, whereas liver core antigen was detected in 14 (73%) of 19 cases. Among HBeAg-negative patients, 50% showed the presence of circulating DNA viral sequences, and HBcAg was identified in five of 26 (19%) cases in serum and in six of 24 (25%) in the liver respectively. In 15 patients, liver fragments permitted examination in parallel by immunofluorescence for HBcAg and molecular hybridization for viral DNA in liver cells. A DNA pattern characteristic of viral replication was found in cases with evidence of active virion production, independently from HBeAg and anti-HBe, and in these patients HBcAg was present both in serum and in hepatocytes. In two cases with free HBV-DNA, without evidence of replicative activity, core antigen was not detected in the liver, but in one patient HBcAg was found in the serum. A similar finding was also noted in another patient, in whom the hybridization pattern was consistent with integration of viral genome into high-molecular-weight cellular DNA. Whether serum HBcAg detected in these patients without HBV-DNA in serum reflects the presence of defective viral particles or of core antigen released as a viral protein remains to be determined.