Real-life versus package insert: a post-marketing study on adverse-event rates of the virosomal hepatitis A vaccine Epaxal® in healthy travellers

There are various methods to collect adverse events (AEs) in clinical trials. The methods how AEs are collected in vaccine trials is of special interest: solicited reporting can lead to over-reporting events that have little or no biological relationship to the vaccine. We assessed the rate of AEs listed in the package insert for the virosomal hepatitis A vaccine Epaxal^®, comparing data collected by solicited or unsolicited self-reporting. In an open, multi-centre post-marketing study, 2675 healthy travellers received single doses of vaccine administered intramuscularly. AEs were recorded based on solicited and unsolicited questioning during a four-day period after vaccination. A total of 2541 questionnaires could be evaluated (95.0% return rate). Solicited self-reporting resulted in significantly higher (p < 0.0001) rates of subjects with AEs than unsolicited reporting, both at baseline (18.9% solicited versus 2.1% unsolicited systemic AEs) and following immunization (29.6% versus 19.3% local AEs; 33.8% versus 18.2% systemic AEs). This could indicate that actual reporting rates of AEs with Epaxal^® may be substantially lower than described in the package insert. The distribution of AEs differed significantly between the applied methods of collecting AEs. The most common AEs listed in the package insert were reported almost exclusively with solicited questioning. The reporting of local AEs was more likely than that of systemic AEs to be influenced by subjects’ sex, age and study centre. Women reported higher rates of AEs than men. The results highlight the need for detailing the methods how vaccine tolerability was reported and assessed.     

Hepatitis A virus-associated fulminant hepatitis with human immunodeficiency virus coinfection

Hepatitis A virus (HAV) commonly causes acute hepatitis in humans and is transmitted through the fecal-oral route or by ingestion of contaminated food or water. HAV infection generally follows a self-limiting course; it can seldom cause fulminant hepatitis that increases the risk of mortality. To the best of our knowledge, this is the first reported fatal case of fulminant hepatitis caused by HAV in a 40-year-old male with human immunodeficiency virus (HIV) infection. The HAV genotype in this case was IA, which has recently become common globally among people living with HIV (PLWHIV), intravenous drug users, and homeless people especially in developed countries. His HIV infection was stabilized by antiretroviral drugs and his CD4 values were stable. He developed acute hepatic encephalopathy, did not respond to repeated plasma exchange therapy, and died rapidly. It is known that HIV co-infection sometimes leads to fulminant non-HAV hepatitis, although evidence supporting a correlation between fulminant hepatitis A risk and HIV infection is still lacking. This case demonstrated the fatal risk of HAV infection in PLWHIV; it was suggested that education about appropriate preventive measures and vaccination are important for preventing HAV infections among PLWHIV.     

IgE anti Hepatitis B virus surface antigen antibodies detected in serum from inner city asthmatic and non asthmatic children

Viral Hepatitis type B (HBV) is a public health concern, but has not been linked to asthma. Immunoglobulin (Ig) G is involved in HBV immune responses; less is known about IgE antibodies (Abs) against HBV in asthma. Given the importance of HBV, we sought to determine whether HBV vaccine contributes to asthma in children, by stimulating specific IgE production. Total IgE, IgE- or IgG-anti-HBVs Abs were studied in vaccinated pediatric asthmatics and non asthmatics. We found: (1) total IgE was higher in asthmatics; (2) total IgE did not correlate with IgE anti-HBVs; (3) IgE anti-HBVs did correlate with IgG-anti-HBVs in all subjects; (4)IgE- and IgG-HBVs Abs were similar in both groups; (5) IgE- or IgG anti-HBVs Abs did not correlate with age. Our findings indicate that HBV vaccination induces IgE responses in asthmatics and non asthmatics.     

Experimental hepatitis A virus infection in guinea pigs

Although many of the properties of hepatitis A virus (HAV) are known, several aspects of HAV pathogenesis are still not understood, such as the mechanism underlying the hepatotropism or HAV replication in extrahepatic sites. Detailed studies of these aspects were hampered mostly by the lack of accessible animal models, since only nonhuman primates are susceptible to experimental infections. An alternative animal model would also be of interest to assess the primary replication site and for the evaluation of the safety and efficacy of vaccines. A study was undertaken to determine whether HAV can infect guinea pigs and whether they are useful as a model for studying aspects of HAV pathogenesis and for the evaluation of vaccines. HAV variants adapted to primate or guinea pig tissue culture were used to inoculate guinea pigs intraperitoneally and by the oral route. The animals were observed for clinical disease, shedding of HAV in stools, viremia, seroconversion, evidence for liver damage by biochemical liver function tests, virus presence in the liver, development of hepatic histopathological changes, and occurrence of HAV in extrahepatic organs. The animals developed an active, clinically inapparent infection with specific histopathological changes in the liver. Although virus replication occurred, as shown by RT-PCR and isolation of infectious virus from feces and serum, it seems unlikely that guinea pigs are suitable for studying the clinical features of hepatitis A, because the clinical and laboratory parameters remained normal. However, guinea pigs appear useful for studying some aspects of HAV pathogenesis and for testing the safety of vaccines.     

Hepatitis A and hepatitis B virus infection in children and adolescents in north-east Italy

The sera of 722 children and adolescents without overt liver disease were tested for hepatitis B surface antigen (HBsAg), antiHBs and anti-hepatitis B core anti-HBc; 658 of the sera were also tested for anti-hepatitis A virus anti-HAV. Except for the "passive" antibody peak observed in babies, the anti-HAV age-specific prevalence was negligible until the age of 3; it then increased, reaching 35% by the age of 15. Serological evidence of HBV was present in 16% of the subjects: this prevalence was almost constant at all ages. The HBsAg carrier rate was highest in children under 5 years of age (7.6%) and decreased with age. However, only one HBsAg carrier was under 1 year of age. Anti-HBs age-specific prevalence increased progressively from 2.7% to 11.4%. Anti-HBc alone was present in 4.1% of the subjects. No significant sex differences were found in the prevalence of HBV serum markers or in the HBsAg carrier rate. Neither HAV nor HBV infection was significantly influenced by place of residence or socioeconomic status. It is concluded that in this area both HAV and HBV are endemic, but while HAV is mainly acquired at school, most of the HBV infections occur within the household. The results suggest that not only perinatal transmission, but also intrafamilial horizontal infection, plays a role in HBV spread among infants.     

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。     

Hepatitis A Virus Incidence Rates and Biomarker Dynamics for Plasma Donors,United States

The United States is currently affected by widespread hepatitis A virus (HAV) outbreaks. We investigated HAV incidence rates among source plasma donors in the United States since 2016. Serial donations from HAV-positive frequent donors were analyzed for common biologic markers to obtain a detailed picture of the course of infection. We found a considerable increase in incidence rates with shifting outbreak hotspots over time. Although individual biomarker profiles were highly variable, HAV RNA typically had a high peak and a biphasic decrease and often remained detectable for several months. One donor had a biomarker pattern indicative of previous exposure. Our findings show that current HAV outbreaks have been spilling over into the plasma donor population. The detailed results presented improve our comprehension of HAV infection and related public health aspects. In addition, the capture of full RNA curves enables estimation of HAV doubling time.     

Factors associated with the immune response to hepatitis A vaccination in HIV-infected patients in the era of highly active antiretroviral therapy

Introduction

HIV seropositivity is considered a risk factor for complications in hepatitis A virus (HAV) infection. HAV vaccination schedules are widely implemented in HIV-infected patients, but the immune response remains impaired.

Methods

We analysed the response to vaccination (antiHAV titres ≥20 IU/l) in 282 HIV-infected patients included in a standard (1440 Elisa Units (EU) at 0, 6 months) or rapidly accelerated schedule (720 EU at 0, 7, 21 days and 6 months) between 1997 and 2009. Factors associated with the response to vaccination were analysed using logistic regression.

Results

The overall response rate was 73.4%. Male sex (OR: 0.16, 95% CI 0.05–0.51) and hepatitis C virus co-infection (OR: 0.30, 95% CI 0.14–0.74) were associated with a lower probability of response. Protective antibody response was associated with a higher CD4/CD8 ratio (OR: 3.69, 95% CI 1.3–10.5) and having received two doses of standard schedule (compared with patients receiving only one dose of the same schedule) (OR: 2.51, 95% CI 1.22–5.15). Three doses of the rapidly accelerated schedule were not more effective than a single dose of 1440 EU (OR: 1.32, 95% CI 0.48–3.63).

Conclusion

The low responses observed in patients receiving a single dose suggest the need to emphasize adhesion to vaccination protocols to avoid failure. The CD4/CD8 ratio may be considered as an immune status marker which could help to better choose the moment of vaccination. Our findings underscore the importance of identifying strategies that optimize the timing and effectiveness of hepatitis A vaccination in HIV-infected patients and of the need for further studies on individual factors such as sex and hepatitis C co-infection that may affect the response to vaccination. Likewise, the sub-optimal effectiveness of three doses of 720 EU in the rapidly accelerated schedule, if confirmed in future studies, might lead to a revision of the current schedule recommended for HIV-infected travellers.     

以RFIL消除慢性乙型肝炎血清RF致的抗HAV-IgM假阳性反应

为了解HAV/HBV双重感染的发生情况,作者检测了121例慢性乙型肝炎患者血清抗HAV-IgM,其中经类风湿因子免疫胶乳(RFIL)处理后抗HAV-IgM仍阳性的7例,未经处理的12例阳性,有5例为假阳性,占41.7％(5/12)。用RFIL能消除因血清中RF所致的抗HAV-IgM假阳性反应,不出现假阴性结果。认为RFIL中和反应是一种简单,经济而有效的排除RF干扰的方法。本组慢性乙型肝炎患者重叠感染甲肝病毒7例,占5.8％,均为慢性活动性肝炎。