Han-Min Jiang

Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial

BACKGROUND Seroprevalence data suggest that a third of the worlds population has been infected with the hepatitis E virus. Our aim was to assess efficacy and safety of a recombinant hepatitis E vaccine, HEV 239 (Hecolin; Xiamen Innovax Biotech, Xiamen, China) in a randomised, double-blind, placebo-controlled, phase 3 trial. METHODS Healthy adults aged 16-65 years in, Jiangsu Province, China were randomly assigned in a 1:1 ratio to receive three doses of HEV 239 (30 microg of purified recombinant hepatitis E antigen adsorbed to 0.8 mg aluminium hydroxide suspended in 0.5 mL buffered saline) or placebo (hepatitis B vaccine) given intramuscularly at 0, 1, and 6 months. Randomisation was done by computer-generated permuted blocks and stratified by age and sex. Participants were followed up for 19 months. The primary endpoint was prevention of hepatitis E during 12 months from the 31st day after the third dose. Analysis was based on participants who received all three doses per protocol. Study participants, care givers, and investigators were all masked to group and vaccine assignments. This trial is registered with ClinicalTrials.gov, number NCT01014845. FINDINGS 11,165 of the trial participants were tested for hepatitis E virus IgG, of which 5285 (47%) were seropositive for hepatitis E virus. Participants were randomly assigned to vaccine (n=56,302) or placebo (n=56,302). 48,693 (86%) participants in the vaccine group and 48,663 participants (86%) in the placebo group received three vaccine doses and were included in the primary efficacy analysis. During the 12 months after 30 days from receipt of the third dose 15 per-protocol participants in the placebo group developed hepatitis E compared with none in the vaccine group. Vaccine efficacy after three doses was 100.0% (95% CI 72.1-100.0). Adverse effects attributable to the vaccine were few and mild. No vaccination-related serious adverse event was noted. INTERPRETATION HEV 239 is well tolerated and effective in the prevention of hepatitis E in the general population in China, including both men and women age 16-65 years. FUNDING Chinese National High-tech R&D Programme (863 programme), Chinese National Key Technologies R&D Programme, Chinese National Science Fund for Distinguished Young Scholars, Fujian Provincial Department of Sciences and Technology, Xiamen Science and Technology Bureau, and Fujian Provincial Science Fund for Distinguished Young Scholars.

Long-Term Efficacy of a Hepatitis E Vaccine

BACKGROUND Hepatitis E virus (HEV) is a leading cause of acute hepatitis. The long-term efficacy of a hepatitis E vaccine needs to be determined. METHODS In an initial efficacy study, we randomly assigned healthy adults 16 to 65 years of age to receive three doses of either a hepatitis E vaccine (vaccine group; 56,302 participants) or a hepatitis B vaccine (control group; 56,302 participants). The vaccines were administered at 0, 1, and 6 months, and the participants were followed for 19 months. In this extended follow-up study, the treatment assignments of all participants remained double-blinded, and follow-up assessments of efficacy, immunogenicity, and safety were continued for up to 4.5 years. RESULTS During the 4.5-year study period, 60 cases of hepatitis E were identified; 7 cases were confirmed in the vaccine group (0.3 cases per 10,000 person-years), and 53 cases in the control group (2.1 cases per 10,000 person-years), representing a vaccine efficacy of 86.8% (95% confidence interval, 71 to 94) in the modified intention-to-treat analysis, rather than (95% confidence interval, 71 to 84) [corrected]. Of the participants who were assessed for immunogenicity and were seronegative at baseline, 87% of those who received three doses of the hepatitis E vaccine maintained antibodies against HEV for at least 4.5 years; HEV antibody titers developed in 9% in the control group. The rate of adverse events was similar in the two groups. CONCLUSIONS Immunization with this hepatitis E vaccine induced antibodies against HEV and provided protection against hepatitis E for up to 4.5 years. (Funded by the Chinese Ministry of Science and Technology and others; ClinicalTrials.gov number, NCT01014845.).

Profile of Acute Infectious Markers in Sporadic Hepatitis E

Laboratory diagnosis of acute infection of hepatitis E virus (HEV) is commonly based on the detection of HEV RNA, IgM and/or rising IgG levels. However, the profile of these markers when the patients present have not been well determined. To clarify the extent of misdiagnosed sporadic hepatitis E in the initial laboratory detection, serial sera of 271 sporadic acute hepatitis cases were collected, detected and the dynamics of each acute marker during the illness course were analyzed. 91 confirmed cases of hepatitis E were identified based on the presentation of HEV RNA, IgM or at least 4 fold rising of IgG levels. 21 (23.1%) hepatitis E cases were false negative for the viral RNA and 40 (44.0%) for rising IgG, because occurrence of these markers were confined to acute phase of infection and viremia had already subsided and antibody level peaked when these patients presented. IgM was detected in 82 (90.1%) cases. It is the most prevalent of the three markers, because the antibody persisted until early convalescence. Nine cases negative for IgM were positive for rising IgG and one was also positive for the viral RNA; all of these nine cases showed high avid IgG in their acute phase sera, which indicated re-infection. In summary, it is not practicable to determine the true occurrence of sporadic hepatitis E. Nevertheless, it could be closely approximated by approach using a combination of all three acute markers.

Protection against hepatitis E virus infection by naturally acquired and vaccine-induced immunity

Immunity acquired from infection or vaccination protects humans from symptomatic hepatitis E. However, whether the risk of hepatitis E virus (HEV) infection is reduced by the immunity remains unknown. To understand this issue, a cohort with 12 409 participants randomized to receive the hepatitis E vaccine Hecolin(®) or placebo were serologically followed up for 2 years after vaccination. About half (47%) of participants were initially seropositive. A total of 139 infection episodes, evidenced by four-fold or greater rise of anti-HEV level or positive seroconversion, occurred in participants who received three doses of treatment. Risk of infection was highest among the baseline seronegative placebo group participants (2.04%). Pre-existing immunity and vaccine-induced immunity lower the risk significantly, to 0.52% and 0.30%, respectively. In conclusion, both vaccine-induced and naturally acquired immunity can effectively protect against HEV infection.

Epidemiology of Zoonotic Hepatitis E: A Community-Based Surveillance Study in a Rural Population in China

Background Hepatitis E is caused by two viral genotype groups: human types and zoonotic types. Current understanding of the epidemiology of the zoonotic hepatitis E disease is founded largely on hospital-based studies. Methods The epidemiology of hepatitis E was investigated in a community-based surveillance study conducted over one year in a rural city in eastern China with a registered population of 400,162. Results The seroprevalence of hepatitis E in the cohort was 38%. The incidence of hepatitis E was 2.8/10,000 person-years. Totally 93.5% of the infections were attributed to genotype 4 and the rest, to genotype 1. Hepatitis E accounted for 28.4% (102/359) of the acute hepatitis cases and 68.9% (102/148) of the acute viral hepatitis cases in this area of China. The disease occurred sporadically with a higher prevalence during the cold season and in men, with the male-to-female ratio of 3∶1. Additionally, the incidence of hepatitis E increased with age. Hepatitis B virus carriers have an increased risk of contracting hepatitis E than the general population (OR = 2.5, 95%CI 1.5–4.2). Pre-existing immunity to hepatitis E lowered the risk (relative risk  = 0.34, 95% CI 0.21–0.55) and reduced the severity of the disease. Conclusions Hepatitis E in the rural population of China is essentially that of a zoonosis due to the genotype 4 virus, the epidemiology of which is similar to that due to the other zoonotic genotype 3 virus.

Safety of an Escherichia coli-expressed bivalent human papillomavirus (types 16 and 18) L1 virus-like particle vaccine An open-label phase I clinical trial

An Escherichia coli-expressed recombinant bivalent human papillomavirus (types 16 and 18) vaccine candidate has been shown to be safe and immunogenic in preclinical trials. The safety of this vaccine was analyzed in an open-label phase I clinical trial in Jiangsu province, China. Thirty-eight healthy women from 18 to 55 y of age were enrolled and vaccinated at 0, 1, and 6 mo. Adverse events that occurred within 30 d after each injection and serious adverse events that occurred throughout the study were recorded. In addition, blood parameters were tested before and after each injection. All but one woman received all 3 doses. Thirty-two (84.2%) of the participants reported adverse events, all adverse events of which were mild, of short duration and resolved spontaneously. No serious adverse events occurred during the study. Changes in blood parameters after each injection were random, mild, and not clinically significant. These preliminary results show that a new Escherichia coli-expressed recombinant HPV 16/18 bivalent vaccine is well tolerated in healthy women and support further immunogenicity and efficacy studies for this HPV vaccine candidate.

Immunogenicity and safety of hepatitis E vaccine in healthy hepatitis B surface antigen positive adults

A recombinant hepatitis E vaccine, Hecolin®, has been proven safe and effective in healthy adults. As hepatitis B surface antigen (HBsAg) positive individuals have a higher risk of poor prognosis after super-infection with hepatitis E virus (HEV), the safety and immunogenicity of Hecolin® in this population should be assessed. The present study is an extending analysis of data from a large randomized controlled clinical trial of Hecolin®. Healthy participants (n = 14,065) without current or previous evidence of chronic liver disease were randomized to receive Hecolin® or placebo (hepatitis B vaccine) and donated their blood samples before vaccination and subsequently over 31 mo. Most of the adverse events were mild and comparable between participants with and without baseline hepatitis B surface antigen (HBsAg). No vaccine-related serious adverse events were reported. Rates of serious adverse events in HBsAg (+) or HBsAg (-) participants were also comparable between both groups. Almost all participants in the Hecolin® group seroconverted to anti-HEV one month after full vaccination. The antibody response rates and levels were similar in HBsAg (+) and HBsAg (-) participants (98.38%, 19.32 Wu/mL vs. 98.69%, 19.00 Wu/mL). The two-year antibody dynamics of HBsAg (+) participants overlapped perfectly with those of HBsAg (-) participants. In conclusion, the safety and immunogenicity of Hecolin® for HBsAg (+) adults is very similar to that for the general population.

Immunogenicity and safety of an E. coli-produced bivalent human papillomavirus (type 16 and 18) vaccine: A randomized controlled phase 2 clinical trial.

BACKGROUND This study aimed to investigate the dosage, immunogenicity and safety profile of a novel human papillomavirus (HPV) types 16 and 18 bivalent vaccine produced by E. coli. METHODS This randomized, double-blinded, controlled phase 2 trial enrolled women aged 18-25 years in China. Totally 1600 eligible participants were randomized to receive 90μg, 60μg, or 30μg of the recombinant HPV 16/18 bivalent vaccine or the control hepatitis B vaccine on a 0, 1 and 6 month schedule. The designated doses are the combined micrograms of HPV16 and 18 VLPs with dose ratio of 2:1. The immunogenicity of the vaccines was assessed by measuring anti-HPV 16 and 18 neutralizing antibodies and total IgG antibodies. Safety of the vaccine was assessed. RESULTS All but one of the seronegative participants who received 3 doses of the HPV vaccines seroconverted at month 7 for anti-HPV 16/18 neutralizing antibodies and IgG antibodies. For HPV 16, the geometric mean titers (GMTs) of the neutralizing antibodies were similar between the 60μg (GMT=10,548) and 90μg (GMT=12,505) HPV vaccine groups and were significantly higher than those in the 30μg (GMT=7596) group. For HPV 18, the GMTs of the neutralizing antibodies were similar among the 3 groups. The HPV vaccine was well tolerated. No vaccine-associated serious adverse events were identified. CONCLUSION The prokaryotic-expressed HPV vaccine is safe and immunogenic in women aged 18-25 years. The 60μg dosage formulation was selected for further investigation for efficacy. CLINICAL TRIALS REGISTRATION NCT01356823.

The prevalence of latent tuberculosis infection in rural Jiangsu, China.

OBJECTIVES Diagnosis and interventional treatment of latent tuberculosis (TB) infection (LTBI) are important components in tuberculosis control. But systematic studies regarding the epidemic of LTBI are still rare in China. The objective of this study was to assess the prevalence and risk factors associated with LTBI based on the results of a domestic TB-specific gamma interferon (IFN-γ) release assay (TB-IGRA) in rural Jiangsu, China. STUDY DESIGN Cross-sectional study of subjects registered in eight villages in Jiangsu, China. METHODS This study was conducted in 2012 in eight villages. After recruitment, individuals with active TB or a history of TB were excluded. The TB-IGRA was performed for diagnosis of LTBI. RESULTS 2169 of 2185 subjects met the requirement and were analysed in this study. 524 (24.3%) had a positive result, and positive rate gradually increased with age (P for trend <0.001). Multivariate analyses showed that increasing age, male gender and a history of TB exposure were risk factors associated with LTBI. Bacillus Calmette-Guérin (BCG) vaccination did not reduce the risk of TB infection in participants (aged ≥20 years). CONCLUSIONS The findings of this study demonstrate that the prevalence of LTBI in China might be overestimated by tuberculin skin test compared with IFN-γ release assay (IGRA). The degree of TB exposure is related to Mycobacterium tubercuium (MTB) infection, and BCG vaccination offers little protection against MTB infection in adults. The early and effective detection and treatment of active TB patients, and screening and intervention for LTBI patients with a high risk of developing active TB could be cost-effective methods for TB control in China.