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Hepatitis E Vaccine Candidate Completely Blocked Disease - full text below, pdf attached, Commentary in next email
 
 
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"In our trial, we found the vaccine well tolerated and efficacious for a general adult population. Further studies are needed to assess the safety and to support the benefits of the vaccine for pregnant women and for people younger than 15 years or older than 65 years.....In our trial, efficacy of recombinant hepatitis E vaccine during the 12 months from the 31st day after the receipt of the third dose was 100·0% (95% CI 72·1-100·0), and protection was noted across all age and sex subgroups. Vaccination was also beneficial under less than perfect circumstances-ie, when participants did not receive all three doses. Vaccine efficacy after two doses was 100·0% (95% CI 9·1-100·0). Therefore, during a hepatitis E outbreak, or for travellers to an endemic area, protection can be quickly obtained by two vaccine doses given within 1 month......Data suggest that individuals with chronic liver disease should be prioritised for hepatitis E vaccination to prevent serious damage from infection.8, 9 However, because we excluded this group, additional study is needed to assess the benefits of HEV 239. Another limitation was the lack of a hepatitis E case in the vaccine group, meaning that the protective antibody concentration could not be assessed. Further analysis of our serology data might provide important information on the vaccine's efficacy against subclinical infection. Both our study and the previous phase 2 study of the vaccine produced in insect cells showed substantial short-term protection; however, the duration of this protection needs further assessment."
 
Hepatitis E Vaccine Candidate Completely Blocked Disease - full text below, pdf attached, Commentary in next email
 
MedPage Today
Published: August 22, 2010
 
Action Points
 
* Explain to interested patients that a large randomized trial in China of an investigational vaccine against the hepatitis E virus showed an efficacy rate of 100%.
 
* Explain further that serologic studies indicate that up to one-third of the world is infected with hepatitis E virus.
 
An investigational vaccine against hepatitis E was shown to be completely effective in a large randomized trial in China, researchers reported.
 
The trial, involving more than 100,000 patients, found that none of the patients who received the full three doses of the vaccine (HEV 239 or Hecolin) developed hepatitis E over a 12-month follow-up, according to Ning-Shao Xia, MD, of Xiamen University in Xiamen, China, and colleagues.
 
In contrast, there were 15 cases of hepatitis E among the participants in the placebo arm (who were given a licensed hepatitis B vaccine) -- for an efficacy rate of 100%, Xia and colleagues reported online in The Lancet.
 
The vaccine efficacy was equally high when the analysis was expanded to include participants who only got two doses and reached 95.5% among those who got at least one dose, the researchers reported.
 
Although the existence of hepatitis E has been known for years, research into the virus has largely been neglected. (See ICAAC: Hepatitis E Virus Finally Gets Some Respect)
 
But hepatitis E is widespread -- estimates suggest that a third of the world's people are infected -- and can cause serious disease and death, especially in the developing world, according to background provided by the researchers.
 
The double-blind, randomized, placebo-controlled trial was done between August, 2007, and June, 2009 in Jiangsu Province in China, where the virus is endemic. In fact, a preliminary analysis of more than 11,000 of the trial participants showed that 47% already had antibodies against hepatitis E, the researchers reported.
 
All told, the investigators randomly assigned 56,302 volunteers to get three doses of the vaccine (delivered intramuscularly at baseline, one, and six months) and 56,302 to get the hepatitis B vaccine on the same schedule.
 
The main analysis included those who got all three doses - 86% in each arm - and were followed for 12 months starting the 31st day after the last dose.
 
In that group, there were no cases in the vaccine arm and 15 in the placebo arm.
 
As well, five additional volunteers -- all in the placebo group -- developed hepatitis E during the period from 14 days after the second dose and before the third dose, the researchers reported, yielding an efficacy rate of 100% among trial participants who got two doses of vaccine.
 
In the entire cohort, there were 23 cases of hepatitis E recorded during the follow-up -- including a case in one volunteer in the vaccine group who had received only one dose, and 22 cases among participants in the placebo group, producing an efficacy rate of 95.5%.
 
The high efficacy rate after two doses suggests that the vaccine can be deployed quickly and would be effective in the context of an outbreak or for travelers to an endemic area, the researchers argued.
 
The researchers concluded that the vaccine was well tolerated and effective among a general adult population. "Further studies are needed to assess the safety and to support the benefits of the vaccine for pregnant women and for people younger than 15 years or older than 65 years." they added.
 
Adverse events were mostly mild and local, including pain and swelling at the injection site, Xia and colleagues reported.
 
The study is "an important event in the prevention and control of hepatitis E." according to Scott Holmberg, MD, of the CDC.
 
In an accompanying comment, Holmberg said that a safe and effective vaccine -- if it's affordable -- "raises the prospect" of routine vaccination to reduce the impact of chronic hepatitis E, as well as epidemic outbreaks.
 
Vaccines, he argued, should not substitute for improvements in sanitation. But, given that sanitary conditions in many places have been slow to improve, "this vaccine might be our best new stopgap in the effort to control the scourge of (hepatitis E) in many parts of the world," he concluded.
 
The study had support from the Chinese National High-tech R&D Programme, the Chinese National Key Technologies R&D Programme, the Chinese National Science Fund for Distinguished Young Scholars, the Fujian Provincial Department of Sciences and Technology, the Xiamen Science and Technology Bureau, and the Fujian Provincial Science Fund for Distinguished Young Scholars.
 
Two of the authors are employees of Xiamen Innovax Biotech, which is developing the vaccine. The remaining authors, including Xia, said they had no conflicts.
 
Holmberg said he had no conflicts.
 
Primary source: The Lancet
 
Source reference: Zhu F-C et al. "Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial." The Lancet 2010; DOI:10.1016/S0140-6736(10)61030-6.
 
Additional source: The Lancet
Source reference:
Scott D Holmberg. "Hepatitis E vaccine: not a moment too soon."The Lancet 2010;DOI:10.1016/S0140-6736(10)61260-3.
 
--------------------------------------
 
The Lancet, Early Online Publication, 23 August 2010
 
Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial
 
Feng-Cai Zhu MSc a, Prof Jun Zhang MD b, Xue-Feng Zhang MSc a, Cheng Zhou MD c, Zhong-Ze Wang MD d, Shou-Jie Huang MD b, Hua Wang MD a, Chang-Lin Yang BSc d, Han-Min Jiang BSc d, Jia-Ping Cai BSc d, Yi-Jun Wang BSc d, Xing Ai MSc a, Yue-Mei Hu MD a, Quan Tang MD a, Xin Yao MSc c, Qiang Yan MSc b, Yang-Ling Xian BSc e, Prof Ting Wu PhD b, Yi-Min Li MD e, Prof Ji Miao PhD b, Prof Mun-Hon Ng PhD b, Prof James Wai-Kuo Shih PhD b, Prof, Dr Ning-Shao Xia MD b Corresponding AuthorEmail Address
 
Summary
 
Background

 
Seroprevalence data suggest that a third of the world's 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 µg 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.
 
Introduction
 
Hepatitis E virus is a major cause of sporadic and epidemic hepatitis.1 Seroprevalence data suggest that a third of the world's population has been infected with the virus.2 Although most cases are in developing countries, hepatitis E is no longer rare and it might be the most common type of acute viral hepatitis in industrialised countries.3
 
Clinically indistinguishable from other types of acute viral hepatitis, hepatitis E tends to be self-limited and usually does not become chronic.4 The severity of illness increases with age; the overall case fatality ratio is estimated to be 1-3%.5 Hepatitis E has a poor prognosis in pregnant women: mortality is 5-25%, and survivors have high rates of spontaneous abortion and stillbirth.6, 7 In patients with chronic liver disease, superinfection with hepatitis E virus often leads to a poor outcome.8, 9 Every year, 13 000-26 000 deaths are estimated in patients with chronic liver disease in industrialised countries.10 In a continuing hepatitis E epidemic in Uganda that has caused illness in more than 10 196 people and 160 deaths, mortality was 13% in children.11
 
At least four genotypes of hepatitis E viruses have been identified.12 Genotypes 1 and 2 were isolated from human beings and are mainly seen in developing countries. Genotypes 3 and 4 are zoonotic, with pigs being the principal reservoir; they have been identified in many sporadic cases and limited foodborne outbreaks mainly affecting middle-aged and elderly men.13-15 Nevertheless, all hepatitis E virus associated with human diseases can be considered as belonging to one serotype.16
 
Two recombinant vaccines have undergone phase 2 clinical trials. One of the vaccines was produced in insect cells and was safe and immunogenic in young men (mean age 25·2 years; SD 6·25), providing 95% protection against hepatitis E in Nepal, where only genotype 1 hepatitis E virus had been isolated.17 The results were encouraging but two questions remained to be answered. The first related to the safety and efficacy of the vaccine in the general population, especially in women and elderly people. The second related to the efficacy of a vaccine originally derived from hepatitis E virus genotype 1 against disease caused by heterogenic hepatitis E virus. The other candidate vaccine, HEV 239 (Hecolin; Xiamen Innovax Biotech, Xiamen, China), was produced in bacterial cells and was safe and efficacious against infection with hepatitis E virus in seronegative participants in a phase 2 trial.18
 
We undertook a randomised, double-blind, placebo-controlled, phase 3 trial to assess the efficacy and safety of HEV 239 in the general population. The trial included men and women from age 16 to 65 years, with or without antibodies against hepatitis E, from a region where both genotypes 1 and 4 cocirculate with the zoonotic genotype 4 predominating.
 
Results
 
122 179 people from 11 townships attended the enrolment visit between August and October, 2007. 112 604 participants fulfilled the eligibility requirements, were randomly assigned to the study group, and received at least one dose of vaccine or placebo. 97 356 participants received all three doses of vaccine or placebo and were included in the analysis of the primary endpoint (figure 1). Table 1 shows the baseline characteristics of study participants.
 
The DSMB confirmed 23 cases of hepatitis E before unblinding (figure 2); details of each case are listed in webappendix pp 4-24. Compared with the general study population, patients with hepatitis E were older (mean 51·3 years, SD 8·2; median 53, range 36-63) and more likely to be men (male-to-female ratio 2·3). The mean maximum serum ALT concentration of patients with hepatitis E was 30·8-times upper limit of normal range (SD 29·3; 18·1, 2·5-96·9), and the mean duration of illness was 57·1 days (SD 39·8; 41, 9-175). 15 patients were admitted to hospital for a mean of 24·4 days (SD 14·5; 20, 9-66). All 23 patients tested positive for hepatitis E virus IgM, 22 were positive for hepatitis E virus RNA, and 14 had a 4-times or greater increase in hepatitis E virus IgG. Of the 13 patients whose viruses were isolated for sequencing, 12 had genotype 4 and one had genotype 1. Of the eight patients who received all three doses and whose viruses underwent sequencing, all had genotype 4.
 
In the primary analysis population 15 participants developed hepatitis E during the 12 months from the 31st day after receipt of the third dose; all 15 were in the placebo group (table 2). Vaccine efficacy against hepatitis E was 100·0% (95% CI 72·1-100·0), and protection extended to all participants throughout the 12 months. Five participants developed hepatitis E during the 14 days after the second dose and before the third dose; all were in the placebo group. Vaccine efficacy after two doses was 100·0% (9·1-100·0).
 
Most randomised participants who received at least one dose of vaccine or placebo were followed up for 19 months from the beginning of the study, and a small proportion of participants were followed up from month 7 of the study. There were 23 cases of hepatitis E during the follow-up, one in the vaccine group (the participant received one dose of the vaccine) and 22 in the placebo group (table 2). Vaccine efficacy for participants who received at least one dose was 95·5% (95% CI 66·3-99·4). There were 17 cases of hepatitis E during the 12 months from the 31st day after the receipt of the final dose (which could be the first, second, or third dose), one in the vaccine group, and 16 in the placebo group. The corresponding vaccine efficacy was 93·8% (95% CI 59·8-99·9%).
 
Figure 3 shows the cumulative incidence of hepatitis E in participants who were followed up for 19 months from the beginning of the study. The difference between the vaccine group and the placebo group was significant (p<0·0001).
 
Most adverse events were mild. Rates of serious adverse events were similar in the vaccine and placebo groups during the entire follow-up, and none were deemed by the DSMB to relate to vaccination (table 3 and webappendix pp 25-28). Participants in the reactogenicity subset were regularly interviewed by investigators after receipt of each dose to assess adverse events (table 3). In this subset, the proportion of all solicited local adverse events identified within 72 h after each dose was greater in the vaccine group (13·5%) than in the placebo group (7·1%; p<0·0001). The vaccine group also had a greater proportion of adverse reactions attributed to pain, swelling, and itching at injection sites, which were the most common local adverse events. The proportion of systemic adverse events were similar for both groups (20·3% vs 19·8%). On the basis of reports by participants not in the reactogenicity subset, the proportion of solicited local adverse events was higher in the vaccine group than in the placebo group (2·8% vs 1·9%) and the rates of solicited systemic adverse events were not significantly different between the two groups (table 3).
 
Serum samples were taken from 11 165 participants before vaccination and 1 month after receipt of the third dose. 5494 (98·7%) of 5567 participants in the vaccine group had an increase in antibody concentration in the samples after vaccination of four times or more from that of the corresponding samples before vaccination. In the samples after vaccination, geometric mean concentration in these participants rose from 0·14 Wu/mL to 19·0 Wu/mL (95% CI 18·6-19·4). By contrast, 119 (2·1%) of 5598 participants in the placebo group showed an antibody response and all the episodes were subclinical infection.
 
Discussion
 
In our trial, efficacy of recombinant hepatitis E vaccine during the 12 months from the 31st day after the receipt of the third dose was 100·0% (95% CI 72·1-100·0), and protection was noted across all age and sex subgroups. Vaccination was also beneficial under less than perfect circumstances-ie, when participants did not receive all three doses. Vaccine efficacy after two doses was 100·0% (95% CI 9·1-100·0). Therefore, during a hepatitis E outbreak, or for travellers to an endemic area, protection can be quickly obtained by two vaccine doses given within 1 month.
 
Side-effects were few and mild and no serious adverse events related to vaccination. HEV 239 is unlikely to induce rare vaccine-related serious adverse events, because the large number of participants in the study affords a power of 85% to detect rare serious adverse events if the rate in the vaccine group is 0·03% and the rate ratio is 5·0 (webappendix p 29).
 
The study site is endemic for infection with hepatitis E virus, with nearly half the participants tested on day 0 being seropositive. The infection rate in the placebo group was 2·1% during the period from 0 months to 7 months. However, most of the infections seemed to be subclinical and incidence of hepatitis E was estimated to be about four per 10 000 person-years (webappendix p 1). The reason for the low attack rate is unknown. In developed countries where the zoonotic hepatitis E genotype 3 predominates, emerging data showed a moderate hepatitis E virus seroprevalence but rare autochthonous cases of hepatitis E.3 These findings suggest that the low attack rate might be a common feature of both zoonotic genotypes, relating to a low-level, but nevertheless widespread, exposure in areas where these viruses are prevalent.
 
Animal studies showed that HEV 239, which is produced with a genotype 1 isolate, confers protection against both genotypes 1 and 4.19 12 of 13 patients with hepatitis E who were typed by sequencing, had genotype 4, all in the placebo group. Therefore, our study substantiates that the vaccine cross protects against genotype 4 in human beings, and the cross protection probably extends to other genotypes as well, given that they belong to the same serotype as the vaccine strain.
 
Data suggest that individuals with chronic liver disease should be prioritised for hepatitis E vaccination to prevent serious damage from infection.8, 9 However, because we excluded this group, additional study is needed to assess the benefits of HEV 239. Another limitation was the lack of a hepatitis E case in the vaccine group, meaning that the protective antibody concentration could not be assessed. Further analysis of our serology data might provide important information on the vaccine's efficacy against subclinical infection. Both our study and the previous phase 2 study of the vaccine produced in insect cells showed substantial short-term protection; however, the duration of this protection needs further assessment.
 
In our trial, we found the vaccine well tolerated and efficacious for a general adult population. Further studies are needed to assess the safety and to support the benefits of the vaccine for pregnant women and for people younger than 15 years or older than 65 years.
 
 
 
 
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