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www.thelancet.com Published online August 23, 2010 DOI:10.1016/S0140-6736(10)61030-6 1

Published Online

August 23, 2010

DOI:10.1016/S0140-

6736(10)61030-6

See Online/Comment

DOI:10.1016/S0140-

6736(10)61260-3

Jiangsu Provincial Centre for

Disease Control and

Prevention, Nanjing, Jiangsu

Province, China (F-C Zhu MSc,

X-F Zhang MSc, H Wang MD,

X Ai MSc, Y-M Hu MD,

Q Tang MD); National Institute

of Diagnostics and Vaccine

Development in Infectious

Diseases, The Key Laboratory of

the Ministry of Education for

Cell Biology and Tumour Cell

Engineering, Xiamen

University, Xiamen, China

(Prof J Zhang MD, S-J Huang MD,Q Yan MSc, Prof T Wu PhD,

Prof J Miao PhD,

Prof M-H Ng PhD,

Prof J W-K Shih PhD,

Prof N-S Xia MD); National

Institute for the Control of

Pharmaceuticals and Biological

Products, Beijing, China

(C Zhou MD, X Yao MSc);

Dongtai Centre for Disease

Control and Prevention,

Dongtai, Jiangsu Province,

China (Z-Z Wang MD,

C-L Yang BSc, H-M Jiang BSc,

J-P Cai BSc, Y-J Wang BSc); and

Xiamen Innovax Biotech,

Xiamen, China (Y-L Xian BSc,Y-M Li MD)

Correspondence to:

Dr Ning-Shao Xia, National

Institute of Diagnostics and

Vaccine Development in

Infectious Diseases, The Key

Laboratory of the Ministry of

Education for Cell Biology and

Tumour Cell Engineering,

Xiamen University, 422nd

Siming South Road, Xiamen,

361005, China

[email protected]

Ecacy and saety o a recombinant hepatitis E vaccine in

healthy adults: a large-scale, randomised, double-blindplacebo-controlled, phase 3 trial

Feng-Cai Zhu, Jun Zhang, Xue-Feng Zhang, Cheng Zhou, Zhong-Ze Wang, Shou-Jie Huang, Hua Wang, Chang-Lin Yang, Han-Min Ji ang,

Jia-Ping Cai, Yi-Jun Wang, Xing Ai, Yue-Mei Hu, Quan Tang, Xin Yao, Qiang Yan, Yang-Ling Xian, Ting Wu, Yi-Min Li, Ji Miao, Mun-Hon Ng,

James Wai-Kuo Shih, Ning-Shao Xia

SummaryBackground Seroprevalence data suggest that a third o the worlds population has been inected with the hepatitis Evirus. Our aim was to assess ecacy and saety o a recombinant hepatitis E vaccine, HEV 239 (Hecolin; XiamenInnovax Biotech, Xiamen, China) in a randomised, double-blind, placebo-controlled, phase 3 trial.

Methods Healthy adults aged 1665 years in, Jiangsu Province, China were randomly assigned in a 1:1 ratio to receivethree doses o HEV 239 (30 g o puried recombinant hepatitis E antigen adsorbed to 08 mg aluminium hydroxidesuspended in 05 mL bufered saline) or placebo (hepatitis B vaccine) given intramuscularly at 0, 1, and 6 months.Randomisation was done by computer-generated permuted blocks and stratied by age and sex. Participants wereollowed up or 19 months. The primary endpoint was prevention o hepatitis E during 12 months rom the 31st dayater 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 withClinicalTrials.gov, number NCT01014845.

Findings 11 165 o the trial participants were tested or hepatitis E virus IgG, o which 5285 (47%) were seropositive orhepatitis 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 andwere included in the primary ecacy analysis. During the 12 months ater 30 days rom receipt o the third dose

15 per-protocol participants in the placebo group developed hepatitis E compared with none in the vaccine group.Vaccine ecacy ater three doses was 1000% (95% CI 7211000). Adverse efects attributable to the vaccine wereew and mild. No vaccination-related serious adverse event was noted.

Interpretation HEV 239 is well tolerated and efective in the prevention o hepatitis E in the general population inChina, including both men and women age 1665 years.

Funding Chinese National High-tech R&D Programme (863 programme), Chinese National Key Technologies R&DProgramme, Chinese National Science Fund or Distinguished Young Scholars, Fujian Provincial Department oSciences and Technology, Xiamen Science and Technology Bureau, and Fujian Provincial Science Fund orDistinguished Young Scholars.

IntroductionHepatitis E virus is a major cause o sporadic and

epidemic hepatitis.1 Seroprevalence data suggest that athird o the worlds population has been inected withthe virus.2 Although most cases are in developingcountries, hepatitis E is no longer rare and it might bethe most common type o acute viral hepatitis inindustrialised countries.3

Clinically indistinguishable rom other types o acuteviral hepatitis, hepatitis E tends to be sel-limited andusually does not become chronic.4The severity o illnessincreases with age; the overall case atality ratio isestimated to be 13%.5 Hepatitis E has a poor prognosisin pregnant women: mortality is 525%, and survivorshave high rates o spontaneous abortion and stillbirth.6,7In patients with chronic liver disease, superinectionwith hepatitis E virus oten leads to a poor outcome.8,9

Every year, 13 00026 000 deaths are estimated inpatients with chronic liver disease in industrialised

countries.10 In a continuing hepatitis E epidemic inUganda that has caused illness in more than 10 196people and 160 deaths, mortality was 13% in children.11

At least our genotypes o hepatitis E viruses havebeen identied.12 Genotypes 1 and 2 were isolated romhuman beings and are mainly seen in developingcountries. Genotypes 3 and 4 are zoonotic, with pigsbeing the principal reservoir; they have been identiedin many sporadic cases and limited oodborne outbreaksmainly aecting middle-aged and elderly men. 1315Nevertheless, all hepatitis E virus associated withhuman diseases can be considered as belonging toone serotype.16

Two recombinant vaccines have undergone phase 2clinical trials. One o the vaccines was produced in


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2 www.thelancet.com Published online August 23, 2010 DOI:10.1016/S0140-6736(10)61030-6

insect cells and was sae and immunogenic in youngmen (mean age 252 years; SD 625), providing 95%protection against hepatitis E in Nepal, where onlygenotype 1 hepatitis E virus had been isolated.17 Theresults were encouraging but two questions remainedto be answered. The rst related to the saety and ecacyo the vaccine in the general population, especially in

women and elderly people. The second related to theecacy o a vaccine originally derived rom hepatitis Evirus genotype 1 against disease caused by heterogenichepatitis E virus. The other candidate vaccine, HEV 239(Hecolin; Xiamen Innovax Biotech, Xiamen, China),was produced in bacterial cells and was sae andecacious against inection with hepatitis E virus inseronegative participants in a phase 2 trial.18

We undertook a randomised, double-blind, placebo-controlled, phase 3 trial to assess the ecacy and saetyo HEV 239 in the general population. The trial includedmen and women rom age 16 to 65 years, with or withoutantibodies against hepatitis E, rom a region where bothgenotypes 1 and 4 cocirculate with the zoonoticgenotype 4 predominating.

Methods

Study design and participantsThis double-blind, randomised, placebo-controlled trialwas done between August, 2007, and June, 2009, inDongtai County, Jiangsu Province, China. On October,2007, ater enrolment in one township (Quindong), andbeore enrolment in ten other townships, the protocol wasmodied so that each o the 10 000 participants in one othe ten townships (Aneng) had serum samples collectedon day 0 and month 7 to assess the level o antibodyprotection through long-term ollow-up. Independentethics committee approval was obtained rom the EthicsCommittee o the Jiangsu Provincial Centre or DiseaseControl and Prevention (JSCDC), and the study was donein accordance with the principles o the Declaration o

Helsinki, the standards o Good Clinical Practice, andChinese regulatory requirements as stipulated by theChinese Food and Drug Administration.

The study was designed by JSCDC and XiamenUniversity. Study sta at JSCDC were responsible or datacollection. A sentinel hepatitis surveillance system wasset up to identiy incident hepatitis cases as they presented.Serial serum samples obtained rom study participantswere independently tested by the Chinese NationalInstitute or the Control o Pharmaceuticals and BiologicalProducts (NICPBP). A contract research organisation(PPD-Excel PharmaStudies, Beijing, China) monitoredand ensured that the trial was done in compliance withthe protocol, evaluated progress, veried that the rights othe participants were protected, and ensured that datawere complete, accurate, and veriable rom source data.An independent data and saety monitoring board(DSMB) was set up to oversee the trial and ensure thesaety o participants and the integrity o the data. TheDSMB reviewed the clinical and laboratory data to conrmthe diagnosis o hepatitis E beore the group assignment(ie, vaccine vs placebo) o trial participants was broken.

Men and women were eligible or enrolment i theywere healthy, aged 1665 years, and understood the studyprocedures (detailed eligibility criteria are described inwebappendix pp 23). Written inormed consent wasobtained rom all participants.

VaccinationThe preparation o HEV 239 vaccine is describedelsewhere.19 The vaccine contains 30 g o the puriedantigen adsorbed to 08 mg aluminium hydroxidesuspended in 05 mL buered saline. A licensedhepatitis B vaccine (Beijing Tiantan Biologic, Beijing,China) containing hepatitis B virus surace antigen in05 mL aluminium hydroxide, was given as placebo.Vaccine doses and placebo doses were repackaged byInnovax under Good Manuacturing Practice conditionsor identical appearance, but labelled with two letterseach according to a random assignment. Three doses ovaccine or placebo were given intramuscularly at 0, 1,and 6 months.

122179 individuals screened

112604 randomly assigned

56302 assigned to vaccine group

7609 did not receive three doses3817 received one dose3792 received two doses

3542 received doses one and two250 received doses one and three

48693 participants were included inprimary efficacy analysis5567 included in immunogenicity subset1316 included in reactogenicity subset

48663 participants were included inprimary efficacy analysis5598 included in immunogenicity subset1329 included in reactogenicity subset

7639 did not receive three doses3874 received one dose3765 received two doses

3504 received doses one and two261 received doses one and three

56302 assigned to placebo group

9575 excluded9263 excluded before vaccination

3652 did not meet inclusion criteria

5611 met exclusion criteria312 excluded before the codes

were broken146 did not meet inclusion criteria

(did not live in the study region)52 did not meet inclusion criteria

(age 65 years)95 received wrong vaccine for

at least one dose19 were not given second dose

at the specified time

Figure 1: Trial prole

The webappendix lists reasons or exclusion (p 30) and or non-completion (p 31).

For the protocol see http://

nidvd.xmu.edu.cn/HEV/

protocol/Protocol_

phase_3_100509.pdf

See Online for webappendix


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Randomisation and masking

Trained local health-care workers enrolled theparticipants, and some o these health-care workersinterviewed participants to assess adverse events andpossible acute hepatitis later in the trial. An independentstatistician prepared a permuted-block 1:1:1:1randomisation list (with 20 codes to a block) using SASsotware. The randomisation list was concealed andtranserred into an immunisation managementcomputer program through which participants werestratied by age and sex, and assigned vaccine codes.The study-group and vaccine code assignments weremasked rom all participants, carers, and investigators(or monitors). The integrity o the masking process wasconrmed by the investigators and DSMB beore the

assignment o study group and vaccine codes was nallyrevealed. Health-care workers rom JSCDC assignedparticipants to the study groups; they did not have anyurther involvement in the trial.

A subset o participants rom one township wasselected or active surveillance o adverse events(reactogenicity subset). Serum samples beoreimmunisation were obtained rom these participants andthose rom another township to establish the baselineconcentration o hepatitis E virus IgG and or assessmento immunogenicity (immunogenicity subset). Fingerprintscanners and digital photographs were used to identiyand track participants throughout immunisation, bloodcollection, and ollow-up.

Hepatitis surveillanceParticipants with suspected hepatitis were identiedthrough an established active hepatitis surveillancesystem comprising 205 sentinels, including162 community clinics, 30 private clinics, 11 centralhospitals located in the townships, and two centralhospitals in the city o Dongtai (webappendix p 32). Acase o hepatitis was dened as a patient presentingwith constitutional symptoms such as atigue, loss oappetite, or both or longer than 3 days with alanineaminotranserase (ALT) exceeding 25-times the upperlimit o normal range. Patients with abnormal

concentrations o ALT were tested at rst presentationby JSCDC or hepatitis A virus IgM, surace antigen ohepatitis B virus, hepatitis B virus core protein IgM,hepatitis C virus immunoglobulin, and hepatitis E virusIgM. Paired serum samples were obtained rom thesepatients at the t ime o presentation and 26 weeks later.Serial samples were sent to the NICPBP to test orhepatitis E virus IgM and IgG, hepatitis E virus RNA,and hepatitis A virus IgM. The DSMB reviewed theclinical and laboratory results and conrmed thediagnoses o hepatitis E beore unblinding. To bedened as an acute hepatitis E patient, a participantneeded to ull three conditions: acute illness lastingor at least 3 days; abnormal serum ALT concentration25-times the upper limit o normal range or greater;

and positive hepatitis E virus IgM and RNA, 4-timesincrease in hepatitis E virus IgG, or both.

Laboratory measurementsThe tests or hepatitis E virus IgM were done by use o twocommercial assays in parallel (Beijing Wantai, Beijing,China; MP Biomedicals, Singapore).11,2025 The assay orhepatitis E virus IgG used antigen more truncated thanthat in the vaccine antigen (Beijing Wantai, China).20,21Hepatitis E virus IgGs were urther quantied andexpressed in WHO units per mL(Wu/mL; webappendix p 2).The lower limit o hepatitis E virus IgG quantication was

0077 Wu/mL.26 For the analysis, the antibody concentrationin samples negative or hepatitis E virus IgG were arbitrarilyset at 00385 Wu/mL. Serum samples o patients withdetectable hepatitis E virus IgM or a two times or greaterrise o hepatitis E virus IgG concentration in paired sampleswere tested or hepatitis E virus RNA.27 Serum sampleswere taken beore the rst vaccine dose and 1 month aterthe third dose rom participants in the immunogenicitysubset to establish concentration o hepatitis E virus IgG.Antibody concentration o 0077 Wu/mL or greater wasdeemed to be a positive nding. Antibody response wasdened as a greater than our-times increase o hepatitis Evirus IgG in an individuals paired sera. All reagents weresupplied by Beijing Wantai Biological Pharmacy Enterprise,Beijing, China.

Vaccine group Placebo group

Randomised participants* 56 302 56 302

Men 24 511 (435%) 24 567 (436%)

Age (years) 4414 (1140) 4413 (1140)

Age group (years)

1620 2520 (4%) 2480 (4%)

2130 4598 (8%) 4653 (8%)

3140 12 684 (23%) 12 688 (23%)

4150 18 292 (32%) 18 310 (33%)

5160 14 644 (26%) 14 657 (26%)

6165 3564 (6%) 3514 (6%)

Per-protocol population (three doses) 48 693 48 663

Male to emale ratio 074 074

Mean age (years) 4472, SD 1109 4468, SD 1110

Immunogenicity subset 5567 5598

Male to emale ratio 064 065

Mean age (years) 4522 (1075) 4525 (1082)

Anti-HEV prevalence 4776% (46444909) 4691% (45604823)

GMC (Wu/mL) 014 (013014) 013 (013014)

Reactogenicity subset 1316 1329

Men 524 (398%) 561 (422%)

Age (years) 4470, SD 1123 4493, SD 1110

Data are number (%), mean (SD), or mean (95% CI). HEV=hepatitis E virus. GMC=geometric mean concentration. *All

randomised participants who received at least one dose o vaccine or placebo. Per-protocol population denotes all

randomised participants who received three doses o vaccine or placebo. Participants in the immunogenicity subset

were rom two townships additionally investigated or antibody response to vaccination. Participants in the

reactogenicity subset were rom one township visited regularly at home by investigators to assess adverse events.

Table 1: Baseline characteristics o participants


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Adverse eventsAter each dose, participants were observed or 30 min orimmediate adverse reactions. Participants in thereactogenicity subset were visited at home by investigatorsat 6 h, 24 h, 48 h, 72 h, 7 days, 14 days, and 28 days atereach dose, and observed or reported adverse eects, iany, were recorded on saety diary cards. Other participants

were asked to report any adverse events to nearby clinics

within 1 month ater each dose. Additionally, investigatorsreviewed all records o admission to hospital and death toidentiy trial participants. Any serious adverse eventswere recorded throughout the study by use o the MedicalDictionary or Regulatory Activities (version 12.0).

Statistical analysisWe estimated that the incidence o hepatitis E or adultsaged 1665 years would be about our cases per10 000 person-years (webappendix p 1). On the assumptiono a vaccine ecacy o 70%, a two-group continuity-corrected test with a one-sided signicance level o005 would have a power o 80% to detect a dierence inincidence with 41 277 participants per group. To

compensate or dropouts, 50 000 participants per groupwere needed.

Prespecied outcome analyses were done in eligibleparticipants who had received at least one dose o eithervaccine, and in those who received all o the three doseso the vaccines. The primary endpoint was prevention ohepatitis E in participants who received three doses ovaccine (ie, the per-protocol population) during the12 months rom the 31st day ater receipt o the thirddose. Vaccine ecacy and 95% CIs were calculated onthe basis o the identied dierence between the vaccinegroup and the placebo group and the accrued person-time. An exact conditional procedure was used to evaluatevaccine ecacy under the assumption that the numberso patients with hepatitis E in the vaccine and placebogroups were independent Poisson random variables.28For robustness, ecacy was also assessed by use o a Coxproportional hazard model, and a log-rank test was usedto compare the cumulative incidence o hepatitis Ebetween the study groups.

Adverse events were summarised or all vaccinationvisits as requencies and percentages according to studygroup. Proportions o events and 95% CIs (unadjustedor multiplicity) were compared between the groups byuse o two-sided Fishers exact test.

Data analysis was done with SAS sotware version 9.1.All reported p values are two-sided with an value

o 005.

Role o the unding sourceThe sponsor o the study had no role in study design,data collection, data analysis, data interpretation, orwriting o the report. The corresponding author had ullaccess to all the data in the study and had nalresponsibility or the decision to submit or publication.

Results122 179 people rom 11 townships attended the enrolmentvisit between August and October, 2007. 112 604participants ullled the eligibility requirements, wererandomly assigned to the study group, and received atleast one dose o vaccine or placebo. 97 356 participants

For more on the Medical

Dictionary for Regulatory

Activities see http://www.

meddramsso.com/

9812 fatigue or loss of appetite 3 days

4931 vaccine group4881 placebo group

Determined by DSMB

23 confirmed hepatitis E1 vaccine group, onset 719 months

22 placebo group (one onset 015months, five onset 156 months,and 16 onset 719 months)

200 not hepatitis E103 vaccine group

97 placebo group

223 ALT 25 ULN104 vaccine group119 placebo group

15 hepatitis E in per-protocol cohort0 vaccine group

15 placebo group

55 had at least one of three acuteHEV infectious markers: HEV-IgM,

rising HEV-IgG, or HEV-RNA28 vaccine group27 placebo group

145 had none of three acuteHEV infectious markers:HEV-IgM, rising HEV-IgG,or HEV-RNA75 vaccine group70 placebo group

46 did not meet with the definitionof hepatitis E25 vaccine group

5 with rising IgG only20 with IgM only

21 placebo group3 with rising IgG only

18 with IgM only

9 met the definition of hepatitis E,

but were excluded from theconfirmed hepatitis E by the DSMBbefore unblinding according to theirclinical and laboratory profiles3 vaccine group

1 in per-protocol group2 received one dose

6 placebo group

3 in per-protocol group1 received two doses

2 received three doses but onsetbefore the third dose

34 non-E viral hepatitis16 hepatitis A

9 vaccine group7 placebo group

16 acute hepatitis B8 vaccine group8 placebo group

2 hepatitis C1 vaccine group1 placebo group

166 without acute viral hepatitismarkers85 vaccine group81 placebo group

Figure 2: Flowchart o surveillance and certication o acute hepatitis E

Sentinel hepatitis surveillance system was set up to monitor study participants or development o acute hepatitis

(webappendix p 32). A case o acute hepatitis was dened as a participant who presented with constitutional

signs, such as atigue, nausea or at least 3 days, and alanine aminotranserase (ALT) exceeding 25-times the

upper limit o normal range (ULN). Clinical and laboratory ndings were assessed by an independent data and

saety monitoring board (DSMB). The DSMB reviewed clinical and laboratory data to conrm the diagnosis o

hepatitis E beore the group assignment o trial participants was broken. HEV=hepatitis E virus.


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received all three doses o vaccine or placebo and wereincluded in the analysis o the primary endpoint(gure 1). Table 1 shows the baseline characteristics ostudy participants.

The DSMB conrmed 23 cases o hepatitis E beoreunblinding (gure 2); details o each case are listed inwebappendix pp 424. Compared with the general studypopulation, patients with hepatitis E were older (mean513 years, SD 82; median 53, range 3663) and morelikely to be men (male-to-emale ratio 23). The meanmaximum serum ALT concentration o patients withhepatitis E was 308-times upper limit o normal range(SD 293; 181, 25969), and the mean duration oillness was 571 days (SD 398; 41, 9175). 15 patientswere admitted to hospital or a mean o 244 days(SD 145; 20, 966). All 23 patients tested positive or

hepatitis E virus IgM, 22 were positive or hepatitis Evirus RNA, and 14 had a 4-times or greater increase inhepatitis E virus IgG. O the 13 patients whose viruseswere isolated or sequencing, 12 had genotype 4 and onehad genotype 1. O the eight patients who received allthree doses and whose viruses underwent sequencing,all had genotype 4.

In the primary analysis population 15 participantsdeveloped hepatitis E during the 12 months rom the 31stday ater receipt o the third dose; all 15 were in theplacebo group (table 2). Vaccine ecacy againsthepatitis E was 1000% (95% CI 7211000), andprotection extended to all participants throughout the12 months. Five participants developed hepatitis E duringthe 14 days ater the second dose and beore the third

dose; all were in the placebo group. Vaccine ecacy atertwo doses was 1000% (911000).

Most randomised participants who received at least onedose o vaccine or placebo were ollowed up or 19 monthsrom the beginning o the study, and a small proportion oparticipants were ollowed up rom month 7 o the study.There were 23 cases o hepatitis E during the ollow-up,one in the vaccine group (the participant received one

Follow-up

(month ostudy)

Vaccine group Placebo group Vaccine ecacy

(95% CI)

p value

Number o

participants/

person-years at risk

Number

o cases

Incidence

(per 10 000

person-years)

Number o

participants/

person-years at risk

Number

o cases

Incidence

(per 10 000

person-years)

Per-protocol

Whole group (three doses) 719 48 693/48 5946 0 00 48 663/48 5551 15 31 1000% (7211000)


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dose o the vaccine) and 22 in the placebo group (table 2).Vaccine ecacy or participants who received at least onedose was 955% (95% CI 663994). There were 17 caseso hepatitis E during the 12 months rom the 31st day aterthe receipt o the nal dose (which could be the rst,second, or third dose), one in the vaccine group, and 16 in

the placebo group. The corresponding vaccine ecacywas 938% (95% CI 598999%).

Figure 3 shows the cumulative incidence o hepatitis Ein participants who were ollowed up or 19 months romthe beginning o the study. The dierence betweenthe vaccine group and the placebo group wassignicant (p


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ticipants in the placebo group showed an antibodyresponse and all the episodes were subclinical inection.

DiscussionIn our trial, ecacy o recombinant hepatitis E vaccineduring the 12 months rom the 31st day ater the receipto the third dose was 1000% (95% CI 7211000), andprotection was noted across all age and sex subgroups.Vaccination was also benecial under less than perectcircumstancesie, when participants did not receive allthree doses. Vaccine ecacy ater two doses was 1000%

(95% CI 911000). Thereore, during a hepatitis Eoutbreak, or or travellers to an endemic area, protectioncan be quickly obtained by two vaccine doses givenwithin 1 month.

Side-eects were ew and mild and no serious adverseevents related to vaccination. HEV 239 is unlikely toinduce rare vaccine-related serious adverse events,because the large number o participants in the studyaords a power o 85% to detect rare serious adverseevents i the rate in the vaccine group is 003% and therate ratio is 50 (webappendix p 29).

The study site is endemic or inection with hepatitis Evirus, with nearly hal the participants tested on day 0being seropositive. The inection rate in the placebogroup was 21% during the period rom 0 months to

7 months. However, most o the inections seemed to besubclinical and incidence o hepatitis E was estimated tobe about our per 10 000 person-years (webappendix p 1).The reason or the low attack rate is unknown. Indeveloped countries where the zoonotic hepatitis Egenotype 3 predominates, emerging data showed amoderate hepatitis E virus seroprevalence but rareautochthonous cases o hepatitis E.3 These ndingssuggest that the low attack rate might be a commoneature o 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, coners protectionagainst both genotypes 1 and 4.19 12 o 13 patients withhepatitis E who were typed by sequencing, had genotype 4,all in the placebo group. Thereore, our study substantiatesthat the vaccine cross protects against genotype 4 inhuman beings, and the cross protection probably extendsto other genotypes as well, given that they belong to thesame serotype as the vaccine strain.

Data suggest that individuals with chronic liver diseaseshould be prioritised or hepatitis E vaccination to preventserious damage rom inection.8,9 However, because weexcluded this group, additional study is needed to assessthe benets o HEV 239. Another limitation was the lack

Number o adverse events (rate, 95% CI) p value*

Vaccine group Placebo group

(Continued rom previous page)

Total vaccinated cohort

Number o participants who received more than one dose 56 302 56 302

Unsolicited events within 30 days ater each dose

All 6771 (120%, 1176123) 6724 (119%, 11681221) 0666

Grade 3 839 (15%, 139159) 792 (14%, 131151) 0241

Serious adverse events within 30 days ater each dose

All 248 (04%, 039050) 245 (04%, 038049) 0892

Admission to hospital 238 (04%, 037048) 233 (04%, 036047) 0817

Disability 0 (00%, 000001) 0 (00%, 000001)

Death 10 (00%, 001003) 12 (00%, 001004) 0670

Serious adverse events during period rom month 2 to month 6 and

rom month 7 to month 19

All 1423 (25%, 240266) 1430 (25%, 241267) 0894

Admission to hospital 1328 (24%, 223249) 1336 (24%, 225250) 0875

Disability 0 (00%, 000001) 0 (00%, 000001)

Death 95 (02%, 014021) 94 (02%, 013020) 0942

Grade 3 pain, headache, and atigue were dened as prevention o normal activities; grade 3 swelling was dened as a diameter o more than 30 mm; grade 3 itch was

dened as body itch; and grade 3 ever was dened as temperature greater than 390C. Symptoms with requency more than 1% in any group are listed. The webappendix

details all serious adverse events ( pp 2528). *p values are two-sided and were calculated by Fishers exact test. Unsolicited adverse events included any adverse events that

happened rom day 4 to day 30 ater each dose and any adverse events within 3 days ater each dose but had not been listed in the diary card or registering solicited adverse

events. Most oten unsolicited adverse events in the study included upper respiratory tract inection, headache, ever, and gastritis. The data and saety monitoring board

did not deem any o the serious adverse events to be related to vaccination. 22 participants died within 30 days ater each vaccination. O the ten participants in the vaccine

group that died, eight died as the result o an accident, one died o a cerebral haemorrhage, and one died o liver cancer ater 10 years with chronic hepatitis B.

O 12 participants in the placebo group that died, six died as the result o an accident, three died o myocardial inarction, two died o cerebral haemorrhage, and one died o

stomach cancer.

Table 3: Saety outcomes


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o a hepatitis E case in the vaccine group, meaning that

the protective antibody concentration could not beassessed. Further analysis o our serology data mightprovide important inormation on the vaccines ecacyagainst subclinical inection. Both our study and theprevious phase 2 study o the vaccine produced in insectcells showed substantial short-term protection; however,the duration o this protection needs urther assessment.

In our trial, we ound the vaccine well tolerated andecacious or a general adult population. Further studiesare needed to assess the saety and to support the benetso the vaccine or pregnant women and or peopleyounger than 15 years or older than 65 years.

Contributors

All authors contributed towards acquisition o data or statistical analyses,

or interpretation o data, writing and revising the report, and nalapproval. F-CZ and JZ contributed equally to this work.

Hecolin study group

Field management and data collection F-C Zhu, X-F Zhang, Z-Z Wang,H Wang, C-L Yang, H-M Jiang, J-P Cai, Y-J Wang, X Ai, Y-M Hu, Q Tang,L Li, H-X Pan, W-Z Zhou, F-Y Meng, W-M Dai, Y Wu, Y-J Zhang, X Huo,J-L Hu, Q Liang, S-X Xiu, J Xu, R-J Jiang, Y-Z Chen, H-Q Zhang,H-M Gao, Y-S Chen, Y-P Yuan, L Chen, Y-G Zhou, Y Jing (JiangsuProvincial Centre or Disease Control and Prevention, Nanjing, China).Laboratory contribution C Zhou, X Yao (National Institute or the Controlo Pharmaceuticals and Biological Products, Beijing, China). Statisticalanalysis Y-H Wang, X-Y Kong, P-C Hu, Y-J Yu (PPD-Excel, Beijing,China); P Liu, J-X Li (Southeast University, Nanjing, China). Medicalwriting (protocol and article) J Zhang, S-J Huang, M-H Ng, JW-K Shih,Y-M Li, Y Xiang, Q Yan, T Wu, J-J Di, J Miao, N-S Xia (Xiamen University,Xiamen, China); F-C Zhu, X-F Zhang (Jiangsu Provincial Centre orDisease Control and Prevention, Nanjing, China). Data and safetymonitoring committee F Chen (Nanjing Medical University, Nanjing,China), F-B Tao (Anhui Medical University, Heei, China), L-D Diao(Consultant board o vaccination or Ministry o Health, China), D-Y Tian(Tongji Hospital, Huazhong University o Science and Technology,Wuhan, China), J-J Jiang (The First Aliated Hospital o Fujian MedicalUniversity, Fujian, China).

Conficts o interest

Y-LX and Y-ML are employees o the Xiamen Innovax. The other authorsdeclare that they have no conficts o interest.

Acknowledgments

We thank the volunteers or their participation in this clinical study andRobert H Purcell o the National Institute o Allergy and InectiousDiseases, National Institutes o Health (Bethesda, MD, USA) or hisvaluable suggestions and input. This trial was unded by multiplegrants rom the Chinese Government: Chinese National High-techR&D Programme (863 programme; 2006AA02A209 and

2005DFA30820); Chinese National Key Technologies R&D Programme(2009ZX10004-704); Chinese National Science Fund or DistinguishedYoung Scholars (30925030); Fujian Provincial Department o Sciencesand Technology (2004YZ01); Xiamen Science and Technology Bureau(3502Z20041008); and Fujian Provincial Science Fund orDistinguished Young Scholars (2009J06020).

Reerences1 Labrique AB, Thomas DL, Stoszek SK, Nelson KE. Hepatitis E:

an emerging inectious disease. Epidemiol Rev1999; 21: 16279.

2 Purcell RH, Emerson SU. Prevention. In: Thomas HC, Lemon S,Zuckerman AJ, eds. Viral hepatitis, 3rd edn. Malden, MA:Blackwell Publishing, 2005: 63545.

3 Dalton HR, Bendall R, Ijaz S, Banks M. Hepatitis E: an emerginginection in developed countries. Lancet Infect Dis 2008; 8: 698709.

4 Krawczynski K, Aggarwal R, Kamili S. Epidemiology, clinical andpathologic eatures, diagnosis, and experimental models. In:Thomas HC, Lemon S, Zuckerman AJ, eds. Viral hepatitis, 3rd edn.Malden, MA: Blackwell Publishing, 2005: 62434.

5 Emerson SU, Purcell RH. Hepatitis E virus. Rev Med Virol2003;13: 14554.

6 Khuroo MS, Teli MR, Skidmore S, So MA, Khuroo MI. Incidenceand severity o viral hepatitis in pregnancy. Am J Med1981;70: 25255.

7 Khuroo MS, Kamili S. Aetiology, clinical course and outcome osporadic acute viral hepatitis in pregnancy.J Viral Hepat2003;10: 6169.

8 Kumar Acharya S, Kumar Sharma P, Singh R, et al. Hepatitis Evirus (HEV) inection in patients with cirrhosis is associated withrapid decompensation and death.J Hepatol2007; 46: 38794.

9 Hamid SS, Atiq M, Shehzad F, et al. Hepatitis E virussuperinection in patients with chronic liver disease. Hepatology2002; 36: 47478.

10 FitzSimons D, Hendrickx G, Vorsters A, Van Damme P. Hepatitis Aand E: update on prevention and epidemiology. Vaccine 2010;28: 58388.

11 Teshale EH, Howard CM, Grytdal SP, et al. Hepatitis E epidemic,Uganda. Emerg Infect Dis 2010; 16: 12629.

12 Emerson S, Anderson D, Arankalle A, et al. Hepevirus. In:Fauquet CM, Mayo MA, Manilo J, Desselberger U, Ball LA, eds.Virus taxonomy: eighth report o the international committee ontaxonomy o viruses. London: Elsevier Academic Press;2004: 85357.

13 Purcell RH, Emerson SU. Hepatitis E: an emerging awarenesso an old disease.J Hepatol2008; 48: 494503.

14 Lu L, Li C, Hagedorn CH. Phylogenetic analysis o globalhepatitis E virus sequences: genetic diversity, subtypes andzoonosis. Rev Med Virol2006; 16: 536.

15 Pavio N, Renou C, Di Liberto G, Boutrouille A, Eloit M. Hepatitis E:a curious zoonosis. Front Biosci 2008; 13: 717283.

16 Worm HC, Wirnsberger G. Hepatitis E vaccines: progressand prospects. Drugs 2004; 64: 151731.

17 Shrestha MP, Scott RM, Joshi DM, et al. Saety and ecacy o arecombinant hepatitis E vaccine. N Engl J Med2007; 356: 895903.

18 Zhang J, Liu CB, Li RC, et al. Randomized-controlled phase IIclinical trial o a bacterially expressed recombinant hepatitis E

vaccine. Vaccine 2009; 27: 186974.19 Li SW, Zhang J, Li YM, et al. A bacterially expressed particulate

hepatitis E vaccine: antigenicity, immunogenicity and protectivityon primates. Vaccine 2005; 23: 2893901.

20 Zhang J, Ge SX, Huang GY, et al. Evaluation o antibody-based andnucleic acid-based assays or diagnosis o hepatitis E virus inectionin a rhesus monkey model.J Med Virol2003; 71: 51826.

21 Bendall R, Ellis V, Ijaz S, Thurairajah P, Dalton HR. Serologicalresponse to hepatitis E virus genotype 3 inection: IgG quantitation,avidity, and IgM response.J Med Virol2008; 80: 95101.

22 Dalton HR, Hazeldine S, Banks M, et al. Locally acquiredhepatitis E in chronic liver disease. Lancet2007; 369: 1260.

23 Dalton HR, Bendall RP, Keane FE, et al. Persistent carriage ohepatitis E virus in patients with HIV inection. N Engl J Med2009;361: 102527.

24 Said B, Ijaz S, Kaatos G, et al. Hepatitis E outbreak on cruise ship.Emerg Infect Dis 2009; 15: 173844.

25 Chen HY, Lu Y, Howard T, et al. Comparison o a newimmunochromatographic test to enzyme-linked immunosorbentassay or rapid detection o immunoglobulin M antibodies tohepatitis E virus in human sera. Clin Diagn Lab Immunol2005;12: 59398.

26 Zhou C, Huang WJ, Yao X, et al. Evaluation o the diagnostic kitsor hepatitis E and establishment o a quantication method ordetecting anti-HEV IgG. Chin J Microbiol Immunol2009; 29: 85457.

27 Li RC, Ge SX, Li YP, et al. Seroprevalence o hepatitis E virusinection, rural southern Peoples Republic o China.Emerg Infect Dis 2006; 12: 168288.

28 Chan I, Bohidar N. Exact power and sample size or vaccine ecacystudies. Commun Stat Theory Methods 1998; 27: 130522.


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Comment


Hepatitis E vaccine: not a moment too soon

Hepatitis E virus (HEV) remains one o the least

understood and perplexing viruses pathogenic to

human beings. From 5% to 20% o people in developed

countries show a steady increase in the titre o anti-HEV

IgG with increasing age,1 but inection with the prevalent

genotype in Europe and the USA, genotype 3, rarely

results in symptoms. Although this genotype has been

recovered rom eral and domestic pigsand sometimes

rom people who have eaten raw pork or oal

convincing epidemiological evidence that this zoonotic

reservoir is the source o most human exposures orinections remains elusive.2

Unlike the situation in developed countries, HEV

inection with genotypes 1, 2, and 4, which predominate

in developing countries, is not merely an academic

quandary but a major cause o disease and death. Some

areas o east and south Asia are highly endemic or the

virus. Large outbreaks (tens o thousands o cases) have

occurred in India3,4 and China5,6 since 1955; these were

deemed to have been waterborne. More recently there

have been very large outbreaks in southern Sudan7 and

nearby northern Uganda,8

in what seem to be susceptibleArican populations in which HEV outbreaks had not

previously been recorded. In these outbreaks, the testing

o drinking water rom wells did not reveal the virus or

coliorms, and continued provision o clean water did

not prevent additional inections. Several other lines

o evidence suggest that some o these outbreaks are

attributable to person-to-person transmission.9

Whatever the source, these outbreaks have typically

extended over many months with especially high

mortality in pregnant women and inants younger than

2 years, oten with case-atality rates o 1025%. In

view o the protracted nature o the epidemics and the

associated substantial morbidity and mortality, the need

or public health interventions to interrupt transmission

has been urgent. Unortunately, interventions ocused

on basic sanitationeg, latrine-digging, education on

hand-washing and provision o soap, and guarding

unprotected surace water rom usehave not

noticeably reduced these outbreaks. Thus it is natural to

wonder whether vaccination would be eective in these

epidemic or highly endemic situations.

The approach to vaccine-antigen production has been

to ocus on the ORF 2 capsid protein-producing section

o the HEV genome, the same capsid antigen as used

or enzyme immunoassays or detection o the virus.

A recombinant vaccine produced in insect cells by the

US Army with GlaxoSmithKline Biologicals (Rixensart,

Belgium) was sae and eective when given to almost

900 young Nepalese Army recruits,10 but there are neither

plans or urther studies nor, apparently, or eventual

commercial production o this vaccine. An earlier phase 2

trial11 o the bacterial recombinant vaccine described by

Zhu and colleagues12 in the The Lancet today was used in

457 healthy Chinese adults and 155 high-school studentsand seemed to coner protection, although inection was

deduced rom asymptomatic seroconversion or rise in

antibody titres and not by virological testing.

Thus the report by Zhu and colleagues12 o a successul

phase 3 study o this vaccine is an important event in the

prevention and control o hepatitis E. The numbers o

recipients o the vaccine (48 693) and placebo (hepatitis B

vaccine, 48 663) in the primary analysis o this study were

suciently large, and the number o people (15) inected

with HEV in the placebo group, conrmed by testing

or HEV-RNA, is convincing and credible about thevaccines ecacy (100%, 95% CI 7211000) and saety.

To assess vaccine saety and ecacy in populations most

at risk o serious HEV-associated disease and death,

uture researchers will need to include pregnant women

and young inants. Also, the duration o protection

aorded by this vaccine remains unknown. Still, the

Published Online

August 23, 2010

DOI:10.1016/S0140-

6736(10)61260-3

See Online/Articles

DOI:10.1016/S0140-

6736(10)61030-6

Coloured transmission electron micrograph of hepatitis E virus particles (purple)

Science

PhotoL

ibrary


10/10

Comment

2 www thelancet com Published online August 23 2010 DOI:10 1016/S0140-6736(10)61260-3

recorded 100% vaccine ecacy in recipients o two

vaccinations a month apart suggests that HEV vaccinecan be an important component in outbreak control.

In highly endemic regions, a sae and eective vaccine

(i aordable) raises the prospect o routine HEV

vaccination to reduce both sporadic and epidemic HEV.

Because these considerations are crucial to decisions

on vaccine production, nancing, and immunisation

policies, public health and industry leaders should

immediately begin work to dene the public health roles

or an HEV vaccine.

Vaccines should never be a substitute or, or reason

to delay, basic improvements in overall sanitation.However, in view o the slow rate o improvement o

sanitary conditions in many areas o Asia and Arica, this

vaccine might be our best new stopgap in the eort to

control the scourge o HEV in many parts o the world.

Scott D HolmbergDivision o Viral Hepatitis, National Center or HIV, Hepatitis,

TB and STD Prevention, Centers or Disease Control and

Prevention, Atlanta, GA 30333, USA

[email protected]

I declare that I have no conficts o interest.

1 Kuniholm MH, Purcell RH, McQuillan GM, Engle RE, Wasley A, Nelson KE.Epidemiology o hepatitis E in the United States: results rom the ThirdNational Health and Nutrition Examination Survey, 19881994.J Infect Dis2009; 200: 4856.

2 Teshale EH, Hu DJ, Holmberg SD. The two aces o hepatitis E virus.Clin Infect Dis 2010; 51: 32834.

3 Viswanathan R. Inectious hepatitis in Delhi (195556): a critical study;epidemiology. Indian J Med Res 1957; 45: 4958.

4 Naik SR, Aggarwal R, Salunke PN, Mehrotra NN. A large waterborne viralhepatitis E epidemic in Kanpur, India. Bull World Health Organ 1992;70: 597604.

5 Zhang H, Cao XY, Liu CB, et al. Epidemiology o hepatitis E in China.Gastroenterol Jpn 1991; 26: 13538.

6 Bi SL, Purdy MA, McCaustland KA, Margolis HS, Bradley DW. The sequenceo hepatitis E virus isolated directly rom a single source during an outbreakin China. Virus Res 1993; 28: 23347.

7 Guthmann JP, Klovstad H, Boccia D, et al. A large outbreak o hepatitis E

among a displaced population in Darur, Sudan, 2004: the role o watertreatment methods. Clin Infect Dis 2006; 42: 168591.

8 Teshale EH, Howard CM, Grytdal S, et al. Hepatitis E, Uganda.Emerg Infect Dis 2010; 16: 12629.

9 Teshale EH, Grytdal SP, Howard C, et al. Evidence o person-to-persontransmission o hepatitis E virus (HEV) during a large outbreak in northernUganda. Clin Infect Dis 2010; 50: 100610.

10 Shresta MP, Scott RM, Joshi DM, et al. Saety and ecacy o a recombinanthepatitis E vaccine. N Engl J Med 2007; 356: 895903.

11 Zhang J, Liu CB, Li RC, et al. Randomized-controlled phase II clinical trial o abacterially expressed recombinant hepatitis E vaccine. Vaccine 2009;27: 186974.

12 Zhu F-C, Zhang J, Zhang X-F, et al. Ecacy and saety o a recombinanthepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet 2010; published onlineAug 23. DOI:10.1016/S0140-6736(10)61030-6.

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