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V.Thibault_janv.-14 1
Virus de l'hépatite A et E
Virus et marqueurs diagnostiques
Vincent THIBAULT
Laboratoire de Virologie
Hôpitaux Universitaires
Pitié-Salpêtrière – Charles Foix
Paris - France
V.Thibault_janv.-14 2
Hépatites virales
parentéral
non A, non BB
1965 D
1977
A
1972
féco-oral
mode de transmission préférentiel
F, G, TTV, autres…
C
1990
E
1991
Vaccin
Vaccin
(Vaccin)
V.Thibault_janv.-14 3
150
150
Historique VHA
 Avant J.C.: “La Jaunisse” (Ikterus / kirrhos)
 1745 : Cockayne, hépatites épidémiques
 1908 : McDonald, "notion de virus…"
 Reproduction de la maladie 1942 :
 Volontaires (Voegt, Havens), Paul 1943 ingestion feces/serum
 Entité clinique :
 17-18ème siècle - 1923 Blumer - 1947 McCallum (VHA "infectious"-VHB "serum")
Transmission nosocomiale (préparation vaccinale : variole, fièvre jaune…)
 Visualisation : 1973 (Feinstone)
 Développement de la sérologie : épidémiologie
 1979 : culture (Provost et Hilleman)
 1981... : Clonage, Séquences nucléotidiques
 1991… : Vaccination
 2006 : Déclaration obligatoire
V.Thibault_janv.-14 4
1995 : Vaccin
1996 : recommandations
1999 : recommandations
Virus de l'hépatite A
V.Thibault_janv.-14 5
V.Thibault_janv.-14 6
Virus de l’Hépatite A
ARN (+)
Vpg
Capside
27-32nm
• Famille : Picornaviridae
(entérovirus type 72)
• Genre : hépatovirus
• Taille 27-32 nm
• Non enveloppé
• Structure icosaèdrique
• ARN simple brin,
• polarité positive
• lié de façon covalente à
une protéine Vpg
V.Thibault_janv.-14 7








VP1VP3VP2
VP4 2AProtéines de surface
immunogénicité
3D (POL)3C (PRO)2C2B1D1C1B 3
A-B
2A
P1 prot. Capside
Vpg
2.5kDa
P2 P3
0 7478
1A
AAA
Structurales Non structurales
IRES
Traduction
(eIF-4G)
3D (POL)3C (PRO)2C2BVP1VP3VP2
3
A-B
VP4
2A
poly-
protéine
2 227 AA
?
Liaison NTP
Hélicase
Vpg
Protéase
ARN
Polymérase
RéplicationVP1VP3VP2
VP4 2A
VP0
Maturation finale
X5 – X12
V.Thibault_janv.-14 8
Cycle de multiplication du VHA en culture de cellules
P3
P2
P1
Traduction
Synthèse
de la polyprotéine
+
-
-
+
Réplication
Maturation
Libération
du génome
Attachement
Relargage
Réticulum
endoplasmique
Espace
de Disse
Canalicule
biliaire
Empaquetage
VHA : physiopathologie
V.Thibault_janv.-14 9
Absence d'effet cytopathique direct :
cytolyse résultant du processus immun
de défense de l'hôte,
médiation cellulaire
médiation humorale
Membrane hijacking by HAV blurs the
classic distinction between ‘enveloped’ and
‘non-enveloped’ viruses and has broad
implications for mechanisms of viral egress
from infected cells as well as host immune
responses.
Feng et al. 2013 Nature 496, 367
V.Thibault_janv.-14 10
Agents Stabilité
Chaleur
Autoclavage (121°C, 20')
100°C
60°C
température ambiante
4°C
Congelé
Inactivation
Inactivation
Stable 1 heure
Stable 1 mois (selles, eaux, sols)
Plusieurs jours sur surface sèche
4 h. Sur les mains
Stable plusieurs mois
Stable des mois ou années
Acide-base pH 1 : stable 5 h.
PH 3-11 : stable au moins 30'
U.V. Inactivation
Chimiques
Chlore, ozone,
glutaraldéhyde, iode
Inactivation
Alcool 70° 3' : inactivation partielle
Propriétés Physiques du VHA
VHA et agents physiques ou chimiques
V.Thibault_janv.-14 11
http://www.invs.sante.fr/publications/2009/guide_hepatite_a
Variabilité génétique
 Comparaison nucléotidique
 6 Génotypes : IA,B ; II; IIIA,B ; IV-VI
Homme : génotype I (90%), (III, II)
Singes : IV, V, VI
 Sérotype unique
Nombre limité d'épitopes antigéniques VP1, VP3
Tests immunologiques
Vaccination (HM175, CR326)
 virus inactivé cultivé sur MRC-5
V.Thibault_janv.-14 12
3D (POL)3C (PRO)2C2B1D1C1B 3
A-B
2A
P1 prot. Capside
Vpg
2.5kDa
P2 P3
0 7478
1A
AAA
Structurales Non structurales
Répartition mondiale des génotypes
V.Thibault_janv.-14 13
Génotypes infectant l'homme en noir , les singes en rouge.
Souche PA21 (génotype IIIA), isolée d'un singe Panamanian Owl en vert.
Cristina J, Costa-Mattioli M. Virus Res. 2007 Aug;127(2):151-7.
Genetic Characterization of
Hepatitis A genotypes
V.Thibault_janv.-14 14
G. Vaughan et al. Infection, Genetics and
Evolution 21 (2014) 227–243
V.Thibault_janv.-14 15
Desbois et al. J CLIN MICROBIOLOGY,
2010, 48, 9:3306–3315
IA
IB
IIB
IIA
IIIB
IIIA
VP1 sequences (900 nt.)
West Africa
Autochtones
Diffusion du génotype IIA en
France à partir d'une origine
Africaine
Epidemiology and Genetic
Characterization of Hepatitis
A Virus Genotype IIA
Génotypes et sévérité de l'hépatite
V.Thibault_janv.-14 16
Hepatitis A Virus Genotype and Its Correlation With the Clinical
Outcome of Acute Hepatitis A in Korea: 2006–2008
Yun et al. J. Med. Virol. 83:2073–2081 (2011)
•n=556 (497 ARN positifs) Sept. 2006 à Août 2008
•Génotype IIIA induit des symptômes plus sévères
Comparative Analysis of Disease Severity Between Genotypes IA
and IIIA of Hepatitis A Virus
Yoon et al. J. Med. Virol. 83:1308–1314 (2011)
•n=111, comparaison de deux périodes 1998 et 1999 (IA) (n = 45) et 2009
(IIIA) (n = 66)
•IIIA plus sévère (ALAT et durée hospitalisation)
Globalement, pas de consensus pour un lien direct entre le
génotype et la sévérité de l'atteinte hépatique –
Données en faveur de facteurs liés à l'hôte (TIM-HAVCR).
V.Thibault_janv.-14 17
Symptomes
Ictère
VHA : Paramètres Biologiques
Semaines
Ag foie
VHA Sang
VHA Selles
0 1 2 3 4 5 6 7 8 9 10 24
IgM
IgG
protection contre réinfection
Ac anti-VHA = hépatite A ancienne ou vaccination
IgM anti-VHA = hépatite aiguë A (clinique)
IgM HAV uniquement à bon escient !
 Vaccination : 8 à 20 % d'IgM VHA + dans les 2 à 3 semaines suivant l'injection…
V.Thibault_janv.-14 18
Roque Afonso et al. CID 2006:42 -887
82 %
11 %
1 %
Faux positifs
 Alaska : test "réflexe" si Ig-VHA totales +  Ig M HAV
32 % de faux + (Castrodale CID 2005:41;e86)
 NE RECHERCHER L'IgM anti-VHA QU'EN CAS D'HEPATITE AIGUË
IgM HAV :
A répéter, parfois…
V.Thibault_janv.-14 19
Lee HK et al. Eur J Gastroenterol
Hepatol. 2013 ;25(6):665-8
Diagnostic
 Sérologie +++
 IgM anti VHA : infection récente
 IgG anti VHA : infection passée ou vaccination
 IgM et IgG anti VHA
 Diagnostic direct (-) [uniquement dans le cadre d'études]
 Virémie : techniques sensibles (105 v./mL)
 Recherche de virus dans les selles, prolongée, importante
(109v./mL), épidémiologie
V.Thibault_janv.-14 20
 Marqueurs biochimiques
 Transaminases (ALAT, ASAT)
 Bilirubine
 Phosphatase alcaline
 Facteurs de coagulation
Salive :
IgG (ELISA)
Génome viral (RT-PCR)
V.Thibault_janv.-14 21
Durée de la virémie: conséquences cliniques et biologiques
Duration of viremia in hepatitis A virus
infection
Bower et al. Journal of Infectious Diseases
2000;182:12–7
6-7 5-6 2-5 Log particules/mL
Suivi de 13 patients : durée moyenne 95 jours
dont 2 avec rechute (1-2 mois)
Suivi de 27 patients
High and Persistent Excretion of Hepatitis A
Virus in Immunocompetent Patients
Tjon et al.
Journal of Medical Virology 78:1398–1405 (2006)
V.Thibault_janv.-14 22
Rezende et al., Hepatology 38:613-618 (2003)
Hépatite fulminante Evolution bénigne
Limite de
quantification
50 Hépatites A dont 19 fulminantes (10 OLT)
Hépatite fulminante :
-virémie (p=0.03) *
-bilirubine -(p=0.04) *
-age (p=0.09)
-génotype non IA (p=0.09)
Fujiwara K et al.
J. Med Virol. 2011 Feb;83(2):201-7.
Hepatitis A viral load in relation to
severity of the infection.
11 patients with fulminant hepatitis
10 with severe acute hepatitis
70 with self-limited acute hepatitis
Quantification de la virémie ?
Hépatite A : le vaccin
virus inactivé
 AVAXIM 160U suspension injectable seringue préremplie
 Virus de l'hépatite A souche GBM cultivée sur cellules diploïdes humaines MRC-5 ,
inactivé
 HAVRIX 1 440 U Elisa/ml susp inj IM Ad en seringue
 HAVRIX 720 U Elisa/0,5 ml susp inj IM Enf/Nour en seringue
 Souche HM 175 du virus de l'hépatite A cultivée sur cellules humaines diploïdes
MRC5
V.Thibault_janv.-14 23
 Le schéma vaccinal habituel comprend 1 dose suivie d'un rappel (1 dose) 6 à
12 mois plus tard.
 La persistance des anticorps anti-VHA après vaccination n'est
actuellement pas connue . Les données disponibles suggèrent la persistance
des anticorps anti-VHA à un niveau protecteur au moins jusqu'à 20 ans
après primo-immunisation.
Hepatitis A Vaccine versus Immune Globulin for Post-exposure Prophylaxis
Victor et al. 2007 N Engl J Med 357;17
V.Thibault_janv.-14 24
Grippe
SRAS ?
Hépatite E ?Hépatite E ? GrippeHépatite E
Historique VHE
 Découverte dépendante de la connaissance des virus des hépatites
1955 : Inde, hépatite chez des personnes immunisées contre le
VHA, épidémie particulière. "NANBH"
 Entité clinique 1980 - similitude avec l’hépatite A :
 Inde : prévalence de l’hépatite A importante
 Epidémie : autre virus des hépatites, contamination par l’eau
 1983 : reproduction de l’hépatite non A-non B chez un volontaire
immunisé contre VHA (Balayan)
 Hépatite à J36
 J28-45, visualisation de particules virales > VHA (27-30nm)
 Reproduction de l’infection chez le singe (cynomolgus)
 Hépatite "non A - non B" à transmission entérique (ENANB)
 1990 : Reyes et al. clonage et séquençage  "VHE"
 1991 : Tam et al. VHE
 2000 : Panda et al. cDNA infectieux
V.Thibault_janv.-14 25
Hepatitis E Virus in Pork Liver Sausage, France
V.Thibault_janv.-14 26
Hepatitis E virus (HEV) particles in the cell culture supernatant of pork liver sausage sample
Berto et al. Emerg Infect Dis 2013 Feb . http://dx.doi.org/10.3201/eid1902.121255
VHE
V.Thibault_janv.-14 27
Virus non enveloppé
Sphérique (SRV)
Surface irrégulière
Capside 27-34 nm
Symétrie icosaédrique
ARN simple brin
hélice droite
polarité +
7,5kb
poly-A extrémité 3’
Stabilité
Au laboratoire : instable(-70 à +8°C)
Décongélation/congélation
Tractus GI : stable (pH)
Famille : Hepeviridae
Genre : Hepevirus
Organisation génomique
Hétérogénéité génétique
 Au moins 4 groupes majeurs (<20% hétérogénéité ORF2) subdivisés
en 24 sous groupes dont homologues animaux
 Epitopes majeurs : parties C-ter de l’ORF3 et ORF2 (aa 452-617)
 Protection croisée entre différentes souches : un seul sérotype
 Développement de tests sérologiques (performances équivalentes entre
les différents types ?)
 Vaccin : ORF 2 recombinante
V.Thibault_janv.-14 28
Non structurales Structurales
28 5109 71245’ NC
3’NC
Poly-A
ARN polarité +7 200 nt
Protéines
immunogènes
DIAGNOSTIC
Vaccin
MeT Y Pro P X Hel RdRp
ORF3
ORF2 (core-CRE)
Génotypes 1-4
5109
5123
114 AA
660 AA
V.Thibault_janv.-14 29
Phylogenetic tree based on full-length sequences of HEV strains.
Kamar et al. Clinical Microbiology
Reviews 2014 p. 116–138
Transmission inter-espèces
V.Thibault_janv.-14 30
R. Johne et al. / Infection, Genetics and Evolution 27 (2014) 212–229
Ne mangez
pas de
gerbilles !
Etudes des souches de l'homme et du porc en France
V.Thibault_janv.-14 31
Bouquet et al. Emerging Infectious Diseases Vol. 17, No. 11, November 2011
Homologie des souches de
l'homme et du porc
V.Thibault_janv.-14 32
Bouquet et al. Emerging Infectious Diseases Vol. 17, No. 11, November 2011
Evolution VHE
V.Thibault_janv.-14 33
Purdy MA, Khudyakov YE. Evolutionary history and population
dynamics of hepatitis e virus. PLoS One. 2010 Dec 17;5(12):e14376.
Anthropotropic
enzootic
536 to 1344 years ago
Evolution VHE
V.Thibault_janv.-14 34
Purdy MA, Khudyakov YE. Evolutionary history and population
dynamics of hepatitis e virus. PLoS One. 2010 Dec 17;5(12):e14376.
Anthroponose
Zoonose
536 à 1344 ans
Grandes épidémies + cas sporadiques
Pays en voie de développement
Eau de boisson (moussons)
Rares en France
Symptomatiques
Mortalité chez la femme enceinte
 Pays industrialisés
 Cas autochtones
 Nourriture (eau ?)
 Asymptomatique++
 Séroprévalence croissante
avec âge
 Graves sur hépatopathie
 Pas de cas sévère chez femme
enceinte
 Formes persistantes chez
l'immunodéprimé
 Atteintes neurologiques (5.5%)
Répartition des différents génotypes
V.Thibault_janv.-14 35
Aggarwal Hepatology 2011
V.Thibault_janv.-14 36
Smith & Simmonds, Liver International 2014
DOI:10.1111/liv.12629
Distribution aléatoire des souches FH (noir)
et des souches non FH
(A) Génotype 1
(B) Génotype 4
Variants viraux et sévérité de l'hépatite
Un génotype plus sévère ?
Jeblaoui et al. Clinical Infectious Diseases 2013;57(4):e122–6
V.Thibault_janv.-14 37
I. Ahmad et al. / Virus Research 161 (2011) 47– 58
Culture et Modèles animaux
V.Thibault_janv.-14 38
• Culture
 Difficile
 Culture primaire d’hépatocytes de macaques (cynomolgus)
 Cellules PLC/PRF/5 hépatocarcinome et "A549" cellules cancer
poumon (Tanaka et al. J. Gen Virol. 2007; Takahashi et al. Arch. Virol. 2012)
 Cellule embryonnaire
• Modèles animaux
 Primates : reproduction de la pathologie humaine
 Volontaires...
 VHE du porc, du poulet
 Présence d’Ac chez poulet, porc, rat, souris, mouton...
Lapin… Ma H et al. Experimental infection of rabbits with rabbit and genotypes 1
and 4 hepatitis E viruses. PLoS One. 2010 Feb 11;5(2):e9160
Résistance thermique du VHE…
V.Thibault_janv.-14 39
Colson et al. JID 2010:202
VHE dans des suspensions fécales :
Inactivation : 70°C 10' ou 95°C 1 min;
56 °C 30 min maintien de l'infectiosité
Tanaka et al. J. Gen Virol. 2007
Barnaud et al. August 2012 Volume 78 Number 15 Applied and Environmental Microbiology p. 5153–5159
V.Thibault_janv.-14 40
Symptomes
Ictère
VHE : Paramètres Biologiques
Jours
VHE Sang
VHE Selles
0 10 20 30 40 50 60 70 80 90 100 200
IgM
IgG
Titre peu élevé
protection contre réinfection ?
Khuroo MS, Khuroo MS.
Seroepidemiology of a second epidemic of hepatitis
E in a population that had recorded first epidemic
30 years before and has been under surveillance
since then.
Hepatol Int. 2010 Feb 3;4(2):494-9
Virémie et excrétion fécale
V.Thibault_janv.-14 41
Aggarwal et al. THE LANCET • Vol 356 • September 23, 2000, p1081-1082
Détection du RNA-VHE chez 20 patients ayant une hépatite E aiguë
Virémie Selles
Chandra NS et al. Dynamics of HEV viremia, fecal shedding
and its relationship with transaminases and antibody
response in patients with sporadic acute hepatitis E.
Virol J. 2010 Sep 6;7:213
HEV – virémie-
transmission
V.Thibault_janv.-14 42
Matsubayashi K, et al. Transfusion.
2008 Jul;48(7):1368-75.
serum
salive
selle
IgG
IgM
Concentré de plaquettes à J0
Transfusé à un homme de 64
ans traité pour Lymphome
non-Hodgkinien par GM
autologue
Immunodépression, hépatite chronique et
stratégie diagnostique
V.Thibault_janv.-14 43
Kamar et al. American Journal of Transplantation 2008; 8: 1744–1748
Dans le cadre d'une investigation chez un patient immuno déprimé,
La détection du génome viral (RT-PCR) sera privilégiée !
(ceci s'applique pour de nombreux diagnostics viraux - PCR)
Suivi du traitement
V.Thibault_janv.-14 44
Abravanel et al. CID 2015:60 (1 January)
0
1
2
3
4
5
6
7
8
CVVHElogCopies/mL
Dates
Suivi charges virales plasmatiques VHE
seuil de quantification
Détectable Détectable
RIBAVIRINE
Valeur prédictive de la détection d'ARN dans les selles 3 mois après le début de
la ribavirine : rechute ?
Stratégie Diagnostique Pratique
 Hépatite aigue sans immunosuppression
1. IgM anti-VHE
 Délai d'obtention du résultat rapide
2. Recherche du génome du VHE (Sang et Selles)
 Fiabilité des tests ?
 Hépatite dans un contexte d'immunosuppression
1. Recherche du génome du VHE (Sang et Selles)
 hépatite chronique, fibrose
2. Eventuellement quantification ARN-VHE : suivi du traitement
3. Marqueurs sérologiques sans intérêt clinique
 Recherche d'anticorps (IgG) anti-VHE
 Intérêt ?
 Fiabilité des tests ?
V.Thibault_janv.-14 45
Influence des tests...
V.Thibault_janv.-14 46
0.25 2.5
Test Wantai
Test Genelabs
GL : 3.6%
Wantai: 16.2%
Séroprévalence VHE
500 don. Sang (UK)
Bendall et al. 2010 J. Med. Virol. 82:799-805
Marseille : 64 transplantés (reins, foie)
•Test Adaltis : 10.9% positifs (86% immunoblots +)
•Test Wantai : 31.3% positifs (80% immunoblots +)
Rossi-Tamisier et al. 2013 J. Clin. Virol. 56:62-64
Toulouse : 88 greffe de moelle
•Test Adaltis : 12.5% positifs
•Test Wantai : 36.4% positifs
Abravanel et al. 2012 J. Clin. Virol. 54:152-155
Corée : 147 bilans de santé
•Test Genelabs: 14.3% positifs
•Test Wantai : 23.1% positifs
Park et al. 2012 BMC Inf. Dis. 12:142
Des tests performants
V.Thibault_janv.-14 47
S.D. Pas et al. J Clinical Virology 58 (2013) 629– 634
•MP Diagnostics, (IgM v3.0; MP Biomedicals, Singapore, former Genelabs (GL))
•Dia.Pro (Milan, Italy),
•DRG(Marburg, Germany),
•DSI (RPC Diagnostic Systems, Nizhniy,Novgorod, Russia)
•MP Products (Diacheck; The Netherlands)
•Wantai Biological Pharmacy (PE2-assay; Beijing, China)
•Mikrogen (recomWell; Neuried, Germany)
En Pratique
(à adapter en fonction du lieu géographique ?)
 Hépatite aiguë
 IgM VHA et VHE
 IgM HBc – AgHBs
 Hépatite C
 Notions sérologiques pour d’autres virus (EBV, CMV, herpès)
 Immunodépression et cytolyse persistante
 RT-PCR VHE (sang et selles)
 Hépatite B – Hépatite C
 Autres causes
V.Thibault_janv.-14 48
Stratégie Diagnostique
Se donner les moyens de faire le diagnostic
Diagnostic IgG IgM RT-PCR
Certain +/- ++ +
Probable +/- - +
Douteux +++ - -
Immunité
ancienne
+ - -
V.Thibault_janv.-14 49
Diagnostic Direct
Recherche du génome sur
prélèvements sang et selles
Diagnostic Indirect
Recherche de l'immunité antivirale
IgM anti VHE
IgG anti VHE
Huang S et al. 2010 Profile of Acute Infectious Markers
in Sporadic Hepatitis E. PLoS ONE 5(10): e13560
VHE et traitement
 Efficacité du PEG-IFN
 Efficacité de la ribavirine chez les patients
Pas de mécanisme virologique précis décrit
V.Thibault_janv.-14 50
Haagsma EB et al Liver Transpl. 2010 Apr;16(4):474-7
Mallet V et al. Ann Intern Med. 2010 Jul 20;153(2):85-9.
Kamar N et al. Nephrol Dial Transplant. 2010 Aug;25(8):2792-5.
Kamar N et al. Gastroenterology. 2010 Nov;139(5):1612-8.
Protéines et vaccins
V.Thibault_janv.-14 51
S. Kamili / Virus Research 161 (2011) 93– 100
Baculovirus
GlaxoSmithKline
E. coli
Hecolin;
Xiamen Innovax Biotech
VHE et vaccination
V.Thibault_janv.-14 52
Risque cumulé d'un premier épisode
d'hépatite E
Moyenne géométrique du taux
d'anticorps anti-VHE
20 μg d'antigène rHEV (capside exprimée
dans baculovirus) dans 0.5 ml de PBS sur
0.5 mg d'hydroxyde d'aluminium.
3 injections
Shrestha,et al 2007 N Engl J Med 356;9
Efficacité : 95,5% après 3 doses
Incidence :
•Placebo : 66/896=7.37%
•Vaccin : 3/898=0.33%
VHE et vaccination
V.Thibault_janv.-14 53
Zhu et al Lancet. 2010 Sep 11;376(9744):895-902
HEV 239 (Hecolin; Xiamen Innovax Biotech,
Xiamen, China), produced in bacterial cells :
safe and efficacious against infection with
hepatitis E virus in seronegative participants in
a phase 2 trialIncidence :
•Placebo : 15/48 663=0.031%
•Vaccin : 0/48 693
Difficultés diagnostiques
V.Thibault_janv.-14 54
http://www.invs.sante.fr/Espace-professionnels/Centres-nationaux-de-reference/Liste-et-coordonnees-des-CNR
V.Thibault_janv.-14 55
VHE : M. Q. , 62 ans
GR (fin 2008)
VHE Sang
VHE Selles
18/10/12 18/11 18/01/13
IgM ?
IgG ?
PFC SD
15/01/13
Génome VHE
IgM VHE
- +

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Thibault vha vhe- 2015

  • 1. V.Thibault_janv.-14 1 Virus de l'hépatite A et E Virus et marqueurs diagnostiques Vincent THIBAULT Laboratoire de Virologie Hôpitaux Universitaires Pitié-Salpêtrière – Charles Foix Paris - France
  • 2. V.Thibault_janv.-14 2 Hépatites virales parentéral non A, non BB 1965 D 1977 A 1972 féco-oral mode de transmission préférentiel F, G, TTV, autres… C 1990 E 1991 Vaccin Vaccin (Vaccin)
  • 4. Historique VHA  Avant J.C.: “La Jaunisse” (Ikterus / kirrhos)  1745 : Cockayne, hépatites épidémiques  1908 : McDonald, "notion de virus…"  Reproduction de la maladie 1942 :  Volontaires (Voegt, Havens), Paul 1943 ingestion feces/serum  Entité clinique :  17-18ème siècle - 1923 Blumer - 1947 McCallum (VHA "infectious"-VHB "serum") Transmission nosocomiale (préparation vaccinale : variole, fièvre jaune…)  Visualisation : 1973 (Feinstone)  Développement de la sérologie : épidémiologie  1979 : culture (Provost et Hilleman)  1981... : Clonage, Séquences nucléotidiques  1991… : Vaccination  2006 : Déclaration obligatoire V.Thibault_janv.-14 4 1995 : Vaccin 1996 : recommandations 1999 : recommandations
  • 5. Virus de l'hépatite A V.Thibault_janv.-14 5
  • 6. V.Thibault_janv.-14 6 Virus de l’Hépatite A ARN (+) Vpg Capside 27-32nm • Famille : Picornaviridae (entérovirus type 72) • Genre : hépatovirus • Taille 27-32 nm • Non enveloppé • Structure icosaèdrique • ARN simple brin, • polarité positive • lié de façon covalente à une protéine Vpg
  • 7. V.Thibault_janv.-14 7         VP1VP3VP2 VP4 2AProtéines de surface immunogénicité 3D (POL)3C (PRO)2C2B1D1C1B 3 A-B 2A P1 prot. Capside Vpg 2.5kDa P2 P3 0 7478 1A AAA Structurales Non structurales IRES Traduction (eIF-4G) 3D (POL)3C (PRO)2C2BVP1VP3VP2 3 A-B VP4 2A poly- protéine 2 227 AA ? Liaison NTP Hélicase Vpg Protéase ARN Polymérase RéplicationVP1VP3VP2 VP4 2A VP0 Maturation finale X5 – X12
  • 8. V.Thibault_janv.-14 8 Cycle de multiplication du VHA en culture de cellules P3 P2 P1 Traduction Synthèse de la polyprotéine + - - + Réplication Maturation Libération du génome Attachement Relargage Réticulum endoplasmique Espace de Disse Canalicule biliaire Empaquetage
  • 9. VHA : physiopathologie V.Thibault_janv.-14 9 Absence d'effet cytopathique direct : cytolyse résultant du processus immun de défense de l'hôte, médiation cellulaire médiation humorale Membrane hijacking by HAV blurs the classic distinction between ‘enveloped’ and ‘non-enveloped’ viruses and has broad implications for mechanisms of viral egress from infected cells as well as host immune responses. Feng et al. 2013 Nature 496, 367
  • 10. V.Thibault_janv.-14 10 Agents Stabilité Chaleur Autoclavage (121°C, 20') 100°C 60°C température ambiante 4°C Congelé Inactivation Inactivation Stable 1 heure Stable 1 mois (selles, eaux, sols) Plusieurs jours sur surface sèche 4 h. Sur les mains Stable plusieurs mois Stable des mois ou années Acide-base pH 1 : stable 5 h. PH 3-11 : stable au moins 30' U.V. Inactivation Chimiques Chlore, ozone, glutaraldéhyde, iode Inactivation Alcool 70° 3' : inactivation partielle Propriétés Physiques du VHA
  • 11. VHA et agents physiques ou chimiques V.Thibault_janv.-14 11 http://www.invs.sante.fr/publications/2009/guide_hepatite_a
  • 12. Variabilité génétique  Comparaison nucléotidique  6 Génotypes : IA,B ; II; IIIA,B ; IV-VI Homme : génotype I (90%), (III, II) Singes : IV, V, VI  Sérotype unique Nombre limité d'épitopes antigéniques VP1, VP3 Tests immunologiques Vaccination (HM175, CR326)  virus inactivé cultivé sur MRC-5 V.Thibault_janv.-14 12 3D (POL)3C (PRO)2C2B1D1C1B 3 A-B 2A P1 prot. Capside Vpg 2.5kDa P2 P3 0 7478 1A AAA Structurales Non structurales
  • 13. Répartition mondiale des génotypes V.Thibault_janv.-14 13 Génotypes infectant l'homme en noir , les singes en rouge. Souche PA21 (génotype IIIA), isolée d'un singe Panamanian Owl en vert. Cristina J, Costa-Mattioli M. Virus Res. 2007 Aug;127(2):151-7.
  • 14. Genetic Characterization of Hepatitis A genotypes V.Thibault_janv.-14 14 G. Vaughan et al. Infection, Genetics and Evolution 21 (2014) 227–243
  • 15. V.Thibault_janv.-14 15 Desbois et al. J CLIN MICROBIOLOGY, 2010, 48, 9:3306–3315 IA IB IIB IIA IIIB IIIA VP1 sequences (900 nt.) West Africa Autochtones Diffusion du génotype IIA en France à partir d'une origine Africaine Epidemiology and Genetic Characterization of Hepatitis A Virus Genotype IIA
  • 16. Génotypes et sévérité de l'hépatite V.Thibault_janv.-14 16 Hepatitis A Virus Genotype and Its Correlation With the Clinical Outcome of Acute Hepatitis A in Korea: 2006–2008 Yun et al. J. Med. Virol. 83:2073–2081 (2011) •n=556 (497 ARN positifs) Sept. 2006 à Août 2008 •Génotype IIIA induit des symptômes plus sévères Comparative Analysis of Disease Severity Between Genotypes IA and IIIA of Hepatitis A Virus Yoon et al. J. Med. Virol. 83:1308–1314 (2011) •n=111, comparaison de deux périodes 1998 et 1999 (IA) (n = 45) et 2009 (IIIA) (n = 66) •IIIA plus sévère (ALAT et durée hospitalisation) Globalement, pas de consensus pour un lien direct entre le génotype et la sévérité de l'atteinte hépatique – Données en faveur de facteurs liés à l'hôte (TIM-HAVCR).
  • 17. V.Thibault_janv.-14 17 Symptomes Ictère VHA : Paramètres Biologiques Semaines Ag foie VHA Sang VHA Selles 0 1 2 3 4 5 6 7 8 9 10 24 IgM IgG protection contre réinfection Ac anti-VHA = hépatite A ancienne ou vaccination IgM anti-VHA = hépatite aiguë A (clinique)
  • 18. IgM HAV uniquement à bon escient !  Vaccination : 8 à 20 % d'IgM VHA + dans les 2 à 3 semaines suivant l'injection… V.Thibault_janv.-14 18 Roque Afonso et al. CID 2006:42 -887 82 % 11 % 1 % Faux positifs  Alaska : test "réflexe" si Ig-VHA totales +  Ig M HAV 32 % de faux + (Castrodale CID 2005:41;e86)  NE RECHERCHER L'IgM anti-VHA QU'EN CAS D'HEPATITE AIGUË
  • 19. IgM HAV : A répéter, parfois… V.Thibault_janv.-14 19 Lee HK et al. Eur J Gastroenterol Hepatol. 2013 ;25(6):665-8
  • 20. Diagnostic  Sérologie +++  IgM anti VHA : infection récente  IgG anti VHA : infection passée ou vaccination  IgM et IgG anti VHA  Diagnostic direct (-) [uniquement dans le cadre d'études]  Virémie : techniques sensibles (105 v./mL)  Recherche de virus dans les selles, prolongée, importante (109v./mL), épidémiologie V.Thibault_janv.-14 20  Marqueurs biochimiques  Transaminases (ALAT, ASAT)  Bilirubine  Phosphatase alcaline  Facteurs de coagulation Salive : IgG (ELISA) Génome viral (RT-PCR)
  • 21. V.Thibault_janv.-14 21 Durée de la virémie: conséquences cliniques et biologiques Duration of viremia in hepatitis A virus infection Bower et al. Journal of Infectious Diseases 2000;182:12–7 6-7 5-6 2-5 Log particules/mL Suivi de 13 patients : durée moyenne 95 jours dont 2 avec rechute (1-2 mois) Suivi de 27 patients High and Persistent Excretion of Hepatitis A Virus in Immunocompetent Patients Tjon et al. Journal of Medical Virology 78:1398–1405 (2006)
  • 22. V.Thibault_janv.-14 22 Rezende et al., Hepatology 38:613-618 (2003) Hépatite fulminante Evolution bénigne Limite de quantification 50 Hépatites A dont 19 fulminantes (10 OLT) Hépatite fulminante : -virémie (p=0.03) * -bilirubine -(p=0.04) * -age (p=0.09) -génotype non IA (p=0.09) Fujiwara K et al. J. Med Virol. 2011 Feb;83(2):201-7. Hepatitis A viral load in relation to severity of the infection. 11 patients with fulminant hepatitis 10 with severe acute hepatitis 70 with self-limited acute hepatitis Quantification de la virémie ?
  • 23. Hépatite A : le vaccin virus inactivé  AVAXIM 160U suspension injectable seringue préremplie  Virus de l'hépatite A souche GBM cultivée sur cellules diploïdes humaines MRC-5 , inactivé  HAVRIX 1 440 U Elisa/ml susp inj IM Ad en seringue  HAVRIX 720 U Elisa/0,5 ml susp inj IM Enf/Nour en seringue  Souche HM 175 du virus de l'hépatite A cultivée sur cellules humaines diploïdes MRC5 V.Thibault_janv.-14 23  Le schéma vaccinal habituel comprend 1 dose suivie d'un rappel (1 dose) 6 à 12 mois plus tard.  La persistance des anticorps anti-VHA après vaccination n'est actuellement pas connue . Les données disponibles suggèrent la persistance des anticorps anti-VHA à un niveau protecteur au moins jusqu'à 20 ans après primo-immunisation. Hepatitis A Vaccine versus Immune Globulin for Post-exposure Prophylaxis Victor et al. 2007 N Engl J Med 357;17
  • 24. V.Thibault_janv.-14 24 Grippe SRAS ? Hépatite E ?Hépatite E ? GrippeHépatite E
  • 25. Historique VHE  Découverte dépendante de la connaissance des virus des hépatites 1955 : Inde, hépatite chez des personnes immunisées contre le VHA, épidémie particulière. "NANBH"  Entité clinique 1980 - similitude avec l’hépatite A :  Inde : prévalence de l’hépatite A importante  Epidémie : autre virus des hépatites, contamination par l’eau  1983 : reproduction de l’hépatite non A-non B chez un volontaire immunisé contre VHA (Balayan)  Hépatite à J36  J28-45, visualisation de particules virales > VHA (27-30nm)  Reproduction de l’infection chez le singe (cynomolgus)  Hépatite "non A - non B" à transmission entérique (ENANB)  1990 : Reyes et al. clonage et séquençage  "VHE"  1991 : Tam et al. VHE  2000 : Panda et al. cDNA infectieux V.Thibault_janv.-14 25
  • 26. Hepatitis E Virus in Pork Liver Sausage, France V.Thibault_janv.-14 26 Hepatitis E virus (HEV) particles in the cell culture supernatant of pork liver sausage sample Berto et al. Emerg Infect Dis 2013 Feb . http://dx.doi.org/10.3201/eid1902.121255
  • 27. VHE V.Thibault_janv.-14 27 Virus non enveloppé Sphérique (SRV) Surface irrégulière Capside 27-34 nm Symétrie icosaédrique ARN simple brin hélice droite polarité + 7,5kb poly-A extrémité 3’ Stabilité Au laboratoire : instable(-70 à +8°C) Décongélation/congélation Tractus GI : stable (pH) Famille : Hepeviridae Genre : Hepevirus
  • 28. Organisation génomique Hétérogénéité génétique  Au moins 4 groupes majeurs (<20% hétérogénéité ORF2) subdivisés en 24 sous groupes dont homologues animaux  Epitopes majeurs : parties C-ter de l’ORF3 et ORF2 (aa 452-617)  Protection croisée entre différentes souches : un seul sérotype  Développement de tests sérologiques (performances équivalentes entre les différents types ?)  Vaccin : ORF 2 recombinante V.Thibault_janv.-14 28 Non structurales Structurales 28 5109 71245’ NC 3’NC Poly-A ARN polarité +7 200 nt Protéines immunogènes DIAGNOSTIC Vaccin MeT Y Pro P X Hel RdRp ORF3 ORF2 (core-CRE) Génotypes 1-4 5109 5123 114 AA 660 AA
  • 29. V.Thibault_janv.-14 29 Phylogenetic tree based on full-length sequences of HEV strains. Kamar et al. Clinical Microbiology Reviews 2014 p. 116–138
  • 30. Transmission inter-espèces V.Thibault_janv.-14 30 R. Johne et al. / Infection, Genetics and Evolution 27 (2014) 212–229 Ne mangez pas de gerbilles !
  • 31. Etudes des souches de l'homme et du porc en France V.Thibault_janv.-14 31 Bouquet et al. Emerging Infectious Diseases Vol. 17, No. 11, November 2011
  • 32. Homologie des souches de l'homme et du porc V.Thibault_janv.-14 32 Bouquet et al. Emerging Infectious Diseases Vol. 17, No. 11, November 2011
  • 33. Evolution VHE V.Thibault_janv.-14 33 Purdy MA, Khudyakov YE. Evolutionary history and population dynamics of hepatitis e virus. PLoS One. 2010 Dec 17;5(12):e14376. Anthropotropic enzootic 536 to 1344 years ago
  • 34. Evolution VHE V.Thibault_janv.-14 34 Purdy MA, Khudyakov YE. Evolutionary history and population dynamics of hepatitis e virus. PLoS One. 2010 Dec 17;5(12):e14376. Anthroponose Zoonose 536 à 1344 ans Grandes épidémies + cas sporadiques Pays en voie de développement Eau de boisson (moussons) Rares en France Symptomatiques Mortalité chez la femme enceinte  Pays industrialisés  Cas autochtones  Nourriture (eau ?)  Asymptomatique++  Séroprévalence croissante avec âge  Graves sur hépatopathie  Pas de cas sévère chez femme enceinte  Formes persistantes chez l'immunodéprimé  Atteintes neurologiques (5.5%)
  • 35. Répartition des différents génotypes V.Thibault_janv.-14 35 Aggarwal Hepatology 2011
  • 36. V.Thibault_janv.-14 36 Smith & Simmonds, Liver International 2014 DOI:10.1111/liv.12629 Distribution aléatoire des souches FH (noir) et des souches non FH (A) Génotype 1 (B) Génotype 4 Variants viraux et sévérité de l'hépatite Un génotype plus sévère ? Jeblaoui et al. Clinical Infectious Diseases 2013;57(4):e122–6
  • 37. V.Thibault_janv.-14 37 I. Ahmad et al. / Virus Research 161 (2011) 47– 58
  • 38. Culture et Modèles animaux V.Thibault_janv.-14 38 • Culture  Difficile  Culture primaire d’hépatocytes de macaques (cynomolgus)  Cellules PLC/PRF/5 hépatocarcinome et "A549" cellules cancer poumon (Tanaka et al. J. Gen Virol. 2007; Takahashi et al. Arch. Virol. 2012)  Cellule embryonnaire • Modèles animaux  Primates : reproduction de la pathologie humaine  Volontaires...  VHE du porc, du poulet  Présence d’Ac chez poulet, porc, rat, souris, mouton... Lapin… Ma H et al. Experimental infection of rabbits with rabbit and genotypes 1 and 4 hepatitis E viruses. PLoS One. 2010 Feb 11;5(2):e9160
  • 39. Résistance thermique du VHE… V.Thibault_janv.-14 39 Colson et al. JID 2010:202 VHE dans des suspensions fécales : Inactivation : 70°C 10' ou 95°C 1 min; 56 °C 30 min maintien de l'infectiosité Tanaka et al. J. Gen Virol. 2007 Barnaud et al. August 2012 Volume 78 Number 15 Applied and Environmental Microbiology p. 5153–5159
  • 40. V.Thibault_janv.-14 40 Symptomes Ictère VHE : Paramètres Biologiques Jours VHE Sang VHE Selles 0 10 20 30 40 50 60 70 80 90 100 200 IgM IgG Titre peu élevé protection contre réinfection ? Khuroo MS, Khuroo MS. Seroepidemiology of a second epidemic of hepatitis E in a population that had recorded first epidemic 30 years before and has been under surveillance since then. Hepatol Int. 2010 Feb 3;4(2):494-9
  • 41. Virémie et excrétion fécale V.Thibault_janv.-14 41 Aggarwal et al. THE LANCET • Vol 356 • September 23, 2000, p1081-1082 Détection du RNA-VHE chez 20 patients ayant une hépatite E aiguë Virémie Selles Chandra NS et al. Dynamics of HEV viremia, fecal shedding and its relationship with transaminases and antibody response in patients with sporadic acute hepatitis E. Virol J. 2010 Sep 6;7:213
  • 42. HEV – virémie- transmission V.Thibault_janv.-14 42 Matsubayashi K, et al. Transfusion. 2008 Jul;48(7):1368-75. serum salive selle IgG IgM Concentré de plaquettes à J0 Transfusé à un homme de 64 ans traité pour Lymphome non-Hodgkinien par GM autologue
  • 43. Immunodépression, hépatite chronique et stratégie diagnostique V.Thibault_janv.-14 43 Kamar et al. American Journal of Transplantation 2008; 8: 1744–1748 Dans le cadre d'une investigation chez un patient immuno déprimé, La détection du génome viral (RT-PCR) sera privilégiée ! (ceci s'applique pour de nombreux diagnostics viraux - PCR)
  • 44. Suivi du traitement V.Thibault_janv.-14 44 Abravanel et al. CID 2015:60 (1 January) 0 1 2 3 4 5 6 7 8 CVVHElogCopies/mL Dates Suivi charges virales plasmatiques VHE seuil de quantification Détectable Détectable RIBAVIRINE Valeur prédictive de la détection d'ARN dans les selles 3 mois après le début de la ribavirine : rechute ?
  • 45. Stratégie Diagnostique Pratique  Hépatite aigue sans immunosuppression 1. IgM anti-VHE  Délai d'obtention du résultat rapide 2. Recherche du génome du VHE (Sang et Selles)  Fiabilité des tests ?  Hépatite dans un contexte d'immunosuppression 1. Recherche du génome du VHE (Sang et Selles)  hépatite chronique, fibrose 2. Eventuellement quantification ARN-VHE : suivi du traitement 3. Marqueurs sérologiques sans intérêt clinique  Recherche d'anticorps (IgG) anti-VHE  Intérêt ?  Fiabilité des tests ? V.Thibault_janv.-14 45
  • 46. Influence des tests... V.Thibault_janv.-14 46 0.25 2.5 Test Wantai Test Genelabs GL : 3.6% Wantai: 16.2% Séroprévalence VHE 500 don. Sang (UK) Bendall et al. 2010 J. Med. Virol. 82:799-805 Marseille : 64 transplantés (reins, foie) •Test Adaltis : 10.9% positifs (86% immunoblots +) •Test Wantai : 31.3% positifs (80% immunoblots +) Rossi-Tamisier et al. 2013 J. Clin. Virol. 56:62-64 Toulouse : 88 greffe de moelle •Test Adaltis : 12.5% positifs •Test Wantai : 36.4% positifs Abravanel et al. 2012 J. Clin. Virol. 54:152-155 Corée : 147 bilans de santé •Test Genelabs: 14.3% positifs •Test Wantai : 23.1% positifs Park et al. 2012 BMC Inf. Dis. 12:142
  • 47. Des tests performants V.Thibault_janv.-14 47 S.D. Pas et al. J Clinical Virology 58 (2013) 629– 634 •MP Diagnostics, (IgM v3.0; MP Biomedicals, Singapore, former Genelabs (GL)) •Dia.Pro (Milan, Italy), •DRG(Marburg, Germany), •DSI (RPC Diagnostic Systems, Nizhniy,Novgorod, Russia) •MP Products (Diacheck; The Netherlands) •Wantai Biological Pharmacy (PE2-assay; Beijing, China) •Mikrogen (recomWell; Neuried, Germany)
  • 48. En Pratique (à adapter en fonction du lieu géographique ?)  Hépatite aiguë  IgM VHA et VHE  IgM HBc – AgHBs  Hépatite C  Notions sérologiques pour d’autres virus (EBV, CMV, herpès)  Immunodépression et cytolyse persistante  RT-PCR VHE (sang et selles)  Hépatite B – Hépatite C  Autres causes V.Thibault_janv.-14 48
  • 49. Stratégie Diagnostique Se donner les moyens de faire le diagnostic Diagnostic IgG IgM RT-PCR Certain +/- ++ + Probable +/- - + Douteux +++ - - Immunité ancienne + - - V.Thibault_janv.-14 49 Diagnostic Direct Recherche du génome sur prélèvements sang et selles Diagnostic Indirect Recherche de l'immunité antivirale IgM anti VHE IgG anti VHE Huang S et al. 2010 Profile of Acute Infectious Markers in Sporadic Hepatitis E. PLoS ONE 5(10): e13560
  • 50. VHE et traitement  Efficacité du PEG-IFN  Efficacité de la ribavirine chez les patients Pas de mécanisme virologique précis décrit V.Thibault_janv.-14 50 Haagsma EB et al Liver Transpl. 2010 Apr;16(4):474-7 Mallet V et al. Ann Intern Med. 2010 Jul 20;153(2):85-9. Kamar N et al. Nephrol Dial Transplant. 2010 Aug;25(8):2792-5. Kamar N et al. Gastroenterology. 2010 Nov;139(5):1612-8.
  • 51. Protéines et vaccins V.Thibault_janv.-14 51 S. Kamili / Virus Research 161 (2011) 93– 100 Baculovirus GlaxoSmithKline E. coli Hecolin; Xiamen Innovax Biotech
  • 52. VHE et vaccination V.Thibault_janv.-14 52 Risque cumulé d'un premier épisode d'hépatite E Moyenne géométrique du taux d'anticorps anti-VHE 20 μg d'antigène rHEV (capside exprimée dans baculovirus) dans 0.5 ml de PBS sur 0.5 mg d'hydroxyde d'aluminium. 3 injections Shrestha,et al 2007 N Engl J Med 356;9 Efficacité : 95,5% après 3 doses Incidence : •Placebo : 66/896=7.37% •Vaccin : 3/898=0.33%
  • 53. VHE et vaccination V.Thibault_janv.-14 53 Zhu et al Lancet. 2010 Sep 11;376(9744):895-902 HEV 239 (Hecolin; Xiamen Innovax Biotech, Xiamen, China), produced in bacterial cells : safe and efficacious against infection with hepatitis E virus in seronegative participants in a phase 2 trialIncidence : •Placebo : 15/48 663=0.031% •Vaccin : 0/48 693
  • 55. V.Thibault_janv.-14 55 VHE : M. Q. , 62 ans GR (fin 2008) VHE Sang VHE Selles 18/10/12 18/11 18/01/13 IgM ? IgG ? PFC SD 15/01/13 Génome VHE IgM VHE - +

Notes de l'éditeur

  1. janvier 15
  2. 6
  3. HAV genome organization and polyprotein processing. The positive-strand (messenger sense) RNA genome contains a single open reading frame encoding a polyprotein that is proteolytically processed by the viral protease, 3Cpro (shown in red, cleaving at sites identified by red triangles), a yet-to-be-identified cellular protease (arrow), and an unknown proteolytic activity (black diamond) to release the mature structural (blue) and nonstructural (tan and red) proteins. At the bottom is shown the structure of a replication competent, subgenomic HAV RNA replicon (HAVLuc- _VP4) which encodes the reporter firefly luciferase gene (Luc) in lieu of the capsid protein coding sequence (with the exception of the 4 N-terminal codons of VP4 and the 13 C-terminal codons of VP1).22
  4. A molecular view of the HAV life cycle. (a) The virus enters the hepatocyte via an interaction with a cellular receptor, the identity of which remains uncertain. (b) This is followed by uncoating of the viral particle and release of the positive-sense RNA genome into the cell. (c) An internal ribosome entry site within the 5_ nontranslated segment of the genome mediates cap-independent translation of the viral polyprotein. (d) The polyprotein undergoes co- and post-translational proteolytic processing directed by the viral protease, 3Cpro (see Fig. 2). (e) Nonstructural viral proteins assemble into a membrane-bound RNA replicase, bind the 3_ end of the genomic RNA and commence synthesis of a negative-strand copy of the viral genome. (f). The negative-strand copy of the genome is used as template for synthesis of multiple new copies of genomic positive-strand RNA. (g) Some of this newly synthesized positive- sense RNA is recycled for further RNA synthesis or translation (dashed lines). (h) Other positive-strand RNA molecules are packaged into new viral particles formed by assembly of the structural proteins, followed by final cleavage of the VP1-2A precursor by an unknown cellular protease (VP1/2A junction), and the “maturation” cleavage of the VP4/VP2 junction (see Fig. 2). (i) Newly assembled HAV particles are secreted by the cell across the apical membrane of the hepatocyte into the biliary canaliculus, from which they are passed into the bile and small intestine.
  5. Korea has recently experienced a nationwide outbreak of hepatitis A. This study aimed to investigate hepatitis A virus (HAV) genotypes and to compare clinical features between patients infected with HAV genotype IA and those with genotype IIIA. From September 2006 to August 2008, 595 patients with symptomatic hepatitis A were enrolled prospectively in four hospitals in Korea. Among them, 556 patients participated in this study by providing serum or stool samples for genotypic analysis. HAV RNA was detected in 499 patients (89.7%). Major genotypes included IA (n ¼ 244, 48.9%) and IIIA (n ¼ 244, 48.9%), and the remaining genotype was IB (n ¼ 11, 2.2%). From September 2006 to August 2007, the distribution of genotypes IA and IIIA were 64.6% and 35.6%, respectively, which changed to 42.3% and 54.6%, respectively, from September 2007 to August 2008, indicating change of circulating HAV genotypes in the study period from IA to IIIA. Major patterns of amino acid substitution in the VP3/VP1 junction region were observed at position 512 (P ! L) in genotype IA and at 520 (R ! K) in genotype IIIA. Patients with genotype IIIA infection showed significantly higher aminotransferase levels, prothrombin time, and leukocyte count, with more severe symptoms than those with genotype IA at the time of admission. These results suggest the occurrence of a change of circulating HAV genotypes in recent community-wide outbreaks of hepatitis A in Korea, and genotype IIIA infection, compared with genotype IA infection, might show more severe clinical manifestations. Although hepatitis A is a major health problem worldwide, it has not yet been clarified whether or not viral factors affect the clinical characteristics. This study aimed to investigate if a genotype of hepatitis A virus (HAV) affects disease severity among adolescent and adult populations. Clinical data and specimens were collected from patients 16-years-of-age with acute hepatitis A at two university hospitals in Korea during the two study periods: 1998 and 1999 (n ¼ 45), and 2009 (n ¼ 66). Nucleotide sequencing of the complete VP1 region of the HAV isolates was performed for phylogenetic analysis and genotyping. Clinical parameters related to disease severity were compared by HAV genotype to determine its clinical relevance. Of the 87 patients, 47 were male and the mean age was 29.8 8.1 years. The genotype IIIA (93.0%, 53/57) was predominant in the year 2009, whereas IA (93.3%, 28/30) was the major genotype in 1998 and 1999. When comparing disease severity between the two HAV genotypes, the patients with genotype IIIA were older and had higher alanine aminotransferase (ALT) levels, prolonged prothrombin times and lower serum albumin levels. In a multivariate logistic regression model, higher ALT levels 1,000 IU/L (odds ratio [OR] 11.7, 95% confidence interval [CI] 2.5–54.0) and longer hospitalization (OR 22.49, 95%CI 4.6–132.5) were associated independently with genotype IIIA. In conclusion, this study indicates that HAV genotype might be one of the viral factors responsible for the disease severity of hepatitis A. J. Med. Virol. 83:1308–1314, 2011.
  6. Background The diagnosis of acute hepatitis A virus (HAV) infection is made on the basis of the presence of anti-HAV immunoglobulin M (IgM) antibodies in patients with clinical features of acute hepatitis. Some patients show a negative serology at initial presentation, which may complicate the diagnosis of hepatitis A (HA). The aim of this study was to examine the characteristics of HA patients with an initially negative anti-HAV IgM test result. Materials and methods Patients with symptomatic acute hepatitis who underwent IgM anti-HAV testing at a single center were enrolled consecutively, with tests repeated in patients with negative initial serology. Results A total of 684 patients with acute hepatitis were tested, of whom 620 patients were initially or eventually diagnosed with HA. Anti-HAV IgM was initially negative in 67 of the 620 HA patients (10.9%), but was later confirmed by subsequent retests. These patients had on average a shorter time lapse from the onset of symptoms to the initial test, a higher rate of fever, and lower alanine aminotransferase and bilirubin levels compared with those with a positive initial serology. Cutoff index (COI) values of anti-HAV IgM were correlated positively with the duration of time from the onset of symptoms to the initial test. Fever, lower bilirubin levels, and higher COI values were predictive of seroconversion to anti-HAV positivity in patients with a negative initial serology. Conclusion Taking into account the window period of HAV infection, anti-HAV IgM tests should be repeated, particularly in patients with features of the initial phase of hepatitis and a high COI value of anti-HAV IgM.
  7. The hepatitis A virus (HAV) is the most common etiological cause of acute hepatitis infections in humans in industrialized countries. Investigations into the viral load during HAV viremia, however, are rare. Therefore, correlation studies between viral load, biochemical, and specific serological markers have been undertaken. The group of sera comprised a series of multiple consecutive blood samples drawn from 11 patients at different times after onset of the disease. During the period up to 70 days after the onset of icterus, the individual range was at 1103 to 3104 HAV genome equivalents/ml. From day 75 until 120 after onset of the disease, the levels traced were at 103. In one case, it was possible to trace 1.25104 genome equivalents/ml up to 180 days after onset of icterus and in two cases even up to 408 and 490 days viral load levels of 5103 and 4104 were detected, respectively. The same sera were used to measure IgM class antibodies to hepatitis A virus and the total anti-HAV. The results demonstrate that a direct correlation to peak levels of viral load exists with peak serum transaminase levels, but neither with peak anti- HAV IgM levels nor with total anti-HAV. Decreasing amounts of anti-HAV IgM tend to occur with decreasing amounts of HAV genome equivalents; and, vice versa, increasing amounts of total anti-HAV are accompanied by decreasing amounts of HAV genome equivalents. The longest duration of viremia was found in patients infected with HAV genotype IA. J Med Virol. 2011 Feb;83(2):201-7. Hepatitis A viral load in relation to severity of the infection. Fujiwara K, Kojima H, Yasui S, Okitsu K, Yonemitsu Y, Omata M, Yokosuka O. Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan. A correlation between hepatitis A virus (HAV) genomes and the clinical severity of hepatitis A has not been established. The viral load in sera of hepatitis A patients was examined to determine the possible association between hepatitis A severity and HAV replication. One hundred sixty-four serum samples from 91 Japanese patients with sporadic hepatitis A, comprising 11 patients with fulminant hepatitis, 10 with severe acute hepatitis, and 70 with self-limited acute hepatitis, were tested for HAV RNA. The sera included 83 serial samples from 20 patients. Viral load was measured by real-time RT-PCR. The detection rates of HAV RNA from fulminant, severe acute, and acute hepatitis were 10/11 (91%), 10/10 (100%), and 55/70 (79%), respectively. Mean values of HAV RNA at admission were 3.48 ± 1.30 logcopies/ml in fulminant, 4.19 ± 1.03 in severe acute, and 2.65 ± 1.64 in acute hepatitis. Patients with severe infection such as fulminant hepatitis and severe acute hepatitis had higher initial viral load than patients with less severe infection (P < 0.001). Viremia persisted for 14.2 ± 5.8 days in patients with severe infection and 21.4 ± 10.6 days in those with acute hepatitis after clinical onset (P = 0.19). HAV RNA was detectable quantitatively in the majority of the sera of hepatitis A cases during the early convalescent phase by real-time PCR. Higher initial viral replication was found in severely infected patients. An excessive host immune response might follow, reducing the viral load rapidly as a result of the destruction of large numbers of HAV-infected hepatocytes, and in turn severe disease might be induced
  8. Geographic distribution of hepatitis E virus (HEV) subtypes recovered from humans (n = 100) and swine (n = 43), France, May 2008–November 2009. Black, human HEVs; red, swine HEVs; triangles, subtype 3c; squares, subtype 3e; dots, subtype 3f; diamonds, strains of undefined subtype. Regions with a high density of HEV are named.
  9. The pathogenesis of HEV infection responsible for liver pathology and clinical disease is not well understood. The main target for the virus is the hepatocyte, where it replicates and is released to bile and gastrointestinal tract. Viremia is regularly seen during the virus replication. The exact mechanism of hepatocytic death is uncertain. In experimentally infected non-human primates, the peak of liver lesions, measured by alanine aminotransferase activity elevation, is concordant with the virus disappearance from stool at the time of dynamic humoral immune response; the role of cellular immunity has not been researched adequately, especially HEV-specific immune response in the liver. Non-human primates (chimpanzees, rhesus and cynomolgus macaques) are most widely used animal models for the study of HEV infection, its pathogenesis and vaccine trials. Several other animal models including pigs, rabbits and chickens have recently been established for the study of various aspects of HEV infection. Infectivity studies in susceptible primates were of significance in molecular studies of the virus itself. Preclinical vaccine trials with the use of various recombinant HEV capsid proteins and viral DNA established basic platform for formulation of HEV vaccine applied in HEV-endemic regions (China, Nepal).
  10. Background Hepatitis E virus (HEV) is an enterically transmitted hepatropic virus. It segregates as four genotypes. All genotypes infect humans while only genotypes 3 and 4 also infect several animal species. It has been suggested that hepatitis E is zoonotic, but no study has analyzed the evolutionary history of HEV. We present here an analysis of the evolutionary history of HEV. Methods and Findings The times to the most recent common ancestors for all four genotypes of HEV were calculated using BEAST to conduct a Bayesian analysis of HEV. The population dynamics for genotypes 1, 3 and 4 were analyzed using skyline plots. Bayesian analysis showed that the most recent common ancestor for modern HEV existed between 536 and 1344 years ago. The progenitor of HEV appears to have given rise to anthropotropic and enzootic forms of HEV, which evolved into genotypes 1 and 2 and genotypes 3 and 4, respectively. Population dynamics suggest that genotypes 1, 3 and 4 experienced a population expansion during the 20th century. Genotype 1 has increased in infected population size ~30–35 years ago. Genotype 3 and 4 have experienced an increase in population size starting late in the 19th century until ca.1940-45, with genotype 3 having undergone additional rapid expansion until ca.1960. The effective population size for both genotype 3 and 4 rapidly declined to pre-expansion levels starting in ca.1990. Genotype 4 was further examined as Chinese and Japanese sequences, which exhibited different population dynamics, suggesting that this genotype experienced different evolutionary history in these two countries. Conclusions HEV appears to have evolved through a series of steps, in which the ancestors of HEV may have adapted to a succession of animal hosts leading to humans. Analysis of the population dynamics of HEV suggests a substantial temporal variation in the rate of transmission among HEV genotypes in different geographic regions late in the 20th Century.
  11. 126 patients Hep E aigues Complications neuro 5.5% Polyradiculonévrite inflammatoire 1 Guillain Barré 1 plexoradiculite brachiale bilatérale 1 encéphalite 1 ataxie + myopathie des ceintures
  12. Figure 1. Distribution of HEV genotypes in viral isolates obtained from humans and animals (predominantly pigs). The colors used for a country and the circle associated with it, represent the predominant HEV genotypes of human and animal isolates, respectively, from that country. The figure is based on data from Okamoto, 2007.5
  13. Background & Aims: Fulminant hepatitis is a rare outcome of infection with hepatitis E virus. Several recent reports suggest that virus variation is an important determinant of disease progression. To critically examine the evidence that virus-specific factors underlie the development of fulminant hepatitis following hepatitis E virus infection. Methods: Published sequence information of hepatitis E virus isolates from patients with and without fulminant hepatitis was collected and analysed using statistical tests to identify associations between virus polymorphisms and disease outcome. Results: Fulminant hepatitis has been reported following infection with all four hepatitis E virus genotypes that infect humans comprising multiple phylogenetic lineages within genotypes 1, 3 and 4. Analysis of virus sequences from individuals infected by a common source did not detect any common substitutions associated with progression to fulminant hepatitis. Re-analysis of previously reported associations between virus substitutions and fulminant hepatitis suggests that these were probably the result of sampling biases. Conclusions: Host-specific factors rather than virus genotype, variants or specific substitutions appear to be responsible for the development of fulminant hepatitis.
  14. Fig. 5. Proposed replication cycle of hepatitis E virus. The viral particles are concentrated on the surface of target cells through heparin sulfate proteoglycans acting as attachment factors (red wavy lines) (step 1) and subsequently bind a specific yet uncharacterized receptor (step 2), following which the particles are internalized (step 3). The virus then uncoats (step 4) to release genomic RNA (red noodles) that is translated in the cytoplasm into nonstructural proteins (step 5). These nonstructural proteins include the RNA dependent RNA polymerase that replicates the positive sense genomic RNA into negative sense transcripts (purple noodles) (step 6); the latter then act as templates for the synthesis of a 2.2 kb subgenomic RNA (step 7a) as well as full-length positive sense transcripts (step 7b). The positive sense subgenomic RNA is translated into ORF2 (blue) and ORF3 (crimson) proteins (step 8). The ORF2 protein packages the genomic RNA to assemble new virions (step 9) while the ORF3 protein may optimize the host cell environment for viral replication. The ORF3 protein is also associated with endomembranes (step 10a) or plasma membranes (step 10b) and may aid in viral egress. Recent studies suggest that mature virions are associated with the ORF3 protein and lipids (step 11), which are subsequently removed through a process that is not understood at present, to resume a fresh infection cycle. It is believed that the primary site of HEV replication is the liver, with hepatocytes being the most likely cell type. However, in vitro results also support infection and replication in non-hepatic cell types such as A549 lung carcinoma cells and in Caco-2 colon carcinoma cells. In pigs experimentally infected with swine HEV, while positive-sense viral RNA was detected in almost all tissues at some point during the infection, negative-sense replicative RNA intermediates were detected primarily in the small intestine, lymph node, colon and liver (Williams et al., 2001). In a recent report from hepatitis E patients, HEV RNA was detected in peripheral blood mononuclear cells, but there was no evidence for viral replication in this compartment (Ippagunta et al., 2010).
  15. Tanaka et al. Since little was known about the thermal stability of HEV, the newly developed culture system for HEV was used to examine the thermal stability of HEV. In the current study, HEV in the faecal suspension was inactivated by incubation at 70 uC for 10 min or at 95 uC for 1 min; however, upon incubation at 56 uC for 30 min, the HEV was still infectious, corroborating the previous report by Emerson et al. (2005). In the present study, the faecal suspension was heat-treated without the addition of proteins as stabilizing factors. Therefore, the temperature that would be required to inactivate virus embedded in an uncooked or undercooked meat or viscera from infected pigs, wild boars or deer is expected to be higher than that estimated in the present study. Using a faecal suspension with high load of Hepatitis E virus (HEV) (2.06107 copies ml”1, genotype 3), we developed an efficient cell-culture system for HEV in a hepatocarcinoma cell line (PLC/PRF/5). HEV progeny released in the culture medium were passaged five times successively in PLC/PRF/5 cells. The initial day of appearance and load of HEV detectable in the culture supernatant after inoculation were dependent on the titre of seed virus in the inoculum. When 6.46104 copies of HEV were inoculated on monolayers of PLC/PRF/5 cells in six-well microplates, HEV RNA was first detected in the culture medium on day 14 post-inoculation and increased to 9.16105 copies ml”1 on day 60. When 8.66105 copies of HEV were inoculated, HEV RNA was initially detected on day 12 and reached the highest titre of 8.66107 copies ml”1 on day 60. HEV incubated at temperatures higher than 70 6C did not grow in PLC/PRF/5 cells, while HEV incubated at 56 6C for 30 min was infectious. Convalescent serum samples with IgM-class HEV antibodies obtained from patients infected with HEV of genotype 1, 3 or 4 neutralized the genotype 3 virus, indicating that HEV antibodies are broadly cross-reactive. Serum samples obtained from patients 8.7 or 24.0 years after the onset of HEV infection also prevented the propagation of HEV in PLC/PRF/5 cells, suggesting the presence of long-lasting HEV antibodies with neutralizing activity in individuals with past HEV infection. Takahashi et al. Abstract Recent evidence has indicated the cross-species transmission of hepatitis E virus (HEV) from pigs and wild boars to humans, causing zoonosis, mostly via consumption of uncooked or undercooked animal meat/viscera. However, no efficient cell culture system for swine and boar HEV strains has been established. We inoculated A549 cells with 12 swine and boar HEV strains of liver, feces, or serum origin at an HEV load of C2.0 9 104 copies per well and found that the HEV progeny replicated as efficiently as human HEV strains, with a maximum load of *108 copies/ml. However, the HEV load in the culture medium at 30 days post-inoculation differed markedly by inoculum, ranging from 1.0 9 102 to 1.1 9 107 copies/ml upon inoculation at a lower load of approximately 105 copies per well. All progeny were passaged successfully onto A549 and PLC/PRF/5 cells. In sharp contrast, no progeny viruses were detectable in the culture supernatant upon inoculation with 13 swine and boar HEV strains at an HEV load of \1.8 9 104 copies per well. The present study also demonstrates that swine liver sold as food can be infectious, supporting the risk of zoonotic food-borne HEV infection.
  16. Background. The source and route of autochthonous hepatitis E virus (HEV) infections are not clearly established in industrialized countries despite evidence that it is a zoonosis in pigs. We investigated the role of figatellu, a traditional pig liver sausage widely eaten in France and commonly consumed raw, as a source of HEV infection. Methods. A case-control study was conducted of 3 patients who presented autochthonous hepatitis E and 15 members of their 3 different families. Anti-HEV immunoglobulin G and immunoglobulin M antibody testing was performed with commercial assays. HEV RNA was detected in serum samples of patients and in pig liver sausages by means of real-time polymerase chain reaction and sequenced by means of in-house sequencing assays. Genetic links between HEV sequences were analyzed. Results. Acute or recent HEV infection, defined by detection of anti-HEV immunoglobulin M antibodies and/ or HEV RNA, was observed in 7 of 13 individuals who ate raw figatellu and 0 of 5 individuals who did not eat raw figatellu ( ). Moreover, HEV RNA of genotype Pp.041 3 was recovered from 7 of 12 figatelli purchased in supermarkets, and statistically significant genetic links were found between these sequences and those recovered from patients who ate raw figatellu. Conclusion. Our findings strongly support the hypothesis of HEV infection through ingestion of raw figatellu.
  17. Clinical course of transfusion-transmitted hepatitis E with kinetics of (A) HEV RNA, (B) serologic, and (C) biochemical markers after transfusion. The patient had transfusion of PLT concentrates contaminated with HEV on Day 0. (A) HEV RNA load was represented as log copies per mL of serum () or saliva () or per g of feces (). There were no data between Day 0 and Day 44 in feces and saliva. (B) Cutoff values of anti-HEV IgM () and IgG () antibodies are 30 and 13, respectively. (C) Medications were administered with IFN-a from Day 43 through Day 62 and with PSL from Day 59 through Day 112. () ALT; () AST; () total serum bilirubin. BACKGROUND: Five cases of transfusion transmission of hepatitis E virus (HEV) have been reported so far. The infection routes of the causative donors remain unclear, however. Also, the progress of virus markers in the entire course of HEV infection has not been well documented. STUDY DESIGN AND METHODS: Nucleic acid testing was performed by real-time reverse transcription-polymerase chain reaction targeting the open reading frame 2 region of HEV. Full-length nucleotide sequences of HEV RNA were detected by direct sequencing. RESULTS: Lookback study of a HEV-positive donor revealed that the platelets (PLTs) donated from him 2 weeks previously contained HEV RNA and were transfused to a patient. Thirteen relatives including the donor were ascertained to enjoy grilled pork meats together in a barbecue restaurant 23 days before the donation. Thereafter, his father died of fulminant hepatitis E and the other 6 members showed serum markers of HEV infection. In the recipient, HEV was detected in serum on Day 22 and reached the peak of 7.2 log copies per mL on Day 44 followed by the steep increase of alanine aminotransferase. Immunoglobulin G anti-HEV emerged on Day 67; subsequently, hepatitis was resolved. HEV RNA sequences from the donor and recipient were an identical, Japan-indigenous strain of genotype 4. HEV RNA was detectable up to Day 97 in serum, Day 85 in feces, and Day 71 in saliva. CONCLUSION: A transfusion-transmitted hepatitis E case by blood from a donor infected via the zoonotic food-borne route and the progress of HEV markers in the entire course are demonstrated. Further studies are needed to clarify the epidemiology and the transfusion-related risks for HEV even in industrialized countries.
  18. Hepatitis E Virus-Related Cirrhosis in Kidney and Kidney–Pancreas-Transplant Recipients Hepatitis E virus (HEV) infection was thought to be responsible for acute hepatitis that did not become chronic. However, we have recently reported that HEV infection can evolve to chronic hepatitis, at least in solid-organ transplant patients. We report on two cases of rapidly progressive of HEV-related cirrhosis that occurred in two organ-transplant patients. Case 1: A kidney–pancreas-transplant patient developed acute HEV hepatitis 60 months after transplantation, which evolved to chronicity as defined by persisting elevated liver-enzyme levels and positive serum HEV RNA. At 22 months after the acute phase, she presented with cirrhosis and portal hypertension, that is ascites and esophagus varices. Case 2: A kidney-transplant patient developed acute hepatitis 36 months after transplantation, which persisted and remained unexplained for 38 months. Then, HEV RNA was searched for in their serum and stools, and was found to be positive in both. Retrospective analysis of available stored serum, mainly the serum obtained at the acute phase, confirmed the diagnosis of chronic hepatitis E. In both cases, a liver biopsy showed cirrhosis. We conclude that HEV infection cannot only evolve to chronic hepatitis, but can also be responsible for rapidly progressing cirrhosis in organ-transplant patients.
  19. Hepatitis E Virus-Related Cirrhosis in Kidney and Kidney–Pancreas-Transplant Recipients Hepatitis E virus (HEV) infection was thought to be responsible for acute hepatitis that did not become chronic. However, we have recently reported that HEV infection can evolve to chronic hepatitis, at least in solid-organ transplant patients. We report on two cases of rapidly progressive of HEV-related cirrhosis that occurred in two organ-transplant patients. Case 1: A kidney–pancreas-transplant patient developed acute HEV hepatitis 60 months after transplantation, which evolved to chronicity as defined by persisting elevated liver-enzyme levels and positive serum HEV RNA. At 22 months after the acute phase, she presented with cirrhosis and portal hypertension, that is ascites and esophagus varices. Case 2: A kidney-transplant patient developed acute hepatitis 36 months after transplantation, which persisted and remained unexplained for 38 months. Then, HEV RNA was searched for in their serum and stools, and was found to be positive in both. Retrospective analysis of available stored serum, mainly the serum obtained at the acute phase, confirmed the diagnosis of chronic hepatitis E. In both cases, a liver biopsy showed cirrhosis. We conclude that HEV infection cannot only evolve to chronic hepatitis, but can also be responsible for rapidly progressing cirrhosis in organ-transplant patients.
  20. Hepatitis E virus ORF2 recombinant proteins, expressed in Escherichia coli or baculovirus expression systems, evaluated for their immunogenicity and efficacy in pre-clinical models. The blue colored bars indicate proteins that have undergone clinical evaluation, the light colored vertical bar indicates the location of the neutralizing epitope.
  21. Background Hepatitis E virus (HEV) is an important cause of viral hepatitis. We evaluated the safety and efficacy of an HEV recombinant protein (rHEV) vaccine in a phase 2, randomized, double-blind, placebo-controlled trial. Methods In Nepal, we studied 2000 healthy adults susceptible to HEV infection who were randomly assigned to receive three doses of either the rHEV vaccine or placebo at months 0, 1, and 6. Active (including hospital) surveillance was used to identify acute hepatitis and adverse events. The primary end point was the development of hepatitis E after three vaccine doses. Results A total of 1794 subjects (898 in the vaccine group and 896 in the placebo group) received three vaccine doses; the total vaccinated cohort was followed for a median of 804 days. After three vaccine doses, hepatitis E developed in 69 subjects, of whom 66 were in the placebo group. The vaccine efficacy was 95.5% (95% confidence interval [CI], 85.6 to 98.6). In an intention-to-treat analysis that included all 87 subjects in whom hepatitis E developed after the first vaccine dose, 9 subjects were in the vaccine group, with a vaccine efficacy of 88.5% (95% CI, 77.1 to 94.2). Among subjects in a subgroup randomly selected for analysis of injection-site findings and general symptoms (reactogenicity subgroup) during the 8-day period after the administration of any dose, the proportion of subjects with adverse events was similar in the two study groups, except that injection-site pain was increased in the vaccine group (P = 0.03). Conclusions In a high-risk population, the rHEV vaccine was effective in the prevention of hepatitis E. (ClinicalTrials.gov number, NCT00287469.)
  22. 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. 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. 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 (hepatitisB 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.