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    HEV vaccine in China

    2018-11-28 11:26:46DongNaMouJingyiAlexanderPloss
    特別健康·下半月 2018年9期

    DongNa MouJingyi AlexanderPloss

    [Abstract] Hepatitis E caused by hepatitis E virus (HEV) is one of the most common, enterically transmitted forms of viral hepatitis. At least 20 million cases of HEV are reported every year. HEV causes usually an acute, self-limited infection but frequently results in fatal disease in pregnant women and chronic infection in immunocompromised patients. Current treatment consisting of pegylated interferon and ribavirin is non-specific and has considerable side effects. A vaccine based primarily on inducing neutralizing antibodies has been developed but it is currently only licensed in China. The vaccine used a truncated ORF2 amino acid (aa) sequence of genotype (gt) 1 to neutralized gt 4, the most prevalent gt in China. In this study we analyzed the impact and accessibility of the HEV vaccine in China. By performing a sequence analysis of the viral capsid sequences from different HEV gt with the ORF2 sequences from the vaccine strain we attempted to make inferences about the efficacy of the vaccine against different HEV gt which have been reported to infect humans.

    【中圖分類號】R392 【文獻標識碼】A 【文章編號】2095-6851(2018)09--01

    1 Introduction

    1.1 Hepatitis E

    Hepatitis E has4 different transmission models,fecal-oral,food-borne,blood-borne and vertical transmission.Although HEV usually causes self-limiting infection with low mortality rates in the western world.It has a high risk of developing chronic hepatitis in immunocompromised patients with substantial mortality rates.Moreover,the diseasemay cause fever,fatigue,loss of appetite,nausea,vomiting,abdominal,pain,jaundice,dark urine,clay-colored stool,and joint pain.Hepatitis E more frequently develops into an acute liver disease,and about3% fatalof all cases.It would complicate by hepatic encephalopathy,hemorrhage,hepatorenal syndrome and secondary infection.Above 70% of the cases are found in15-39 yrs people.

    1.2 Hepatitis E epidemiology

    WHO reported around20 million people are infected each year and about 70,000 deaths per year caused by Hepatitis E globally.The disease has been brought to and isolated in low endemic areas by travelers from high prevalence regions.Reportedly20-40%,the highest seroprevalence of the disease is often found in countries of low socioeconomic status and poor sanitation.Outbreaks happen commonly during rainy season.Or usually occur through water conduits that pass through soil that is contaminated with human excrements,in urban underdeveloped areas.There is also a large proportion of sporadic HEV cases in endemic areas.The mode of transmission or risk factors is not known and whether animal spread plays a role remains a mystery.Specifically in China,Hepatitis E has a prevalence rate of17%.

    1.3 Hepatitis E virus

    HEVis a single-stranded positive-sense RNA genome which encodes3open reading frames ORF1,ORF2,ORF3.The generation of N-terminal truncated virus-like particles have identified3definitive domains,S,M,and P domain.The E2s domain of the capsid protein(pro) has been identified as the major immune target.Recent study shows another enveloped types of HEV.The envelop only includs the phospholipid bilayer membrane.Thus,the eHEV also called “quasi-enveloped”(qHEV).The fraction of HEV enveloped in patient is not fully understand but,presumably,qHEV exists mainly in the serum and less likely in feces since bile salt can destroy the phospholipid bilayer in the gut.ORF1encodes the polypeptide involved in viral replication and pro processing.ORF2encodes capsid pro.ORF3encodes a small,cytoskeleton-associated phosphoprotein.ORF3overlaps ORF2.Neither the assembly nor release of HEV are characterized.It is believed that the ORF2pro packages the viral genome and plays a role in the assembly of progeny virions.The ORF3pro is believed involving in viral egress.A recently study found that it localizes at ER as a transmembrane pro membranes and forms multimeric complexes.More important is that HEV ORF3has ion channel activity.The functional ion channel required for releasing of infectious virions from host cells.HEV ORF3s function as a viroporin may have a potential to be drug target.

    HEVvariants have7 gtwhere gt 5 and 6 have not been reported infection to human.HEV gt1to4 are classfied by the different geographical region.According to WHO HEV gt1is the most prevalent gt in Asia and Africa.As the travellers from other area travel to Asia and Africa,there are HEV casesin Europe,North America and Australia.All gt can form both eHEV and HEV.Membranes form and the ratio of the HEV to eHEV for each gt remained unknown.The life cycle of HEV is unknown,due to the lack of a well-conditioned cell-culture system of HEV.

    1.4 The immune mechanism

    HEV pro capsid is partially enclosed and consist of homodimers of the E2domain.These dimers protrude from the viral surface and involved in the host cell to initiate infection.Several monoclonal antibodies(mAbs) have raised to against all4gt of HEV.A team from Xiamen university showed that gt1HEV is preferentially neutralized by mAb 8C11and specifically involved in the capsid pro at the groove region of E2domain.The mAb 8G12interacts at the dimer interface region,which neutralizes all4gt of HEV.It has a protective,neutralizing capacity that significantly blocks virus infection to host cells.The HEV neutralization mechanism identical with E2domain of capsid pro was instrumental in the development of a vaccine for HEV.

    2 Material and Methods

    7 complete genome sequences(seq) were downloaded from NCBI.The accession numbers are M80581,M74506,HQ389543,HQ634346,AB573435,AB856243,KJ496144.Using translation tool ExPaSy translate all 7 ORF2gt of genes into pro seq.We compare the multiple gene by Multiple Sequence Alignment and CLUSTALW.The accession number of the vaccine HEV p239 is KR027560 from NCBI.Also,a marketing research was did.

    3 Results

    3.1 Vaccine safety and efficacy

    The only approved vaccine HEVP239 also called Hecolin,is in the postmarketing surveillance.So far there is no data about the HEV infected population <16 or> 65 yrs.Serious adverse events rarely happen after the injection of the hepatitis E vaccination.All clinical trials data suggest that the HEVP239 vaccine is well tolerated.The clinical trial reported that in both groups,exist inadvertently administered the vaccine during pregnancy.Although this sample size is small and further study is needed,these data preliminarily suggest that the HEVP239 vaccine is well-tolerated in pregnant women.

    By the report of vaccine,it is effective in the prevention of hepatitis E in the general population in China.If participant did not vaccinate all3doses,it was also beneficial under less than perfect circumstances.The vaccine efficacy after two doses was100%.Therefore the protection against HEV can be quickly obtained by two vaccine doses given within one month during a hepatitis E outbreak,or for travellers to an endemic area.Immunization with this hepatitis E vaccine for up to about4 to 5 years,can induce antibodies against HEV and provid protection against hepatitis E.

    3.2 Price and Accessibility

    As Chinese government does not own the patent of vaccines,they have to call for procurement bid and allocate to different qualified local clinical organization.The price range of HEV vaccine dependes on INNOVAX company and local governments.It is110-190 yuan/dose and might lower than the actual cost.People can only voluntarily vaccinated after informed.More importantly,vaccines can only injected in the particular hospitals.Vaccinees must be able to recognize the official sign of the vaccination certified center and bring personal Vaccination Certificate or Prophylatic inoculation card of the vaccinee.

    3.3 Limited efficacy of vaccine induced cross-neutralizing potential ofin ORF2across different genotypes and antibodies against qHEV

    The minor difference of the ORF2pro among the gtwas shown.There is no big difference between the whole seq and p239 seq.The details for the aa seq shows that in mAb12A10,has4 different sites but in mAb 8G12is less identical among the gt.There is cross-protection between gt1and gt4 of HEV.Also the previse infection of HEV may cause the cross-genotype and cross-host-species protection.However,the cross-protection of the vaccine is uncertain because the limited number of aa and epitopes in the vaccine HEVp239.

    Vaccine induced antibodies against ORF2which is accessible in non-enveloped HEV.But,HEV mostly enters the body through fecal-oral transmission.Non-enveloped HEV is the predominant HEV species in feces whereas qHEV can be found in the blood.Thus,if HEV were transmitted through direct blood contact,the fraction of HEV that is enveloped may not be efficiently neutralized by vaccine induced antibodies,thereby potentially limiting the efficacy of the vaccine.

    4 Discussion

    Each dose of the vaccine is about16.4-28.3dollar,if the government intend to vaccinate the whole country,the expense would be around23-41.8 billion dollar.It occupies about12-22% of the total health expense of the China.Moreover,in some remote region,people cannot easily get the vaccine in designated medical premises for all3dose.We do not recommend coerciveness of this vaccine.However,if there is a severe outbreak of the hepatitis E,government may consider to partly vaccinate some region or partly cover the cost of the vaccination.Based on the high population mobility,it is less effective to vaccinate a specific region than to vaccinate the particular group or people with certain occupation.

    Since Hecolin is a truncated ORF2aa seq of gt1,the vaccine facing a limit in mechanism to neutralize other gt rather than only neutralize the certain gt.Meanwhile,the HEV may mutate and by finding the certain mechanism and the component,the vaccine is not efficiency as it expect.Although the vaccine exits for 5 years,and no safety problem reported,there is still no data for the special populations including the <16,and >65 yrs,pregnant women,persons suffering underlying liver disease or those who are immunosuppressed.In fact,those groups are facing greater threat of HEV infection.

    References

    Donald B.S.,Michael A.P.,Peter S.(2013).Genetic Variability and the Classification of Hepatitis E Virus.Journal of virology.87 (8),4161-4169.

    Li,S.,Tang,X.,Seetharaman,J.,et al,(2009).Dimerization of hepatitis E virus capsid protein E2s domain is essential for virus–host interaction.PLoS pathogens,5(8),p.e1000537.

    Qiang Ding,Brigitte Heller,Juan M.V.Capuccino.(2017).Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles.PNAS.114 (5),1147–1152.

    Surjit M,Jameel S,Lal SK.(2004) The ORF2 protein of hepatitis E virus binds the 59 region of viral RNA.Journal of Virology; 78: 320–328.

    Tang,X.,Yang,C.,Gu,Y.,et al (2011) Structural basis for the neutralization and genotype specificity of hepatitis E virus.PNAS.108,10266 –10271

    W.Huang,H.Zhang,Tim J.Harrison et al.(2008).Cross-Protection of Hepatitis E Virus Genotypes 1 and 4 in Rhesus Macaques.Journal of Medical Virology.80 (0),824–832.

    Xin Yin,Xinlei Li,Zongdi Feng.(2016).Role of Envelopment in the HEV Life Cycle.Viruses.8 (8),229.

    Yamada K,Takahashi M,Hoshino Y et al.(2009) Construction of an infectious cDNA clone of hepatitis E virus strain JE03-1760F that can propagate efficiently in cultured cells.Journalof General Virology; 90: 457–462.

    Zhao Q,Zhang J,Wu T,et al.(2013) Antigenic determinants of hepatitis E virus and vaccine-induced immunogenicity and efficacy.J Gas- troenterol;48:159–68.

    Zhu,F(xiàn).C.,Zhang,J.,Zhang,X.F.,Zhou,et al.(2010) Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale,randomised,double-blind placebo-controlled,phase 3 trial.Lancet 376,895–902

    Z.Tanga,M.Tangb,Min Zhao.(2015).A novel linear neutralizing epitope of hepatitis E virus.Vaccine.33,3504–3511.

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