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1、Comparative Evaluation of Two Hemagglutinating Encephalomyelitis Coronavirus Vaccine Candidates in Mice Keyan Chen,a,bKui Zhao,aWenqi He,aWei Gao,aChuanbo Zhao,aLi Wang,aWei Pan,aDeguang Song,aChengli Wang,band Feng Gaoa College of Animal Science and Veterinary Medicine, Jilin University, Changchun,
2、 China,aand Laboratory Animal Department, General Hospital of Shenyang Military Area Command, Shenyang, Chinab Porcinehemagglutinatingencephalomyelitis(PHE)iscausedbythecoronavirushemagglutinatingencephalomyelitisvirus (PHE-CoV),andtherecent,rapidspreadofPHE-CoVinpigletsfrommanycountriesemphasizesth
3、eurgentneedforaPHE- CoVvaccine.Hereweuseamurinemodelforevaluationoftheinductionofhumoralandcellularimmuneresponsesbyinacti- vatedandPHE-CoVDNAvaccinesinordertodefi netheimmunecorrelatesforprotectionagainstPHE-CoV.Theinactivated vaccinewascomposedofpurifi edPHE-CoVandaluminumhydroxidegel(alum),whichw
4、aschosenasanadjuvantbecauseofits longhistoryofsafetyforhumanuse.ThePHE-CoVDNAvaccinewasconstructedbysubcloningtheS1geneofPHE-CoVinto thepVAX1vectortocreatetherecombinantplasmidpV-S1.OurresultsshowedthattheinactivatedPHE-CoVvaccine(IPV) elicitedahighlevelofhumoralimmunity,resultingingoodprotectioneff
5、i cacyagainstPHE-CoVchallenge.TheIPVinducedthe IgG1subclassofserumantibodiesandexpressionofthecytokineinterleukin-4(IL-4),suggestingthattheIPVgeneratedapre- dominantlyTh2-typeimmuneresponse.TheDNAvaccinewasfoundtomediateprimarilyacellularimmuneresponsewithhigh levelsofIgG2aandthecytokinesIL-2andgamm
6、ainterferon(IFN-?).However,micethatwerevaccinatedtwicewiththeDNA vaccineandboostedwiththeIPVcouldmountasuffi cientneutralizingantibodyresponseagainstlivePHE-CoV,withlittlevari- ationinIgG1andIgG2alevels,andshowedhighlevelsofIL-2andIL-4.ThisresponsemayactivatebothBandTcellstomounta specifi chumoralan
7、dcellularimmuneresponsethatcould,inturn,elicitaphagocyte-mediateddefenseagainstPHE-CoVinfec- tionstoachieveviralclearance. P orcinehemagglutinatingencephalomyelitis(PHE)isanacute, highly contagious disease in piglets that is caused by the coro- navirus hemagglutinating encephalomyelitis virus (PHE-C
8、oV), which is a member of the Coronaviridae family (6). PHE-CoV infects mainly piglets under the age of 3 weeks and causes vomit- ing, exhaustion, and obvious neurological symptoms. The mor- talityraterangesfrom20to100%(11).In1962,thepathogenwas isolated for the fi rst time in vivo from breastfeedin
9、g pigs suffering from encephalomyelitis in Canada (12). In 1969, an antigenically identicalviruswasisolatedinEnglandfromsucklingpigsshowing anorexia, depression, and vomiting but no clear signs of enceph- alomyelitis(10).Animalsthatdidnotdiehadstuntedgrowth,and thus, the condition was called “vomiti
10、ng and wasting disease” (VWD). Mengeling and Cutlip (22) were later able to reproduce both forms of the disease experimentally using the same fi eld iso- lates. PHE has been reported in all of the major pig-producing countriesofEurope,Asia,andNorthAmerica,whereitappearsto be endemic with no clinical
11、 outbreaks (5, 22). PHE-CoV was fi rst reported in China in 1986; eventually, it occurred both on the mainland and in Taiwan Province (6). Studies of the chemical composition of PHE-CoV (4, 23) have revealed that it is an RNA virus with fi ve polypeptides, four of whichthe nucleocapsid (N), membrane
12、 (M), spike (S), and hemagglutinin-esterase (HE) proteinsare glycosylated. The coronavirus S glycoprotein is a major determinant of neuroviru- lence(16,34)andisresponsibleforviralattachmenttothecellular receptor and for fusion of the viral and cellular membranes, re- sulting in virus entry. The S gl
13、ycoprotein can also induce neutral- izing antibodies in vivo or in vitro, as well as cell-mediated immu- nity (1). Many viral antigens (19), including S1 from transgenic plants, have been demonstrated to be effective at inducing muco- sal and serum immune responses in animals. The natural host of PH
14、E-CoV is the pig, but the virus has been adapted experimen- tally for replication in mice and Wistar rats (36). The virus is neurotropicinmice,butsusceptibilitywasfoundtobeinfl uenced by age and the route of inoculation (37). Under experimental conditions, the disease has been reproduced in most ins
15、tances following oronasal exposure of nonimmune pigs to PHE-CoV duringthefi rstfewweeksoflife(2).Clinicalsignsmayvary,how- ever. In a study in which the virulence of several PHE-CoV fi eld isolates was compared, symptom severity was related to differ- ences in host susceptibility and the apparent vi
16、rulence of each isolate (22). In contrast, older pigs and neonatal pigs that had receivedantibodiesincolostrumwereusuallyclinicallyunaffected when they were exposed to PHE-CoV under otherwise similar conditions (2). Thus, neonatal pigs are usually protected by pas- sively acquired colostral antibodies, and they subsequently de- velop an age-related resistance to the potential clinical effects of the virus. Recently, the incidence of PHE among pigs in many countries was found to be on the rise, r
