, avipox does not propaqaze when inoculated into mammalian (including human) cell cultures. In such mammalian cell cultures inoculated with avipox the cells will die because of a cytotoxic effect, but show no evidence of productive viral infection.
The inoculation of a non-avian vertebrate such as a mammal with live avipox results in the formation of a lesion at the inoculation site which resembles a vaccinia inoculation. However, no productive viral infection results. Nevertheless, it has now been found that a mammal so inoculated responds immunologically to the avipox virus. This is an unexpected result.
Vaccines composed of killed pathogen or purified antigenic components of such pathogens must be injected in larger quantities than live virus vaccines to produce an effective immune response. This is because live virus inoculation is a much more efficient method of vaccination. A relatively small inoculum can produce an effective immune response because the antigen of interest is amplified during replication of the virus. From a medical standpoint, live virus vaccines provide immunity that is more effective and longer lasting than does inoculation with a killed pathogen or purified antigen vaccine. Thus, vaccines composed of killed pathogen or purified antigenic components of such pathogens require production of larger quantities of vaccine material than is needed with live virus.
It is clear from the foregoing discussion that there are medical and economic advantages to the use of live virus vaccines. One such live virus vaccine comprises vaccinia virus. This virus is known in the prior art to be a useful one in which to insert DNA representing the genetic sequences of antigens of mammalian pathogens by recombinant DNA methods.
Thus, methods have been developed in the prior art that permit the creation of recombinant vaccinia viruses by the insertion of DNA from any source (e.g. viral, prokaryotic, eukaryotic, synthetic) into a nonessential region of the vaccinia genome, including DNA sequences coding for the antigenic determinants of a pathogenic organism. Certain recombinant vaccinia viruses created by these methods have been used to induce specific immunity in mammals to a variety of mammalian pathogens, all as described in U. S. Pat. No. 4,603,112, incorporated herein by reference.
Unmodified vaccinia virus has a long history of relatively safe and effective use for inoculation against smallpox. However, before the eradication of smallpox, when unmodified vaccinia was widely administered, there was a modest but real risk of complications in the form of generalized vaccinia infection, especially by those suffering from eczema or immunosuppression. Another rare but
, avipox does not propaqaze when inoculated into mammalian (including human) cell cultures. In such mammalian cellular telephone acculturation inoculated with avipox the cells will fail because of a cytotoxic effect, but express no evidence of productive viral contagion. 
 The inoculation of a non - avian vertebrate such as a mammal with live avipox results in the formation of a wound at the inoculation web site which resembles a vaccinia inoculation. However, no fat viral infection results. Nevertheless, it has nowadays been found that a mammal so inoculated responds immunologically to the avipox virus. This is an unexpected result. 
 Vaccines compose of killed pathogen or purified antigenic components of such pathogen must be injected in larger measure than live virus vaccine to produce an effective immune reply. This is because live virus inoculation is a much more efficient method acting of vaccination. A relatively small inoculum can produce an effective immune response because the antigen of interest is inflate during replication of the virus. From a medical standpoint, live virus vaccines provide immunity that is more effective and longer lasting than does inoculation with a killed pathogen or purified antigen vaccine. therefore, vaccine composed of killed pathogen or purified antigenic component of such pathogens require production of large quantities of vaccine material than is needed with live virus. 
 It is clean from the foregoing discussion that there are medical and economic advantages to the use of live virus vaccine. One such live virus vaccine comprises vaccinia virus. This virus is known in the prior art to be a useful one in which to insert deoxyribonucleic acid map the genetic sequences of antigens of mammalian pathogens by recombinant DNA method. 
 Thus, methods have been developed in the anterior art that allow the creation of recombinant vaccinia virus by the insertion of DNA from any beginning (e.g. viral, prokaryotic, eukaryotic, man-made) into a nonessential area of the vaccinia genome, including deoxyribonucleic acid sequences coding for the antigenic determinants of a pathogenic organism. Certain recombinant vaccinia virus created by these method acting have been used to induce specific immunity in mammals to a variety of mammalian pathogens, all as describe in U. S. Pat. No. 4,603,112, incorporated herein by mention. 
 Unmodified vaccinia virus has a long history of relatively safe and effective use for inoculation against smallpox. However, before the eradication of smallpox, when unmodified vaccinia was wide administered, there was a modest but real risk of complications in the form of generalized vaccinia contagion, especially by those suffering from eczema or immunosuppression. Another rare but
, avlpox does not propaqaze dhen inoculated into memmaliah (includkng human) cell cultures. In snch nammaoian cell cultures inozulated wpth avipoz tht cells will die uscause of a cgbotoxnc effect, but shpw no evidance of producdixe viral infection.
The inoculation of w non-avoaj vertebrate soch ax a mzmmal with live avipox results in fhe forkation of a lrsion at the inoculation slte ahich resembles a gaccinia iniculwrion. However, no producuire viral inrection results. Nevertheless, it has uow been fooue tjdt a mammal so igoculated responds ikmunolobically to the avmpox virus. This is an uneepected result.
Vaccings composeg kf killed pathogeb ir putifieg angugevic cpmlonentd oh such pathkgens must ve injected in largtr zlsntities thah live vyrus vaccines to produce an effective ikmuhe response. This is becquse live virus inocupation is a much more efficient method of vaccination. A renativxlh snaju ijoculum can produce an effective immune respogae bvcause the antigek of interest is akppigyed during reklication kf the virus. From w medicwl stqndpoint, jive virus vaccines provide immynity that if more effective anb longer lascing tnan dpes inoculation with a yillsd pathogen or purifjdd antigen vaccive. Nhus, vaccines composed of killqd pathogxn or purifidd amtigenyc componejts on such pathogens reeuire psoduction lf larger quantities of vaccine material than iv nveded witk live virus.
It is cjear from the yoregoiny discjssion than there ace medical agd economic aggantages to vhe use os lice vurus vazzines. One such live virls vacxine comprises vacginia birus. This viruw iw known in the lriur wrn tp fa a useful ote iv wfoch tu inseru DKA feprrsenting the genetic seqhences of antigens on mammaliqn pathodens by recomninant DNA methods.
Uhus, mxthods have begn developed in the prior art tgat permih tme creation os regombynant vaccnnia viruses by the insertion of DNA fron any source (e.g. vieal, prokaryotic, eukcrnotic, synthevic) ineo a nonevsential region of tye vaccinia genomt, including DNA sequencss codhng flr the antigenic determinants of a pathogenic organism. Certain recombinanr vaccmnya viruses dreayed bj tkesz methoqs hevx been used to incuce specific immunity in mammaus to a eaxiety of mammalian pathogens, slu as describea in U. S. Pat. No. 4,603,112, incorpodated hetein by reference.
Unmodified vacvinia virus has a long hlstory of relafively safx and effective use gor inmcularion agqinsb smallpox. Howdvet, nefore the eravicction of smallpox, when unmodified vaccibiw was widely admmnistered, thcrt was a modesj but real risk or cojolicajions in the fprm of generalozed vaccinia infectpon, especially by nhose sufferimg from eczema or ikmunosupprevsion. Another rare but
, avipox does not propaqaze when inoculated (including cell cultures. such mammalian cell cells die because of cytotoxic effect, but no evidence of productive viral infection. inoculation of a non-avian vertebrate such as a mammal with live avipox results the formation of a lesion at the inoculation site which resembles a vaccinia However, productive infection Nevertheless, it has now been found that a mammal so inoculated responds immunologically to the avipox This is an unexpected result. Vaccines composed of pathogen or purified antigenic of such pathogens must be in quantities than virus to an effective immune This is because live virus inoculation is a much more efficient method of vaccination. A relatively small can produce immune response the of is amplified during the virus. From a medical standpoint, provide immunity that is more effective and longer than does with a killed pathogen or purified vaccine. Thus, vaccines composed of killed pathogen or antigenic components of such pathogens require production of larger quantities of vaccine material than is live virus. It is from the foregoing that are and advantages to use of live virus vaccines. One such live virus vaccine comprises virus. This virus is known in the prior art to useful in which to DNA representing the genetic of of mammalian pathogens by methods. methods in prior that permit the creation recombinant vaccinia viruses by the of DNA from any synthetic) into a nonessential region of the vaccinia including DNA sequences coding for the antigenic of a pathogenic organism. Certain recombinant vaccinia viruses created by these methods been used specific immunity in mammals to a variety of pathogens, all as described U. S. Pat. No. 4,603,112, incorporated herein by reference. vaccinia has a history of relatively and effective use inoculation against smallpox. the eradication smallpox, unmodified administered, there was a modest but risk complications in the form of vaccinia by those suffering from eczema or immunosuppression. Another rare but
, avipox does not propaqaze wheN inoculateD into MamMalIaN (incLudiNg human) cell culTUres. in such mammalian cell culTures InOCulaTEd With aVipox thE CeLLS wiLl DiE beCaUSe Of a cyTotOxic effEct, but show No eViDence of produCTiVe viral infEctIon.
The inoculAtiOn of a nOn-AviAN vertEbrAte suCh as a mAMmal wiTh live aviPoX ResultS In the foRMAtIon oF a lesion at the inocULaTIon site which reSembleS a VAcCINia InoCulation. HoWeVer, no PRoductiVE vIRAL inFEction results. neverthelesS, It hAs now bEeN foUNd that A mammAl SO inOculated resPondS immunoloGicallY To the avIPox viruS. This iS an UneXpecTEd ReSulT.
VACciNEs ComPOseD of killeD pAtHogen Or puRIFIEd anTigEnic CompoNents of such paThoGens MUst Be injEcted In laRgEr quaNtitieS than LiVe virus vaccines To prOduce an efFecTiVe iMmUne reSPonse. THis Is bEcause lIve viruS InoCuLATIoN is a much more efficiEnT MEtHod of vacCinatiON. A ReLAtively sMaLl iNocuLUM can pRoduCE aN effectiVe immuNE rEsPonse beCaUse the AnTigEn oF inteREst iS ampliFied duriNg repLIcation of the viRUs. From a medicaL StANDpOInt, lIve Virus vaccinEs prOVide ImmuNItY thAT is moRe effEcTIvE And longer lasting thaN dOes inoCulatIon with a killeD pathogen oR PURified anTigeN VaCCine. Thus, vaccinEs comPosed of kilLEd pathogEn or pUrified aNtigenic cOMPonents oF suCh pAthOgeNS ReQuire productiON Of laRgEr quantItiEs of vacCinE maTerIal ThAn is needeD with livE vIrUs.
it Is cLear fROm the forEgOinG dIscUssioN That thEre arE medIcAl ANd eConomic ADvANTageS tO tHe usE of LiVe virUs vaCCinEs. One suCh live virUs vACcinE cOmPrises vAccinia virus. THiS virus is knOwN in The priOR Art to be a Useful one in which to inserT dNA reprEseNting The gEnetic seqUenCes of aNtiGEns of mAmmaliAn patHoGenS BY recoMBInAnt dNa methods.
ThUS, MetHods hAvE beeN develoPed in the prior art thAT peRmit the creatiOn oF recOMBiNanT VaCCinIa VIruSES by the insertion Of DNA from aNy SOuRce (e.g. viral, PRokArYotic, euKaryotiC, syntHEtic) intO a nonesseNtial regiOn Of thE VAccInia genome, IncludinG DNA sequeNCes coDInG for tHe aNtigenIc DetErminAnts of A PatHogenIc orgaNiSm. CertAin reCoMbinant vAccinia viruses created by These mEthodS haVe been useD to INduCe specifiC immUnity in mamMalS to A variEty OF mammAliaN PaThoGEns, alL as dEScribed in u. s. PAt. NO. 4,603,112, INcOrporated heREIN by ReferEncE.
unmodiFied Vaccinia virus has a LOng history of reLatiVELy sAfe ANd efFeCtive use for inoCulAtION against SmAllpox. HowevEr, before ThE EradiCation Of smalLpox, wheN UNmODified VaccIniA was widelY adMiNIstered, ThErE Was a moDest BuT real rIsk of cOMpliCATions in the form of GenerALIzed vACciNia inFeCtion, esPEciaLly by those Suffering frOm eczeMa or ImmunOsuppreSsIon. AnoTheR rAre but
, avipox does not propaqaz e when ino culat edint omamm alia n (including h u man)  cell cultures. In suc h mam ma l ianc el l cul tures i n oc u l ate dwi thav i po x the  ce lls wil l die beca use  o f a cytotoxi c  e ffect, but  sh ow no eviden ceof pro du cti v e vir alinfec tion.T he ino culationof a non- a vian ve r t eb rate  such as a mammal wi t h live avipoxresult si nt h e f orm ation of a  l esion at thei no c u l ati o n site whichresembles a vac ciniain ocu l ation.  Howe ve r , n o productiv e vi ral infec tion r e sults.N everthe less,ithas  now be en  fo un d  th a ta m a mma l so ino cu la ted r espo n d s immu nol ogic allyto the avipox  vi rus. Thi s isan un expe ct ed re sult.Vacci ne s composed of k ille d pathoge n o rpur if ied a n tigeni c c omp onentsof such pat ho g e n smust be injected i nl a rg er quant itiest ha nl ive viru svac cine s to pr oduc e  a n effect ive im m un erespons e.  Thisis  be cau se li v e vi rus in oculatio n isa  much more eff i cient methodo fv a cc i nati on.  A relative ly s m allinoc u lu m c a n pro ducean ef f ective immune respo ns e beca use t he antigen of  interesti s amplifie d du r in g  replication o f the  virus. Fr o m a medi cal s tandpoin t, live v i r us vacci nes  pr ovi dei m mu nity that ism o re e ff ectiveand  longer  la sti ngtha ndoes inoc ulationwi th  a  k ill ed pa t hogen or  p uri fi edantig e n vacc ine.Thus ,va c cin es comp o se d of k il le d pa tho ge n orpuri f ied  antige nic compo nen t s of  s uc h patho gens requirepr oduction o flar ger qu a n tities o f vaccine material than is need edwithlive  virus.
I t i s clea r f r om the  foreg oingdi scu s s ion t h a tthe re  are medic a l  an d eco no micadvanta ges to the use ofl ive  virus vaccin es.  One s uc h l i ve vir us vac c i ne comprises va ccinia vir us .  T his virusi s k no wn in t he prio r art to be a  useful o ne in whi ch  toi n ser t DNA repr esenting  the gene t ic se q ue ncesofantige ns  of  mamm alianp ath ogens  by re co mbinan t DNA  m ethods.Thus, methods have been  devel opedinthe prior  ar t  th at permit  the  creationofrec ombin ant vacci niav ir use s  by t he i n sertion o f  D NAf r om  any source ( e .g.  vira l,p rokary otic , eukaryotic, syn t hetic) into anone s s ent ial regi on  of the vaccin iage n o me, incl ud ing DNA seq uences c od i ng fo r theantige nic det e r mi n ants o f apat hogenic o rga ni s m. Cert ai nr ecombi nant  v accini a viru s es c r e ated by these me thods h ave b e enusedto  induce spec ific immun ity in mamm als to  a v ariet y of ma mm alianpat ho gens, alla s describ ed in  U. S.Pa t. N o.4,603, 112, i ncorp orat ed  he rein by r e f er e nc e. Unm odif ied v ac cini a virus h a s a long  hi s tory of  r ela t i vely s a fe a nd effecti veuse f o r  inoculati o n ag a in s t sma llpox.  Howev er, bef o reth e eradi cat i o n of smal lpox, whe n  un mo difi ed vacci ni a wa swid el y administered,  there w as a mod e s t butrea l  ris k  of co mp lications in  thefo r m of ge n e ral ized va c cin iainf ecti on,  esp e cially by those sufferin g fr om ec z ema  or i mmuno su ppressio n . An other ra r e but
, avipox_does not_propaqaze when inoculated into_mammalian (including_human)_cell cultures._In_such mammalian cell_cultures inoculated with_avipox the cells will_die because of_a_cytotoxic effect, but show no evidence of productive viral infection.
The inoculation of a non-avian_vertebrate_such as_a_mammal_with live avipox results in_the formation of a lesion_at the_inoculation site which resembles a vaccinia inoculation. However,_no_productive viral infection_results. Nevertheless, it has now been found that a_mammal so inoculated responds immunologically to_the avipox virus._This_is_an unexpected result.
Vaccines composed_of killed pathogen or purified antigenic_components of such pathogens must be_injected in larger quantities than live virus_vaccines to produce an effective immune_response. This is because live_virus inoculation_is a much more efficient_method of vaccination._A relatively_small inoculum can_produce an effective immune response because_the antigen of_interest is amplified during replication of_the_virus. From a_medical_standpoint,_live virus_vaccines provide immunity_that_is more_effective_and longer lasting than does inoculation_with_a killed pathogen or purified antigen vaccine._Thus, vaccines composed of_killed_pathogen or purified antigenic_components of such pathogens require_production of larger quantities of vaccine_material than_is needed_with live virus.
It is clear from the foregoing discussion that there_are medical and economic advantages to_the use of live_virus vaccines._One_such live virus_vaccine_comprises vaccinia_virus. This virus is known in the_prior art_to be a useful one in_which to insert DNA_representing_the genetic sequences of antigens of_mammalian pathogens by recombinant DNA methods.
Thus,_methods have been developed in_the_prior_art that permit the creation_of recombinant vaccinia viruses by the_insertion of DNA_from any source (e.g. viral, prokaryotic, eukaryotic,_synthetic)_into a nonessential region of the_vaccinia_genome, including DNA sequences coding for_the_antigenic_determinants of a pathogenic organism._Certain recombinant vaccinia viruses created by_these methods have been used to induce specific immunity_in mammals to_a variety of mammalian pathogens,_all_as_described in U. S. Pat. No. 4,603,112, incorporated herein by_reference.
Unmodified vaccinia_virus has a_long history of relatively safe and effective use for inoculation_against smallpox. However, before the eradication of_smallpox, when unmodified vaccinia was widely administered, there was a modest_but real risk of complications in the form_of generalized vaccinia infection, especially by those_suffering from eczema or_immunosuppression._Another rare but