[CANCER RESEARCH (SUPPL.)45, 4689s-4690s, September1985] Unconventional Vaccines: Immunization with Antildiotype Antibody against Viral Diseases' H. Koprowski TheWistarinstitute,Philadelphia,Pennsylvania19104 Theconceptofantiidiotypevaccinesrelatestothegeneration forproductionofAb@inrabbitsdidnotneutralizethevirusbut of immuneresponseto an antigen(virus,bacteria,parasites)by did bind to viral glycoproteins.The Ab@elicitedin mice after immunizationofthehostwithan immunoglobulinthatdefinesa immunizationwiththe Ab@antibodynotonlyboundto viral specificregionon the anti-pathogenantibodymoleculeand in glycoproteinbutalsoneutralizedthevirus(7). In the nonviral turn engendersan antibodythat mimicsin its functionsuch an antigenfieldAb@elicitedbyimmunizationwitha-Id monoclonal anti-pathogenantibody.Thetheoreticalbasisfor thisconcept antibodyagainstanti-fructosanantibodydifferin their reactivity canbe foundinthe immunenetworktheoryfirstproposedby patternsto anti-fructosanantibodiesproducedafter immuniza Jerne(1)inwhichtheinterplayofantigen-bindingsitesonanti tionwithbacteriallevan(10). bodymoleculesandhostimmunocytesleadsto theexistenceof severaltypes of antibodiesdevelopedsequentiallyinthe same Advantagesofa-Id ViralVaccines individualimmunizedagainsta givenantigen(see “Glossary―). The aim of immunizationwithanti-idiotypeantibodyis to The existenceofa-Id antibodiesdirectedto cross-reactive producean antibody(Ab3)reactingwith the antigenin such a idiotypessharedby anti-viralantibodiesofdifferentfinespecific waythatit willprotectthehostfromthedisease.Thishasbeen itiesmaymakeit moredifficultfora virusto escapeimmune achievedin severalviralinfections.As shownin Table1 immu surveillance by antigenic variation. A virus may evade immune nizationof micewith a-Id2led to the developmentofvirus defensesifitexistsinnatureinmanyantigenicvariantformsas reactiveantibodiesinseveralviralsystems.Inthecaseof reo maybethecaseinthehumanT-cellleukemiavirusfamilyorifit virus(2)andSendai(3)it wasalsopossibletogeneratevirus acquires antigenic changes in the course of infection within the specificcytotoxicT-ceIIsafterimmunizationofmicewith mono sameindividualhost; the latter is particularlyimportantin the clonala-Idantibodies.Inthecaseof hepatitisBvirus,theAb@ caseof twootherretroviruses,visna(11)andequineinfectious engenderedbyimmunizationwitha-Id boundto a peptide(4) anemia(12). that may represent part of an a determinantwhich induces Theotherobviousadvantageina-Idvaccinesistheabsence commonId(5). of the viralantigen.Thiscircumventstheoftentortuousand Mice immunizedwith a-Id to Sendai monoclonalantibody sometimesunpredictablesearchfortracesoflivenoninactivated resistedchallengewiththehomologousvirus(3).Withrabies(6) virusina productthatisultimatelyusedforhumanconsumption. andpolioviruses(7)thelevelofneutralizingAb@wasapparently Forinstanceinthecaseofhighlyinfectiousandhighlycontagious too low to protectagainstchallengebuta boosterinjectionwith Venezuelanequineencephalomyelitisvirustheproductionofviral a nonimmunizingdoseof vaccine(toolowfor immunizationof vaccinesthat were completelyinnocuousfor intracerebrallyin naivemice)enabledthesemiceto resistviralchallenge(6).In jectedguineapigsendedincausingdiseaseinhumansimmu thecaseofhepatitisBvirusoneinjectionofa-Iddidnotengender nizedwithsucha vaccine(13—15).Contrastthiswiththe a-Id hepatitisB-specificantibodybutmultipleinjectionsora booster vaccineinwhichviralantigenis in no way involved(16). inoculationwitheither122—137peptideorinactivatedhepatitis Furtheradvantagesofa-Id vaccinesmaybe theirabilityto B virusresultedin an immuneresponse(8). induceimmuneresponsesinhostswhoareincapableofrespond In generala-Id antibodiesthatengenderedantigen-reactiveing directlyto an antigen.For exampleinfantswho do not Ab3werecross-reactiveforidiotopescommontomanyantibody respondwelltovaccinationwithStreptococcuspneumoniaemay preparationsgeneratedindifferentanimalspecies. beableto developimmunitybyimmunizationwitha-Id.Animal The dosageof a-Id seemsto be of importanceinorderto studieshaveshownthattreatmentatbirthwithmonoclonala-Id produceantigen-reactiveAbe.Rabies-reactingAb@wasinduced antibodiesto levan-bindingproteinsfollowedby a boosterinoc afterimmunizationofmicewith2.5 or 1.25 @gofa-Idforoneof ulationwiththe samea-Id antibodygeneratesalevan-specific the threeimmunizinginjectionsbutnot with dosesequalor antibodyresponse(10). greaterthan5 or lessthan1.25 jzg(9).Polio-reactiveAb@was elicitedonlyafterimmunizationofmicewitheither5or0.5 @gof a-Id(7). a-Id forAIDS FunctionsandspecificitiesoftheAb@elicitedbyimmunization Inthecaseof AIDScompleteinactivationoflivinghumanT witha-Id antibodiescannotalwaysbe predictedasshownby cellleukemiavirusIllmaypresentaformidableproblemifwhole theresultsobtainedinmiceimmunizedwithpolyclonalrabbita- virusvaccineswerethe immediategoal.Vaccinesbasedon Id antibodyOneof theanti-rabiesmonoclonalantibodiesused noninfectiousviral components may be in the offing. At the same 1 Presented at the HTLV Symposium, December 6 and 7, 1984, Bethesda, MD. timeproductionofa-Id antibodiesbyimmunizationofanimals This work was supported in part by research grant Al-09706 from the National with purifiedidiotypesobtainedfrom a groupof healthyindivid Institute of Allergy and Infectious Diseases. 2 The abbreviations used are: Id, idiotype; AIDS, acquired immunodeficiency ualswho were exposedto AIDS may be anotheravenueto syndrome. follow.Whenthe a-Idsare produceditis hopedthattheywill CANCERRESEARCHVOL.45 SEPTEMBER1985 4689s Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1985 American Association for Cancer Research. IMMUNIZATION WITH ANTI-Id ANTIBODY Table1 Immunityofmiceagainstvirusesfollowingimmunizationwithanti-idantibodies Anti-Id anti bodies pro a-IdTobacco Wus duced in ClassCross-reactivityImmunity of miceimmunizedwith mosaic Rabbit interspecies antibodies antibodyRabiesPolyclonalSpecificReoPolyclonal Mouse MonoclonalCross-reactiveCross-reactiveinterspeciesNeutralizing CytotoxicT-cel@'neutralizing antibodyHepatitis Aabbit for monoclonalantibody idi otypesNeutralizing PeptideSandalMouseMonoclona?'Non-H-2BRabbitPolyclonalCross-reactive interspeciesBinding to HepatitisBantigenandto challengeVenezuelan restricted122-137 Cytotoxic T cells; resistanceto antibodytiePolioequine encephalomyeli RabbitPolyclonalCross-reactive interspeciesNeutralizing IIMouseMonoclonalCross-reactiveNeutralizing antibody a @c@teasily generated when hybridoma cells are used for @nmunization. b@@ted by immunization with T-cell receptor specific for Sandal virus. cross-reactwith Id sharedby antibodypreparationsfrommany 1.Syngeneicmonoclonalanti-ldiotypeantibodyidentffiesacellsurfacereceptor for reovirus.J.Immunol.,131:2533—2538,1983. differentindividuals.Thedosagefor effectivevaccinationwitha- 3. ErtI,H.C.,andF@mberg,A.W.SandalvirusspecificTcellclones:inductionof Idswouldhavetobecarefullyinvestigated.Whatremainsunpre cytolyticT cellsby an anti-Idiotypicantibodydirectedagainsta helperTcell done.Proc.Nati.Aced.Sci.USA,81:2850—2854,1984. dictableatpresentisnotonlythespecificitybutalsothefunctions 4. Kennedy,A. C., Dreesman,G. A., Sparrow,J. T., Cuiwell,A. R., Sanchez,V., of Abe,i.e.•whetherthey will ultimatelybeableto stopthe lonescu-Matiu,I.,Holhnger,F.B.,Melnick,J.L Inhibitionofacommonhuman infection. anti-hepatitisBsurfaceantigenidiotypebya cyclicsyntheticpeptide.J.Wol., 46: 653-655, 1983. Whateverthe answer may be efforts to proceedare worth 5. Kennedy,A. C., Sanchez,V., tonescu-Matiu,I.,Melnick,J. L, andDreesman, while,particularlysincetoolsto studythis problemarenow G.A.Acommonhumananti-hepatitisBsurfaceantigenidsOtypeisassociated withthegroupaconformation-dependentantigenicdeterminant.Virology,122: availableandnotimeshouldbelostinstartingtheseinvestiga 219—221,1982. tions. 6. Reagan,K.J.,wunner,w.H.,Wiktor,T.,andKoprowski,H.Anti.idiotypic antibodiesinduceneutralizingantibodiestorabiesvirusglycoproteins.J.Virol., 48: 980-666, 1983. Glossary 7. UydeHaag,F. G. C. M., and Osterhaus,A. D. M. E. Inductionofneutralizing antibodyinmiceagainstpoliovirustypeII withmonoclonalanti-idiotypic Inordertociarifytheterminologyusedinthispublicationthefollowingglossary body. J. Immunol, 134: 1225—1229,1985. is offeredtothereader. 8. Kennedy,A.C.,Sparrow.J.T.,Sanchez,V.,Melnick,J.L, andDreesman, G. A. EnhancementofviralhepatitisBantibody(antl-HBs)responsetoa Epitope: antigenic determinant of moleculesother than @nmunogIobulins. synthetic cyclic peptide by priming with anti-idiotype antibodies. Virology, 136: Idiotope: an antigenic determinant formed by the variable regions of the heavy 247—252,1984. and/or light chains of an antibody molecule. An idlotope that mimics an epltope of 9. Koprowsld,H.,Wsktor,T.J.,Reagan,K.,Mactartan,A.,andDietzschold,B.A a foreign protein is referred to as internal image. newgenerationofrabiesvaccines:rabiesglycoproteingenerecombinants, Abs:antibodies that would be induced by and react with epitopes present on an anti-dotypicantibodiesandsyntheticpeptides.In: ModemApproachesto antigen used for vaccination. Vaccines:MolecularandOnemicalBasisofAeSiStancetoWal, Bacterial,and Abe: antibodies generated in response to and reacting with idiotopes of Ab@. Parasitic Diseases. Proceedingsof meeting in September 1984. Cold Spring This set of antibodies is further subdivided into: Harbor, NY: Cold Spring Harbor Laboratory, in press, 1985. Ab@:antibodies binding to framework-associated idiotopes. 10. RUbinStein,L J., Goldberg,B., Inemaux,J., Stein, K. E., and Bone, C. A. Ab,@:antibodiesbinding to combining-site