Welcome to Scribd, the world's digital library. Read, publish, and share books and documents. See more
Download
Standard view
Full view
of .
Save to My Library
Look up keyword
Like this
1Activity
0 of .
Results for:
No results containing your search query
P. 1
Vaccines for Fertility Manipulation (Chp11-12)

Vaccines for Fertility Manipulation (Chp11-12)

Ratings: (0)|Views: 169|Likes:
Published by Cathalijne Zoete
how vaccines are used to manipulate the human fertility
how vaccines are used to manipulate the human fertility

More info:

Published by: Cathalijne Zoete on Aug 06, 2012
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See more
See less

05/13/2014

pdf

text

original

 
Chapter11
VaccinesforFertilityRegulation
P.D.Griffin
TheresearchobjectivesoftheTaskForceonVaccinesforFertilityRegulationare
to
developvaccinesthatwillsafelyandeffectivelyinhibitfertilizationandvaccinesthatwillsafelyandeffectivelydisruptimplantation.Asaresultoffundingconstraints,theactivitiesoftheTaskForceoverthepasteightyearsorsohavefocusedonthedevelopmentofavaccinedesignedtoneutralizethefunctionsofthehormone,humanchoronicgonadotrophin(hCG),whichisproducedbythetrophectodermofthedevelopingembryoandisessentialforimplanta-tionandthemaintenanceofearlypregnancy.Althoughthereisasubstantialamountofanimaldataontheefficacyofthisnovelapproachtofertilityregulation,thereisalackofrelevantinformationonthelong-termsafetyofsuchamethod.TheTaskForce'smandate,therefore,wastoproduceananti-hCGvaccinecapableofelicitinganimmuneresponsespecifictotheintendedtargetmoleculeinordertoavoidcross-reactionsthatwouldleadtometabolicdistur-bances,theriskofimmunopathologyorotherundesirablesideeffects,bearinginmindthatthisvaccinewillbeusedbyhealthyandfertilewomen.Inordertosatisfythisrequirement,theanti-hCGvaccinedevelopedbytheTaskForceisbasedonasyntheticpeptiderepresentingthehCG-specificcarboxyterminalregionoftheB-subunitofthehormone(B-hCG-CTP).Duringthereportingperiod,theTaskForce'sprototypeB-hCG-CTPvaccinehasbeenevalu-atedinaPhaseIclinicaltrial.Theprincipalobjectiveofthisstudy,involvingpreviouslyelectivelysterilizedwomenvolunteers,wastoassessthenatureandintensityofanysideeffectsassociatedwiththevaccine'suseinhumans.
Summary
Althoughthewomentakingpartinthistrialwerenotatriskofbecomingpregnant,anesti-mateoftheefficacyofthevaccinewasobtainedbymeasuringthelevelofanti-hCGantibodiesthatthevaccineelicitedandthenrelatingthistotheamountofhCGtobeneutralizedinthematernalcirculationattheperi-implantationstageofembryonicdevelopment.TheresultsobtainedinthistrialhaveshownthattheB-hCG-CTPvaccinecanelicittheproductionofanti-bodiestohCGandthattheleveloftheseanti-bodiesappearstobehighenoughtoconferanantifertilityeffectinfertilewomen.Moreover,noseriousorunacceptablesideeffectswereob-servedbytheinvestigatorsnorreportedbythetrialvolunteers.Inviewoftheseencouragingresults,theTaskForceisplanninganotherclini-calstudy,thistimetoevaluatetheantifertilityactionofthisprototypevaccineformulationinfertilewomen.ThedurationoftheimmunityelicitedbytheprototypevaccineusedinthePhaseIclinicaltrial,severalweekstoseveralmonths,iswellshortofthe12-24monthssoughtbytheTaskForce.Inaddition,thecomplexcompositionofthevaccineandthelessthanidealnatureofsomeofitsconstituents,wouldmakethisproto-typeunsuitableforwide-scaleuse.InparallelwiththePhaseIclinicalstudy,therefore,workhascontinuedonthedevelopmentofimprovedandmoreacceptableanti-hCGvaccineformula-tions.Thefirstphaseofthisworkinvolvesim-provingthecurrentvaccine,notablybyincorpo-ratingitintobiocompatibleandbiodegradableslow-releasedeliverysystemstoextenditsdura-tionofaction.Resultsobtainedinthesestudiessofar,indicatethathighlevelsofanti-hCG
177
 
RESEARCHINHUMANREPRODUCTION
immunity,persistingforperiodsinexcessof12months,canbeelicitedwithsuchpreparationsinexperimentalanimals.Thesecondphaseofthisworkisconcernedwithoptimizingtheanti-hCGvaccinetothepointwhereitrepresentsasafe,effectiveandacceptablepre-productformula-tion.Preliminaryresultsindicatethattheuseofacombinationofcarefullyselectedandengi-neeredhCGpeptidesgreatlyenhancestheanti-hCGantibodyresponseandthatalternativecar-riers,adjuvantsanddeliverysystems,offerpromiseintermsofproducingananti-hCGvac-cinewithenhancedefficacy,safetyandapro-longeddurationofactivityfollowingasingleinjection.Duringthereportingperiod,theTaskForcehasimplementedanewresearchprogrammetodevelopavaccinedirectedagainstthetrophob-lastoftheperi-implantationembryo.Incontrasttoearlierstudiescarriedoutinthisarea,inwhichclassicalbiochemicalapproacheswereusedtoisolatetrophoblastmembraneproteinantigensofpotentialinterestforvaccinedevel-opment,theTaskForceisemployingmonoclo-nalantibodies(MABs)andrecentlydevelopedbiotechnologicalproceduresinordertoidentify,isolate,characterizeandselectrelevantmole-culesmoreprecisely.Aspermantigenclassifi-cationsystemhasalsobeeninitiatedbytheTaskForce,usingthesametechniquesandproceduresasforthetrophoblastantigenwork,inanefforttostandardizeandrationalizetheinformationbeinggeneratedbythelargenumberofinvesti-gatorsworkinginthisareawithsupportfromotherinternationalandnationalfundingagen-cies.Thisantigenclassificationprojectiscon-sideredbythemajorityoftheinvestigatorsinthefieldtobeanessentialaidtovaccinedevelopment.Inpreparationforthesenewactivities,theTaskForcecarriedoutaninternational,multicentrecollaborativeprojecttoevaluateandassessthelargenumberofanti-trophoblastandanti-spermMABsthatwerealreadyavailable.Atotalof111MABs,29providinglaboratoriesand42evaluatinglaboratorieswereinvolvedinthisproject,theresultsofwhichwerereviewedinaWHO-sponsoredworkshopheldinconjunctionwiththesixthInternationalCongressofImmu-nologyinToronto,Canada,inJuly1986.Asaresultoftheseinitialstudies,anumberofanti-trophoblastandanti-spermMABshavebeenselectedasreagentsfortheidentification,isola-tion,characterizationandselectionofmoleculesforevaluationascomponentsofprototypeanti-trophoblastandanti-spermvaccines.TheTaskForcehascontinued
to
coordinateitsresearchactivitieswithothervaccinedevelop-mentprogrammeswithinWHOandwithotherinternationalandnationalprogrammesengagedinthedevelopmentoffertilityregulatingvac-cines.Thiscoordinationhasinvolvedparticipa-tionbyrepresentativesofotherprogrammesandagenciesinSteeringCommitteemeetingsoftheTaskForceandbySpecialProgrammerepresentativesinrelevantmeetingsofotheragencies.THERATIONALEFORFERTILITYREGULATINGVACCINEDEVELOPMENTAlthoughthenumberoffertilityregulatingmethodscurrentlyavailableisprobablygreaternowthanatanytimeinthepast,itisstillnotadequatetomeetthewidelyvaryingcultural,religious,personalandserviceneedsofallpopu-lations,particularlyofthoseinthedevelopingcountries.Manyofthesemethodsactbyexert-ingapharmacologicalactionatoneormorepointsinthereproductiveprocess,leadingtothealterationorinhibitionofaphysiologicalfunctionandresultinginanantifertilityeffect.Thisdesiredeffectisoftenaccompaniedbylessdesirablesideeffectsofvaryingtypesandinten-sity,which,togetherwiththeincreasingconcernbeingexpressedaboutthesequelaeoflong-termuseofmanyofthesepreparations,ishavingamajorinfluenceontheiracceptabilityandcontinueduse.
If
vaccinescouldbedevelopedwhichwouldsafelyandeffectivelyinhibitfertility,without
178
 
VACCINESFORFERTiliTYREGULATION
producingunacceptablesideeffects,theywould
be
anattractiveadditiontothepresentarmamentariumoffertilityregulatingmethodsandwouldbelikelytohaveasignificantimpactonfamilyplanningprogrammes.Thetheoreti-caladvantagesthatafertilityregulatingvaccine(FRY)wouldhaveovercurrentlyavailablemethodsoffertilityregulationinclude:(a)lackofpharmacologicalactivityandtheoftenatten-dantsideeffects;
(b)
long-lastingactionfollow-ingonlyoneortwoinjections;(c)administra-tionbyaprocedureassociatedwithpositivehealthbenefits;and(d)lowmanufacturingcostandeaseofdeliverywithinexistinghealthservices.EssentialtothedevelopmentofFRVsistheidentificationofcomponentsofthereproductivesystemwhoseneutralizationbyimmunologicalmeanswillresultinasafe,effectiveandaccept-ableantifertilityeffect,aswellastheidentifica-tionofappropriateanimalmodelsinwhichrele-vantpreclinicalstudiesofvaccinesafetyandefficacycan
be
carriedout.OPTIONSFORFERTILITYREGULATINGVACCINEDEVELOPMENTMammalianreproductionisahighlycomplexbiologicalprocessinvolvingdiverseandspecial-izedmolecularsystemsandourknowledgeofthenumberandtypeofmoleculesthatarebothspecifictoandessentialforsuccessfulreproduc-tionisrapidlyincreasingastheresultofbothclinicalandbasicresearchinthereproductivesciences.Immunizationstudieshavedemon-stratedthatmanyofthesechemicalentities,whensuitablymodified,arecapableofelicitinganimmuneresponsewhichwillneutralizethebiologicalactivityordestroythestructuralintegrityoftheparentmolecule,therebyreduc-ingorinhibitingfertilityintheimmunizedani-mal.Furthermore,thereisasubstantialbodyofinformationlinkingnaturallyoccurringimmu-nitytosomeofthesemoleculeswithcertaintypesofinfertility.Theseexperimentsofmanandofnatureindicatethattherearemanycom-ponentsofthereproductivetissuesthatcouldformthebasisofantifertilityimmunogensforuseinthedevelopmentofFRVs.Whilstvirtuallyeverystepinthereproductiveprocessisaccessibletoimmuneattack,notallrepresentattractivetargetsforFRVdevelop-ment.Immunizationtosomeofthesetargetmol-eculescanresultinalowlevelofantifertilityefficacyand/orcanproduceunacceptablesideeffects,rangingfromminordisturbancesinendocrinefunctionthrough
to
themoreseriousimmunopathologicalsequelaeofauto-immunityandimmune-complexdisease.Inordertoavoidthesepotentialsideeffectsandhazards,itisnec-essarytoselectcarefullythoseimmunogensthatwillproducesafe,effectiveandacceptableanti-fertilityeffects.Ideally,suchcandidatesforFRVdevelopment,wouldneedtobe:essentialforthesuccessofthereproductiveprocess;accessibletoimmuneattack;specifictotheintendedtargetandnotrepresentedinotherbodytissuesorfluids;locatedinasitewhereaspecificandcon-trolledimmunereactionwillhavenoimmuno-pathologicalorotherundesirableconsequences;andpresentonlytransientlyorinsmallconcen-trations.Thesecriteriaaremetbysomemole-culesinthespermmembrane,thezonapellucidaoftheovum,thetrophoblastcellmembraneoftheperi-implantationblastocyst,andintheearlyplacenta.Inaddition,somesecretedproductsofthesetissues,suchashCGfromthetrophoblast,alsoappeartobepromisingcandidates.Proto-typevaccines,incorporatingnaturalandsyn-theticpreparationsbasedonseveralofthesetissue-specificimmunogens,havebeenproducedandevaluatedinanimalandclinicalstudies.CURRENTRESEARCHONFERTILITYREGULATINGVACCINESThereiscurrentlyamajorinterestinFRVsinmanycountriesandseveralnationalandinterna-tionalagenciesarefundingworkinthisarea.Thesestudiescovervirtuallyallaspectsofbasicresearchonthemoleculareventsinvolvedingametogenesis,comparativeevaluationofinter-actionsbetweenmonoclonalantibodies,biosyn-thesisofantigensusingrecombinantDNAtech-niques,andclinicaltrialsofprototypevaccineformulations.TheNationalInstituteofChildHealthandHumanDevelopment(NICHD)inBethesda,179

You're Reading a Free Preview

Download
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->