MICR 1531 National Acadamy of Science Article - DNA Vaccines

MICR 1531 National Acadamy of Science Article - DNA...

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Unformatted text preview: Proc.Natl.Acad. Sci. USA Vol.90,pp. 11478-11482, December 1993 Immunology DNA vaccines:Protectiveimmunizationsbyparenteral,mucosal, andgene-guninoculations ELLEN F. FYNAN*, ROBERT G. WEBSTERt, DEBORAH H. FULLERt, JOEL R. HAYNES*, JOSEPH C. SANTORO*, AND HARRIET L. ROBINSON*§ *DepartmentofPathology,UniversityofMassachusettsMedicalSchool,55Lake AvenueNorth,Worcester, MA 01655;tDepartmentofVirologyand MolecularBiology,St.JudeChildren'sResearchHospital,332NorthLauderdale, P.O. Box 318,Memphis,TN 38101-0318;andtAgacetusInc.,8520 UniversityGreen,Middleton, WI 53562 Communicated byBernardMoss, September14,1993 ABSTRACT PlasmidDNAsexpressinginfluenzavirushe- magglutininglycoproteinshavebeentestedfortheir abilityto raiseprotective immunityagainstlethal influenzachallengesof thesamesubtype.Intrialsusingtwoinoculationsoffrom50to 300 pgofpurifiedDNA insaline,67-95% oftestmiceand 25-63% oftestchickenshavebeenprotectedagainstalethal influenza challenge. Parenteral routes of inoculation that achievedgoodprotectionincludedintramuscularandintrave- nous injections.Successful mucosalroutesofvaccinationin- cludedDNA dropsadministeredtothenaresortrachea.Byfar themostefficientDNA immunizationswereachievedbyusing ageneguntodeliverDNA-coatedgoldbeadstotheepidermis. Inmice,95% protectionwasachievedbytwoimmunizations withbeadsloadedwithaslittleas0.4pgofDNA.Thebreadth ofroutessupportingsuccessfulDNA immunizations,coupled withtheverysmallamounts ofDNA requiredforgene-gun immunizations, highlight the potential of this remarkably simpletechniqueforthedevelopmentofsubunitvaccines. Gene vaccines, or the use ofantigen-encoding DNAs to vaccinate,representanewapproachtothedevelopmentof subunitvaccines(1-4,29).A subunitvaccinepresentsonly selectedcomponentsofavirustotheimmunesystem.Prior methodsofsubunitvaccinationhaveusedpurifiedproteinsor viralvectors.Eachofthesemethodshassubstantiallimita- tionsthatwouldbeovercomeiftheimmunizingprotein(and onlytheimmunizingprotein)couldbeexpressedinhostcells. Gene vaccines offerthis opportunity, with immunization beingaccomplishedbyhostcellstakingupandexpressingan inoculatedDNA. Inthispaperwe evaluatehow therouteofDNA inocula- tion affects the ability to raise protective immunity. In undertaking the study, we assumed that the efficacy of differentroutesofDNA immunizationwouldreflectboththe efficiencyofinvivotransfection(DNA uptakeandexpres- sion)and the efficiency with which transfectedcellspre- sentedproteinstotheimmunesystem.Studiesinrodentson the transfection efficiency ofinjectedDNA have demon- stratedthatmuscleis100-1000timesmore permissivethan othertissuesfortheuptakeandexpressionofDNA (5-8). Tissuesalsodifferintheefficiencywithwhichtheypresent antigenstotheimmunesystem.Tissues,suchastheskinand themucosalliningsoftherespiratorytractandthegut,that serveasbarriersagainsttheentryof pathogenshaveasso- ciated lymphoid tissues thatprovide highlevels oflocal immune surveillance(9-15).Suchtissuesalsocontaincells thatare specialized for majorhistocompatibilityclass II-...
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MICR 1531 National Acadamy of Science Article - DNA...

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