This renewal applicationis focusedon three aspectsin the development of novel geneticallyengineered mucosal immunogensconstructedprimarily from a saliva-bindingregion (SBR)of surfaceprotein AgYII of Streptococcus mutuns and a nontoxiccomponentof choleratoxin (CT),the A2/B subunits,as potential candidatesfor inclusion in a vaccine againstdental caries.
SpecificAim 1 will addressthe mechanisms underlyingimmunologicalmemory that maintains long-term and recallablesalivaryIgA antibodyresponses when SBR-CTA2A3is administeredto mice by the intranasalroute, which has previously been shown to be particularlyeffective for inducingthese responses. The followingwill be investigated:the generation and characteristsicsof antigen-specificmemory B and T cells, and the cytokinesthey produce,in the nasal lymphoid tissue and the cervical lymph nodes that drain it; the ability of these cells to serve as precursorsof IgA antibody-secretingcells in salivaryglands;and the uptake and retention of antigenby these tissues.
SpecificAim 2 will develop and refine furthermucosal immunogensbased on the sametechnology, to improve the production and immunologicalproperties of SBR-CTA2/B,to construct and evaluate immunogensfrom other segmentsof AgI/II that may be importantfor protection againstdental caries, and to evaluatethe use of similar immunogensconstructedfrom S. mutuns glucosyltransferase. The immunogens will be evaluated for their immunogenicityin terms of the salivary IgA and serum antibodiesinduced in mice when administeredby the intragastricand intranasalroutes.
SpecificAim 3 will determinethe ability of SBR- CTA2A3 to induce salivary IgA and serumantibody responsesto S. mutuns AgmI in adult human volunteers immunizedorally or intranasallywith this immunogen. This is planned as a small-scale,preclinical experiment,that takes advantageof the known safety and immunogenicity of CTB itself when administeredto humans by these routes, and the previously demonstratedability of CTB to serve as a carrier for other protein antigenscoupled to it either chemicallyorgenetically when these are administeredto experimental animalsby oral orintranasalroutes. The informationobtained will permit clinicaltrials to be proposed for the evaluation of these and similarimmunogensas vaccinesagainst dentalcaries, and demonstratethe utility of this technology for inducing mucosal immuneresponsesthat may be applicableagainstother human infections. 'ERFORMANCE SITE@) (organization,city, state) University of Alabama at Birmingham,Birmingham, Alabama KEY PERSONNEL. See instructionson Page 11.' UsecontinuaH0npages as needed to provide the requiredinformation in the format shown below. Name Organization Role on Project Russell, Michael W. University of Alabama at Birmingham Principal Investigator Wu, Hong-Yin University of Alabama at Birmingham Co-Investigator Jespersgaard,Christina. University of Alabama at Birmingham Post-doctoralFellow Hollingshed,Susan K. Universityof Alabama at Birmingham Co-Investigator PHS 398 (Rev. 5/95) Pa e2 BB Numberpagesconsecutivelyat the bottomthroughout the application. Donat use sufkessuch as 3a, 3b. cc PrincipalInvestigator/ProgramDirector (Last,first, middle): 'RUSSELL, Michael W. ~~ Type the name of the rincipal investigator/program director at the top of each printedpage and each continuation page. (For type specifications,see instructions on page 6.p RESEARCHGRANT TABLE OF CONTENTS Page Numbers Face Page ................................................................................................................................................ 1 Description,
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