Project Grant R01DE033759

FLOSS: A NOVEL METHOD FOR ORAL MUCOSAL VACCINATION - FLOSS: A NOVEL METHOD FOR ORAL MUCOSAL VACCINATION THE OVERALL GOAL OF THIS PROPOSAL IS TO DEVELOP A NOVEL METHOD OF ORAL CAVITY MUCOSAL VACCINATION. THE MUCOSAL SURFACES SERVE AS PORTALS OF ENTRY FOR A VAST MAJORITY OF PATHOGENS SUCH AS INFLUENZA VIRUS AND HIV. IT IS RECOGNIZED THAT A STRONG IMMUNE RESPONSE AT BOTH THE MUCOSAL AND SYSTEMIC COMPARTMENTS IS MORE EFFECTIVE AT COMBATING THESE INFECTIONS THAN AN IMMUNE RESPONSE IN JUST THE SYSTEMIC COMPARTMENT. HOWEVER, PARENTERAL INJECTIONS DO NOT STIMULATE STRONG MUCOSAL IMMUNITY. TO ACHIEVE THIS, VACCINES MUST BE DELIVERED THROUGH THE MUCOSAL SURFACES. FURTHERMORE, MUCOSAL VACCINATIONS CAN BE PAINLESS AND BETTER ACCEPTED (OF COURSE DEPENDS ON THE ROUTE) AS COMPARED TO PAINFUL SHOTS. THE ORAL CAVITY IS AN EXTREMELY ATTRACTIVE ROUTE FOR DELIVERING VACCINES DUE TO IT'S EASE OF ACCESSIBILITY AND THE RELATIVELY MILD ENVIRONMENT COMPARED TO THE STOMACH. WITHIN THE ORAL CAVITY, THE BUCCAL AND SUBLINGUAL MUCOSA HAVE BEEN EXTENSIVELY RESEARCHED, HOWEVER, POOR PERMEABILITY OF VACCINES THROUGH THESE MUCOSAL TISSUES HAS MADE IT DIFFICULT TO TRANSLATE THESE ROUTES TO THE CLINIC. NONETHELESS, RESEARCH HAS SHOWN THAT IF VACCINES ARE DELIVERED THROUGH THE ORAL CAVITY, IMMUNE RESPONSES CAN BE STIMULATED IN THE DISTANT VAGINAL, RESPIRATORY, AND INTESTINAL MUCOSA, OFFERING PROTECTION AT ALL THESE OTHER SITES. IN OTHER WORDS, THE ORAL CAVITY HAS POTENTIAL TO BE USED FOR VACCINATION AGAINST A BROAD RANGE OF PATHOGENS SUCH AS INFLUENZA AND HIV. THEREFORE, A BREAKTHROUGH IN SUCCESSFUL DELIVERY OF VACCINES THROUGH THE ORAL CAVITY COULD HAVE A PARADIGM-SHIFTING IMPACT ON VACCINATIONS. HERE WE PROPOSE THAT A FLOSS CAN BE USED TO TARGET THE JUNCTIONAL EPITHELIUM FOR VACCINATION. THE JUNCTIONAL EPITHELIUM IS A UNIQUE EPITHELIAL TISSUE THAT HAS EXCEPTIONALLY HIGH PERMEABILITY AND PROVIDES A DOORWAY INTO THE MUCOSA. HOWEVER, BECAUSE IT IS LOCATED AT THE BASE OF THE GUM POCKET IT IS HARDER TO TARGET. WE POSTULATE THAT THE FLOSS, A COMMON DENTAL DEVICE USED BY MILLIONS, COULD BE COATED WITH A VACCINE AND USED FOR VACCINATION. OUR HYPOTHESIS IS THAT FLOSS-BASED VACCINATION THROUGH THE JUNCTIONAL EPITHELIUM CAN STIMULATE SYSTEMIC AND MUCOSAL HUMORAL AND CELLULAR IMMUNE RESPONSES AGAINST DIFFERENT ANTIGENS. THIS HYPOTHESIS IS BACKED BY OUR STRONG PRELIMINARY DATA. THE OBJECTIVE OF THIS RESEARCH PROPOSAL IS TO BUILD ON THIS PRELIMINARY DATA AND DEVELOP THIS NOVEL METHOD OF VACCINATION INTO A RELIABLE AND REPRODUCIBLE METHOD OF VACCINATION. THE AIMS ARE: I) COMPREHENSIVE CHARACTERIZATION OF IMMUNE RESPONSE GENERATED THROUGH JUNCTIONAL EPITHELIUM IMMUNIZATION IN MICE, II) CHARACTERIZATION OF THE NATURE OF IMMUNE STIMULATION FOLLOWING JUNCTIONAL EPITHELIUM VACCINATION IN MICE, AND III) CHARACTERIZATION OF SYSTEMIC AND MUCOSAL IMMUNITY FROM FLOSS-BASED VACCINATION IN PIGS. THIS NEW APPROACH OF VACCINATION WILL BE ASSESSED IN MICE AND PIGS, WHICH INCREASES THE TRANSLATIONAL POTENTIAL OF THIS WORK. BECAUSE THE FLOSS IS NEEDLE FREE, IT IS PAINLESS AND COULD BE SELF-APPLIED. IT ALSO HAS POTENTIAL TO BE DISTRIBUTED THROUGH POSTAL MAIL, WHICH COULD MAKE VACCINATION CAMPAIGNS EASIER. OVERALL, THIS RESEARCH PROPOSES TO ESTABLISH A NEW PARADIGM IN ORAL MUCOSAL VACCINATION, WHICH HAS POTENTIAL FOR SIGNIFICANT IMPACT ON PUBLIC HEALTH.