University Of Victoria

DEVELOPMENT OF A CHIMERIC SYPHILIS VACCINE CANDIDATE TO COMBAT LOCAL, DISSEMINATED AND CONGENITAL SYPHILIS INFECTION - PROJECT SUMMARY IN SEVERAL HIGH-INCOME NATIONS, INCLUDING THE UNITED STATES, INFECTIOUS SYPHILIS HAS BEEN RESURGENT FOR OVER TWO DECADES NOW, WHILE SYPHILIS IS STILL ENDEMIC IN LOW- AND MIDDLE-INCOME COUNTRIES. SYPHILIS IS THEREFORE STILL A PUBLIC GLOBAL HEALTH CONCERN, PARTICULARLY BECAUSE IT CAN LEAD TO NEUROLOGICAL SEQUELAE SUCH AS DEMENTIA AND STROKE-LIKE SYNDROMES, AS WELL AS CARDIOVASCULAR MANIFESTATIONS POTENTIALLY LEADING TO DEATH. FURTHERMORE, ABOUT HALF A MILLION PREGNANCIES ARE ADVERSELY AFFECTED BY CONGENITAL TRANSMISSION OF THE PATHOGEN EVERY YEAR. THE PARTIAL SUCCESS OF RECENT SYPHILIS CONTROL CAMPAIGNS PROMOTED BY THE CDC AND WHO CLEARLY HIGHLIGHTS THE NECESSITY OF DEVISING NOVEL WAYS TO CONTROL THIS SERIOUS INFECTION. THE AVAILABILITY OF AN EFFECTIVE SYPHILIS VACCINE COULD MAKE A SIGNIFICANT DIFFERENCE IN THE GLOBAL EFFORT TO CONTROL THE SPREAD OF THIS SERIOUS INFECTION. OVER THE LAST DECADE, OUR RESEARCH PROGRAMS HAVE HAD THE FOCUS OF IDENTIFYING VACCINE CANDIDATES AMONG THE SURFACE-EXPOSED ANTIGENS OF THE SYPHILIS AGENT, TREPONEMA PALLIDUM SUBSP. PALLIDUM (T. PALLIDUM). THESE STUDIES HAVE LED TO THE DISCOVERY THAT THE T. PALLIDUM REPEAT (TPR) PROTEIN FAMILY AND THE TP0751 VASCULAR ADHESIN ARE CRITICAL PROTEINS IN THE PROCESSES OF CHANCRE DEVELOPMENT/IMMUNE EVASION AND SYSTEMIC DISSEMINATION, RESPECTIVELY. WHEN TESTED IN IMMUNIZATION/CHALLENGE EXPERIMENTS IN THE RABBIT MODEL OF SYPHILIS, THESE ANTIGENS WERE SHOWN TO PROVIDE SIGNIFICANT PROTECTION AGAINST INFECTION. FURTHERMORE, WITHIN THESE ANTIGENS, WE HAVE BEEN ABLE TO PINPOINT THE EPITOPES NECESSARY TO GENERATE A PROTECTIVE HOST RESPONSE. TO REDUCE THE COMPLEXITY AND PRODUCTION COSTS OF OUR VACCINE CANDIDATES, WE HAVE DEVELOPED A CHIMERIC PROTEIN PLATFORM WHERE THE NON-FUNCTIONAL LOOPS OF THE TP0751 PROTEIN ARE EXCHANGED WITH CONSERVED EPITOPES FROM THE TPR PROTEINS. THIS APPROACH PROVIDES A SINGLE CONSTRUCT THAT RETAINS THE CRITICAL TP0751 EPITOPES WHILE ALLOWING PRESENTATION OF PROTECTIVE EPITOPES FROM OTHER ANTIGENS IN A STABLE AND SOLUBLE SCAFFOLD. THIS PROPOSAL ENCOMPASSES THE NEXT PHASE OF THIS RESEARCH ENDEAVOR CONSISTING OF INVESTIGATIONAL NEW DRUG (IND)-ENABLING PRE-CLINICAL STUDIES. TO THIS END, WE WILL CREATE FUTURE GENERATIONS OF THE CHIMERA VACCINE CANDIDATE TO ASSESS THE LEVEL OF INDUCED IMMUNOREACTIVITY AND PROTECTION, AFTER WHICH THE VACCINE DELIVERY FORMULATION WILL BE OPTIMIZED WITH THE LEAD CANDIDATE BY PERFORMING IN VIVO IMMUNIZATION/CHALLENGE EXPERIMENTS, TOXICITY AND STABILITY TESTS, AND STUDIES INVESTIGATING COMPATIBILITY WITH SCALE-UP PRODUCTION. COLLECTIVELY THESE STUDIES ARE ANTICIPATED TO PROVIDE US WITH AN EFFICACIOUS SYPHILIS VACCINE CANDIDATE THAT IS READY FOR CLINICAL STUDIES.

EXTRACELLULAR MATRIX ADHESINS OF TREPONEMA PALLIDUM

EXTRACELLULAR MATRIX ADHESINS OF TREPONEMA PALLIDUM

INTEGRATIVE ANALYSIS OF CHANGE IN COGNITION AND HEALTH

2D QUANTITATIVE GEOACOUSTIC MAPPING OF LAYERED MUDDY SEABEDS

WAVE PROCESSES IN ARCTIC SEAS, OBSERVED FROM TERRASAR-X

DEVELOPMENT OF A DIRECT DIAGNOSTIC TEST FOR INFECTIOUS AND CONGENITAL SYPHILIS - PROJECT SUMMARY CURRENT DIAGNOSTIC TESTS FOR SYPHILIS ARE NON-OPTIMAL, IN THAT THEY CANNOT DIFFERENTIATE ACTIVE FROM PAST INFECTION, CANNOT DIAGNOSE CONGENITAL SYPHILIS, AND HAVE LOW SENSITIVITY IN EARLY AND LATE DISEASE. WITH THE NUMBER OF INFECTIOUS AND CONGENITAL SYPHILIS CASES RAPIDLY EXPANDING IN THE US AND WORLDWIDE, CURBING THE SPREAD OF DISEASE WILL BE AIDED BY DEVELOPMENT OF A BETTER DIAGNOSTIC TEST THAT IS DEFINITIVE, EASILY INTERPRETED, AND COMPATIBLE WITH A POINT-OF-CARE TEST FORMAT. IN THIS RESEARCH APPLICATION WE PROPOSE TO DEVELOP A DIRECT SYPHILIS DIAGNOSTIC TEST THAT: (1) EXHIBITS HIGH SENSITIVITY AND SPECIFICITY AT ALL DISEASE STAGES; (2) CAN DIFFERENTIATE ACTIVE VERSUS PAST INFECTIONS; (3) CAN DIFFERENTIATE SYPHILIS FROM YAWS; (4) CAN ALLOW ACCURATE DISEASE STAGING; AND (5) CAN BE ADAPTED TO A POINT-OF-CARE FORMAT FOR EASE OF TESTING IN REMOTE AREAS.

QUANTIFYING GEOACOUSTIC UNCERTAINTY AND SEABED VARIABILITY FOR PROPAGATION UNCERTAINTY

PROPOSAL IN SUPPORT OF LATERAL MIXING EXPERIMENT

BAYESIAN AMBIENT NOISE INVERSION FOR GEOACOUSTIC UNCERTAINTY ESTIMATION (SPECIAL RESEARCH AWARD IN OCEAN ACOUSTICS PROGRAM FOR QUIJANO)

DISPERSION OF SOUND IN MARINE SEDIMENTS

BAYESIAN INVERSION OF SCATTERING DATA (SPECIAL RESEARCH AWARD IN OCEAN ACOUSTICS - PROGRAM STEININGER)

INVERSION FOR GEOACOUSTIC MODEL PARAMETERS IN THE ONR SHALLOW WATER EXPERIMENT (SW06)

GEOACOUSTIC INVERSION IN SHALLOW WATER

MODELING AND DATA ANALYSIS OF LOCAL AND PROPAGATING NON-LINEAR INTERNAL WAVES IN LUZON STRAITS

INVERSION FOR GEOACOUSTIC MODEL PARAMETERS IN COMPLEX SHALLOW WATER ENVIRONMENTS

PROBABILISTIC GEOACOUSTIC INVERSION IN COMPLEX ENVIRONMENTS

INVERSION FOR GEOACOUSTIC MODEL PARAMETERS IN COMPLEX OCEANIC ENVIRONMENTS

OCEAN SURFACE WAVE OPTICAL ROUGHNESS: INNOVATIVE MEASUREMENT AND MODELING

INVERSION FOR GEOACOUSTIC MODEL PARAMETERS IN COMPLEX SHALLOW WATER ENVIRONMENTS

MODELING AND PARAMETERIZATION OF MEAN AND EDDYING FLOW OVER TOPOGRAPHY

SCIENTIFIC GRAND CHALLENGES AND NEW PERSPECTIVES IN APPLIED MATHEMATICS: OCEAN, ATMOSPHERIC AND CLIMATE SCIENCES - A CONFERENCE IN HONOUR OF PROFESSOR

EFFECTS OF INVASIVE PLANT REMOVAL

THE ROLE OF BIOLOGICALLY-GENERATED TURBULENCE IN THE UPPER OCEAN