R01AI194419

PROTECTIVE EFFICACY AND IMMUNOGENICITY OF A LIVE ATTENUATED CHLAMYDIA STRAIN - PROJECT SUMMARY THE MAIN GOAL OF THIS PROJECT IS TO RIGOROUSLY EVALUATE THE IMMUNOGENICITY AND PROTECTIVE EFFICACY OF A MUTANT, LIVE ATTENUATED CHLAMYDIA TRACHOMATIS (CT) VACCINE STRAIN IN AN ESTABLISHED NONHUMAN PRIMATE (NHP) MODEL THAT ACCURATELY MIMICS MANY ASPECTS OF HUMAN CT INFECTION. THIS WORK IS HIGHLY SIGNIFICANT, AS CT IS THE LEADING CAUSE OF BACTERIAL SEXUALLY TRANSMITTED INFECTION AND AN IMPORTANT CAUSATIVE AGENT OF MORBIDITY IN WOMEN. ALTHOUGH THE DEVELOPMENT OF AN EFFECTIVE CT VACCINE IS AN URGENT MEDICAL PRIORITY, NO APPROVED VACCINES EXIST AND IT IS IMPERATIVE TO PURSUE NEW CANDIDATES. HISTORICAL EVIDENCE SUPPORTS THE VACCINE EFFICACY OF WHOLE CHLAMYDIA ORGANISMS IN PROTECTING THE REPRODUCTIVE TRACT FROM REINFECTION, PRIMARILY USING C. MURIDARUM INFECTIONS IN A MOUSE MODEL. RECENT ADVANCES IN CHLAMYDIA GENETIC ENGINEERING NOW ALLOW FOR THE DEVELOPMENT OF GENETICALLY ATTENUATED STRAINS WHICH CAN BE EVALUATED AS LIVE VACCINES IN PRECLINICAL MODELS. WE RECENTLY CHARACTERIZED A HUMAN-TROPIC CT MUTANT WITH A DISRUPTION IN GARD (CT∆GARD); THIS MUTANT IS SENSITIVE TO AN INTRACELLULAR, IFNΓ ACTIVATED DEFENSE MECHANISM AND WE DEMONSTRATED THAT THIS STRAIN WAS ATTENUATED IN THE FEMALE NHP GENITAL TRACT. IN A PILOT VACCINE EFFICACY STUDY, WE FURTHER DEMONSTRATED THAT IMMUNIZATION OF MACAQUES WITH CT∆GARD WAS SAFE AND ELICITED PROTECTION AGAINST SUBSEQUENT CHALLENGE WITH WILDTYPE CT. A UNIQUE FEATURE OF THIS STRAIN IS THAT IT ARRESTS AT AN INTRACELLULAR STAGE AND THUS PRESENTS A BROAD ARRAY OF DESIRABLE T AND B CELL ANTIGENS THAT ARE BROADLY CONSERVED ACROSS CIRCULATING CT STRAINS. WE WILL FIRST GENERATE AN IMPROVED GENETICALLY ATTENUATED CT STRAIN THAT HARBORS A CLEAN DELETION OF GARD, AND WE WILL SUBSEQUENTLY GENETICALLY AND PHENOTYPICALLY VALIDATE ITS ATTENUATION PHENOTYPE. WE WILL THEN CONDUCT AN IMMUNOGENICITY AND EFFICACY STUDY IN FEMALE MACAQUES TO DETERMINE THE OPTIMAL DOSING REGIMEN OF LIVE ATTENUATED CT FOR ELICITING PROTECTIVE CELLULAR AND HUMORAL IMMUNE RESPONSES, AND ALSO PROTECTIVE EFFICACY, AGAINST CHALLENGE WITH A WILD TYPE CIRCULATING CLINICAL CT STRAIN. THESE STUDIES WILL INVESTIGATE THE POTENTIAL FOR A LIVE ATTENUATED HUMAN TROPIC VACCINE CANDIDATE IN A MACAQUE PRECLINICAL MODEL AND PAVE THE WAY FOR GREATER UNDERSTANDING OF IMMUNE CORRELATES OF PROTECTION AGAINST CT.

University Of Washington

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Seattle, Washington 981951016 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)