Project Grant R44AI162404

FINAL PRECLINICAL TESTING AND FORMULATION OF A SCALABLE, LIVE-ATTENUATED SARS-COV-2 VACCINE - PROJECT SUMMARY THERE IS A CRITICAL NEED FOR EFFECTIVE SARS-COV-2 VACCINES THAT CAN BE RAPIDLY PRODUCED AT LARGE SCALE. GIVEN OUR RUDIMENTARY UNDERSTANDING OF THE IMMUNOLOGICAL RESPONSES TO THE VIRUS, A VACCINE THAT ENGENDERS A BROAD-BASED RESPONSE (INNATE, HUMORAL, AND CELLULAR), IS PARTICULARLY APPEALING. FURTHER, WITH LITTLE OR NO A PRIORI KNOWLEDGE OF KEY IMMUNOLOGICAL TARGETS, A VACCINE THAT CAN PRESENT ALL OF A VIRUS' ANTIGENS TO THE HOST IS IDEAL. IN RESPONSE, USING ITS UNIQUE COMPUTATIONAL ALGORITHM, CODAGENIX HAS DESIGNED AND COMPLETED INITIAL PRE-CLINICAL TESTING OF AN INTRANASAL, LIVE-ATTENUATED SARS-COV-2 VACCINE, CDX-005, THAT 1) ACTIVATES INNATE, HUMORAL, AND CELLULAR IMMUNE RESPONSES, 2) PRESENTS EVERY VIRAL ANTIGEN IN ITS NATURAL CONFORMATION TO THE INOCULATED HOST, AND 3) WILL BE INEXPENSIVE, FAST, AND EASY TO PRODUCE AT SCALE. THIS IS THE ONLY LAV BEING DEVELOPED FOR THE US MARKET. THE VACCINE GROWS ROBUSTLY IN FULLY CHARACTERIZED GMP CELLS AND PRE-CLINICAL DATA SUGGEST THAT A SINGLE, LOW, INTRANASAL DOSE IN THE RANGE OF 104-106 PFU WILL BE PROTECTIVE. PRE-CLINICAL TESTING IN SYRIAN GOLDEN HAMSTERS DEMONSTRATED THE SAFETY, ATTENUATION, AND EFFICACY OF CDX-005 IN VIVO, AND A PHASE I CLINICAL TRIAL WILL BE BEGINNING IN THE UK IN 2020 USING PRODUCT MANUFACTURED OVERSEAS. OUR GOAL IS TO PRODUCE AND DISTRIBUTE THE CDX-005 SARS-COV-2 VACCINE IN THE UNITED STATES. TO THIS END, CODAGENIX HAS HAD PRE-IND COMMUNICATIONS WITH AND GUIDANCE FROM THE FDA. WE PROPOSE TO COMPLETE ADDITIONAL PRE- CLINICAL STUDIES IN RESPONSE TO FDA RECOMMENDATIONS AND TO DEVELOP A FORMULATION THAT IS STABLE FOR EXTENDED PERIODS AT 4C TO REDUCE SHIPPING COSTS, SIMPLIFY END-USER STORAGE, AND MAKE IT EASIER TO ADMINISTER THE VACCINE. ACCORDINGLY, IN AIM 1, WE WILL DEVELOP A CDX-005 FORMULATION THAT IS STABLE FOR EXTENDED PERIODS AT 2-8C. STARTING WITH OUR FROZEN FORMULATION AS A BASE, WE WILL TEST EXCIPIENTS FOR THEIR ABILITY TO STABILIZE A LIQUID VACCINE USING FORCED DEGRADATION, ACCELERATED STABILITY TESTING, AND LONG-TERM STABILITY TESTING PROTOCOLS. IN AIM 2, WE WILL DETERMINE THE TOXICITY, IMMUNOGENICITY, BIODISTRIBUTION, ATTENUATION, AND EFFICACY OF LATE PASSAGE CDX-005 IN SYRIAN GOLDEN HAMSTERS. IN PREPARATION FOR AN IND FILING, WE WILL 1) ASSESS TOXICITY BY HISTOPATHOLOGY AND HEMATOLOGY AFTER INOCULATION WITH CDX-005, 2) EXAMINE CDX-005 IMMUNOGENICITY BY SERUM IGG ELISA, PLAQUE REDUCTION NEUTRALIZATION, AND TH1/TH2 RESPONSE BY QPCR, 3) DETERMINE CDX-005 BIODISTRIBUTION AND ATTENUATION BY QPCR AND TCID50 IN TISSUES AND EXCRETIONS, AND 4) ASSESS CDX-005 EFFICACY BY SARS-COV-2 CHALLENGE. IN PARALLEL WITH THE PROPOSED WORK, WE WILL BRING CDX-005 MANUFACTURING CAPABILITIES TO THE US, CONDUCT A PHASE I CLINICAL TRIAL IN THE UK, AND SEQUENCE THE VIRUS FROM TISSUES IN THESE PATIENTS TO TEST FOR POSSIBLE REVERSION. WE RECOGNIZE THAT OTHER SARS-COV-2 VACCINES MAY REACH THE MARKET BEFORE CDX-005. WHILE THESE WILL BE A TREMENDOUS BOON SHORT TERM IN THE FIGHT AGAINST SARS-COV-2, THE ARE EXPECTED TO BE ONLY PARTIALLY PROTECTIVE. IN CONTRAST, WE ANTICIPATE THAT CDX-005, AS AN LAV, WILL PROVIDE A MUCH MORE ROBUST AND LONGER LASTING PROTECTION MAKING IT A MORE ATTRACTIVE CHOICE IN THE LONG TERM MARKET.