DIFFERENT MECHANISMS DETERMINE PLAQUE SIZE IN ATTENUATED AND UNDERATTENUATED VACCINE STRAINS

Abstract

LIVE-ATTENUATED VACCINES MIMIC NATURAL INFECTION WITHOUT CAUSING DISEASE; THIS COMPREHENSIVE STIMULATION OF THE IMMUNE RESPONSE CONFERS LONG TERM PROTECTION, AN IMPORTANT ADVANTAGE OF THESE VACCINES. LIVE-ATTENUATED VACCINES RELY ON SERIAL PASSAGING TO SELECT FOR NON-VIRULENT STRAINS. THIS PROCESS RELIES ON CHANCE, WHICH PROLONGS DEVELOPMENT TIME AND INCREASES COSTS. ANY MEANS OF OPTIMIZING THE SCREENING PROCESS FOR PROSPECTIVE CANDIDATE VACCINES WOULD GREATLY ADDRESS THIS CHALLENGE. A KEY ASSUMPTION IS THAT ATTENUATED STRAINS HAVE IMPAIRED REPLICATION, AND VIRUSES WITH IMPAIRED REPLICATION GIVE RISE TO SMALL PLAQUES IN A PLAQUE ASSAY. HOWEVER, THIS TRAIT DOES NOT RELIABLY HOLD. WE STUDIED THE MAHIDOL UNIVERSITY LIVE-ATTENUATED DENGUE VACCINE, WHOSE STRAINS WERE SELECTED PRIMARILY BASED ON THE SMALL PLAQUE PHENOTYPE. IN CLINICAL TRIALS, DENV2 PDK53 WAS SAFE, WHILST DENV3 PGMK30FRHL3 CAUSED DISEASE. OUR ANALYSIS OF THE HOST CELL RESPONSE TO INFECTION INDICATES THAT DIFFERENT MECHANISMS