A live attenuated tetravalent dengue vaccine development in Thailand : progress problem and opportunities

ABSTRACT

The discovery at the University of Hawaii that dengue viruses could be propa­gated serially in Primary Dog Kidney (PDK) cells offered an initial step for development of live dengue vaccines. At Mahidol University, dengue 1, 2 and 4 viruses could successfully propagate in PDK cells, whereas dengue 3 virus could not and was to serially passaged in primary green monkey kidney (PGMK) cells. Certain biological attributes were used for selection of candidate dengue vaccine viruses. Progeny viruses in PDK and PGMK cells revealed progressive modification in phenotypic markers of all 4 dengue serotypes. Seven monovalent dengue vaccine candidates were selected and used in phase 1 clinical trials in flavivirus non-immune subjects. Monovalent dengue 1, 2 and 4 candidate vaccines were proved to be safe and immunogenic. These 3 acceptably attenuated dengue vaccines could be used for immunization in one injection resulted in strong neutralizing antibodies against dengue 1, 2 and 4 serotypes in all vaccines. This marked an important milestone in using products based on PDK cell passage. Using underattenuated dengue 3 progeny adapted in PGMK revealed viral interference in the tetravalent combination. After fixing the dengue 3 problem, opportunity of having an ideal tetravalent dengue vaccine with balanced immunogenicity is now opened.