Dengue Tetravalent Vaccine Containing a Common 30 Nucleotide Deletion in the 3'-UTR of Dengue Types 1, 2, 3, and 4

The invention relates to a dengue virus tetravalent vaccine containing a common 30-nucleotide deletion (delta30) in the 3'-untranslated region (UTR) of the genome of dengue virus serotypes 1, 2, 3, and 4. The previously identified delta30 attenuating mutation, created in dengue virus type 4 (DEN4) by the removal of 30 nucleotides from the 3'-UTR, is also capable of attenuating a wild-type strain of dengue virus type 1 (DEN1). Removal of 30 nucleotides from the DEN1 3'-UTR in a highly conserved region homologous to the DEN4 region encompassing the delta30 mutation yielded a recombinant virus attenuated in rhesus monkeys to a level similar to recombinant virus DEN4delta30. This established the transportability of the delta30 mutation and its attenuation phenotype to a dengue virus type other than DEN4. The effective transferability of the delta30 mutation establishes the usefulness of the delta30 mutation to attenuate and improve the safety of commercializable dengue virus vaccines of any serotype.

A tetravalent dengue virus vaccine containing dengue virus types 1, 2, 3, and 4 each attenuated by the delta30 mutation is being developed. The presence of the delta30 attenuating mutation in each virus component precludes the reversion to a wild-type virus by intertypic recombination. In addition, because of the inherent genetic stability of deletion mutations, the delta30 mutation represents an excellent alternative for use as a common mutation shared among each component of a tetravalent vaccine.