MONKEYS IMMUNIZED WITH INTERTYPIC CHIMERIC DENGUE VIRUSES ARE PROTECTED AGAINST WILD-TYPE VIRUS CHALLENGE

Dengue epidemics caused by the four dengue virus serotypes continue to pose a major public health problem in most tropical and subtropical r egions, A safe and effective vaccine against dengue is still not avail able, The current strategy for dengue immunization favors the use of a vaccine containing each of the four serotypes, We previously employed full-length dengue type 4 virus (DEN4) cDNA to construct a viable int ertypic dengue virus of type 1 or type 2 antigenic specificity that co ntained the genes for the capsid-premembrane-envelope (C-pre-M-E) stru ctural proteins of DEN1 or pre-M and E structural proteins of DENZ sub stituting for the corresponding DEN4 genes, Chimeras DEN1/DEN4 and DEN 2/DEN4, which express the nonstructural proteins of DEN4 and the C-pre -III-E structural proteins of DEN1 or the pre-hl-E structural proteins of DEN2, and therefore the antigenicity of type 1 or type 2, were use d to immunize rhesus monkeys, Other monkeys were inoculated with paren tal DEN1, DENZ, or cDNA-derived DEN4. Three of four monkeys immunized with DEN1/DEN4 developed neutralizing antibodies against DEN1 and were protected against subsequent DEN1 challenge, All four monkeys immuniz ed with DEN2/DEN4 developed antibodies against DEN2 and were protected against subsequent DEN2 challenge, DEN1- and DEN2-immunized monkeys w ere protected against homologous virus challenge, but DEN4-immunized a nimals became viremic on cross-challenge with DEN1 or DEN2, In a secon d experiment, eight monkeys were immunized with equal mixtures of DEN1 /DEN4 and DEN2/DEN4, Each of these monkeys developed neutralizing anti bodies against both DEN1 and DENZ and were protected against subsequen t challenge with DEN1 or DEN2, Chimeric dengue viruses similar to thos e described here could be used to express serotype-specific antigens i n a live attenuated tetravalent human vaccine.