Induction of protective immunity against Dengue virus type 2: comparison of candidate live attenuated and recombinant vaccines.

Dengue (DEN) viruses (serotypes 1 to 4) are mosquito-borne flaviviruses which cause about fifty million human infections annually and represent an expanding public health problem in the tropics. At present, there are no safe and effective vaccines which induce protective immunity to all four serotypes of DEN. Natural infection or vaccination with native and recombinant proteins may induce an immune response to the surface envelope E-protein which was shown to be protective to super-infection with homologous serotype of the virus. Purified recombinant E-protein was made in the baculovirus-Spodoptera frugiperda expression system. This protein induced neutralizing antibodies in mice. These results prompted us to immunize cynomolgus monkeys (Macaca fascicularis) with either a live attenuated DEN-2 vaccine or the recombinant E-protein complexed to aluminum hydroxide. After immunization, the monkeys were challenged with the homologous DEN virus. Serum was collected at several time points and a virus-specific antibody response including a virus neutralizing antibody response was measured. Antibody kinetics and levels were similar to those recorded in humans with a natural DEN-virus infection. Virus isolation and type specific RT-PCR were performed on the serum samples. The virus was isolated from sham vaccinated control monkeys but not from monkeys vaccinated with the live attenuated vaccine. One of the two monkeys immunized with the recombinant E-protein was also protected. Taken together these data indicate the potential of both candidate vaccines and stress the need for evaluation of different antigen presentation systems for the development of a subunit vaccine approach for DEN.