Heterologous prime-boost immunization induces protection against dengue virus infection in cynomolgus macaques.

Currently licensed dengue vaccines do not induce long-term protection in children without prior dengue virus exposure. A better understanding of the mechanism by which the immune system prevents dengue virus infection is urgently needed to improve vaccine efficacy. In this study, the induction of protective antibody responses against dengue virus infection was tested in a non-human primate model using the heterologous prime-boost vaccination approach. Groups of cynomolgus macaques were immunized with a priming dose of attenuated dengue viruses and followed by two booster doses of virus-like particles in four monovalent arms, or in the tetravalent arm (prM + E)-expressing plasmids. At 1 month post-immunization, all macaques had elevated levels of neutralizing antibodies, and live viral challenges revealed an overall protective efficacy of 91% (40/44 macaques protected) against infection with clinical isolates. Breakthrough infections occurred in macaques with distinctive antibody profiles at the time of challenge: two macaques had the lowest neutralizing antibodies against the respective DENV-1 and -4 challenge strains among the respective groups, whereas two other DENV-4-infected macaques exhibited high levels of neutralizing and virus-binding antibodies. The ratio of antibodies recognizing a DENV-4-specific epitope and those that bound viral particles was at the lowest levels in the latter DENV-4-infected macaques, indicating an underrepresentation of antibodies targeting the serotype-specific epitope. Protection among macaques challenged with DENV-2 or -3 coincided with vigorous EDIII-binding antibody responses induced by booster immunization. A combination of attenuated viruses for priming and non-infectious particle-based antigens for boosting may be a more effective means of preventing dengue. [ABSTRACT FROM AUTHOR]