Viral vaccines for dengue: the present and the future

Abstract

Infection with dengue viruses, of which there are four antigenically distinct serotypes, has reemerged as a significant global public health threat. Sequential infection in areas of hyperendemicity, where multiple serotypes co-circulate, has the potential to trigger life-threatening disease. Therefore, a safe and effective dengue vaccine must be ‘tetravalent’ capable of providing solid and long-lasting immunity to all four serotypes. The development of a vaccine against dengue has been a high priority of the World Health Organization (WHO) for decades. Currently, six different virus-based vaccines are in various stages of development. Two of these are traditional tissue culture-based live attenuated vaccines whereas the remaining four are chimeric recombinant vaccine viruses developed using infectious clone technology. In all these instances, the vaccine viruses are monovalent in that each one is specific to one dengue serotype. A tetravalent dengue vaccine is based on producing vaccine formulations by mixing all four monovalent vaccine viruses. Recent studies in both monkeys and man have shown that such tetravalent formulations can elicit unbalanced immune responses due to the phenomenon of viral interference. While efforts are under way to optimize the tetravalent formulations, the inherent risk of viral interference associated with the current strategy of producing tetravalent dengue vaccine warrants investigation of other recombinant viral systems that eliminate this risk, especially the replication-defective adenovirusbased vector system that may permit the creation of a single vaccine vector capable of conferring tetravalent protection.