111 Update on dengue vaccines

Abstract

Forty percent of the world’s population is at risk for dengue, and 100 million apparent infections are estimated to occur annually. In a minority of cases, dengue fever progresses to severe disease at the time of defervescence, inducing a capillary leak syndrome accompanied by thrombocytopenia that can result in shock and organ failure. Thus the medical need for a dengue vaccine is obvious. The 4 dengue virus serotypes are transmitted by Aedes mosquitoes, and protective immunity against the infecting serotype (homotypic immunity) is long lived and thought to be conferred by virus-neutralizing antibodies and some T cell help. However, antibodies induced by one serotype often cross-react with the other serotypes. If antibodies fail to neutralize and instead opsonize, they can enable the virus to infect IgG receptor-bearing cells. This phenomenon, termed antibody-dependent enhancement, is thought to play a role in the pathogenesis of severe dengue, and is of concern to vaccine developers. Several investigational dengue vaccines are currently in clinical development, and many different vaccination approaches are being explored. These span from live-attenuated dengue viruses to chimera between yellow fever and dengue viruses, to subunit, DNA, and whole virus inactivated vaccines. A recent Phase 2b study of the vaccine most advanced in development did not show statistically significant protection against disease due to any serotype, adding much uncertainty to the entire field. Our understanding of the contributions of humoral and cell mediated responses to protection and to pathogenesis is clearly less than perfect, and selection, presentation and adjuvantation of antigens need thought and attention.